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WO2025231269A1 - Antibacterial compounds - Google Patents

Antibacterial compounds

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Publication number
WO2025231269A1
WO2025231269A1 PCT/US2025/027339 US2025027339W WO2025231269A1 WO 2025231269 A1 WO2025231269 A1 WO 2025231269A1 US 2025027339 W US2025027339 W US 2025027339W WO 2025231269 A1 WO2025231269 A1 WO 2025231269A1
Authority
WO
WIPO (PCT)
Prior art keywords
optionally substituted
compound
pharmaceutically acceptable
solvate
acceptable salt
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/US2025/027339
Other languages
French (fr)
Inventor
Deidre Michelle Johns
Lloyd Payne
Graham HONE
Greg Basarab
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Arrepath Inc
Original Assignee
Arrepath Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Arrepath Inc filed Critical Arrepath Inc
Publication of WO2025231269A1 publication Critical patent/WO2025231269A1/en
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
    • C07F9/6571—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms
    • C07F9/657163—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms the ring phosphorus atom being bound to at least one carbon atom
    • C07F9/657181—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms the ring phosphorus atom being bound to at least one carbon atom the ring phosphorus atom and, at least, one ring oxygen atom being part of a (thio)phosphonic acid derivative
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
    • C07F9/6571—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms
    • C07F9/6574—Esters of oxyacids of phosphorus

Definitions

  • 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-R 1 , or absent; R 1 is hydrogen, optionally substituted alkyl, -OH, -CN, -C(O)R 8 , or -C(O)N(R 9 ) 2 ; R 8 is optionally substituted C1-C5 alkyl; each R 9 is independently hydrogen or optionally substituted C 1 -C 3 alkyl; 1 WSGR Ref: 60134-709.601 or two R 9 groups attached to the same
  • 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.
  • an agent includes a plurality of such agents
  • 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.
  • 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.
  • Oxa refers to the -O- radical.
  • 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).
  • an alkyl comprises one to thirteen carbon atoms (e.g., C1-C13 alkyl).
  • an alkyl comprises two to fifteen carbon atoms (e.g., C 2 -C 15 alkyl).
  • an alkyl comprises three to fifteen carbon atoms (e.g., C3-C15 alkyl).
  • 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., C 5 -C 15 alkyl). In certain embodiments, an alkyl comprises six to fifteen carbon atoms (e.g., C 6 -C 15 alkyl). In certain embodiments, an alkyl comprises seven to fifteen carbon atoms (e.g., C7-C15 alkyl). In certain embodiments, an alkyl comprises eight to fifteen carbon atoms (e.g., C 8 -C 15 alkyl).
  • an alkyl comprises one to eight carbon atoms (e.g., C 1 -C 8 alkyl). In other embodiments, an alkyl comprises one to five carbon atoms (e.g., C1-C5 alkyl). In other embodiments, an alkyl comprises one to four carbon atoms (e.g., C1- C4 alkyl). In other embodiments, an alkyl comprises one to three carbon atoms (e.g., C1-C3 alkyl). In other embodiments, an alkyl comprises one to two carbon atoms (e.g., C 1 -C 2 alkyl). In other embodiments, an alkyl comprises one carbon atom (e.g., C1 alkyl).
  • 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., C 2 -C 5 alkyl). In other embodiments, an alkyl comprises three to five carbon atoms (e.g., C 3 -C 5 alkyl).
  • 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.
  • 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.
  • Alkoxy refers to a radical bonded through an oxygen atom of the formula –O-alkyl, where alkyl is an alkyl chain as defined above.
  • 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.
  • 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.
  • 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.
  • 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, 5 WSGR Ref: 60134-709.601 and the like.
  • 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.
  • an alkynyl comprises two to twelve carbon atoms.
  • an alkynyl comprises two to eight carbon atoms.
  • an alkynyl comprises two to six carbon atoms.
  • an alkynyl comprises three to fifteen carbon atoms.
  • an alkynyl comprises four to fifteen carbon atoms.
  • an alkynyl comprises five to fifteen carbon atoms.
  • an alkynyl comprises six to fifteen carbon atoms. In other embodiments, 6 WSGR 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.
  • 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.
  • 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.
  • an alkylene comprises one to eight carbon atoms (e.g., C 1 -C 8 alkylene). In other embodiments, an alkylene comprises one to five carbon atoms (e.g., C1-C5 alkylene). In other embodiments, an alkylene comprises one to four carbon atoms (e.g., C 1 -C 4 alkylene). In other embodiments, an alkylene comprises one to three carbon atoms (e.g., C 1 -C 3 alkylene). 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).
  • an alkylene comprises five to eight carbon atoms (e.g., C 5 -C 8 alkylene). 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).
  • 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.
  • an alkenylene comprises two to eight carbon atoms (e.g., C 2 -C 8 alkenylene).
  • an alkenylene comprises two to five carbon atoms (e.g., C2-C5 alkenylene).
  • 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., C 2 -C 3 alkenylene). In other embodiments, an alkenylene comprises two carbon atoms (e.g., C 2 alkenylene). 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., C 3 -C 5 alkenylene).
  • 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.
  • an alkynylene comprises two to eight carbon atoms (e.g., C 2 -C 8 alkynylene).
  • an alkynylene comprises two to five carbon atoms (e.g., C2-C5 alkynylene).
  • an alkynylene comprises two to four carbon atoms (e.g., C 2 -C 4 alkynylene). In other embodiments, an alkynylene comprises two to three carbon atoms (e.g., C 2 -C 3 alkynylene). 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., C 3 -C 5 alkynylene).
  • 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.
  • 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, -R a , -O-R b -R a , -N(R a )-R b -R a , -R b - OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a ) 2 , -R b -N(R a ) 2
  • Aryl is optionally substituted with a substituent selected from the group consisting of , , , , 12 WSGR 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 of L is -N(R j )-, -C(R n ) 2 -, or -O-; R S is optionally substituted C 1 -C 5 alkyl, optionally substituted C 2 -C 5 alkenyl, optionally substituted C2-C5 alkynyl, -OR j , or -N(R j )2; each R P is independently optionally substituted C 1 -C 5 alkyl, optionally substituted C 2 -C 5 alkenyl, optionally substituted C 2 -C 5 alkynyl, -OR j , or
  • Aralkyl refers to a radical of the formula -R c -aryl where R c is an alkylene chain as defined above, for example, methylene, ethylene, and the like.
  • the alkylene chain part of the 13 WSGR 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.
  • Aralkenyl refers to a radical of the formula –R d -aryl where R d is 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.
  • "Aralkynyl" refers to a radical of the formula -R e -aryl, where R e is 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.
  • Alkoxy refers to a radical bonded through an oxygen atom of the formula -O-R c -aryl where R c is 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.
  • 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.
  • 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.”
  • monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • An unsaturated carbocyclyl is also referred to as "cycloalkenyl.”
  • 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.
  • carbocyclyl is meant to include carbocyclyl radicals that are optionally substituted by one or more substituents 14 WSGR Ref: 60134-709.601 independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo, oxo, thioxo, cyano, nitro, -R a , -R b -OR a , -R b -OC(O)-R a , -R b - OC(O)-OR a , -R b -OC(O)-N(R a ) 2 , -R b -N(R a ) 2 , -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a ) 2 , -R b -C(O)OR a
  • Carbocyclyl is optionally substituted with a substituent aminopyrrolidin-1-yl, and optionally substituted piperazin-1-yl; or two adjacent atoms of the carbocyclyl are substituted by the divalent group consisting of L is -N(R j )-, -C(R n )2-, or -O-;
  • R S is optionally substituted C 1 -C 5 alkyl, optionally substituted C 2 -C 5 alkenyl, optionally substituted C 2 -C 5 alkynyl, -OR j , or -N(R j ) 2 ;
  • each R P is independently optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, optionally substituted C2-C5 alkynyl, -OR j , or -N(R j )2; or two R P are taken together to form an optionally substituted 3 to 10-membered heterocycly
  • each R n is independently hydrogen, halogen, or optionally substituted C 1 -C 3 alkyl; or two R n groups attached to the same carbon atom are optionally cyclized to form a C3-C6 carbocyclyl; or two R n groups attached to the same carbon atom are optionally cyclized to form a 3 to 6- membered heterocyclyl.
  • 16 WSGR Ref: 60134-709.601 "Carbocyclylalkyl” refers to a radical of the formula –R c -carbocyclyl where R c is an alkylene chain as defined above. The alkylene chain part of the carbocyclylalkyl radical is optionally substituted as described above for an alkylene chain.
  • Carbocyclylalkynyl refers to a radical of the formula –R c -carbocyclyl where R c is an alkynylene chain as defined above.
  • the alkynylene chain and the carbocyclyl radical is optionally substituted as defined above.
  • Carbocyclylalkoxy refers to a radical bonded through an oxygen atom of the formula – O-R c -carbocyclyl where R c is an alkylene chain as defined above.
  • alkylene chain and the carbocyclyl radical is optionally substituted as defined above.
  • Halo or “halogen” refers to bromo, chloro, fluoro or iodo substituents.
  • 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.
  • the alkyl part of the fluoroalkyl radical is optionally substituted as defined above for an alkyl group.
  • 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.
  • 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).
  • 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-thio
  • 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, -R a , -R b -OR a , -R b -OC(O)-R a , - 17 WSGR Ref: 60134-709.601 R b -OC(O)-OR a , -R b -OC(O)-N(R a )2, -R b -N(R a )2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2,
  • Heterocyclyl is optionally substituted with a substituent 18 WSGR Ref: 60134-709.601 1-yl, and optionally substituted piperazin-1-yl; or two adjacent atoms of the heterocyclyl are substituted by the divalent group consisting of L is -N(R j )-, -C(R n )2-, or -O-;
  • R S is optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, optionally substituted C 2 -C 5 alkynyl, -OR j , or -N(R j ) 2 ;
  • each R P is independently optionally substituted C 1 -C 5 alkyl, optionally substituted C 2 -C 5 alkenyl, optionally substituted C2-C5 alkynyl, -OR j , or -N(R j )2; or two R P are taken together to form an optionally substituted 3 to 10-
  • 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.
  • N-heterocyclyl radicals include, but are not limited to, 1-morpholinyl, 1- piperidinyl, 1-piperazinyl, 1-pyrrolidinyl, pyrazolidinyl, imidazolinyl, and imidazolidinyl.
  • 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.
  • heterocyclylalkyl refers to a radical of the formula –R c -heterocyclyl where R c is 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.
  • heterocyclylalkyl radical refers to a radical bonded through an oxygen atom of the formula –O-R c -heterocyclyl where R c is 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.
  • 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.
  • 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).
  • 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, 20 WSGR 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,
  • 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, -R a , -O-R b -R a , -N(R a )-R b -R a , -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b - OC(O)-N(R a )2, -R b -N(R
  • Heteroaryl is optionally substituted with a substituent aminopyrrolidin-1-yl, and optionally substituted piperazin-1-yl; 22 WSGR Ref: 60134-709.601 or two adjacent atoms of the heteroaryl are substituted by the divalent group consisting of L is -N(R j )-, -C(R n )2-, or -O-; R S is optionally substituted C 1 -C 5 alkyl, optionally substituted C 2 -C 5 alkenyl, optionally substituted C 2 -C 5 alkynyl, -OR j , or -N(R j ) 2 ; each R P is independently optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, optionally substituted C2-C5 alkynyl, -OR j , or -N(R j )2; or two R P are taken together to form an optionally substituted
  • 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.
  • 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 23 WSGR Ref: 60134-709.601 heteroaryl radical.
  • a C-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.
  • Heteroarylalkyl refers to a radical of the formula –R c -heteroaryl, where R c is 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.
  • Heteroarylalkoxy refers to a radical bonded through an oxygen atom of the formula – O-R c -heteroaryl, where R c is 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.
  • 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.
  • geometric isomer refers to E or Z geometric isomers (e.g., cis or trans) of an alkene double bond.
  • positional isomer refers to structural isomers around a central ring, such as ortho-, meta-, and para- isomers around a benzene ring.
  • 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 exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibrium include: 24 WSGR 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 of 2 H, 3 H, 11 C, 13 C and/or 14 C.
  • the compound is deuterated in at least one position.
  • 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.
  • structures depicted herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by 13 C- or 14 C-enriched carbon are within the scope of the present disclosure.
  • the compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds.
  • the compounds may be labeled with isotopes, such as for example, deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C).
  • isotopes such as for example, deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C).
  • Isotopic substitution with 2 H, 3 H, 11 C, 13 C, 14 C, 15 C, 12 N, 13 N, 15 N, 16 N, 17 O, 18 O, 14 F, 15 F, 16 F, 17 F, 18 F, 33 S, 34 S, 35 S, 36 S, 35 Cl, 37 Cl, 79 Br, 81 Br, 125 I are all contemplated.
  • isotopic substitution with 18 F is contemplated.
  • the compounds disclosed herein have some or all of the 1 H atoms replaced with 2 H 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. 25 WSGR Ref: 60134-709.601
  • 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.
  • Deuterium-transfer reagents suitable for use in nucleophilic substitution reactions are readily available and may be employed to transfer a deuterium- substituted carbon atom under nucleophilic substitution reaction conditions to the reaction substrate.
  • CD3I is illustrated, by way of example only, in the reaction schemes below.
  • Deuterium-transfer reagents, such as lithium aluminum deuteride (LiAlD4) are employed to transfer deuterium under reducing conditions to the reaction substrate.
  • LiAlD 4 is illustrated, by way of example only, in the reaction schemes below.
  • 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.
  • 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-exchangeable 1 H 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.
  • "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.
  • “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.
  • 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.
  • salts of amino acids such as arginates, gluconates, and galacturonates
  • Acid addition salts of basic compounds are, in some embodiments, prepared by 27 WSGR 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.
  • “Pharmaceutically acceptable base addition salt” refers to those salts that retain the biological effectiveness and properties of the free acids, which are not undesirable.
  • 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.
  • solvates refers to a composition of matter that is the solvent addition form.
  • 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.
  • the term “subject” or “patient” encompasses mammals.
  • 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.
  • the mammal is a human.
  • “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.
  • 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.
  • MDR Multi-drug resistant
  • pan-drug resistant bacterial infections pose a public health risk with potentially dire consequences.
  • 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).
  • LPS lipopolysaccharides
  • LOS lipooligosaccharises
  • 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.
  • 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 29 WSGR Ref: 60134-709.601 aeruginosa, Acinetobacter baumannii, Klebsiella pneumoniae, Escherichia coli, Haemophilus influenzae, and Neisseria gonorrhoeae.
  • 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.
  • AstraZeneca reported the first known LpxH inhibitor, AZ1, a sulfonyl piperazine (J. Bacteriol.2015, 197(10), 1726–1734).
  • Karale et al. reported one antibacterial sulfonyl piperidine with a similar structure to that reported by AstraZeneca.
  • LpxH Inhibitory Compounds [0070] In one aspect, provided herein is a LpxH inhibitory compound.
  • One embodiment provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein, 30 WSGR 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-R 1 , or absent; R 1 is hydrogen, optionally substituted alkyl, -OH, -CN, -C(O)R 8 , or -C(O)N(R 9 ) 2 ; R 8 is optionally substituted C 1 -C 5 alkyl; each R 9 is independently hydrogen or optionally substituted C1-C3 alkyl; or two R 9 groups attached to the same atom are optionally cyclized
  • 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-R 1 , or absent; R 1 is hydrogen, optionally substituted alkyl, -OH, -CN, -C(O)R 8 , or -C(O)N(R 9 ) 2 ; R 8 is optionally substituted C1-C5 alkyl; each R 9 is independently hydrogen or optionally substituted C1-C3 alkyl; or two R 9 groups attached to the same atom are optionally cyclized to form a 3 to 6-
  • One embodiment provides a compound of Formula (I-b), or a pharmaceutically acceptable salt or solvate thereof, 33 WSGR 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-R 1 , or absent; R 1 is hydrogen, optionally substituted alkyl, -OH, -CN, -C(O)R 8 , or -C(O)N(R 9 ) 2 ; R 8 is optionally substituted C1-C5 alkyl; each R 9 is independently hydrogen or optionally substituted C 1 -C 3 alkyl; or two R 9
  • 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 C 1 -C 3 alkyl; E is O, N-R 1 , or absent; R 1 is hydrogen, optionally substituted alkyl, -OH, -CN, -C(O)R 8 , or -C(O)N(R 9 )2; 35 WSGR Ref: 60134-709.601 R 8 is optionally substituted C1-C5 alkyl; each R 9 is independently hydrogen or optionally substituted C 1 -C 3 alkyl; or two R 9
  • G is *-C(R 4 )2-C(R 5 )2-; where the * denotes the bond to N. 36 WSGR Ref: 60134-709.601 [0076] In some embodiments, G is *-CH2-C(R 5 )2-; where the * denotes the bond to N. [0077] In some embodiments, G is *-C(R 4 ) 2 -CH 2 -; where the * denotes the bond to N. [0078] In some embodiments, G is -CH 2 -CH 2 -. [0079] In some embodiments, G is *-C(R 4 )2-C(R 5 )2-C(R 6 )2-; where the * denotes the bond to N.
  • G is -CH2-CH2-CH2-, *-CH2-CH2-CHF-, or *-CH2-CH2-CF2-; where the * denotes the bond to N.
  • G is -CH2-CH2-CH2-.
  • G is *-C(R 4 )2-C(R 7 )2-O-; where the * denotes the bond to N.
  • G is *-CH 2 -CH 2 -O-; where the * denotes the bond to N.
  • G is *-C(R 4 ) 2 -C(R 5 ) 2 -N(R 3 )-; where the * denotes the bond to N.
  • 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-R 1 , or absent; R 1 is hydrogen, optionally substituted alkyl, -OH, -CN, -C(O)R 8 , or -C(O)N(R 9 )2; R 8 is optionally substituted C1-C5 alkyl; each R 9 is independently hydrogen or optionally substituted C 1 -C 3 alkyl; or two R 9 groups attached to the same atom are optionally cyclized to form a 3 to 6-membered heterocyclyl;
  • 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-R 1 , or absent; R 1 is hydrogen, optionally substituted alkyl, -OH, -CN, -C(O)R 8 , or -C(O)N(R 9 ) 2 ; R 8 is optionally substituted C1-C5 alkyl; each R 9 is independently hydrogen or optionally substituted C1-C3 alkyl; 38 WSGR Ref: 60134-709.601 or two R 9 groups attached to the same
  • 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; 39 WSGR Ref: 60134-709.601 E is O, N-R 1 , or absent; R 1 is hydrogen, optionally substituted alkyl, -OH, -CN, -C(O)R 8 , or -C(O)N(R 9 ) 2 ; R 8 is optionally substituted C 1 -C 5 alkyl; each R 9 is independently hydrogen or optionally substituted C1-C3 alkyl; or two
  • 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; 40 WSGR Ref: 60134-709.601 each R is independently hydrogen, deuterium, halogen, -CN, or optionally substituted C 1 -C 3 alkyl; E is O, N-R 1 , or absent; R 1 is hydrogen, optionally substituted alkyl, -OH, -CN, -C(O)R 8 , or -C(O)N(R 9 )2; R 8 is optionally substituted C1-C5 alkyl; each R 9 is independently hydrogen or optionally substituted C 1 -C 3 alkyl; or two
  • each R 4 is independently hydrogen, deuterium, or optionally substituted C1-C3 alkyl; and each R 5 is independently hydrogen, deuterium, or optionally substituted C 1 -C 3 alkyl.
  • each R 4 is independently hydrogen, deuterium, or C 1 -C 3 alkyl, wherein the alkyl is optionally substituted with one or more halogen, hydroxy, methoxy, amino, -NHMe, or -NMe 2 ; and each R 5 is independently hydrogen, deuterium, or C 1 -C 3 alkyl, wherein the alkyl is optionally substituted with one or more halogen, hydroxy, methoxy, amino, -NHMe, or -NMe2.
  • each R 4 is independently hydrogen, deuterium, or optionally substituted C 1 alkyl; and each R 5 is independently hydrogen, deuterium, or optionally substituted C1 alkyl.
  • 41 WSGR Ref: 60134-709.601 [0093] In some embodiments, each R 4 is independently hydrogen, deuterium, or optionally substituted C 1 alkyl, wherein the alkyl is optionally substituted with one or more halogen, hydroxy, methoxy, amino, -NHMe, or -NMe 2 ; and each R 5 is 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.
  • each R 4 is independently hydrogen, deuterium, or -CH 3 ; and each R 5 is independently hydrogen, deuterium, or -CH3.
  • each R 4 is independently hydrogen or deuterium; and each R 5 is independently hydrogen, deuterium, or halogen.
  • each R 4 is independently hydrogen or deuterium; and each R 5 is independently hydrogen, deuterium, or fluorine.
  • each R 4 is independently hydrogen or deuterium; and each R 5 is independently hydrogen or deuterium.
  • B is an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl.
  • B is an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, or optionally substituted C-heterocyclyl.
  • B is an optionally substituted aryl, optionally substituted C- heteroaryl, optionally substituted carbocyclyl, or optionally substituted C-heterocyclyl.
  • 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.
  • 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.
  • B is an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted 4 to 10-membered carbocyclyl, or optionally substituted 4 to 10-membered heterocyclyl.
  • B is an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted 5 to 10-membered carbocyclyl, or optionally substituted 5 to 10-membered heterocyclyl.
  • B is an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted 5 to 8-membered carbocyclyl, or optionally substituted 5 to 8- membered heterocyclyl.
  • B is an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted 4 to 8-membered carbocyclyl, or optionally substituted 4 to 8- membered heterocyclyl.
  • 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.
  • B is an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted 5 to 8-membered carbocyclyl, or optionally substituted 4 to 8- membered heterocyclyl.
  • 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.
  • B is an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted 5 to 8-membered carbocyclyl, or optionally substituted 5 to 8- membered heterocyclyl.
  • 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.
  • B is an optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted 5 to 8-membered carbocyclyl.
  • B is an optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted 5 to 8-membered heterocyclyl.
  • B is an optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted 5 to 8-membered C-heterocyclyl.
  • B is an optionally substituted aryl, optionally substituted 5 to 8-membered carbocyclyl, or optionally substituted 5 to 8-membered heterocyclyl.
  • B is an optionally substituted heteroaryl, optionally substituted 5 to 8-membered carbocyclyl, or optionally substituted 5 to 8-membered heterocyclyl.
  • B is an optionally substituted aryl or optionally substituted heteroaryl.
  • B is an optionally substituted carbocyclyl.
  • B is an optionally substituted 4- to 8-membered carbocyclyl.
  • 43 WSGR Ref: 60134-709.601 [00119] In some embodiments, B is an optionally substituted 5- to 8-membered carbocyclyl.
  • B is an optionally substituted 5- to 6-membered carbocyclyl.
  • B is an optionally substituted 4-membered carbocyclyl.
  • B is an optionally substituted 5-membered carbocyclyl.
  • B is an optionally substituted 6-membered carbocyclyl. [00124] In some embodiments, B is an optionally substituted heterocyclyl. [00125] In some embodiments, B is an optionally substituted 4 to 8-membered heterocyclyl. [00126] In some embodiments, B is an optionally substituted 5 to 8-membered heterocyclyl. [00127] In some embodiments, B is an optionally substituted 4 to 6-membered heterocyclyl. [00128] In some embodiments, B is an optionally substituted 5 to 6-membered heterocyclyl. [00129] In some embodiments, B is an optionally substituted 4-membered heterocyclyl.
  • B is an optionally substituted 5-membered heterocyclyl. [00131] In some embodiments, B is an optionally substituted 6-membered heterocyclyl. [00132] In some embodiments, B is an optionally substituted C-heterocyclyl. [00133] In some embodiments, B is an optionally substituted 4 to 8-membered C- heterocyclyl. [00134] In some embodiments, B is an optionally substituted 5 to 8-membered C- heterocyclyl. [00135] In some embodiments, B is an optionally substituted 4 to 6-membered C- heterocyclyl.
  • B is an optionally substituted 5 to 6-membered C- heterocyclyl.
  • B is an optionally substituted 4-membered C-heterocyclyl.
  • B is an optionally substituted 5-membered C-heterocyclyl.
  • B is an optionally substituted 6-membered C-heterocyclyl.
  • B is an optionally substituted heteroaryl.
  • B is an optionally substituted 5- to 10-membered heteroaryl.
  • B is an optionally substituted 6- to 10-membered heteroaryl.
  • B is an optionally substituted 5- to 6-membered heteroaryl.
  • B is an optionally substituted 5-membered heteroaryl.
  • B is an optionally substituted substituted substituted pyrrolyl, optionally substituted pyrazolyl, optionally substituted imidazolyl, or optionally substituted thiophenyl.
  • B is an optionally substituted substituted pyrrolyl.
  • B is an optionally substituted substituted pyrazolyl.
  • B is an optionally substituted substituted imidazolyl. In some embodiments, B is an optionally substituted substituted thiophenyl. [00146] In some embodiments, B is an optionally substituted 6-membered heteroaryl. [00147] 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. [00148] In some embodiments, B is an optionally substituted 9-membered heteroaryl. [00149] In some embodiments, B is an optionally substituted pyrazolopyrimidinyl.
  • B is an optionally substituted 10-membered heteroaryl. [00151] In some embodiments, B is an optionally substituted aryl. [00152] In some embodiments, B is an optionally substituted phenyl. [00153] In some embodiments, B is not . [00154] In some embodiments, B is not . [00155] In some embodiments, B is not .
  • B is substituted with one or more substituent selected from the group consisting of: 45 WSGR Ref: 60134-709.601 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(R j )-, -C(R n ) 2 -, or -O-; R S is optionally substituted C 1 -C 5 alkyl, optionally substituted C 2 -C 5 alkenyl, optionally substituted C2-C5 alkynyl, -OR j , or -N(R j )2; each R P is independently optionally substituted C 1 -C 5 alkyl, optionally substituted C 2 -C 5 alkenyl, optionally substituted C 2 -C 5 alkyny
  • 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(R j )-, -C(R n )2-, or -O-;
  • R S is optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, optionally substituted C 2 -C 5 alkynyl, -OR j , or -N(R j ) 2 ;
  • each R P is independently optionally substituted C 1 -C 5 alkyl, optionally substituted C 2 -C 5 alkenyl, optionally substituted C2-C5 alkynyl, -OR j , or -N(R j )2;
  • 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(R j )-, -C(R n )2-, or -O-;
  • R S is optionally substituted C 1 -C 5 alkyl, optionally substituted C 2 -C 5 alkenyl, optionally substituted C 2 -C 5 alkynyl, -OR j , or -N(R j ) 2 ; each R P is independently optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, optionally substituted C2-C5 alkynyl, -
  • 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(R j )-, -C(R n ) 2 -, or -O-;
  • R S is optionally substituted C 1 -C 5 alkyl, optionally substituted C 2 -C 5 alkenyl, optionally substituted C2-C5 alkynyl, -OR j , or -N(R j )2;
  • each R P is independently optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, optionally substituted C 2 -C 5 alkynyl, -OR j , or -N(R j ) 2 ; or two R P are taken together to form
  • 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(R j )-, -C(R n ) 2 -, or -O-;
  • R S is optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, optionally substituted C2-C5 alkynyl, -OR j , or -N(R j )2;
  • each R P is independently optionally substituted C 1 -C 5 alkyl, optionally substituted C 2 -C 5 alkenyl, optionally substituted C2-C5 alkynyl, -OR j , or -N(R j )2; or two R P are taken
  • 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(R j )-, -C(R n ) 2 -, or -O-;
  • R S is optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, optionally substituted C2-C5 alkynyl, -OR j , or -N(R j )2;
  • each R P is independently optionally substituted C 1 -C 5 alkyl, optionally substituted C 2 -C 5 alkenyl, optionally substituted C 2 -C 5 alkynyl, -OR j , or -N(R j ) 2 ; or two R P are taken together to form an
  • 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(R j )-, -C(R n )2-, or -O-;
  • R S is optionally substituted C 1 -C 5 alkyl, optionally substituted C 2 -C 5 alkenyl, optionally substituted C2-C5 alkynyl, -OR j , or -N(R j )2;
  • each R P is independently optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, optionally substituted C 2 -C 5 alkynyl, -OR j , or -N(R j ) 2 ; or two R P are
  • B is substituted with one or more substituent selected from the group consisting of: 52 WSGR 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(R j )-, -C(R n ) 2 -, or -O-;
  • R S is optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, optionally substituted C 2 -C 5 alkynyl, -OR j , or -N(R j ) 2 ; each R P is independently optionally substituted C 1 -C 5 alkyl, optionally substituted C 2 -C 5 alkenyl, optionally substituted C2-C5 alkynyl, -OR j , or -N(R j )
  • 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 of L is -N(R j )-, -C(R n )2-, or -O-; 53 WSGR Ref: 60134-709.601
  • 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(R j )-, -C(R n ) 2 -, or -O-;
  • R S is optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, optionally substituted C2-C5 alkynyl, -OR j , or -N(R j )2; each R j is independently hydrogen or optionally substituted C 1 -C 3 alkyl;
  • each R k is independently hydrogen, halogen, optionally substituted C1-C3 alkyl, or -OH;
  • B is substituted with one or more substituent selected from the group consisting of: optionally substituted morpholinyl; L is -N(R j )-, -C(R n ) 2 -, or -O-; R S is optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, optionally substituted C2-C5 alkynyl, -OR j , or -N(R j )2; each R j is independently hydrogen or optionally substituted C 1 -C 3 alkyl; 54 WSGR Ref: 60134-709.601 each R k is independently hydrogen, halogen, optionally substituted C1-C3 alkyl, or -OH; each R m is independently optionally substituted C 1 -C 3 alkyl; and each R n is independently hydrogen, halogen, or optionally substituted C 1 -C 3 alkyl.
  • B is substituted with one or more substituent selected from the group consisting of: L is -N(R j )-, -C(R n ) 2 -, or -O-; R S is optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, optionally substituted C2-C5 alkynyl, -OR j , or -N(R j )2; each R j is independently hydrogen or optionally substituted C 1 -C 3 alkyl; each R k is independently hydrogen, halogen, optionally substituted C1-C3 alkyl, or -OH; each R m is independently optionally substituted C1-C3 alkyl; and each R n is independently hydrogen, halogen, or optionally substituted C 1 -C 3 alkyl.
  • B is substituted with one or more substituent selected from the group consisting of: optionally substituted morpholinyl; L is -N(R j )-, -C(R n ) 2 -, or -O-; R S is optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, optionally substituted C2-C5 alkynyl, -OR j , or -N(R j )2; each R j is independently hydrogen or optionally substituted C 1 -C 3 alkyl; each R k is independently hydrogen, halogen, optionally substituted C1-C3 alkyl, or -OH; each R m is independently optionally substituted C1-C3 alkyl; and each R n is independently hydrogen, halogen, or optionally substituted C 1 -C 3 alkyl.
  • B is substituted with one or more substituent selected from the group consisting of: 55 WSGR Ref: 60134-709.601
  • L is -N(R j )-, -C(R n )2-, or -O-;
  • R S is optionally substituted C 1 -C 5 alkyl, optionally substituted C 2 -C 5 alkenyl, optionally substituted C 2 -C 5 alkynyl, -OR j , or -N(R j ) 2 ; each R j is independently hydrogen or optionally substituted C1-C3 alkyl;
  • each R k is independently hydrogen, halogen, optionally substituted C1-C3 alkyl, or -OH;
  • B is substituted with one or more substituent selected from the group consisting of: halogen, and optionally substituted morpholinyl;
  • L is -N(R j )-, -C(R n )2-, or -O-;
  • B is substituted with one or more substituent selected from the group consisting of: L is -N(R j )-, -C(R n )2-, or -O-;
  • R S is optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, optionally substituted C 2 -C 5 alkynyl, -OR j , or -N(R j ) 2 ; each R j is independently hydrogen or optionally substituted C1-C3 alkyl; each R m is independently optionally substituted C1-C3 alkyl; and each R n is independently hydrogen, halogen, or optionally substituted C 1 -C 3 alkyl.
  • B is substituted with one or more substituent selected from the group consisting of: 56 WSGR Ref: 60134-709.601 amino, cyano, halogen, optionally substituted morpholinyl; L is -N(R j )-, -C(R n )2-, or -O-; R S is optionally substituted C 1 -C 5 alkyl, optionally substituted C 2 -C 5 alkenyl, optionally substituted C2-C5 alkynyl, -OR j , or -N(R j )2; each R j is independently hydrogen or optionally substituted C1-C3 alkyl; each R k is independently hydrogen, halogen, optionally substituted C 1 -C 3 alkyl, or -OH; and each R n is independently hydrogen, halogen, or optionally substituted C1-C3 alkyl.
  • B is substituted with one or more substituent selected from the group consisting of: L is -N(R j )-, -C(R n )2-, or -O-;
  • R S is optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, optionally substituted C 2 -C 5 alkynyl, -OR j , or -N(R j ) 2 ; each R j is independently hydrogen or optionally substituted C 1 -C 3 alkyl; each R k is independently hydrogen, halogen, optionally substituted C1-C3 alkyl, or -OH; and each R n is independently hydrogen, halogen, or optionally substituted C 1 -C 3 alkyl.
  • B is substituted with one or more substituent selected from the group consisting of: optionally substituted morpholinyl; L is -N(R j )-, -C(R n ) 2 -, or -O-; R S is optionally substituted C1-C3 alkyl, -OR j , or -N(R j )2; each R j is independently hydrogen or optionally substituted C1-C2 alkyl; and each R n is independently hydrogen, halogen, or optionally substituted C 1 -C 2 alkyl.
  • B is substituted with one or more substituent selected from the group consisting of: 57 WSGR Ref: 60134-709.601
  • L is -N(R j )-, -C(R n ) 2 -, or -O-
  • R S is optionally substituted C1-C3 alkyl, -OR j , or -N(R j )2
  • each R j is independently hydrogen or optionally substituted C1-C2 alkyl
  • each R n is independently hydrogen, halogen, or optionally substituted C 1 -C 2 alkyl.
  • 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(R j )-, -C(R n ) 2 -, or -O-;
  • R S is optionally substituted C1-C2 alkyl, -OR j , or -N(R j )2; each R j is independently hydrogen or -CH 3 ; and each R n is independently hydrogen, halogen, or -CH 3 .
  • B is substituted with one or more substituent selected from the group consisting of: L is -N(R j )-, -C(R n )2-, or -O-; R S is optionally substituted C 1 -C 2 alkyl, -OR j , or -N(R j ) 2 ; each R j is independently hydrogen or -CH 3 ; and each R n is independently hydrogen, halogen, or -CH3.
  • B is substituted with one or more substituent selected from the group consisting of: amino, cyano, halogen, and optionally substituted morpholinyl;
  • L is -N(R j )-, -C(R n )2-, or -O-;
  • R S is optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, optionally substituted C 2 -C 5 alkynyl, -OR j , or -N(R j ) 2 ;
  • each R j is independently hydrogen or optionally substituted C1-C3 alkyl; or two R j groups are optionally cyclized to form an optionally substituted C 3 -C 7 carbocyclyl; or two R j groups are optionally cyclized to form an optionally substituted 3 to 7-membered heterocyclyl;
  • each R n is independently hydrogen, halogen, or optional
  • B is substituted with one or more substituent selected from the group consisting of: ;
  • L is -N(R j )-, -C(R n ) 2 -, or -O-;
  • B is substituted with one or more substituents selected from: alkyl, amino, cyano, halogen, and optionally substituted morpholinyl. [00181] In some embodiments, B is substituted with one or more substituents selected from: . 59 WSGR Ref: 60134-709.601 [00182] In some embodiments, B is substituted with one or more substituents selected , [00183] In some embodiments, B is substituted with one or more substituents selected [00184] In some embodiments, B is substituted with one or more substituents selected from: [00185] In some embodiments, B is substituted with one or more substituents selected from: .
  • B is substituted with one or more substituents selected from: .
  • B is substituted with one or more substituents selected from: .
  • B is substituted with one or more substituents selected from: ;
  • L is -N(R j )-, -C(R n ) 2 -, or -O-;
  • R S is optionally substituted C 1 -C 5 alkyl, optionally substituted C 2 -C 5 alkenyl, optionally substituted C2-C5 alkynyl, -OR j , or -N(R j )2;
  • B is substituted with one or more substituents selected from: ; R S is optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, or optionally substituted C 2 -C 5 alkynyl; and each R j is independently hydrogen or -CH 3 .
  • R S is optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, or optionally substituted C 2 -C 5 alkynyl; and each R j is independently hydrogen or -CH 3 .
  • B is substituted with one or more substituents selected from: ;
  • R S is -CH3, -CH2F, -CHF2, -CF3, -CH2OCH3, -CH2NH2, or -CH2CH2NH2; and
  • R j is hydrogen or -CH 3 .
  • B is substituted with one or more substituents selected from: R S is -CH3, -CH2F, -CHF2, -CF3, -CH2OCH3, -CH2NH2, or -CH2CH2NH2.
  • R S is -CH 3 , -CH 2 F, -CHF 2 , or -CF 3 .
  • B is substituted with one or more substituents selected from: .
  • B is substituted with one or more substituents selected from: ;
  • R S is -CH 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 OCH 3 , -CH 2 NH 2 , or -CH 2 CH 2 NH 2 .
  • R S is -CH 3 , -CH 2 F, -CHF 2 , -CF 3 , or -CH 2 OCH 3 .
  • R S is -CH 3 , - 61 WSGR Ref: 60134-709.601 CH2F, -CHF2, or -CF3. In some embodiments, R S is -CH3. In some embodiments, R S is - CF 3 . In some embodiments, R S is -CHF 2 . In some embodiments, R S is -CH 2 F. [00195] In some embodiments, B is substituted with one or more substituents selected from: . In some embodiments, B is substituted with one or more substituents selected from: some embodiments, B is substituted with one or more substituents selected from: .
  • B is substituted with one or more substituents selected from: In some embodiments, B is substituted with one or more substituents selected from: [00197] In some embodiments, B is substituted with one or more substituents selected from: ; R S is optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, or optionally substituted C2-C5 alkynyl. In some embodiments R S is -CH3, -CH2F, -CHF2, -CF3, - CH 2 OCH 3 , -CH 2 NH 2 , or -CH 2 CH 2 NH 2 . [00198] In some embodiments, B is substituted with one or more substituents selected from: .
  • B is substituted with one or more substituents selected from: ; R S is -OR j , or -N(R j )2; each R j is independently hydrogen or optionally substituted C1-C3 alkyl; or two R j groups are optionally cyclized to form an optionally substituted 3 to 7- membered heterocyclyl.
  • B is substituted with one or more substituents selected from: ; R S is -OR j , or -N(R j )2; each R j is independently hydrogen or optionally substituted C1-C3 alkyl.
  • B is substituted with one or more substituents selected from: ; R S is -OR j , or -N(R j ) 2 ; each R j is independently hydrogen or -CH 3 .
  • B is substituted with one or more substituents selected from: .
  • B is substituted with one or more substituents selected from: ; R S is optionally substituted C 1 -C 5 alkyl, optionally substituted C 2 -C 5 alkenyl, or optionally substituted C2-C5 alkynyl.
  • each R n is independently hydrogen, -F, -Cl, or -CH3.
  • B is substituted with one or more substituents selected from: R S is -CH3, -CH2F, -CHF2, -CF3, -CH2OCH3, -CH2NH2, or -CH2CH2NH2.
  • R S is -CH3, -CH2F, -CHF2, -CF3, -CH2OCH3, -CH2NH2, or -CH2CH2NH2.
  • R S is -CH3, -CH2F, -CHF2, or -CF3.
  • B is substituted with one or more substituents selected from: .
  • R S is -OR j , or -N(R j ) 2 ; each R n is independently hydrogen, -F, -Cl, or -CH3; each R j is independently hydrogen or optionally substituted C 1 -C 3 alkyl; or two R j groups are optionally cyclized to form an optionally substituted 3 to 7- membered heterocyclyl.
  • B is substituted with one or more substituents selected from: R S is -OR j , or -N(R j )2; each R n is independently hydrogen, -F, -Cl, or -CH 3 ; each R j is independently hydrogen or optionally substituted C 1 -C 3 alkyl.
  • B is substituted with one or more substituents selected from: R S is -OR j , or -N(R j )2; each R n is independently hydrogen, -F, or -CH3; each R j is independently hydrogen or -CH 3 .
  • B is substituted with one or more substituents selected .
  • B is substituted with one or more substituents selected from: L is -NH-, -N(CH3)-, -CH2-, or -O-; wherein each R P is independently optionally substituted C 1 -C 3 alkyl; or two R P are taken together to form an optionally substituted 3 to 10-membered heterocyclyl.
  • B is substituted with one or more substituents selected from: ; L is -NH-, -N(CH3)-, or -CH2-; wherein each R P is independently optionally substituted C 1 -C 3 alkyl; or two R P are taken together to form an optionally substituted 3 to 10-membered heterocyclyl.
  • B is substituted with one or more substituents selected from: L is -NH-, -N(CH3)-, or -CH2-; wherein each R P is independently optionally substituted C 1 -C 3 alkyl.
  • B is substituted with one or more substituents selected .
  • B is substituted with one or more substituents selected from: 65 WSGR Ref: 60134-709.601 alkyl, amino, cyano, halogen, optionally substituted morpholinyl, optionally substituted 3-aminopyrrolidin-1-yl, and optionally substituted piperazin-1-yl.
  • B is substituted with one or more substituents selected from: optionally substituted 3-aminopyrrolidin-1-yl, and optionally substituted piperazin-1-yl.
  • 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.
  • B is substituted with one or more substituents selected from: aminopyrrolidin-1-yl, and optionally substituted piperazin-1-yl.
  • 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.
  • B is substituted with one or more substituents selected from: aminopyrrolidin-1-yl, and optionally substituted piperazin-1-yl.
  • 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.
  • B is substituted with one or more substituents selected from: , optionally substituted 3-aminopyrrolidin-1-yl, and optionally substituted piperazin-1-yl.
  • B is substituted with one or more substituents selected optionally substituted morpholinyl, optionally substituted 3-aminopyrrolidin-1-yl and optionally substituted piperazin-1-yl.
  • B is substituted with one or more substituents selected from: optionally substituted 3-aminopyrrolidin-1-yl and optionally substituted piperazin-1-yl.
  • B is substituted with one or more substituents selected from: optionally substituted 3-aminopyrrolidin-1-yl, and optionally substituted piperazin-1-yl; each R j is independently hydrogen or optionally substituted C1-C3 alkyl; or two R j groups are optionally cyclized to form an optionally substituted C 3 -C 7 carbocyclyl; or two R j groups are optionally cyclized to form an optionally substituted 3 to 7-membered heterocyclyl; and each R k is independently hydrogen, halogen, optionally substituted C1-C3 alkyl, or -OH; or two R k groups attached to the same carbon atom are optionally cyclized to form a C 3 -C 6 carbocyclyl; or two R k groups attached to the same carbon atom are optionally cyclized to form a 3 to 6- membered heterocyclyl.
  • B is substituted with one or more substituents selected from: 68 WSGR Ref: 60134-709.601 aminopyrrolidin-1-yl, and optionally substituted piperazin-1-yl; each R j is independently hydrogen or optionally substituted C 1 -C 3 alkyl; or two R j groups are optionally cyclized to form an optionally substituted C 3 -C 7 carbocyclyl; or two R j groups are optionally cyclized to form an optionally substituted 3 to 7-membered heterocyclyl; and each R k is independently hydrogen, halogen, optionally substituted C 1 -C 3 alkyl, or -OH; or two R k groups attached to the same carbon atom are optionally cyclized to form a C3-C6 carbocyclyl; or two R k groups attached to the same carbon atom are optionally cyclized to form a 3 to 6- membered heterocyclyl.
  • B is substituted with one or more substituents selected from: alkyl, amino, cyano, halogen, and optionally substituted morpholinyl; each R j is independently hydrogen or optionally substituted C 1 -C 3 alkyl; and each R k is independently hydrogen, halogen, optionally substituted C1-C3 alkyl, or -OH.
  • B is substituted with one or more substituents selected from: each R j is independently hydrogen or optionally substituted C1-C3 alkyl; and each R k is independently hydrogen, halogen, optionally substituted C 1 -C 3 alkyl, or -OH.
  • B is substituted with one or more substituents selected from: alkyl, amino, cyano, halogen, optionally substituted morpholinyl; each R j is independently hydrogen, -CH 3 , -CH 2 F, -CHF 2 , or -CF 3 ; and each R k is independently hydrogen, -F, -Cl, -CH 3 , -CH 2 F, -CHF 2 , -CF 3 , or -OH.
  • B is substituted with one or more substituents selected from: each R j is independently hydrogen, -CH 3 , -CH 2 F, -CHF 2 , or -CF 3 ; and each R k is independently hydrogen, -F, -Cl, -CH3, -CH2F, -CHF2, -CF3, or -OH.
  • B is substituted with one or more substituents selected from: alkyl, amino, cyano, halogen, and optionally substituted morpholinyl; each R j is independently hydrogen or -CH 3 ; and each R k is independently hydrogen, -F, -CH3, or -OH.
  • B is substituted with one or more substituents selected from: 70 WSGR Ref: 60134-709.601 each R j is independently hydrogen or -CH3; and each R k is independently hydrogen, -F, -CH 3 , or -OH. [00233] In some embodiments, B is substituted with one or more substituents selected from: each R j is independently hydrogen or -CH 3 . [00234] In some embodiments, B is substituted with one or more substituents selected from: . [00235] In some embodiments, B is substituted with one or more substituents selected from: . [00236] In some embodiments, B is substituted with one or more substituents selected from: .
  • each R k is independently hydrogen, -F, or -CH 3 . In some embodiments, each R k is independently hydrogen or -CH3. In some embodiments, each R k is independently hydrogen or -F. In some embodiments, each R k is independently -F. In some embodiments, each R k is independently -H. [00237] In some embodiments, B is substituted with one or more substituents selected from: . [00238] In some embodiments, B is substituted with one or more substituents selected from: each R j is independently hydrogen or -CH 3 . [00239] In some embodiments, B is substituted with one or more substituents selected from: each R j is independently hydrogen or -CH3.
  • B is substituted with one or more substituents selected from: each R j is independently hydrogen or -CH 3 .
  • B is substituted with one or more substituents selected from: each R j is independently hydrogen or -CH 3 .
  • B is substituted with one or more substituents selected from: each R j is independently hydrogen or -CH 3 .
  • B is substituted with one or more substituents selected from: each R j is independently hydrogen or -CH3; and each R k is independently hydrogen, -F, -Cl, -CH3, or -OH.
  • B is substituted with one or more substituents selected from: ; each R j is independently hydrogen or -CH 3 ; and each R k is independently hydrogen, -F, or -CH3.
  • B is substituted with one or more substituents selected from: .
  • B is substituted with one or more substituents selected from: optionally substituted 3-aminopyrrolidin-1-yl.
  • 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.
  • B is substituted with one or more substituents selected from: .
  • B is substituted with one or more substituents selected from: optionally substituted piperazin-1-yl.
  • B is substituted with one or more substituents selected from: piperazin-1-yl optionally substituted with one or more groups selected from -CH 3 .
  • B is substituted with one or more substituents selected from: .
  • B is substituted with one or more substituents selected from: ; each R m is independently optionally substituted C 1 -C 3 alkyl; or two R m groups are optionally cyclized to form an optionally substituted 3 to 6-membered heterocyclyl.
  • B is substituted with one or more substituents selected from: ; each R m is independently optionally substituted C1-C3 alkyl.
  • B is substituted with one or more substituents selected each R m is independently unsubstituted C 1 -C 3 alkyl.
  • B is substituted with one or more substituents selected from: .
  • two adjacent atoms of B are substituted by the divalent group consisting each R j is independently hydrogen or optionally substituted C 1 -C 3 alkyl; or two R j groups are optionally cyclized to form an optionally substituted C3-C7 carbocyclyl; or two R j groups are optionally cyclized to form an optionally substituted 3 to 7-membered heterocyclyl.
  • two adjacent atoms of B are substituted by the divalent group consisting each R j is independently hydrogen or -CH 3 .
  • two adjacent atoms of B are substituted by the divalent group consisting each R j is independently hydrogen or optionally substituted C1-C3 alkyl; or two R j groups are optionally cyclized to form an optionally substituted C 3 -C 7 carbocyclyl; or two R j groups are optionally cyclized to form an optionally substituted 3 to 7-membered heterocyclyl.
  • two adjacent atoms of B are substituted by the divalent group consisting .
  • B is substituted with one or more substituents selected from: [00260] In some embodiments, B is substituted with one or more substituents selected from: 74 WSGR Ref: 60134-709.601 [00261] In some embodiments, B is substituted with one or more substituents selected [00262] In some embodiments, B is substituted with one or more substituents selected fro , 75 WSGR Ref: 60134-709.601 [00263] In some embodiments, B is substituted with one or more substituents selected [00264] In some embodiments, B is substituted with one or more substituents selected 76 WSGR Ref: 60134-709.601 [00265] In some embodiments, B is substituted with one or more substituents selected .
  • B is substituted with one or more substituents selected 77 WSGR Ref: 60134-709.601 [00267] In some embodiments, B is substituted with one or more substituents selected [00268] In some embodiments, B is substituted with one or more substituents selected [00269] In some embodiments, B is substituted with one or more substituents selected 78 WSGR Ref: 60134-709.601 [00270] In some embodiments, B is substituted with one or more substituents selected [00271] In some embodiments, B is substituted with one or more substituents selected [00272] In some embodiments, B is substituted with one or more substituents selected 79 WSGR Ref: 60134-709.601 [00274] In some embodiments, X is N.
  • X is C-R. 80 WSGR Ref: 60134-709.601
  • Y is N.
  • Y is C-R.
  • Z is N.
  • Z is C-R.
  • X is CR; Y is CR; and Z is CR.
  • X is CH; Y is CH; and Z is CH.
  • X is N; Y is CR; and Z is CR.
  • each R is independently hydrogen, deuterium, halogen, - CN, or optionally substituted C 1-2 alkyl.
  • each R is independently hydrogen, deuterium, halogen, - CN, or optionally substituted C 1 alkyl.
  • each R is independently hydrogen, deuterium, halogen, - CN, or -CH3.
  • each R is independently hydrogen, deuterium, or halogen.
  • each R is independently hydrogen, deuterium, or -F.
  • each R is independently hydrogen or deuterium.
  • E is absent.
  • E is O or N-R 1 .
  • E is O.
  • E is N-R 1 .
  • E is O or absent.
  • E is N-R 1 or absent.
  • R 1 is hydrogen, optionally substituted C1-C5 alkyl, -OH, - CN, -C(O)R 8 , or -C(O)N(R 9 )2.
  • R 1 is hydrogen, optionally substituted C 1 -C 5 alkyl, -OH, - CN, -C(O)CH 3 , -C(O)NH 2 , -C(O)NH(CH 3 ), or -C(O)N(CH 3 ) 2 .
  • R 1 is hydrogen, optionally substituted C1-C5 alkyl, -OH, - CN, -C(O)CH 3 , or -C(O)N(CH 3 ) 2 .
  • R 1 is hydrogen, -CH 3 , -CH 2 CO 2 H, -CH(CH 3 )CO 2 H, -OH, -CN, -C(O)CH3, or -C(O)N(CH3)2.
  • R 1 is hydrogen, optionally substituted C1-C5 alkyl, -OH, or -CN.
  • R 1 is hydrogen or optionally substituted C1-C5 alkyl.
  • R 1 is hydrogen or optionally substituted C1-C4 alkyl.
  • R 1 is hydrogen or optionally substituted C1-C3 alkyl.
  • R 1 is hydrogen or optionally substituted C 1 -C 2 alkyl. In some embodiments, R 1 is hydrogen or optionally substituted C 1 alkyl. In some embodiments, R 1 is hydrogen or -CH 3 . [00302] In some embodiments, R 1 is hydrogen. [00303] In some embodiments, R 1 is optionally substituted alkyl. In some embodiments, R 1 is optionally substituted C 1 -C 5 alkyl. In some embodiments, R 1 is optionally substituted C 1 - C4 alkyl. In some embodiments, R 1 is optionally substituted C1-C3 alkyl. In some embodiments, R 1 is optionally substituted C1-C2 alkyl.
  • R 1 is optionally substituted C1 alkyl. In some embodiments, R 1 is C 1 -C 5 alkyl substituted with one or more group selected from -CO 2 H. In some embodiments, R 1 is -H, -CH 2 CO 2 H, or -CH(CH 3 )CO 2 H. In some embodiments, R 1 is -CH2CO2H or -CH(CH3)CO2H. In some embodiments, R 1 is -CH2CO2H. In some embodiments, R 1 is -CH(CH 3 )CO 2 H. [00304] In some embodiments, R 1 is -OH. [00305] In some embodiments, R 1 is -C(O)R 8 .
  • R 1 is -C(O)CH3. [00307] In some embodiments, R 1 is -C(O)N(R 9 ) 2 . [00308] In some embodiments, R 1 is -C(O)N(CH3)2.
  • R L is optionally substituted C4-C12 alkyl, optionally substituted -(C 1 -C 3 alkylene)-O-(C 1 -C 10 alkyl), optionally substituted -(C 1 -C 3 alkylene)-N(C 1 -C 3 alkyl)(heteroaryl), optionally substituted C 4 -C 12 alkenyl, optionally substituted C 4 -C 12 alkynyl, optionally substituted carbocyclyl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclylalkyl, or optionally substituted C-heterocyclyl.
  • 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: 82 WSGR Ref: 60134-709.601 e ach 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.
  • 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: e ach Rw is independently hydrogen, , , , , alkyl, amino, cyano, halogen, optionally substituted morpholinyl, optionally substituted 3-aminopyrrolidin-1-yl, or optionally substituted piperazin-1-yl; and 83 WSGR Ref: 60134-709.601 E is O or NH.
  • 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: e ach 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.
  • 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: 84 WSGR Ref: 60134-709.601 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; and E is O or NH.
  • 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: 85 WSGR Ref: 60134-709.601 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; and E is O or NH.
  • 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: 86 WSGR Ref: 60134-709.601 e ach 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.
  • 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: e ach Rw is independently hydrogen, , , , , alkyl, amino, cyano, halogen, optionally substituted morpholinyl, optionally substituted 3-aminopyrrolidin-1-yl, or optionally substituted piperazin-1-yl; and 87 WSGR Ref: 60134-709.601 E is O or NH.
  • 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.
  • 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: 88 WSGR Ref: 60134-709.601 e ach 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.
  • 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: e ach Rw is independently hydrogen, , , , , alkyl, amino, cyano, halogen, optionally substituted morpholinyl, optionally substituted 3-aminopyrrolidin-1-yl, or optionally substituted piperazin-1-yl; and 89 WSGR Ref: 60134-709.601 E is O or NH.
  • 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(C 1 -C 6 alkyl); e ach 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 R v is independently hydrogen or C 1 -C 6 alkyl; and E is O or NH.
  • R L is optionally substituted C4-C12 alkyl, optionally substituted -(C 1 -C 3 alkylene)-O-(C 1 -C 10 alkyl), optionally substituted -(C 1 -C 3 alkylene)-N(C 1 -C 3 alkyl)(heteroaryl), optionally substituted C 4 -C 12 alkenyl, optionally substituted C 4 -C 12 alkynyl, optionally substituted carbocyclyl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclylalkyl, or optionally substituted C-heterocyclyl, wherein R L is not 4-piperidinyl.
  • R L is 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 C 4 -C 12 alkenyl, optionally substituted C 4 -C 12 alkynyl, optionally substituted carbocyclyl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclylalkyl, or optionally substituted 4- to 5-membered C-heterocyclyl.
  • R L is optionally substituted C 4 -C 12 alkyl, 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.
  • R L is optionally substituted C 4 -C 12 alkyl, optionally substituted -(C 1 -C 3 alkylene)-O-(C 1 -C 10 alkyl), optionally substituted -(C 1 -C 3 alkylene)-N(C 1 -C 3 alkyl)(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.
  • R L is optionally substituted C4-C12 alkyl, optionally substituted -(C 1 -C 3 alkylene)-O-(C 1 -C 10 alkyl), optionally substituted -(C 1 -C 3 alkylene)-N(C 1 -C 3 alkyl)(heteroaryl), optionally substituted C 4 -C 12 alkenyl, optionally substituted C 4 -C 12 alkynyl, optionally substituted carbocyclyl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclylalkyl, or optionally substituted 4-membered C-heterocyclyl.
  • R L is 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 C 4 -C 12 alkenyl, optionally substituted C 4 -C 12 alkynyl, optionally substituted 3- to 6-membered carbocyclyl, optionally substituted aralkyl, optionally 91 WSGR Ref: 60134-709.601 substituted heteroarylalkyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclylalkyl, or optionally substituted 4-membered C-heterocyclyl.
  • R L is optionally substituted C 4 -C 12 alkyl, 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.
  • R L is optionally substituted C 4 -C 12 alkyl, optionally substituted -(C 1 -C 3 alkylene)-O-(C 1 -C 10 alkyl), optionally substituted -(C 1 -C 3 alkylene)-N(C 1 -C 3 alkyl)(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.
  • R L is optionally substituted C4-C12 alkyl, optionally substituted -(C 1 -C 3 alkylene)-O-(C 1 -C 10 alkyl), optionally substituted -(C 1 -C 3 alkylene)-N(C 1 -C 3 alkyl)(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.
  • R L is optionally substituted C4-C12 alkyl, optionally substituted -(C 1 -C 3 alkylene)-O-(C 1 -C 10 alkyl), optionally substituted -(C 1 -C 3 alkylene)-N(C 1 -C 3 alkyl)(heteroaryl), optionally substituted C 4 -C 12 alkenyl, optionally substituted C 4 -C 12 alkynyl, 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.
  • R L is optionally substituted C 4 -C 12 alkyl, optionally substituted -(C1-C3 alkylene)-O-(C1-C10 alkyl), optionally substituted -(C1-C3 alkylene)-N(C1-C3 alkyl)(heteroaryl), optionally substituted C 4 -C 12 alkenyl, optionally substituted C 4 -C 12 alkynyl, 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.
  • R L is optionally substituted C 4 -C 12 alkyl, 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, 92 WSGR Ref: 60134-709.601 optionally substituted carbocyclyl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted carbocyclylalkyl, or optionally substituted heterocyclylalkyl.
  • R L is optionally substituted C4-C12 alkyl, optionally substituted -(C1-C3 alkylene)-O-(C1-C10 alkyl), optionally substituted C4-C12 alkenyl, optionally substituted C 4 -C 12 alkynyl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted carbocyclylalkyl, or optionally substituted heterocyclylalkyl.
  • R L is optionally substituted C4-C12 alkyl, optionally substituted -(C 1 -C 3 alkylene)-O-(C 1 -C 10 alkyl), optionally substituted C 4 -C 12 alkenyl, optionally substituted C 4 -C 12 alkynyl, optionally substituted aralkyl or optionally substituted carbocyclylalkyl.
  • R L is optionally substituted C 4 -C 12 alkyl, optionally substituted -(C 1 -C 3 alkylene)-O-(C 1 -C 10 alkyl), optionally substituted C 4 -C 12 alkenyl, optionally substituted C4-C12 alkynyl, or optionally substituted carbocyclylalkyl.
  • R L is optionally substituted C4-C12 alkyl, optionally substituted -(C 1 -C 3 alkylene)-O-(C 1 -C 10 alkyl), optionally substituted C 4 -C 12 alkenyl, or optionally substituted C4-C12 alkynyl.
  • R L is optionally substituted C4-C12 alkyl or optionally substituted -(C 1 -C 3 alkylene)-O-(C 1 -C 10 alkyl). [00338] In some embodiments, R L is optionally substituted C 4 -C 10 alkyl or optionally substituted -(C1-C3 alkylene)-O-(C1-C8 alkyl).
  • R L is optionally substituted C 4 -C 12 alkyl, optionally substituted -(C 1 -C 3 alkylene)-O-(C 1 -C 10 alkyl), optionally substituted -(C 1 -C 3 alkylene)-N(C 1 -C 3 alkyl)(heteroaryl), optionally substituted C4-C12 alkenyl, optionally substituted C4-C12 alkynyl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted carbocyclylalkyl, or optionally substituted heterocyclylalkyl.
  • R L is optionally substituted C 4 -C 12 alkyl, optionally substituted -(C1-C3 alkylene)-O-(C1-C10 alkyl), optionally substituted -(C1-C3 alkylene)-N(C1-C3 alkyl)(heteroaryl), optionally substituted C 4 -C 12 alkenyl, optionally substituted C 4 -C 12 alkynyl, optionally substituted carbocyclylalkyl, or optionally substituted heterocyclylalkyl.
  • R L is 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 C 5 -C 10 alkenyl, optionally substituted C 5 -C 10 alkynyl, optionally substituted carbocyclyl, optionally substituted aralkyl, optionally substituted 93 WSGR Ref: 60134-709.601 heteroarylalkyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclylalkyl, or optionally substituted C-heterocyclyl.
  • R L is optionally substituted C 4 -C 10 alkyl, 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.
  • R L is optionally substituted C5-C12 alkyl, optionally substituted -(C 1 -C 3 alkylene)-O-(C 1 -C 10 alkyl), optionally substituted -(C 1 -C 3 alkylene)-N(C 1 -C 3 alkyl)(heteroaryl), optionally substituted C 5 -C 12 alkenyl, optionally substituted C 5 -C 12 alkynyl, optionally substituted carbocyclyl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted carbocyclylalkyl, or optionally substituted heterocyclylalkyl.
  • R L is optionally substituted C4-C12 alkyl, optionally substituted -(C1-C3 alkylene)-O-(C1-C10 alkyl), optionally substituted C4-C12 alkenyl, or optionally substituted C 4 -C 12 alkynyl. [00345] In some embodiments, R L is optionally substituted C4-C12 alkyl, optionally substituted C4-C12 alkenyl, or optionally substituted C4-C12 alkynyl.
  • R L is optionally substituted C 5 -C 12 alkyl, optionally substituted C 5 -C 12 alkenyl, or optionally substituted C 5 -C 12 alkynyl. [00347] In some embodiments, R L is optionally substituted C6-C12 alkyl, optionally substituted C 6 -C 12 alkenyl, or optionally substituted C 6 -C 12 alkynyl. [00348] In some embodiments, R L is an optionally substituted C 4 -C 12 alkyl. [00349] In some embodiments, R L is an optionally substituted C5-C12 alkyl.
  • R L is an optionally substituted, linear C4-C10 alkyl.
  • R L is an optionally substituted, linear C 5 -C 10 alkyl.
  • R L is an optionally substituted C 4 -C 12 alkenyl.
  • R L is an optionally substituted C4-C10 alkenyl.
  • R L is an optionally substituted C 4 -C 12 alkynyl.
  • R L is an optionally substituted C 4 -C 10 alkynyl.
  • R L is an optionally substituted carbocyclyl. [00357] In some embodiments, R L is an optionally substituted C3-C8 carbocyclyl. [00358] In some embodiments, R L is an optionally substituted C 4 -C 8 carbocyclyl. [00359] In some embodiments, R L is an optionally substituted C5-C8 carbocyclyl. [00360] In some embodiments, R L is an optionally substituted C5-C7 carbocyclyl. 94 WSGR Ref: 60134-709.601 [00361] In some embodiments, R L is an optionally substituted C5-C6 carbocyclyl.
  • R L is an optionally substituted 4-membered carbocyclyl.
  • R L is an optionally substituted aralkyl.
  • R L is an optionally substituted heteroarylalkyl.
  • R L is an optionally substituted carbocyclylalkyl.
  • R L is an optionally substituted heterocyclylalkyl.
  • R L is an optionally substituted C-heterocyclyl.
  • R L is an optionally substituted 4 to 8-membered C- heterocyclyl.
  • R L is an optionally substituted 5 to 6-membered C- heterocyclyl.
  • R L is an optionally substituted 4 to 5-membered C- heterocyclyl.
  • R L is an optionally substituted 4 to 6-membered C- heterocyclyl.
  • R L is an optionally substituted 6 membered C- heterocyclyl.
  • R L is an optionally substituted C-pyperidinyl.
  • R L is a substituted C-pyperidinyl.
  • R L is an optionally substituted 5 membered C- heterocyclyl. [00376] In some embodiments, R L is an optionally substituted 4 membered C- heterocyclyl. [00377] In some embodiments, R L is an optionally substituted oxetanyl. [00378] In some embodiments, R L is an optionally substituted C-azetidinyl. [00379] In some embodiments, R L is optionally substituted -(C 1 -C 3 alkylene)-N-(C 1 -C 3 alkyl)(heteroaryl).
  • R L is optionally substituted -(C1-C3 alkylene)-N- (CH 3 )(heteroaryl). In some embodiments, R L is optionally substituted –(CH 2 ) 3 -N- (CH 3 )(heteroaryl). In some embodiments, R L is optionally substituted –(CH 2 ) 2 -N- (CH3)(heteroaryl). [00381] In some embodiments, R L is optionally substituted -(C1-C2 alkylene)-O-(C1-C10 alkyl).
  • R L is optionally substituted -(C1 alkylene)-O-(C1-C10 alkyl). 95 WSGR Ref: 60134-709.601 [00383] In some embodiments, R L is optionally substituted -CH2O(C1-C10 alkyl).
  • R L is selected from the group consisting of: [00385] In some embodiments, R L is selected from the group consisting of: [00386] In some embodiments, R L is selected from the group consisting of: 96 WSGR Ref: 60134-709.601 97 WSGR Ref: 60134-709.601 98 WSGR Ref: 60134-709.601 [00389] In some embodiments, R L is selected from the group consisting of: 99 WSGR Ref: 60134-709.601 [00390] In some embodiments, R L is selected from the group consisting of: 100 WSGR Ref: 60134-709.601 , , , [ 101 WSGR Ref: 60134-709.601 .
  • R L is selected from the group consisting of: 102 WSGR Ref: 60134-709.601 103 WSGR Ref: 60134-709.601 .
  • L is -N(R j )-, -C(R n )2-, or -O-.
  • L is - N(R j )-.
  • L is -C(R n )2-.
  • L is -O-.
  • L is -NH-, -N(CH 3 )-, -CH 2 -, -CHF-, -CF 2 -, -C(CH 3 )H-, -C(CH 3 ) 2 -, or -O-.
  • L is -NH-, -N(CH 3 )-, -CH 2 -, -CHF-, -CF 2 -, -C(CH 3 )H-, or -C(CH 3 ) 2 -.
  • L is -CH2-, -CHF-, -CF2-, -C(CH3)H-, -C(CH3)2-, or -O-.
  • L is -CH 2 -, -CHF-, -CF 2 -, -C(CH 3 )H-, or -C(CH 3 ) 2 -.
  • L is - CH 2 -.
  • L is -NH-, -N(CH 3 )-, -CH 2 -, or -O-.
  • L is - NH- or -N(CH3)-.
  • R S is optionally substituted C 1 -C 5 alkyl, optionally substituted C 2 -C 5 alkenyl, optionally substituted C 2 -C 5 alkynyl, -OR j , or -N 2 .
  • R S is optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, -OR j , or -N(R j )2.
  • R S is optionally substituted C 1 -C 4 alkyl, -OR j , or -N 2 .
  • R S is optionally substituted C 1 - C 4 alkyl. In some embodiments, R S is optionally substituted C 1 -C 3 alkyl. In some embodiments, R S is optionally substituted C1-C2 alkyl. In some embodiments, R S is optionally substituted C1 alkyl. In some embodiments, R S is unsubstituted C 1 -C 3 alkyl. In some embodiments, R S is C 1 -C 3 alkyl optionally substituted with -F. In some embodiments, R S is optionally substituted -OR j , or - N(R j )2. In some embodiments, R S is optionally substituted -OR j .
  • R S is optionally substituted N(R j )2. In some embodiments, R S is optionally substituted -OH, -OCH3, - OCH 2 CH 3 , --NH 2 , -NHCH 3 , or -N(CH 3 ) 2 .
  • each R P is independently optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, optionally substituted C2-C5 alkynyl, -OR j , or - N(R j ) 2 . In some embodiments, each R P is independently optionally substituted C 1 -C 3 alkyl, -OR j , or -N(R j )2.
  • each R P is independently optionally substituted C1-C3 alkyl. In some embodiments, each R P is independently C1-C3 alkyl optionally substituted by -F. In some embodiments, each R P is independently -CH 3 , -CH 2 CH 3 , -OCH 3 , -OCH 2 CH 3 , -NH 2 , - NHCH 3 , or -N(CH 3 ) 2 . In some embodiments, each R P is independently -CH 3 , -CH 2 CH 3 , OCH 3 , or -OCH2CH3. In some embodiments, each R P is independently -CH3.
  • two R P are taken together to form an optionally substituted 3 to 10-membered heterocyclyl. In some embodiments, two R P are taken together to form an optionally substituted 4 to 10- 104 WSGR Ref: 60134-709.601 membered heterocyclyl. In some embodiments, two R P are taken together to form an optionally substituted 5 to 6-membered heterocyclyl.
  • each R j is independently hydrogen or optionally substituted C1-C3 alkyl; or two R j groups are optionally cyclized to form an optionally substituted C3-C7 carbocyclyl; or two R j groups are optionally cyclized to form an optionally substituted 3 to 7-membered heterocyclyl.
  • each R j is independently hydrogen or optionally substituted C 1 -C 3 alkyl; or two R j groups are optionally cyclized to form an optionally substituted C 3 -C 7 carbocyclyl; or two R j groups are optionally cyclized to form an optionally substituted 4 to 7-membered heterocyclyl.
  • each R j is independently hydrogen or optionally substituted C1-C3 alkyl; or two R j groups are optionally cyclized to form an optionally substituted C3-C6 carbocyclyl; or two R j groups are optionally cyclized to form an optionally substituted 3 to 6-membered heterocyclyl.
  • each R j is independently hydrogen or optionally substituted C 1 -C 3 alkyl; or two R j groups are optionally cyclized to form an optionally substituted C 3 -C 5 carbocyclyl; or two R j groups are optionally cyclized to form an optionally substituted 3 to 5-membered heterocyclyl.
  • each R j is independently hydrogen or optionally substituted C1-C3 alkyl; or two R j groups are optionally cyclized to form an optionally substituted C3-C4 carbocyclyl; or two R j groups are optionally cyclized to form an optionally substituted 4-membered heterocyclyl.
  • each R j is independently hydrogen or optionally substituted C 1 -C 3 alkyl; or two R j groups are optionally cyclized to form an optionally substituted C 3 -C 4 carbocyclyl.
  • each R j is independently hydrogen or optionally substituted C1-C3 alkyl; or two R j groups are optionally cyclized to form an optionally substituted C 3 carbocyclyl.
  • each R j is independently hydrogen or optionally substituted C1-C3 alkyl.
  • each R j is independently hydrogen or optionally 105 WSGR Ref: 60134-709.601 substituted C1-C2 alkyl.
  • each R j is independently hydrogen or optionally substituted C 1 alkyl.
  • each R j is independently hydrogen or -CH 3 .
  • each R k is independently hydrogen, halogen, optionally substituted C1-C3 alkyl, or -OH; or two R k groups attached to the same carbon atom are optionally cyclized to form a C3-C6 carbocyclyl; or two R k groups attached to the same carbon atom are optionally cyclized to form a 3 to 6- membered heterocyclyl.
  • each R k is independently hydrogen, halogen, optionally substituted C 1 -C 3 alkyl, or -OH; or two R k groups attached to the same carbon atom are optionally cyclized to form a C3-C5 carbocyclyl; or two R k groups attached to the same carbon atom are optionally cyclized to form a 3 to 5- membered heterocyclyl.
  • each R k is independently hydrogen, halogen, optionally substituted C 1 -C 3 alkyl, or -OH; or two R k groups attached to the same carbon atom are optionally cyclized to form a C3-C4 carbocyclyl; or two R k groups attached to the same carbon atom are optionally cyclized to form a 4- membered heterocyclyl.
  • each R k is independently hydrogen, halogen, optionally substituted C 1 -C 3 alkyl, or -OH; or two R k groups attached to the same carbon atom are optionally cyclized to form a C 3 -C 4 carbocyclyl.
  • each R k is independently hydrogen, halogen, optionally substituted C 1 -C 3 alkyl, or -OH; or two R k groups attached to the same carbon atom are optionally cyclized to form a C 3 carbocyclyl.
  • each R k is independently hydrogen, halogen, optionally substituted C 1 -C 3 alkyl, or -OH.
  • each R k is independently hydrogen, halogen, optionally substituted C1-C2 alkyl, or -OH.
  • each R k is independently hydrogen, halogen, optionally substituted C1 alkyl, or -OH.
  • each R k is independently hydrogen, -F, -OH, or -CH 3 . In some embodiments, each R k is independently hydrogen, -F, or -CH3. In some embodiments, 106 WSGR Ref: 60134-709.601 each R k is independently hydrogen or -CH3.In some embodiments, each R k is independently hydrogen. [00412] In some embodiments, each R m is independently optionally substituted C 1 -C 3 alkyl; or two R m groups are optionally cyclized to form an optionally substituted 3 to 6-membered heterocyclyl.
  • each R m is independently optionally substituted C1-C3 alkyl; [00414] or two R m groups are optionally cyclized to form an optionally substituted 5 to 6-membered heterocyclyl. [00415] In some embodiments, each R m is independently optionally substituted C1-C3 alkyl; or two R m groups are optionally cyclized to form an optionally substituted 4-membered heterocyclyl. [00416] In some embodiments, each R m is independently optionally substituted C1-C3 alkyl. In some embodiments, each R m is independently optionally substituted C 1 -C 2 alkyl.
  • each R m is independently optionally substituted C1 alkyl. In some embodiments, each R m is independently -CH3. [00417] In some embodiments, each R n is independently hydrogen, halogen, or optionally substituted C 1 -C 3 alkyl; or two R n groups attached to the same carbon atom are optionally cyclized to form a C3-C6 carbocyclyl; or two R n groups attached to the same carbon atom are optionally cyclized to form a 3 to 6- membered heterocyclyl.
  • each R n is independently hydrogen, halogen, or optionally substituted C 1 -C 3 alkyl; or two R n groups attached to the same carbon atom are optionally cyclized to form a C 3 -C 4 carbocyclyl; or two R n groups attached to the same carbon atom are optionally cyclized to form a 4- membered heterocyclyl.
  • each R n is independently hydrogen, halogen, or optionally substituted C1-C3 alkyl; or two R n groups attached to the same carbon atom are optionally cyclized to form a C 3 -C 4 carbocyclyl.
  • each R n is independently hydrogen, halogen, or optionally substituted C 1 -C 3 alkyl. In some embodiments, each R n is independently hydrogen, halogen, or optionally substituted C 1 -C 2 alkyl. In some embodiments, each R n is independently hydrogen, halogen, or optionally substituted C1 alkyl. In some embodiments, each R n is independently hydrogen, -F, or -CH3. [00421] In some embodiments, R 8 is optionally substituted C 1 -C 5 alkyl. In some embodiments, R 8 is optionally substituted C1-C4 alkyl.
  • R 8 is optionally substituted C1-C3 alkyl. In some embodiments, R 8 is optionally substituted C1-C2 alkyl. In some embodiments, R 8 is optionally substituted C 1 -C 1 alkyl. In some embodiments, R 8 is -CH 3 . [00422] In some embodiments, each R 9 is independently hydrogen or optionally substituted C1-C3 alkyl; or two R 9 groups attached to the same atom are optionally cyclized to form a 3 to 6-membered heterocyclyl.
  • each R 9 is independently hydrogen or optionally substituted C1-C3 alkyl; or two R 9 groups attached to the same atom are optionally cyclized to form a 4 to 6-membered heterocyclyl.
  • each R 9 is independently hydrogen or optionally substituted C1-C3 alkyl; or two R 9 groups attached to the same atom are optionally cyclized to form a 5 to 6-membered heterocyclyl.
  • each R 9 is independently hydrogen or optionally substituted C 1 -C 3 alkyl.
  • each R 9 is independently hydrogen or optionally substituted C1-C2 alkyl.
  • each R 9 is independently hydrogen or optionally substituted C 1 alkyl. In some embodiments, each R 9 is independently hydrogen or -CH 3 . [00426]
  • One embodiment provides a LpxH inhibitory compound, or a pharmaceutically acceptable salt or solvate thereof, having a structure presented in Table 1.
  • the LpxH inhibitory compound described herein is administered as a pure chemical.
  • 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, 21 st Ed. Mack Pub. Co., Easton, PA (2005)).
  • Another embodiment provides a pharmaceutical composition
  • 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.
  • Another embodiment provides a method of preparing a pharmaceutical composition
  • 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.
  • a pharmaceutical composition comprising at least one LpxH inhibitory compound as described herein, or a stereoisomer, pharmaceutically acceptable salt, 124 WSGR 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.
  • One embodiment provides a pharmaceutical composition
  • 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.
  • 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.
  • 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.
  • 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. [00439] 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.
  • 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.
  • 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.
  • suitable nontoxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, 125 WSGR Ref: 60134-709.601 sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like.
  • pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, 125 WSGR 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, 21 st Ed. Mack Pub. Co., Easton, PA (2005)).
  • 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.
  • the injection formulation is an aqueous formulation.
  • the injection formulation is a non-aqueous formulation.
  • the injection formulation is an oil-based formulation, such as sesame oil, or the like.
  • compositions 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.
  • 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.
  • 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. [00445] Oral doses typically range from about 1.0 mg to about 1000 mg, one to four times, or more, per day.
  • 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.
  • 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.
  • One embodiment provides a pharmaceutical composition
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 127 WSGR 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.
  • 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.
  • At least one Gram-negative pathogen is selected from the group consisting of Escherichia coli, Enterobacter cloacae, Klebsiella pneumoniae, Citrobacter freundii or Proteus mirabilis.
  • the pathogen is a pandrug-resistant (PDR) pathogen.
  • the pathogen is an extensively drug-resistant (XDR) pathogen.
  • the pathogen is a multidrug-resistant (MDR) pathogen.
  • the pathogen is an extended spectrum beta-lactamase positive pathogen.
  • the pathogen is a carbapenemase positive pathogen.
  • 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.
  • TMP/SMX-resistant Trimethoprim/Sulfamethoxazole-resistant
  • 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 128 WSGR 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.
  • 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 [00461] In some embodiments, the LpxH inhibitory compounds disclosed herein are synthesized according to the following examples.
  • Step 4 tert-butyl N-(2-(5-bromoindoline-1-carbonyl)phenyl)-N-methylmethanesulfonamide
  • SOCl2 250 mL
  • 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.
  • Step 5 N-(2-(5-(benzylthio)indoline-1-carbonyl)phenyl)-N-methylmethanesulfonamide
  • phenylmethanethiol 4.56 g, 36.65 mmol
  • Pd2(dba)3 1.8 g, 1.96 mmol
  • Xant-phos 2.26 g, 3.91 mmol
  • DIPEA DIPEA
  • Step 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.
  • Step 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.
  • 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 H 2 O (100 mL), then mixture was stirred at room temperature overnight.
  • 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.
  • Step 4 N-(2-(5-(benzylthio)indoline-1-carbonyl)phenyl)methanesulfonamide
  • N-(2-(5-bromoindoline-1-carbonyl)phenyl)-N-methylmethanesulfonamide 10 g, 24.45 mmol
  • phenylmethanethiol 4.56 g, 36.65 mmol
  • Pd 2 (dba) 3 1.8 g, 1.96 mmol
  • Xant-phos (2.26 g, 3.91 mmol)
  • DIPEA DIPEA
  • Step 3 methyl 2-bromo-5-((methylamino)methyl)-4-nitrobenzoate.
  • methyl 2-bromo-5-(bromomethyl)-4-nitrobenzoate 2.1 g, 5.949 mmol
  • THF tetrahydrofuran
  • methylamine MeOH 1.3 mL
  • the mixture was stirred for 1 h at room temperature.
  • 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 70 o C.
  • Step 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).
  • Step 1 tert-butyl 4-(3-(methoxycarbonyl)phenyl)piperazine-1-carboxylate
  • methyl 3-bromobenzoate 2.0 g, 9.3 mmol
  • RuphosPdG4 791 mg, 0.93 mmol
  • Cs2CO3 6.04 g, 18.6 mmol
  • dioxane 40 mL
  • tert-butyl piperazine-1-carboxylate 2.08 g, 11.2 mmol
  • Example 2 (5-(heptylsulfonyl)indolin-1-yl)(3-(piperazin-1- yl)phenyl)methanone
  • Step 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.
  • 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.
  • 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.
  • Example 4 2-(5-(heptylsulfonyl)indoline-1-carbonyl)benzoic acid 146 WSGR Ref: 60134-709.601
  • Step 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.
  • Step 2 N-(2-(5-(hexylsulfonyl)indoline-1-carbonyl)phenyl)-N-methylmethanesulfonamide
  • m-CPBA 266 mg, 1.54 mmol
  • Step 2 N-(2-(5-((2-cyclobutylethyl)sulfonyl)indoline-1-carbonyl)phenyl)-N- methylmethanesulfonamide 148 WSGR Ref: 60134-709.601
  • m-CPBA 82 mg, 0.44 mmol
  • Step 2 N-methyl-N-(2-(5-(pentylsulfonyl)indoline-1-carbonyl)phenyl)methanesulfonamide
  • m-CPBA 330 mg, 1.914 mmol
  • Example 8 N-methyl- -(2-(5-((5-methylhexyl)sulfonyl)indoline-1- carbonyl)phenyl)methanesulfonamide
  • Step 1 N-methyl-N-(2-(5-((5-methylhexyl)thio)indoline-1-carbonyl)phenyl)methanesulfonamide
  • N-(2-(5-mercaptoindoline-1-carbonyl)phenyl)-N-methylmethanesulfonamide (128 mg, 0.353 mmol) and Cs 2 CO 3 (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
  • Step 2 N-methyl-N-(2-(5-((5-methylhexyl)sulfonyl)indoline-1- carbonyl)phenyl)methanesulfonamide
  • m-CPBA 168 mg, 0.98 mmol
  • Step 2 N-(2-(5-((2-cyclopropylethyl)sulfonyl)indoline-1-carbonyl)phenyl)-N- methylmethanesulfonamide
  • m- CPBA 261 mg, 1.484 mmol
  • Step 2 N-(2-(5-((3-cyclopentylpropyl)sulfonyl)indoline-1-carbonyl)phenyl)-N- methylmethanesulfonamide
  • m-CPBA 249 mg, 1.44 mmol
  • Step 2 N-(2-(5-(heptylthio)-2, 3-dihydro-1H-pyrrolo [3, 2-b] pyridine-1-carbonyl) phenyl)-N- methylmethanesulfonamide
  • heptane-1-thiol 91 mg, 0.696 mmol
  • Pd 2 (dba) 3 53 mg, 0.058 mmol
  • 153 WSGR Ref 60134-709.601 DIEA(224 mg , 1.74 mmol) under Ar.
  • Step 3 N-(2-(5-(heptylsulfonyl)-2, 3-dihydro-1H-pyrrolo [3,2-b] pyridine-1-carbonyl)phenyl)- N-methylmethanesulfonamide
  • N-(2-(5-(heptylthio)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1- carbonyl)phenyl)-N-methylmethanesulfonamide 125 mg, 0.271 mmol
  • DCM(5 mL) m-CPBA(140 mg, 0.813 mmol)
  • Example 12 Heptyl (imino) (1-(3-(piperazin-1-yl) benzoyl) indolin-5-yl)-l6- sulfanone
  • Step 1 tert-butyl 4-(3-(5-bromoindoline-1-carbonyl) phenyl) piperazine-1-carboxylate
  • 5-bromoindoline 90 mg, 0.454 mmol
  • MeCN MeCN
  • 3-(4-(tert- butoxycarbonyl) piperazin-1-yl) benzoic acid 139 mg, 0.454 mmol
  • TCFH 190 mg, 0.681 mmol
  • NMI 111 mg, 1.362 mmol
  • Step 2 tert-butyl 4-(3-(5-(heptylthio) indoline-1-carbonyl) phenyl) piperazine-1-carboxylate
  • heptane-1-thiol 58 mg, 0.444 mmol
  • Pd2 (dba)3 33 mg, 0.037 mmol
  • DPPF(40 mg, 0.074 mmol) DIEA(143 mg , 1.11 mmol) under Ar.
  • Step 3 tert-butyl 4-(3-(5-(heptylsulfonimidoyl) indoline-1-carbonyl) phenyl) piperazine-1- carboxylate
  • tert-butyl 4-(3-(5-(heptylthio) indoline-1-carbonyl) phenyl) piperazine-1- carboxylate 100 mg, 0.186 mmol
  • MeOH 3 phenyl-l3-iodanediyl diacetate
  • ammonium carbomate 44 mg, 0.465 mmol
  • Step 4 heptyl (imino) (1-(3-(piperazin-1-yl) benzoyl) indolin-5-yl)-l6-sulfanone
  • DCM dimethyl sulfoxide
  • Step 2 N-(2-(5-((7-hydroxyheptyl)sulfonyl)indoline-1-carbonyl)phenyl)-N- methylmethanesulfonamide
  • m-CPBA 273 mg, 1.580 mmol
  • 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
  • Step 2 tert-butyl (8-((1-(2-(N-methylmethylsulfonamido)benzoyl)indolin-5- yl)sulfonyl)octyl)carbamate
  • 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).
  • Step 3 tert-butyl N-(2-(5-((8-aminooctyl)sulfonyl)indoline-1-carbonyl)phenyl)-N- methylmethanesulfonamide
  • tert-butyl (8-((1-(2-(N-methylmethylsulfonamido)benzoyl)indolin-5- yl)sulfonyl)octyl)carbamate 250 mg, 0.402 mmol
  • HCl/dioxane 4 mol/L, 6 mL
  • Step 2 N-methyl-N-(2-(5-((6-methylheptyl)sulfonyl)indoline-1- carbonyl)phenyl)methanesulfonamide
  • m-CPBA 388 mg, 2.25 mmol
  • reaction mixture was extracted with DCM and water.
  • the crude was purified by Prep-HPLC (CH3CN/H2O, 0.1% NH 3 •H 2 O) 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.
  • Step 2 N-(2-(5-(heptylsulfonimidoyl) indoline-1-carbonyl) phenyl)-N- methylmethanesulfonamide
  • N-(2-(5-(heptylthio)indoline-1-carbonyl)phenyl)-N-methylmethanesulfonamide 65 mg, 0.141 mmol
  • MeOH MeOH
  • phenyl-l3-iodanediyl diacetate 136 mg, 0.423 mmol
  • ammonium carbomate 40 mg, 0.423 mmol
  • Example 17 N-(2-(5-((2-hydroxyhexyl) sulfonyl) indoline-1-carbonyl) phenyl)-N-methylmethanesulfonamide
  • Step 1 N-(2-(5-((2-hydroxyhexyl)thio)indoline-1-carbonyl)phenyl)-N- methylmethanesulfonamide
  • 2-butyloxirane 199 mg, 0.55 mmol
  • Bu 3 P 0.014 mL, 0.055 mmol
  • Step 2 N-(2-(5-((2-hydroxyhexyl) sulfonyl) indoline-1-carbonyl) phenyl)-N- methylmethanesulfonamide
  • N-(2-(5-((2-hydroxyhexyl) thio) indoline-1-carbonyl) phenyl)-N- methylmethanesulfonamide 50 mg, 0.108 mmol
  • m-CPBA 55 mg, 0.324 mmol
  • Example 18 (6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)(5- (heptylsulfonyl)indolin-1-yl)methanone Step 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) was dissolved in ACN (8 mL) and TCFH (350 mg, 1.25 mmol) was dissolved in ACN
  • Step 2 tert-butyl (7-((1-(2-(N-methylmethylsulfonamido)benzoyl)indolin-5- yl)sulfonyl)heptyl)carbamate
  • 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.
  • 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.
  • Example 20 N-methyl-N-(2-(5-((6,6,6-trifluorohexyl)sulfonyl)indoline-1- carbonyl)phenyl)methanesulfonamide 163 WSGR Ref: 60134-709.601
  • Step 1 N-methyl-N-(2-(5-((6,6,6-trifluorohexyl)thio)indoline-1- carbonyl)phenyl)methanesulfonamide
  • N-(2-(5-mercaptoindoline-1-carbonyl)phenyl)-N-methylmethanesulfonamide 140 mg, 0.386 mmol
  • Cs 2 CO 3 (252 mg, 0.772 mmol
  • KI 20 mg
  • Step 2 N-methyl-N-(2-(5-((6,6,6-trifluorohexyl)sulfonyl)indoline-1- carbonyl)phenyl)methanesulfonamide
  • m- CPBA 137 mg, 0.791 mmol
  • Step 2 N-(2-(5-((3-cyclopropylpropyl)sulfonyl)indoline-1-carbonyl)phenyl)-N- methylmethanesulfonamide
  • m-CPBA 280 mg, 1.622 mmol
  • Example 22 N-(4-chloro-2-(5-(heptylsulfonyl)indoline-1-carbonyl)-1H- pyrrol-1-yl)methanesulfonamide
  • Step 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.
  • Example 23 N-(5-(5-(heptylsulfonyl)indoline-1-carbonyl)-3-methyl-1H- pyrazol-1-yl)methanesulfonamide 167 WSGR Ref: 60134-709.601 Prepared N-(5-(5-(heptylsulfonyl)indoline-1-carbonyl)-3-methyl-1H-pyrazol-1- yl)methanesulfonamide essentially as described for Example 22.
  • Example 24 N-(2-(3,3-difluoro-5-(heptylsulfonimidoyl)indoline-1- carbonyl)phenyl)methanesulfonamide
  • Step 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.
  • Example 26 N-(3-(5-(heptylsulfonyl)indoline-1-carbonyl)pyrazolo[1,5- a]pyrimidin-2-yl)methanesulfonamide
  • Step 1 Ethyl 2-(N-(methylsulfonyl)methylsulfonamido)pyrazolo[1,5-a]pyrimidine-3-carboxylate
  • DIPEA 3-(5-(heptylsulfonyl)indoline-1-carbonyl)pyrazolo[1,5- a]pyrimidin-2-yl)methanesulfonamide
  • Example 28 N-(2-(5-(heptylsulfonyl)indoline-1-carbonyl)-1H-pyrrol-1-yl)me thanesulfonamide
  • Step 1 N-(2-(5-(heptylthio)indoline-1-carbonyl)-1H-pyrrol-1-yl)methanesulfonamide
  • 5-(heptylthio)indoline 174mg, 0.698 mmol
  • TCFH 295 mg, 1.0478mmol
  • NMI 201 mg, 2.451mmol
  • Example 29 N-(3-methyl-5-(5-((5-methylhexyl)sulfonyl)indoline-1- carbonyl)-1H-pyrazol-1-yl)methanesulfonamide
  • Step 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.
  • reaction mixture flushed with argon, and stirred at 100 o C 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.
  • Step 3 N-(2-(5-(heptylthio)indoline-1-carbonyl)phenyl)methanesulfonamide
  • 2-(methylsulfonamido)benzoic acid 103 mg, 0.481 mmol
  • SOCl 2 2 mL
  • the reaction was stirred at 80 o C for 1 h.
  • SOCl2 was concentrated, the resdual was dissolved in DCM, 5-(heptylthio)indoline (80 mg, 0.321 mmol) in DCM (2 mL) and TEA (96 mg, 0.962 mmol) was added.
  • the mixture was stirred at r.t for 1 h.
  • Step 2 3-(5-(heptylthio)indoline-1-carbonyl)pyrazolo[1,5-a]pyrimidine-6-carbaldehyde
  • 5-(heptylthio)indoline 249 mg, 1 mmol
  • TCFH 560 mg, 2 mmol
  • NMI 246 mg, 3 mmol
  • Step 2 N-methyl-N-(2-(5-(piperidin-4-ylthio)indoline-1-carbonyl)phenyl)methanesulfonamide
  • tert-butyl 4-((1-(2-(N-methylmethylsulfonamido)benzoyl)indolin-5- yl)thio)piperidine-1-carboxylate 250 mg, 0.458 mmol
  • TFA 522 mg, 4.58 mmol
  • Step 3 N-(2-(5-((1-(4-chlorothiazol-2-yl)piperidin-4-yl)thio)indoline-1-carbonyl)phenyl)-N- methylmethanesulfonamide
  • N-methyl-N-(2-(5-(piperidin-4-ylthio)indoline-1- carbonyl)phenyl)methanesulfonamide (252 mg, 0.566 mmol) in DMF (3 mL) was added Cs 2 CO 3 (368 mg, 1.132 mmol) and 2-bromo-4-chlorothiazole (118 mg, 0.594 mmol). The mixture was stirred at 80 o C overnight.
  • Example 34 (7-(((2-aminoethyl)amino)methyl)pyrazolo[1,5-a]pyrimidin-3- yl)(5-(heptylsulfonyl)indolin-1-yl)methanone
  • Step 1 ethyl 7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate
  • HCl aqueous solution 8 mL
  • Step 2 ethyl 7-(bromomethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate 182 WSGR Ref: 60134-709.601
  • ethyl ethyl 7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate 3.0 g, 14.63 mmol
  • BPO 353 mg, 1.46 mmol
  • NBS 2.84 g, 16.09 mmol
  • Step 3 ethyl 7-(((2-((tert-butoxycarbonyl)amino)ethyl)amino)methyl)pyrazolo[1,5- a]pyrimidine-3-carboxylate
  • ethyl 7-(bromomethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate 700 mg, 2.47 mmol
  • tert-butyl (2-aminoethyl)carbamate 396 mg, 2.47 mmol
  • K 2 CO 3 (682 mg, 4.94 mmol
  • Step 4 ethyl 7-(((tert-butoxycarbonyl)(2-((tert- butoxycarbonyl)amino)ethyl)amino)methyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate
  • the solution of ethyl 7-(((2-((tert-butoxycarbonyl)amino)ethyl)amino)methyl)pyrazolo[1,5- a]pyrimidine-3-carboxylate (800 mg, 2.20 mmol) , Boc 2 O (527mg, 2.42 mmol) in EtOH(10 mL) was stirred at 50°C for 2 h.
  • Step 5 7-(((tert-butoxycarbonyl)(2-((tert- butoxycarbonyl)amino)ethyl)amino)methyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
  • ethyl 7-(((tert-butoxycarbonyl)(2-((tert- butoxycarbonyl)amino)ethyl)amino)methyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate 400 mg, 0.86 mmol
  • NaOH 138 mg, 3.45 mmol
  • THF 10 mL
  • H2O 10 mL
  • Step 6 tert-butyl (2-((tert-butoxycarbonyl)amino)ethyl)((3-(5-(heptylthio)indoline-1- carbonyl)pyrazolo[1,5-a]pyrimidin-7-yl)methyl)carbamate
  • tert-butoxycarbonyl 2-((tert-butoxycarbonyl)amino)ethyl)amino)methyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
  • TCFH 266 mg, 0.95 mmol
  • NMI 180 mg, 2.20 mmol
  • Step 7 tert-butyl (2-((tert-butoxycarbonyl)amino)ethyl)((3-(5-(heptylsulfonyl)indoline-1- carbonyl)pyrazolo[1,5-a]pyrimidin-7-yl)methyl)carbamate
  • tert-butyl (2-((tert-butoxycarbonyl)amino)ethyl)((3-(5-(heptylthio)indoline-1- carbonyl)pyrazolo[1,5-a]pyrimidin-7-yl)methyl)carbamate (338 mg, 0.50 mmol) in DCM (8 mL) was added m-CPBA (180 mg, 1.01 mmol) at 0°C and the solution was stirred at room temperature overnight.
  • Example 36 (S)-N-(2-(5-((5-methylheptyl)sulfonyl)indoline-1- carbonyl)phenyl)methanesulfonamide Step 1: methyl (S)-5-methylheptanoate To the solution of methyl acrylate (1.1 g, 12.0 mmol), Zn(780 mg, 12.0 mmol) and NiCl 2 (620 mg, 4.8 mmol) in Py (24 mL),the reaction mixture were stirred at 50°C for 30 min.
  • Step 4 (S)-N-(2-(5-((5-methylheptyl)thio)indoline-1-carbonyl)phenyl)methanesulfonamide
  • (S)-5-methylheptyl methanesulfonate 72 mg, 0.34 mmol
  • N-(2-(5- mercaptoindoline-1-carbonyl)phenyl)methanesulfonamide 60 mg, 0.17 mmol
  • NaH (16 mg, 0.34 mmol
  • Step 5 (S)-N-(2-(5-((5-methylheptyl)sulfonyl)indoline-1-carbonyl)phenyl)methanesulfonamide
  • m- CPBA 25 mg, 0.142 mmol
  • Example 37 N-(2-(5-(heptylsulfonyl)indoline-1-carbonyl)-4- morpholinophenyl)methanesulfonamide
  • Step 1 methyl 5-bromo-2-(N-(methylsulfonyl)methylsulfonamido)benzoate
  • MsCl 3.84 g, 25.0 mmol
  • the 189 WSGR Ref: 60134-709.601 reaction mixture was quenched with HCl (2N, 6 mL) and extracted with EtOAc 3 times. The combined organic layers was washed with brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound as a colorless oil (310 mg, yield: 91%). The residue was used directly in next step without further purification.
  • Step 2 methyl 2-(5-(heptylsulfonimidoyl)indoline-1-carbonyl)benzoate
  • methyl 2-(5-(heptylthio)indoline-1-carbonyl)benzoate 230 mg, 0.56 mmol
  • MeOH MeOH
  • ammonium carbomate 134.4 mg, 1.4 mmol
  • phenyl-l3- iodanediyl diacetate 360.4 mg, 1.12 mmol
  • Step 3 2-(5-(heptylsulfonimidoyl)indoline-1-carbonyl)benzoic acid
  • methyl 2-(5-(heptylsulfonimidoyl)indoline-1-carbonyl)benzoate 240 mg, 0.54 mmol
  • LiOH.H2O 68.4 mg, 1.63 mmol
  • H2O 3 mL
  • Example 39 N-(4-(((3-aminopropyl)amino)methyl)-2-(5- (heptylsulfonyl)indoline-1-carbonyl)phenyl)methanesulfonamide Prepared N-(4-(((3-aminopropyl)amino)methyl)-2-(5-(heptylsulfonyl)indoline-1- carbonyl)phenyl)methanesulfonamide essentially as described in preparation Example 53.
  • Example 40 N-(4-(((3-aminopropyl)amino)methyl)-2-(5- (heptylsulfonimidoyl)indoline-1-carbonyl)phenyl)methanesulfonamide
  • Step 1 tert-butyl (3-((tert-butoxycarbonyl)amino)propyl)(3-(5-(heptylthio)indoline-1-carbonyl)- 4-(methylsulfonamido)benzyl)carbamate
  • 5-(((tert-butoxycarbonyl)(3-((tert- butoxycarbonyl)amino)propyl)amino)methyl)-2-(methylsulfonamido)benzoic acid 260 mg, 0.518mmol
  • Step 2 tert-butyl (3-((tert-butoxycarbonyl)amino)propyl)(3-(5-(heptylsulfonimidoyl)indoline-1- carbonyl)-4-(methylsulfonamido)benzyl)carbamate
  • tert-butyl (3-((tert-butoxycarbonyl)amino)propyl)(3-(5-(heptylthio)indoline-1- carbonyl)-4-(methylsulfonamido)benzyl)carbamate 130 mg, 0.177 mmol
  • MeOH phenyl-l3-iodanediyl diacetate
  • ammonium carbomate 43 mg, 0.433 mmol
  • Step 3 N-(4-(((3-aminopropyl)amino)methyl)-2-(5-(heptylsulfonimidoyl)indoline-1- carbonyl)phenyl)methanesulfonamide
  • tert-butyl 3-((tert-butoxycarbonyl)amino)propyl)(3-(5- (heptylsulfonimidoyl)indoline-1-carbonyl)-4-(methylsulfonamido)benzyl)carbamate (60 mg, 0.078 mmol) in DCM(3 mL) was added TFA(60 mg, 0.52 mmol).
  • Example 42 6-chloro-4-(5-(heptylsulfonyl)indoline-1-carbonyl)nicotinic acid
  • Step 1 3-(ethoxycarbonyl)isonicotinic acid
  • diethyl pyridine-3,4-dicarboxylate 5 g, 22.42 mmol
  • H 2 O 60 mL
  • NaOH 900 mg, 22.42 mmol
  • Step 2 ethyl 4-(5-(heptylthio)indoline-1-carbonyl)nicotinate
  • Step 3 3-(ethoxycarbonyl)-4-(5-(heptylsulfonyl)indoline-1-carbonyl)pyridine 1-oxide
  • ethyl 4-(5-(heptylthio)indoline-1-carbonyl)nicotinate (1.75 g, 4.11 mmol) in DCM (15 mL)
  • m-CPBA 4.25 g, 24.65 mmol
  • Step 4 ethyl 6-chloro-4-(5-(heptylsulfinyl)indoline-1-carbonyl)nicotinate
  • Example 43 6-(5-(heptylsulfonyl)indoline-1-carbonyl)-3-methyl-3,4- dihydroquinazolin-2(1H)-one
  • Step 1 3-methyl-2-oxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid
  • MeOH MeOH
  • H 2 O H 2 O
  • NaOH 400 mg, 10 mmol
  • Step 2 6-(5-(heptylthio)indoline-1-carbonyl)-3-methyl-3,4-dihydroquinazolin-2(1H)-one
  • 3-methyl-2-oxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 117 mg, 0.567 mmol
  • 5-(heptylthio)indoline 141 mg, 0.567 mmol
  • MeCN 5 mL
  • TCFH 238 mg, 0.850 mmol
  • NMI 139 mg, 1.701 mmol
  • Example 46 N-(4-(2-aminoethoxy)-2-(5-(heptylsulfonimidoyl)indoline-1- carbonyl)phenyl)methanesulfonamide Prepared from N-(4-(2-aminoethoxy)-2-(5-(heptylsulfonimidoyl)indoline-1- carbonyl)phenyl)methanesulfonamide essentially as described in Example 45 using t tert-butyl (2-hydroxyethyl)carbamate to obtain the title compound.
  • Example 48 6-(5-(heptylsulfonyl)indoline-1-carbonyl)-3-methyl-3,4-dihydro- 2H-benzo[e][1,3]oxazin-2-one
  • Step 1 6-(5-(heptylthio)indoline-1-carbonyl)-3-methyl-3,4-dihydro-2H-benzo[e][1,3]oxazin-2- one
  • To a solution of 3-methyl-2-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazine-6-carboxylic acid(100 mg, 0.484 mmol) and 5-(heptylthio)indoline(180.8 mg, 0.726 mmol) in Pyridine (8 mL) was added POCl3(111.4 mg, 0.726 mmol
  • the mixture was stirred at rt for 2h.
  • Example 50 7-(5-(heptylsulfonyl)indoline-1-carbonyl)-3,4-dimethyl-3,4- dihydroquinazolin-2(1H)-one
  • Step 1 7-(5-(heptylthio)indoline-1-carbonyl)-3,4-dimethyl-3,4-dihydroquinazolin-2(1H)-one
  • NMI 66 mg, 0.81 mmol
  • TCFH 112 mg, 0.4 mmol
  • Step 2 N-(2-(5-(heptylthio)-2, 3-dihydro-1H-pyrrolo[3,2-b]pyridine-1- carbonyl)phenyl)methanesulfonamide
  • 2-(methylsulfonamido)benzoic acid 300 mg, 1.4 mmol
  • SOCl 2 2 mL
  • the reaction was stirred at 80 o C for 1 h.SOCl2 was concentrated, the resdual was dissolved in DCM, N-(2-(5-(heptylthio)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1- carbonyl)phenyl)methanesulfonamide (270 mg, 1.08 mmol) in DCM(2 mL) and TEA(218 mg, 2.16 mmol) was added.
  • Step 3 N-(2-(5-(heptylsulfonimidoyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1- carbonyl)phenyl)methanesulfonamide
  • N-(2-(5-(heptylthio)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1- carbonyl)phenyl)methanesulfonamide 150 mg, 0.335 mmol
  • MeOH(5 mL) phenyl-l3-iodanediyl diacetate
  • ammonium carbomate 80 mg, 0.838 mmol.
  • Example 54 N-(4-cyano-2-(5-(heptylsulfonyl)indoline-1-carbonyl)-1H- pyrrol-1-yl)methanesulfonamide Prepared N-(4-cyano-2-(5-(heptylsulfonyl)indoline-1-carbonyl)-1H-pyrrol-1- yl)methanesulfonamide essentially as described in preparation Example 24.
  • Step 2 1-chloroheptan-3-one To a solution of hept-1-en-3-one (800 mg, 7.143 mmol) in TMSCl (10 mL) was added water (1 mL) at room temperature. The mixture was stirred for 1h at room temperature.
  • Step 3 1-(indolin-5-ylthio)heptan-3-one To a solution of 5-thiocyanatoindoline (300 mg, 1.705 mmol) in EtOH (7 mL) were added Na 2 S in water (5 mL) at room temperature. The mixture was stirred for 1h at 50°C.
  • Example 56 7-amino-4-(5-(heptylsulfonyl)indoline-1-carbonyl)-2H- chromen-2-one
  • Step 1 ethyl 7-amino-2-oxo-2H-chromene-4-carboxylate To a solution of 3-aminophenol (10.0 g, 91.74 mmol) and diethyl 2-oxosuccinate sodium salt (21.18 g, 100.9 mmol) in EtOH (80 mL).
  • Step 2 ethyl 7-(((benzyloxy)carbonyl)amino)-2-oxo-2H-chromene-4-carboxylate
  • ethyl 7-amino-2-oxo-2H-chromene-4-carboxylate 2.1 g, 9.01 mmol
  • NaHCO 3 1.51 g, 18.02 mmol
  • H 2 O 20 mL
  • CbzCl 1.68 g, 9.9 mmol
  • Step 3 7-(((benzyloxy)carbonyl)amino)-2-oxo-2H-chromene-4-carboxylic acid
  • ethyl 7-(((benzyloxy)carbonyl)amino)-2-oxo-2H- chromene-4-carboxylate 1.0 g, 2.72 mmol
  • NaOH 130 mg, 3.27 mmol
  • THF 10 mL
  • H 2 O 10 mL
  • Step 4 benzyl (4-(5-(heptylthio)indoline-1-carbonyl)-2-oxo-2H-chromen-7-yl)carbamate 7-(((benzyloxy)carbonyl)amino)-2-oxo-2H-chromene-4-carboxylic acid (840 mg, 2.47 mmol) was dissolved into SOCl 2 (2 mL) in a 50 mL bottom flask, the mixture was heated to 80°C and stirred for 1 hour.
  • Step 6 7-amino-4-(5-(heptylsulfonyl)indoline-1-carbonyl)-2H-chromen-2-one
  • benzyl (4-(5-(heptylsulfonyl)indoline-1-carbonyl)-2-oxo-2H-chromen-7- yl)carbamate 140 mg, 0.23 mmol
  • Pd/C 14 mg
  • Example 57 N-(2-fluoro-6-(5-(heptylsulfonyl)indoline-1- carbonyl)phenyl)methanesulfonamide
  • Step 1 methyl 3-fluoro-2-methanesulfonamidobenzoate
  • the crude product was purified by Prer- HPLC using a XBridge Prep OBD C18 Column, 30*150 mm, 5 ⁇ m column (eluent: Water (10 mM NH4HCO3) and ACN, 39% to 59% (v/v)) to yield N- ⁇ 2-fluoro-6-[5-(heptane-1-sulfonyl)-2,3-dihydroindole-1- carbonyl]phenyl ⁇ methanesulfonamide (44.5 mg, 11.08% yield, 99.6% purity) as an off-white solid.
  • Example 58 N-(5-(5-(heptylsulfonyl)indoline-1-carbonyl)-2-(piperazin-1- yl)pyrimidin-4-yl)methanesulfonamide Step 1.
  • ethyl 4-amino-2-[4-(tert-butoxycarbonyl)piperazin-1-yl]pyrimidine-5-carboxylate The solution of ethyl 4-amino-2-chloropyrimidine-5-carboxylate (3 g, 14.880 mmol, 1 equiv) in ACN (100 mL) and tert-butyl piperazine-1-carboxylate (4.16 g, 22.320 mmol, 1.5 equiv) was added dropwise into the mixture. Then added K2CO3 (4.11 g, 29.760 mmol, 2 equiv) .
  • Step 2 ethyl 2-[4-(tert-butoxycarbonyl)piperazin-1-yl]-4-methanesulfonamidopyrimidine-5- carboxylate
  • ethyl 4-amino-2-[4-(tert-butoxycarbonyl)piperazin-1-yl]pyrimidine-5- carboxylate (1 g, 2.846 mmol, 1 equiv) in DMF (10 mL) and added NaH (0.14 g, 5.834 mmol, 2.05 equiv) 0 °C under N2.
  • reaction mixture was stirred at r.t for a period of 0.5h Then added MsCl (0.39 g, 3.415 mmol, 1.2 equiv) at 0 °C. The reaction mixture was stirred at r.t for a period of 16h.diluted with water (100 mL) and extracted with EA (100 mL x 3). The mixture were dried over anhydrous sodium sulfate, filtered, and concentrated.
  • Trimethylaluminium (127.56 mg, 1.770 mmol, 2 equiv) at 0 °C under N2. The resulting mixture was stirred at 100°C for additional 16 h. The resulting mixture was concentrated under reduced pressure, then purified by C18 reversed column (H2O/ACN ) to afford tert-butyl 4- ⁇ 5-[5-(heptylsulfanyl)-2,3-dihydroindole-1-carbonyl]-4- methanesulfonamidopyrimidin-2-yl ⁇ piperazine-1-carboxylate (280 mg, 50.01%yield, 71.061%purity) . LCMS (ES, m/z), calcd.
  • Example 59 N-(2-(5-(heptylsulfonyl)indoline-1-carbonyl)-5-(piperazin-1- yl)thiophen-3-yl)methanesulfonamide 216 WSGR Ref: 60134-709.601
  • Step 1 methyl 5-bromo-3-(methylsulfonamido)thiophene-2-carboxylate
  • methyl 3-amino-5-bromothiophene-2-carboxylate (1 g, 4.236 mmol, 1 equiv) and pyridine (0.67 g, 8.472 mmol, 2 equiv) in DCM (20 mL).
  • tert-butyl 4-(5-(5-(heptylsulfonyl)indoline-1-carbonyl)-4-(methylsulfonamido)thiophen- 2-yl)piperazine-1-carboxylate To a stirred solution of tert-butyl 4-[4-methanesulfonamido-5-(methoxycarbonyl)thiophen-2- yl]piperazine-1-carboxylate (300 mg, 0.715 mmol, 1 equiv) and Intermediate 6, 5-(heptane-1- sulfonyl)-2,3-dihydro-1H-indole (301.86 mg, 1.073 mmol, 1.5 equiv) in toluene (8 mL, 0.002 mmol) .
  • MIC Minimum Inhibitory Concentration Determination
  • Test Media Cation-adjusted Mueller-Hinton broth (CAMHB) was used for MIC testing of all organisms.
  • Broth Microdilution MIC Methodology MIC values were determined using a broth microdilution procedure described by CLSI (1, 2). Automated liquid handlers (Multidrop 384, Labsystems, Helsinki, Finland; Biomek 2000 and Biomek FX, Beckman Coulter, Fullerton CA) were used to conduct serial dilutions and liquid transfers.
  • the daughter plates were loaded with 190 ⁇ L per well of CAMHB using the Multidrop 384.
  • the daughter plates were completed on the Biomek FX instrument which transferred 2 ⁇ L of drug solution from each well of a mother plate to the corresponding well of each daughter plate in a single step.
  • a standardized inoculum of each test organism was prepared per CLSI methods (1).
  • the inoculum for each organism was dispensed into sterile reservoirs divided by length (Beckman Coulter), and the Biomek 2000 was used to inoculate the plates.
  • Daughter plates were placed on the Biomek 2000 work surface in reverse orientation so that inoculation took place from low to high drug concentration.
  • Example 2 — LpxH Biochemical Assay – IC50 (nM) 219 WSGR Ref: 60134-709.601 220 WSGR Ref: 60134-709.601 221 WSGR Ref: 60134-709.601 Table 3 methylmethanesul fonamide 222 WSGR Ref: 60134-709.601 N- methylmethanesul fonamide 223 WSGR Ref: 60134-709.601 ethanesulfonamid e 224 WSGR Ref: 60134-709.601 ethanesulfonamid e 225 WSGR Ref: 60134-709.601 mide 226 WSGR Ref: 60134-709.601 sulfonamide 227 WSGR Ref: 60134-709.601 carbonyl)phenyl)m ethanesulfonamid e 228 WSGR Ref: 60134-709.601 carbonyl)phenyl)m ethanes
  • Example 1 Oral capsule 233 WSGR Ref: 60134-709.601
  • the active ingredient is a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof.
  • a capsule for oral administration is prepared by mixing 1-1000 mg of active ingredient with starch or other suitable powder blend.
  • Example 2 Solution for injection
  • the active ingredient is a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, and is formulated as a solution in sesame oil at a concentration of 10-100 mg-eq/mL.
  • the examples and embodiments described herein are for illustrative purposes only and various modifications or changes suggested to persons skilled in the art are to be included within the spirit and purview of this application and scope of the appended claims. Numbered Embodiments [00543] Some numbered examples of embodiments follow. embodiments follow.
  • a compound of Formula (I-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-R 1 , or absent; R 1 is hydrogen, optionally substituted alkyl, -OH, -CN, -C(O)R 8 , or -C(O)N(R 9 ) 2 ; R 8 is optionally substituted C1-C5 alkyl; each R 9 is independently hydrogen or optionally substituted C1-C3 alkyl; or two R 9 groups attached to the same atom are optionally cyclized to form a 3 to 6-membered heterocyclyl; R L is
  • a compound of Formula (I-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-R 1 , or absent; R 1 is hydrogen, optionally substituted alkyl, -OH, -CN, -C(O)R 8 , or -C(O)N(R 9 )2; R 8 is optionally substituted C 1 -C 5 alkyl; each R 9 is independently hydrogen or optionally substituted C1-C3 alkyl; or two R 9 groups attached to the same atom are optionally cyclized to form a 3 to 6- membered heterocycl
  • 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 C 1 -C 3 alkyl;
  • E is O, N-R 1 , or absent;
  • R 1 is hydrogen, optionally substituted alkyl, -OH, -CN, -C(O)R 8 , or -C(O)N(R 9 )2;
  • R 8 is optionally substituted C1-C5 alkyl;
  • each R 9 is independently hydrogen or
  • each R 4 is independently hydrogen, deuterium, or optionally substituted C 1 -C 3 alkyl; and each R 5 is independently hydrogen, deuterium, or optionally substituted C 1 -C 3 alkyl.
  • each R 4 is independently hydrogen, deuterium, or C 1 -C 3 alkyl, wherein the alkyl is optionally substituted with one or more halogen, hydroxy, methoxy, amino, -NHMe, or -NMe 2 ; and each R 5 is independently hydrogen, deuterium, or C1-C3 alkyl, wherein the alkyl is optionally substituted with one or more halogen, hydroxy, methoxy, amino, -NHMe, or -NMe2.
  • each R 4 is independently hydrogen, deuterium, or optionally substituted C 1 alkyl; and each R 5 is independently hydrogen, deuterium, or optionally substituted C1 alkyl.
  • each R 4 is independently hydrogen, deuterium, or optionally substituted C 1 alkyl, wherein the alkyl is optionally substituted with one or more halogen, hydroxy, methoxy, amino, -NHMe, or -NMe2; and each R 5 is independently hydrogen, deuterium, or optionally substituted C 1 alkyl, wherein the alkyl is optionally substituted with one or more halogen, hydroxy, methoxy, amino, -NHMe, or -NMe2.
  • each R 4 is 238 WSGR Ref: 60134-709.601 independently hydrogen or deuterium; and each R 5 is independently hydrogen or deuterium.
  • (21) The compound of any one of embodiments 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.
  • (22) The compound of any one of embodiments 1-21, 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.
  • (23) The compound of any one of embodiments 1-22, 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.
  • (24) The compound of any one of embodiments 1- 22, 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.
  • (25) The compound of any one of embodiments 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 C-heterocyclyl.
  • (61) The compound of any one of embodiments 1-55, wherein B is substituted with one or more substituents selected from: ; R S is -CH 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 OCH 3 , -CH 2 NH 2 , or -CH2CH2NH2; and R j is hydrogen or -CH3.
  • (62) The compound of any one of embodiments 1-55, wherein B is substituted with one or more substituents selected from: ; R S is - CH3, -CH2F, -CHF2, -CF3, -CH2OCH3, -CH2NH2, or -CH2CH2NH2.
  • each R k is independently hydrogen, -F, -Cl, -CH3, or -OH.
  • R L is optionally substituted C4-C10 alkyl, optionally substituted -(C 1 -C 3 alkylene)-O-(C 1 -C 8 alkyl), optionally substituted -(C 1 -C 3 alkylene)-N(C1-C3 alkyl)(heteroaryl), optionally substituted C4-C10 alkenyl, optionally substituted C4-C10 alkynyl, optionally substituted carbocyclyl, optionally substituted aralkyl, 249 WSGR Ref: 60134-709.601 optionally substituted heteroarylalkyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclylalkyl, or optionally substituted C-heterocyclyl.
  • R L is 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 C 5 -C 10 alkenyl, optionally substituted C 5 -C 10 alkynyl, optionally substituted carbocyclyl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclylalkyl, or optionally substituted C-heterocyclyl.
  • R L is optionally substituted C 4 -C 10 alkyl, optionally substituted -(C1-C3 alkylene)-O-(C1-C10 alkyl), optionally substituted C4-C10 alkenyl, optionally substituted C 4 -C 10 alkynyl, optionally substituted carbocyclyl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclylalkyl, or optionally substituted C-heterocyclyl.
  • R L is optionally substituted C 5 -C 12 alkyl, optionally substituted -(C 1 -C 3 alkylene)-O-(C 1 -C 10 alkyl), optionally substituted -(C1-C3 alkylene)-N(C1-C3 alkyl)(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.
  • (163) The compound of any one of embodiments 1-130, or a pharmaceutically acceptable salt or solvate thereof, wherein R L is optionally substituted -(C1 alkylene)-O-(C 1 -C 10 alkyl).
  • (174) A compound of any one of embodiments 1-172, or pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of infection by at least one Gram-negative pathogen.
  • (175) Use of a compound of any one of embodiments 1-172, 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.
  • (176) 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 embodiments 1-172, or pharmaceutically acceptable salt or 254 WSGR Ref: 60134-709.601 solvate thereof.
  • 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 embodiments 1-172, or pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

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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; R1 is hydrogen, optionally substituted alkyl, -OH, -CN, -C(O)R8, or -C(O)N(R9)2; R8 is optionally substituted C1-C5 alkyl; each R9 is independently hydrogen or optionally substituted C1-C3 alkyl; 1 WSGR Ref: 60134-709.601 or two R9 groups attached to the same atom are optionally cyclized to form a 3 to 6-membered heterocyclyl; RL is 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-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 R4 is independently hydrogen, deuterium, or optionally substituted C1-C3 alkyl; or two R4 groups together form an oxo; or two R4 groups together form a 3- or 4-membered carbocyclyl; or two R4 groups together form a 4-membered heterocyclyl; each R5 is independently hydrogen, deuterium, halogen, or optionally substituted C1- C3 alkyl; or two R5 groups together form an oxo; or two R5 groups together form a 3- or 4-membered carbocyclyl; or two R5 groups together form 4-membered heterocyclyl; each R6 is independently hydrogen, deuterium, halogen, or optionally substituted C1- C3 alkyl; or two R6 groups together form an oxo; or two R6 groups together form a 3- or 4-membered carbocyclyl; or two R6 groups together form 4-membered heterocyclyl; each R7 is independently hydrogen, deuterium, or optionally substituted C1-C3 alkyl; or two R7 groups together form an oxo; or two R7 groups together form a 3- or 4-membered carbocyclyl; or two R7 groups together form 4-membered heterocyclyl; and R3 is hydrogen or optionally substituted C1-C3 alkyl; with the proviso that B is not . 2 WSGR 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 –NH2 radical. [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. 3 WSGR 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-C15 alkyl). In certain embodiments, an alkyl comprises three to fifteen carbon atoms (e.g., C3-C15 alkyl). In certain embodiments, an alkyl comprises four to fifteen carbon atoms (e.g., C4-C15 alkyl). In certain embodiments, an alkyl comprises five to fifteen carbon atoms (e.g., C5-C15 alkyl). In certain embodiments, an alkyl comprises six to fifteen carbon atoms (e.g., C6-C15 alkyl). In certain embodiments, an alkyl comprises seven to fifteen carbon atoms (e.g., C7-C15 alkyl). In certain embodiments, an alkyl comprises eight to fifteen carbon atoms (e.g., C8-C15 alkyl). In certain embodiments, an alkyl comprises one to eight carbon atoms (e.g., C1-C8 alkyl). In other embodiments, an alkyl comprises one to five carbon atoms (e.g., C1-C5 alkyl). In other embodiments, an alkyl comprises one to four carbon atoms (e.g., C1- C4 alkyl). In other embodiments, an alkyl comprises one to three carbon atoms (e.g., C1-C3 alkyl). In other embodiments, an alkyl comprises one to two carbon atoms (e.g., C1-C2 alkyl). In other embodiments, an alkyl comprises one carbon atom (e.g., C1 alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (e.g., C5-C8 alkyl). In other embodiments, an alkyl comprises two to five carbon atoms (e.g., C2-C5 alkyl). In other embodiments, an alkyl comprises three to five carbon atoms (e.g., C3-C5 alkyl). In other embodiments, the alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (iso-propyl), 1-butyl (n-butyl), 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 Ra is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, - CN, or trifluoromethyl), alkenyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, or trifluoromethyl), alkynyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, amino, - 4 WSGR 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, 5 WSGR 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 Ra is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, or trifluoromethyl), alkenyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, or trifluoromethyl), alkynyl (optionally substituted with halogen, hydroxy, methoxy, amino, - NHMe, -NMe2, morpholino, -CN, or trifluoromethyl), fluoroalkyl, 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, 6 WSGR 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 Ra is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, amino, - NHMe, -NMe2, morpholino, -CN, or trifluoromethyl), alkenyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, or trifluoromethyl), alkynyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, or trifluoromethyl), fluoroalkyl, 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 7 WSGR 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-C8 alkylene). In other embodiments, an alkylene comprises one to five carbon atoms (e.g., C1-C5 alkylene). In other embodiments, an alkylene comprises one to four carbon atoms (e.g., C1-C4 alkylene). In other embodiments, an alkylene comprises one to three carbon atoms (e.g., C1-C3 alkylene). 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-C8 alkylene). 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 Ra is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, or trifluoromethyl), alkenyl (optionally substituted with halogen, hydroxy, methoxy, amino, - NHMe, -NMe2, morpholino, -CN, or trifluoromethyl), alkynyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, or trifluoromethyl), fluoroalkyl, 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 8 WSGR 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-C8 alkenylene). 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-C3 alkenylene). In other embodiments, an alkenylene comprises two carbon atoms (e.g., C2 alkenylene). In other embodiments, an alkenylene comprises five to eight carbon atoms (e.g., C5-C8 alkenylene). In other embodiments, an alkenylene comprises three to five carbon atoms (e.g., C3-C5 alkenylene). Unless stated otherwise specifically in the specification, an alkenylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, - N(Ra)C(O)ORa, -OC(O)-N(Ra)2, -N(Ra)C(O)Ra, -C(=NRa)N(Ra)2, -N(Ra)C(=NRa)Ra, - N(Ra)C(=NRa)N(Ra)2, -N(Ra)S(O)tRa (where t is 1 or 2), -N=S(=O)t(Ra)2 (where t is 0 or 1), - S(O)tORa (where t is 1 or 2), -S(O)tRa (where t is 1 or 2), -O-S(O)tRa (where t is 1 or 2), -O- S(O)tORa (where t is 1 or 2), -S(O)tN(Ra)2 (where t is 1 or 2), and -P(O)(Ra)2, where each Ra is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, amino, - NHMe, -NMe2, morpholino, -CN, or trifluoromethyl), alkenyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, or trifluoromethyl), alkynyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, methyl, fluoromethyl, 9 WSGR 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-C8 alkynylene). 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-C4 alkynylene). In other embodiments, an alkynylene comprises two to three carbon atoms (e.g., C2-C3 alkynylene). 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-C5 alkynylene). Unless stated otherwise specifically in the specification, an alkynylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, - C(O)N(Ra)2, -N(Ra)C(O)ORa, -OC(O)-N(Ra)2, -N(Ra)C(O)Ra, -C(=NRa)N(Ra)2, - N(Ra)C(=NRa)Ra, -N(Ra)C(=NRa)N(Ra)2, -N(Ra)S(O)tRa (where t is 1 or 2), -N=S(=O)t(Ra)2 (where t is 0 or 1), -S(O)tORa (where t is 1 or 2), -S(O)tRa (where t is 1 or 2), -O-S(O)tRa (where t is 1 or 2), -O-S(O)tORa (where t is 1 or 2), -S(O)tN(Ra)2 (where t is 1 or 2), and -P(O)(Ra)2, where each Ra is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, or trifluoromethyl), alkenyl (optionally 10 WSGR 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), - 11 WSGR 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 Ra is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, or trifluoromethyl), alkenyl (optionally substituted with halogen, hydroxy, methoxy, amino, - NHMe, -NMe2, morpholino, -CN, or trifluoromethyl), alkynyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, methyl, fluoromethyl, difluoromethyl, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, methyl, fluoromethyl, difluoromethyl, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, methyl, fluoromethyl, difluoromethyl, or trifluoromethyl), aralkyl (optionally 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 Rb is independently a direct bond or a straight or branched alkylene or alkenylene chain or alkynylene chain, and Rc is a straight or branched alkylene or alkenylene chain, and where each of the Ra, Rb, or Rc substituents is unsubstituted unless otherwise indicated. In some embodiments, “Aryl” is optionally substituted with a substituent selected from the group consisting of , , , , 12 WSGR 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 of L is -N(Rj)-, -C(Rn)2-, or -O-; RS is optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, optionally substituted C2-C5 alkynyl, -ORj, or -N(Rj)2; each RP is independently optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, optionally substituted C2-C5 alkynyl, -ORj, or -N(Rj)2; or two RP are taken together to form an optionally substituted 3 to 10-membered heterocyclyl; each Rj is independently hydrogen or optionally substituted C1-C3 alkyl; or two Rj groups are optionally cyclized to form an optionally substituted C3-C7 carbocyclyl; or two Rj groups are optionally cyclized to form an optionally substituted 3 to 7-membered heterocyclyl; each Rk is independently hydrogen, halogen, optionally substituted C1-C3 alkyl, or -OH; or two Rk groups attached to the same carbon atom are optionally cyclized to form a C3-C6 carbocyclyl; or two Rk groups attached to the same carbon atom are optionally cyclized to form a 3 to 6- membered heterocyclyl; each Rm is independently optionally substituted C1-C3 alkyl; or two Rm groups are optionally cyclized to form an optionally substituted C3-C6 carbocyclyl; or two Rm groups are optionally cyclized to form an optionally substituted 3 to 6-membered heterocyclyl; each Rn is independently hydrogen, halogen, or optionally substituted C1-C3 alkyl; or two Rn groups attached to the same carbon atom are optionally cyclized to form a C3-C6 carbocyclyl; or two Rn groups 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 Rc is an alkylene chain as defined above, for example, methylene, ethylene, and the like. The alkylene chain part of the 13 WSGR 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 Rd is 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 Re is 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 Rc is 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 14 WSGR 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 Ra is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, - CN, or trifluoromethyl), alkenyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, or trifluoromethyl), alkynyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, methyl, fluoromethyl, difluoromethyl, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, methyl, fluoromethyl, difluoromethyl, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, methyl, fluoromethyl, difluoromethyl, or trifluoromethyl), aralkyl (optionally 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 Rb is independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rc is a straight or branched alkylene or alkenylene chain, and where each of the Ra, Rb, or Rc substituents is unsubstituted unless otherwise 15 WSGR Ref: 60134-709.601 indicated. In some embodiments, “Carbocyclyl” is optionally substituted with a substituent aminopyrrolidin-1-yl, and optionally substituted piperazin-1-yl; or two adjacent atoms of the carbocyclyl are substituted by the divalent group consisting of L is -N(Rj)-, -C(Rn)2-, or -O-; RS is optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, optionally substituted C2-C5 alkynyl, -ORj, or -N(Rj)2; each RP is independently optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, optionally substituted C2-C5 alkynyl, -ORj, or -N(Rj)2; or two RP are taken together to form an optionally substituted 3 to 10-membered heterocyclyl; each Rj is independently hydrogen or optionally substituted C1-C3 alkyl; or two Rj groups are optionally cyclized to form an optionally substituted C3-C7 carbocyclyl; or two Rj groups are optionally cyclized to form an optionally substituted 3 to 7-membered heterocyclyl; each Rk is independently hydrogen, halogen, optionally substituted C1-C3 alkyl, or -OH; or two Rk groups attached to the same carbon atom are optionally cyclized to form a C3-C6 carbocyclyl; or two Rk groups attached to the same carbon atom are optionally cyclized to form a 3 to 6- membered heterocyclyl; each Rm is independently optionally substituted C1-C3 alkyl; or two Rm groups are optionally cyclized to form an optionally substituted C3-C6 carbocyclyl; or two Rm groups are optionally cyclized to form an optionally substituted 3 to 6-membered heterocyclyl. each Rn is independently hydrogen, halogen, or optionally substituted C1-C3 alkyl; or two Rn groups attached to the same carbon atom are optionally cyclized to form a C3-C6 carbocyclyl; or two Rn groups attached to the same carbon atom are optionally cyclized to form a 3 to 6- membered heterocyclyl. 16 WSGR Ref: 60134-709.601 "Carbocyclylalkyl" refers to a radical of the formula –Rc-carbocyclyl where Rc is 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 Rc is 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 Rc is 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, - 17 WSGR 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 Ra is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, - CN, or trifluoromethyl), alkenyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, or trifluoromethyl), alkynyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, methyl, fluoromethyl, difluoromethyl, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, methyl, fluoromethyl, difluoromethyl, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, methyl, fluoromethyl, difluoromethyl, or trifluoromethyl), aralkyl (optionally 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 Rb is independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rc is a straight or branched alkylene or alkenylene chain, and where each of the Ra, Rb, or Rc substituents is unsubstituted unless otherwise indicated. In some embodiments, “Heterocyclyl” is optionally substituted with a substituent 18 WSGR Ref: 60134-709.601 1-yl, and optionally substituted piperazin-1-yl; or two adjacent atoms of the heterocyclyl are substituted by the divalent group consisting of L is -N(Rj)-, -C(Rn)2-, or -O-; RS is optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, optionally substituted C2-C5 alkynyl, -ORj, or -N(Rj)2; each RP is independently optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, optionally substituted C2-C5 alkynyl, -ORj, or -N(Rj)2; or two RP are taken together to form an optionally substituted 3 to 10-membered heterocyclyl; each Rj is independently hydrogen or optionally substituted C1-C3 alkyl; or two Rj groups are optionally cyclized to form an optionally substituted C3-C7 carbocyclyl; or two Rj groups are optionally cyclized to form an optionally substituted 3 to 7-membered heterocyclyl; each Rk is independently hydrogen, halogen, optionally substituted C1-C3 alkyl, or -OH; or two Rk groups attached to the same carbon atom are optionally cyclized to form a C3-C6 carbocyclyl; or two Rk groups attached to the same carbon atom are optionally cyclized to form a 3 to 6- membered heterocyclyl; each Rm is independently optionally substituted C1-C3 alkyl; or two Rm groups are optionally cyclized to form an optionally substituted C3-C6 carbocyclyl; or two Rm groups are optionally cyclized to form an optionally substituted 3 to 6-membered heterocyclyl; and each Rn is independently hydrogen, halogen, or optionally substituted C1-C3 alkyl; or two Rn groups attached to the same carbon atom are optionally cyclized to form a C3-C6 carbocyclyl; or two Rn groups attached to the same carbon atom are optionally cyclized to form a 3 to 6- membered heterocyclyl. 19 WSGR 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 Rc is 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 Rc is 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, 20 WSGR 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 21 WSGR 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 Ra is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, amino, - NHMe, -NMe2, morpholino, -CN, or trifluoromethyl), alkenyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, or trifluoromethyl), alkynyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, methyl, fluoromethyl, difluoromethyl, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, methyl, fluoromethyl, difluoromethyl, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, amino, -NHMe, -NMe2, morpholino, -CN, methyl, fluoromethyl, difluoromethyl, or trifluoromethyl), aralkyl (optionally 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 Rb is independently a direct bond, or a straight or branched alkylene or alkenylene chain or alkynylene chain, and Rc is a straight or branched alkylene or alkenylene chain, and where each of the Ra, Rb, or Rc substituents is unsubstituted unless otherwise indicated. In some embodiments, “Heteroaryl” is optionally substituted with a substituent aminopyrrolidin-1-yl, and optionally substituted piperazin-1-yl; 22 WSGR Ref: 60134-709.601 or two adjacent atoms of the heteroaryl are substituted by the divalent group consisting of L is -N(Rj)-, -C(Rn)2-, or -O-; RS is optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, optionally substituted C2-C5 alkynyl, -ORj, or -N(Rj)2; each RP is independently optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, optionally substituted C2-C5 alkynyl, -ORj, or -N(Rj)2; or two RP are taken together to form an optionally substituted 3 to 10-membered heterocyclyl; each Rj is independently hydrogen or optionally substituted C1-C3 alkyl; or two Rj groups are optionally cyclized to form an optionally substituted C3-C7 carbocyclyl; or two Rj groups are optionally cyclized to form an optionally substituted 3 to 7-membered heterocyclyl; each Rk is independently hydrogen, halogen, optionally substituted C1-C3 alkyl, or -OH; or two Rk groups attached to the same carbon atom are optionally cyclized to form a C3-C6 carbocyclyl; or two Rk groups attached to the same carbon atom are optionally cyclized to form a 3 to 6- membered heterocyclyl; each Rm is independently optionally substituted C1-C3 alkyl; or two Rm groups are optionally cyclized to form an optionally substituted C3-C6 carbocyclyl; or two Rm groups are optionally cyclized to form an optionally substituted 3 to 6-membered heterocyclyl; each Rn is independently hydrogen, halogen, or optionally substituted C1-C3 alkyl; or two Rn groups attached to the same carbon atom are optionally cyclized to form a C3-C6 carbocyclyl; or two Rn groups 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 23 WSGR 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 Rc is 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 Rc is 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: 24 WSGR 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 of 2H, 3H, 11C, 13C and/or 14C. 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 by 13C- or 14C-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 with 2H, 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 with 18F 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 the 1H atoms replaced with 2H atoms. The methods of synthesis for deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods. 25 WSGR 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 LiAlD4 is 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. 26 WSGR 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-exchangeable 1H 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 27 WSGR 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 28 WSGR 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 29 WSGR 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, 30 WSGR 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; R1 is hydrogen, optionally substituted alkyl, -OH, -CN, -C(O)R8, or -C(O)N(R9)2; R8 is optionally substituted C1-C5 alkyl; each R9 is independently hydrogen or optionally substituted C1-C3 alkyl; or two R9 groups attached to the same atom are optionally cyclized to form a 3 to 6-membered heterocyclyl; RL is 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-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 R4 is independently hydrogen, deuterium, or optionally substituted C1-C3 alkyl; or two R4 groups together form an oxo; or two R4 groups together form a 3- or 4-membered carbocyclyl; or two R4 groups together form a 4-membered heterocyclyl; each R5 is independently hydrogen, deuterium, halogen, or optionally substituted C1- C3 alkyl; or two R5 groups together form an oxo; or two R5 groups together form a 3- or 4-membered carbocyclyl; or two R5 groups together form 4-membered heterocyclyl; each R6 is independently hydrogen, deuterium, halogen, or optionally substituted C1- C3 alkyl; 31 WSGR Ref: 60134-709.601 or two R6 groups together form an oxo; or two R6 groups together form a 3- or 4-membered carbocyclyl; or two R6 groups together form 4-membered heterocyclyl; each R7 is independently hydrogen, deuterium, or optionally substituted C1-C3 alkyl; or two R7 groups together form an oxo; or two R7 groups together form a 3- or 4-membered carbocyclyl; or two R7 groups together form 4-membered heterocyclyl; and R3 is 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; R1 is hydrogen, optionally substituted alkyl, -OH, -CN, -C(O)R8, or -C(O)N(R9)2; R8 is optionally substituted C1-C5 alkyl; each R9 is independently hydrogen or optionally substituted C1-C3 alkyl; or two R9 groups attached to the same atom are optionally cyclized to form a 3 to 6-membered heterocyclyl; RL is 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-C12 alkenyl, optionally substituted C4-C12 alkynyl, optionally substituted carbocyclyl, optionally substituted aralkyl, optionally 32 WSGR 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 R4 is independently hydrogen, deuterium, or optionally substituted C1-C3 alkyl; or two R4 groups together form an oxo; or two R4 groups together form a 3- or 4-membered carbocyclyl; or two R4 groups together form a 4-membered heterocyclyl; each R5 is independently hydrogen, deuterium, halogen, or optionally substituted C1- C3 alkyl; or two R5 groups together form an oxo; or two R5 groups together form a 3- or 4-membered carbocyclyl; or two R5 groups together form 4-membered heterocyclyl; each R6 is independently hydrogen, deuterium, halogen, or optionally substituted C1- C3 alkyl; or two R6 groups together form an oxo; or two R6 groups together form a 3- or 4-membered carbocyclyl; or two R6 groups together form 4-membered heterocyclyl; each R7 is independently hydrogen, deuterium, or optionally substituted C1-C3 alkyl; or two R7 groups together form an oxo; or two R7 groups together form a 3- or 4-membered carbocyclyl; or two R7 groups together form 4-membered heterocyclyl; and R3 is hydrogen or optionally substituted C1-C3 alkyl; 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, 33 WSGR 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; R1 is hydrogen, optionally substituted alkyl, -OH, -CN, -C(O)R8, or -C(O)N(R9)2; R8 is optionally substituted C1-C5 alkyl; each R9 is independently hydrogen or optionally substituted C1-C3 alkyl; or two R9 groups attached to the same atom are optionally cyclized to form a 3 to 6-membered heterocyclyl; RL is 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-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 R4 is independently hydrogen, deuterium, or optionally substituted C1-C3 alkyl; or two R4 groups together form an oxo; or two R4 groups together form a 3- or 4-membered carbocyclyl; 34 WSGR Ref: 60134-709.601 or two R4 groups together form a 4-membered heterocyclyl; each R5 is independently hydrogen, deuterium, halogen, or optionally substituted C1- C3 alkyl; or two R5 groups together form an oxo; or two R5 groups together form a 3- or 4-membered carbocyclyl; or two R5 groups together form 4-membered heterocyclyl; each R6 is independently hydrogen, deuterium, halogen, or optionally substituted C1- C3 alkyl; or two R6 groups together form an oxo; or two R6 groups together form a 3- or 4-membered carbocyclyl; or two R6 groups together form 4-membered heterocyclyl; each R7 is independently hydrogen, deuterium, or optionally substituted C1-C3 alkyl; or two R7 groups together form an oxo; or two R7 groups together form a 3- or 4-membered carbocyclyl; or two R7 groups together form 4-membered heterocyclyl; and R3 is hydrogen or optionally substituted C1-C3 alkyl. [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-C3 alkyl; E is O, N-R1, or absent; R1 is hydrogen, optionally substituted alkyl, -OH, -CN, -C(O)R8, or -C(O)N(R9)2; 35 WSGR Ref: 60134-709.601 R8 is optionally substituted C1-C5 alkyl; each R9 is independently hydrogen or optionally substituted C1-C3 alkyl; or two R9 groups attached to the same atom are optionally cyclized to form a 3 to 6-membered heterocyclyl; RL is 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-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 R4 is independently hydrogen, deuterium, or optionally substituted C1-C3 alkyl; or two R4 groups together form an oxo; or two R4 groups together form a 3- or 4-membered carbocyclyl; or two R4 groups together form a 4-membered heterocyclyl; each R5 is independently hydrogen, deuterium, halogen, or optionally substituted C1- C3 alkyl; or two R5 groups together form an oxo; or two R5 groups together form a 3- or 4-membered carbocyclyl; or two R5 groups together form 4-membered heterocyclyl; each R6 is independently hydrogen, deuterium, halogen, or optionally substituted C1- C3 alkyl; or two R6 groups together form an oxo; or two R6 groups together form a 3- or 4-membered carbocyclyl; or two R6 groups together form 4-membered heterocyclyl; each R7 is independently hydrogen, deuterium, or optionally substituted C1-C3 alkyl; or two R7 groups together form an oxo; or two R7 groups together form a 3- or 4-membered carbocyclyl; or two R7 groups together form 4-membered heterocyclyl; and R3 is 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. 36 WSGR 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; R1 is hydrogen, optionally substituted alkyl, -OH, -CN, -C(O)R8, or -C(O)N(R9)2; R8 is optionally substituted C1-C5 alkyl; each R9 is independently hydrogen or optionally substituted C1-C3 alkyl; or two R9 groups attached to the same atom are optionally cyclized to form a 3 to 6-membered heterocyclyl; 37 WSGR Ref: 60134-709.601 RL is 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-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 R4 is independently hydrogen, deuterium, or optionally substituted C1-C3 alkyl; or two R4 groups together form an oxo; or two R4 groups together form a 3- or 4-membered carbocyclyl; or two R4 groups together form a 4-membered heterocyclyl; and each R5 is independently hydrogen, deuterium, halogen, or optionally substituted C1-C3 alkyl; or two R5 groups together form an oxo; or two R5 groups together form a 3- or 4-membered carbocyclyl; or two R5 groups 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; R1 is hydrogen, optionally substituted alkyl, -OH, -CN, -C(O)R8, or -C(O)N(R9)2; R8 is optionally substituted C1-C5 alkyl; each R9 is independently hydrogen or optionally substituted C1-C3 alkyl; 38 WSGR Ref: 60134-709.601 or two R9 groups attached to the same atom are optionally cyclized to form a 3 to 6-membered heterocyclyl; RL is 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-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 R4 is independently hydrogen, deuterium, or optionally substituted C1-C3 alkyl; or two R4 groups together form an oxo; or two R4 groups together form a 3- or 4-membered carbocyclyl; or two R4 groups together form a 4-membered heterocyclyl; and each R5 is independently hydrogen, deuterium, halogen, or optionally substituted C1-C3 alkyl; or two R5 groups together form an oxo; or two R5 groups together form a 3- or 4-membered carbocyclyl; or two R5 groups 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; 39 WSGR Ref: 60134-709.601 E is O, N-R1, or absent; R1 is hydrogen, optionally substituted alkyl, -OH, -CN, -C(O)R8, or -C(O)N(R9)2; R8 is optionally substituted C1-C5 alkyl; each R9 is independently hydrogen or optionally substituted C1-C3 alkyl; or two R9 groups attached to the same atom are optionally cyclized to form a 3 to 6-membered heterocyclyl; RL is 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-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 R4 is independently hydrogen, deuterium, or optionally substituted C1-C3 alkyl; or two R4 groups together form an oxo; or two R4 groups together form a 3- or 4-membered carbocyclyl; or two R4 groups together form a 4-membered heterocyclyl; and each R5 is independently hydrogen, deuterium, halogen, or optionally substituted C1-C3 alkyl; or two R5 groups together form an oxo; or two R5 groups together form a 3- or 4-membered carbocyclyl; or two R5 groups 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; 40 WSGR Ref: 60134-709.601 each R is independently hydrogen, deuterium, halogen, -CN, or optionally substituted C1-C3 alkyl; E is O, N-R1, or absent; R1 is hydrogen, optionally substituted alkyl, -OH, -CN, -C(O)R8, or -C(O)N(R9)2; R8 is optionally substituted C1-C5 alkyl; each R9 is independently hydrogen or optionally substituted C1-C3 alkyl; or two R9 groups attached to the same atom are optionally cyclized to form a 3 to 6-membered heterocyclyl; RL is 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-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 R4 is independently hydrogen, deuterium, or optionally substituted C1-C3 alkyl; or two R4 groups together form an oxo; or two R4 groups together form a 3- or 4-membered carbocyclyl; or two R4 groups together form a 4-membered heterocyclyl; and each R5 is independently hydrogen, deuterium, halogen, or optionally substituted C1-C3 alkyl; or two R5 groups together form an oxo; or two R5 groups together form a 3- or 4-membered carbocyclyl; or two R5 groups together form 4-membered heterocyclyl. [0090] In some embodiments, each R4 is independently hydrogen, deuterium, or optionally substituted C1-C3 alkyl; and each R5 is independently hydrogen, deuterium, or optionally substituted C1-C3 alkyl. [0091] In some embodiments, each R4 is 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 R5 is independently hydrogen, deuterium, or C1-C3 alkyl, wherein the alkyl is optionally substituted with one or more halogen, hydroxy, methoxy, amino, -NHMe, or -NMe2. [0092] In some embodiments, each R4 is independently hydrogen, deuterium, or optionally substituted C1 alkyl; and each R5 is independently hydrogen, deuterium, or optionally substituted C1 alkyl. 41 WSGR Ref: 60134-709.601 [0093] In some embodiments, each R4 is 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 R5 is 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 R4 is independently hydrogen, deuterium, or -CH3; and each R5 is independently hydrogen, deuterium, or -CH3. [0095] In some embodiments, each R4 is independently hydrogen or deuterium; and each R5 is independently hydrogen, deuterium, or halogen. In some embodiments, each R4 is independently hydrogen or deuterium; and each R5 is independently hydrogen, deuterium, or fluorine. [0096] In some embodiments, each R4 is independently hydrogen or deuterium; and each R5 is 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. [00100] 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. [00101] 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. [00102] 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. [00103] 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. [00104] 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. 42 WSGR Ref: 60134-709.601 [00105] 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. [00106] 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. [00107] 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. [00108] 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. [00109] 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. [00110] 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. [00111] In some embodiments, B is an optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted 5 to 8-membered carbocyclyl. [00112] In some embodiments, B is an optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted 5 to 8-membered heterocyclyl. [00113] In some embodiments, B is an optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted 5 to 8-membered C-heterocyclyl. [00114] In some embodiments, B is an optionally substituted aryl, optionally substituted 5 to 8-membered carbocyclyl, or optionally substituted 5 to 8-membered heterocyclyl. [00115] In some embodiments, B is an optionally substituted heteroaryl, optionally substituted 5 to 8-membered carbocyclyl, or optionally substituted 5 to 8-membered heterocyclyl. [00116] In some embodiments, B is an optionally substituted aryl or optionally substituted heteroaryl. [00117] In some embodiments, B is an optionally substituted carbocyclyl. [00118] In some embodiments, B is an optionally substituted 4- to 8-membered carbocyclyl. 43 WSGR Ref: 60134-709.601 [00119] In some embodiments, B is an optionally substituted 5- to 8-membered carbocyclyl. [00120] In some embodiments, B is an optionally substituted 5- to 6-membered carbocyclyl. [00121] In some embodiments, B is an optionally substituted 4-membered carbocyclyl. [00122] In some embodiments, B is an optionally substituted 5-membered carbocyclyl. [00123] In some embodiments, B is an optionally substituted 6-membered carbocyclyl. [00124] In some embodiments, B is an optionally substituted heterocyclyl. [00125] In some embodiments, B is an optionally substituted 4 to 8-membered heterocyclyl. [00126] In some embodiments, B is an optionally substituted 5 to 8-membered heterocyclyl. [00127] In some embodiments, B is an optionally substituted 4 to 6-membered heterocyclyl. [00128] In some embodiments, B is an optionally substituted 5 to 6-membered heterocyclyl. [00129] In some embodiments, B is an optionally substituted 4-membered heterocyclyl. [00130] In some embodiments, B is an optionally substituted 5-membered heterocyclyl. [00131] In some embodiments, B is an optionally substituted 6-membered heterocyclyl. [00132] In some embodiments, B is an optionally substituted C-heterocyclyl. [00133] In some embodiments, B is an optionally substituted 4 to 8-membered C- heterocyclyl. [00134] In some embodiments, B is an optionally substituted 5 to 8-membered C- heterocyclyl. [00135] In some embodiments, B is an optionally substituted 4 to 6-membered C- heterocyclyl. [00136] In some embodiments, B is an optionally substituted 5 to 6-membered C- heterocyclyl. [00137] In some embodiments, B is an optionally substituted 4-membered C-heterocyclyl. [00138] In some embodiments, B is an optionally substituted 5-membered C-heterocyclyl. [00139] In some embodiments, B is an optionally substituted 6-membered C-heterocyclyl. [00140] In some embodiments, B is an optionally substituted heteroaryl. [00141] In some embodiments, B is an optionally substituted 5- to 10-membered heteroaryl. 44 WSGR Ref: 60134-709.601 [00142] In some embodiments, B is an optionally substituted 6- to 10-membered heteroaryl. [00143] In some embodiments, B is an optionally substituted 5- to 6-membered heteroaryl. [00144] In some embodiments, B is an optionally substituted 5-membered heteroaryl. [00145] 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. [00146] In some embodiments, B is an optionally substituted 6-membered heteroaryl. [00147] 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. [00148] In some embodiments, B is an optionally substituted 9-membered heteroaryl. [00149] In some embodiments, B is an optionally substituted pyrazolopyrimidinyl. [00150] In some embodiments, B is an optionally substituted 10-membered heteroaryl. [00151] In some embodiments, B is an optionally substituted aryl. [00152] In some embodiments, B is an optionally substituted phenyl. [00153] In some embodiments, B is not . [00154] In some embodiments, B is not . [00155] In some embodiments, B is not . [00156] In some embodiments, B is substituted with one or more substituent selected from the group consisting of: 45 WSGR Ref: 60134-709.601 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-; RS is optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, optionally substituted C2-C5 alkynyl, -ORj, or -N(Rj)2; each RP is independently optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, optionally substituted C2-C5 alkynyl, -ORj, or -N(Rj)2; or two RP are taken together to form an optionally substituted 3 to 10-membered heterocyclyl; each Rj is independently hydrogen or optionally substituted C1-C3 alkyl; or two Rj groups are optionally cyclized to form an optionally substituted C3-C7 carbocyclyl; or two Rj groups are optionally cyclized to form an optionally substituted 3 to 7-membered heterocyclyl; each Rk is independently hydrogen, halogen, optionally substituted C1-C3 alkyl, or -OH; or two Rk groups attached to the same carbon atom are optionally cyclized to form a C3-C6 carbocyclyl; or two Rk groups attached to the same carbon atom are optionally cyclized to form a 3 to 6- membered heterocyclyl; each Rm is independently optionally substituted C1-C3 alkyl; or two Rm groups are optionally cyclized to form an optionally substituted 3 to 6-membered heterocyclyl; each Rn is independently hydrogen, halogen, or optionally substituted C1-C3 alkyl; or two Rn groups attached to the same carbon atom are optionally cyclized to form a C3-C6 carbocyclyl; or two Rn groups attached to the same carbon atom are optionally cyclized to form a 3 to 6- membered heterocyclyl. 46 WSGR Ref: 60134-709.601 [00157] 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-; RS is optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, optionally substituted C2-C5 alkynyl, -ORj, or -N(Rj)2; each RP is independently optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, optionally substituted C2-C5 alkynyl, -ORj, or -N(Rj)2; or two RP are taken together to form an optionally substituted 3 to 10-membered heterocyclyl; each Rj is independently hydrogen or optionally substituted C1-C3 alkyl; or two Rj groups are optionally cyclized to form an optionally substituted C3-C7 carbocyclyl; or two Rj groups are optionally cyclized to form an optionally substituted 3 to 7-membered heterocyclyl; each Rk is independently hydrogen, halogen, optionally substituted C1-C3 alkyl, or -OH; or two Rk groups attached to the same carbon atom are optionally cyclized to form a C3-C6 carbocyclyl; or two Rk groups attached to the same carbon atom are optionally cyclized to form a 3 to 6- membered heterocyclyl; each Rm is independently optionally substituted C1-C3 alkyl; or two Rm groups are optionally cyclized to form an optionally substituted 3 to 6-membered heterocyclyl; each Rn is independently hydrogen, halogen, or optionally substituted C1-C3 alkyl; or two Rn groups attached to the same carbon atom are optionally cyclized to form a C3-C6 carbocyclyl; or two Rn groups attached to the same carbon atom are optionally cyclized to form a 3 to 6- membered heterocyclyl. 47 WSGR Ref: 60134-709.601 [00158] 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-; RS is optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, optionally substituted C2-C5 alkynyl, -ORj, or -N(Rj)2; each RP is independently optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, optionally substituted C2-C5 alkynyl, -ORj, or -N(Rj)2; or two RP are taken together to form an optionally substituted 3 to 10-membered heterocyclyl; each Rj is independently hydrogen or optionally substituted C1-C3 alkyl; or two Rj groups are optionally cyclized to form an optionally substituted C3-C7 carbocyclyl; or two Rj groups are optionally cyclized to form an optionally substituted 3 to 7-membered heterocyclyl; each Rk is independently hydrogen, halogen, optionally substituted C1-C3 alkyl, or -OH; or two Rk groups attached to the same carbon atom are optionally cyclized to form a C3-C6 carbocyclyl; or two Rk groups attached to the same carbon atom are optionally cyclized to form a 3 to 6- membered heterocyclyl; each Rm is independently optionally substituted C1-C3 alkyl; or two Rm groups are optionally cyclized to form an optionally substituted 3 to 6-membered heterocyclyl; each Rn is independently hydrogen, halogen, or optionally substituted C1-C3 alkyl; or two Rn groups attached to the same carbon atom are optionally cyclized to form a C3-C6 carbocyclyl; 48 WSGR Ref: 60134-709.601 or two Rn groups attached to the same carbon atom are optionally cyclized to form a 3 to 6- membered heterocyclyl. [00159] 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-; RS is optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, optionally substituted C2-C5 alkynyl, -ORj, or -N(Rj)2; each RP is independently optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, optionally substituted C2-C5 alkynyl, -ORj, or -N(Rj)2; or two RP are taken together to form an optionally substituted 3 to 10-membered heterocyclyl; each Rj is independently hydrogen or optionally substituted C1-C3 alkyl; or two Rj groups are optionally cyclized to form an optionally substituted C3-C7 carbocyclyl; or two Rj groups are optionally cyclized to form an optionally substituted 3 to 7-membered heterocyclyl; each Rk is independently hydrogen, halogen, optionally substituted C1-C3 alkyl, or -OH; or two Rk groups attached to the same carbon atom are optionally cyclized to form a C3-C6 carbocyclyl; or two Rk groups attached to the same carbon atom are optionally cyclized to form a 3 to 6- membered heterocyclyl; each Rm is independently optionally substituted C1-C3 alkyl; or two Rm groups are optionally cyclized to form an optionally substituted 3 to 6-membered heterocyclyl; each Rn is independently hydrogen, halogen, or optionally substituted C1-C3 alkyl; or two Rn groups attached to the same carbon atom are optionally cyclized to form a C3-C6 carbocyclyl; 49 WSGR Ref: 60134-709.601 or two Rn groups attached to the same carbon atom are optionally cyclized to form a 3 to 6- membered heterocyclyl. [00160] 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-; RS is optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, optionally substituted C2-C5 alkynyl, -ORj, or -N(Rj)2; each RP is independently optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, optionally substituted C2-C5 alkynyl, -ORj, or -N(Rj)2; or two RP are taken together to form an optionally substituted 3 to 10-membered heterocyclyl; each Rj is independently hydrogen or optionally substituted C1-C3 alkyl; or two Rj groups are optionally cyclized to form an optionally substituted C3-C7 carbocyclyl; or two Rj groups are optionally cyclized to form an optionally substituted 3 to 7-membered heterocyclyl; each Rk is independently hydrogen, halogen, optionally substituted C1-C3 alkyl, or -OH; or two Rk groups attached to the same carbon atom are optionally cyclized to form a C3-C6 carbocyclyl; or two Rk groups attached to the same carbon atom are optionally cyclized to form a 3 to 6- membered heterocyclyl; each Rm is independently optionally substituted C1-C3 alkyl; or two Rm groups are optionally cyclized to form an optionally substituted 3 to 6-membered heterocyclyl; each Rn is independently hydrogen, halogen, or optionally substituted C1-C3 alkyl; 50 WSGR Ref: 60134-709.601 or two Rn groups attached to the same carbon atom are optionally cyclized to form a C3-C6 carbocyclyl; or two Rn groups attached to the same carbon atom are optionally cyclized to form a 3 to 6- membered heterocyclyl. [00161] 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-; RS is optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, optionally substituted C2-C5 alkynyl, -ORj, or -N(Rj)2; each RP is independently optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, optionally substituted C2-C5 alkynyl, -ORj, or -N(Rj)2; or two RP are taken together to form an optionally substituted 3 to 10-membered heterocyclyl; each Rj is independently hydrogen or optionally substituted C1-C3 alkyl; or two Rj groups are optionally cyclized to form an optionally substituted C3-C7 carbocyclyl; or two Rj groups are optionally cyclized to form an optionally substituted 3 to 7-membered heterocyclyl; each Rk is independently hydrogen, halogen, optionally substituted C1-C3 alkyl, or -OH; or two Rk groups attached to the same carbon atom are optionally cyclized to form a C3-C6 carbocyclyl; or two Rk groups attached to the same carbon atom are optionally cyclized to form a 3 to 6- membered heterocyclyl; each Rm is independently optionally substituted C1-C3 alkyl; or two Rm groups are optionally cyclized to form an optionally substituted 3 to 6-membered heterocyclyl; each Rn is independently hydrogen, halogen, or optionally substituted C1-C3 alkyl; 51 WSGR Ref: 60134-709.601 or two Rn groups attached to the same carbon atom are optionally cyclized to form a C3-C6 carbocyclyl; or two Rn groups attached to the same carbon atom are optionally cyclized to form a 3 to 6- membered heterocyclyl. [00162] 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-; RS is optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, optionally substituted C2-C5 alkynyl, -ORj, or -N(Rj)2; each RP is independently optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, optionally substituted C2-C5 alkynyl, -ORj, or -N(Rj)2; or two RP are taken together to form an optionally substituted 3 to 10-membered heterocyclyl; each Rj is independently hydrogen or optionally substituted C1-C3 alkyl; each Rk is independently hydrogen, halogen, optionally substituted C1-C3 alkyl, or -OH; each Rm is independently optionally substituted C1-C3 alkyl; and each Rn is independently hydrogen, halogen, or optionally substituted C1-C3 alkyl. [00163] In some embodiments, B is substituted with one or more substituent selected from the group consisting of: 52 WSGR 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-; RS is optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, optionally substituted C2-C5 alkynyl, -ORj, or -N(Rj)2; each RP is independently optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, optionally substituted C2-C5 alkynyl, -ORj, or -N(Rj)2; or two RP are taken together to form an optionally substituted 3 to 10-membered heterocyclyl; each Rj is independently hydrogen or optionally substituted C1-C3 alkyl; each Rk is independently hydrogen, halogen, optionally substituted C1-C3 alkyl, or -OH; each Rm is independently optionally substituted C1-C3 alkyl; and each Rn is independently hydrogen, halogen, or optionally substituted C1-C3 alkyl. [00164] 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 of L is -N(Rj)-, -C(Rn)2-, or -O-; 53 WSGR Ref: 60134-709.601 RS is optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, optionally substituted C2-C5 alkynyl, -ORj, or -N(Rj)2; each Rj is independently hydrogen or optionally substituted C1-C3 alkyl; each Rk is independently hydrogen, halogen, optionally substituted C1-C3 alkyl, or -OH; each Rm is independently optionally substituted C1-C3 alkyl; and each Rn is independently hydrogen, halogen, or optionally substituted C1-C3 alkyl. [00165] 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-; RS is optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, optionally substituted C2-C5 alkynyl, -ORj, or -N(Rj)2; each Rj is independently hydrogen or optionally substituted C1-C3 alkyl; each Rk is independently hydrogen, halogen, optionally substituted C1-C3 alkyl, or -OH; each Rm is independently optionally substituted C1-C3 alkyl; and each Rn is independently hydrogen, halogen, or optionally substituted C1-C3 alkyl. [00166] 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-; RS is optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, optionally substituted C2-C5 alkynyl, -ORj, or -N(Rj)2; each Rj is independently hydrogen or optionally substituted C1-C3 alkyl; 54 WSGR Ref: 60134-709.601 each Rk is independently hydrogen, halogen, optionally substituted C1-C3 alkyl, or -OH; each Rm is independently optionally substituted C1-C3 alkyl; and each Rn is independently hydrogen, halogen, or optionally substituted C1-C3 alkyl. [00167] 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-; RS is optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, optionally substituted C2-C5 alkynyl, -ORj, or -N(Rj)2; each Rj is independently hydrogen or optionally substituted C1-C3 alkyl; each Rk is independently hydrogen, halogen, optionally substituted C1-C3 alkyl, or -OH; each Rm is independently optionally substituted C1-C3 alkyl; and each Rn is independently hydrogen, halogen, or optionally substituted C1-C3 alkyl. [00168] 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-; RS is optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, optionally substituted C2-C5 alkynyl, -ORj, or -N(Rj)2; each Rj is independently hydrogen or optionally substituted C1-C3 alkyl; each Rk is independently hydrogen, halogen, optionally substituted C1-C3 alkyl, or -OH; each Rm is independently optionally substituted C1-C3 alkyl; and each Rn is independently hydrogen, halogen, or optionally substituted C1-C3 alkyl. [00169] In some embodiments, B is substituted with one or more substituent selected from the group consisting of: 55 WSGR Ref: 60134-709.601 L is -N(Rj)-, -C(Rn)2-, or -O-; RS is optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, optionally substituted C2-C5 alkynyl, -ORj, or -N(Rj)2; each Rj is independently hydrogen or optionally substituted C1-C3 alkyl; each Rk is independently hydrogen, halogen, optionally substituted C1-C3 alkyl, or -OH; each Rm is independently optionally substituted C1-C3 alkyl; and each Rn is independently hydrogen, halogen, or optionally substituted C1-C3 alkyl. [00170] 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-; RS is optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, optionally substituted C2-C5 alkynyl, -ORj, or -N(Rj)2; each Rj is independently hydrogen or optionally substituted C1-C3 alkyl; each Rm is independently optionally substituted C1-C3 alkyl; and each Rn is independently hydrogen, halogen, or optionally substituted C1-C3 alkyl. [00171] 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-; RS is optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, optionally substituted C2-C5 alkynyl, -ORj, or -N(Rj)2; each Rj is independently hydrogen or optionally substituted C1-C3 alkyl; each Rm is independently optionally substituted C1-C3 alkyl; and each Rn is independently hydrogen, halogen, or optionally substituted C1-C3 alkyl. [00172] In some embodiments, B is substituted with one or more substituent selected from the group consisting of: 56 WSGR Ref: 60134-709.601 amino, cyano, halogen, optionally substituted morpholinyl; L is -N(Rj)-, -C(Rn)2-, or -O-; RS is optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, optionally substituted C2-C5 alkynyl, -ORj, or -N(Rj)2; each Rj is independently hydrogen or optionally substituted C1-C3 alkyl; each Rk is independently hydrogen, halogen, optionally substituted C1-C3 alkyl, or -OH; and each Rn is independently hydrogen, halogen, or optionally substituted C1-C3 alkyl. [00173] 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-; RS is optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, optionally substituted C2-C5 alkynyl, -ORj, or -N(Rj)2; each Rj is independently hydrogen or optionally substituted C1-C3 alkyl; each Rk is independently hydrogen, halogen, optionally substituted C1-C3 alkyl, or -OH; and each Rn is independently hydrogen, halogen, or optionally substituted C1-C3 alkyl. [00174] 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-; RS is optionally substituted C1-C3 alkyl, -ORj, or -N(Rj)2; each Rj is independently hydrogen or optionally substituted C1-C2 alkyl; and each Rn is independently hydrogen, halogen, or optionally substituted C1-C2 alkyl. [00175] In some embodiments, B is substituted with one or more substituent selected from the group consisting of: 57 WSGR Ref: 60134-709.601 L is -N(Rj)-, -C(Rn)2-, or -O-; RS is optionally substituted C1-C3 alkyl, -ORj, or -N(Rj)2; each Rj is independently hydrogen or optionally substituted C1-C2 alkyl; and each Rn is independently hydrogen, halogen, or optionally substituted C1-C2 alkyl. [00176] 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-; RS is optionally substituted C1-C2 alkyl, -ORj, or -N(Rj)2; each Rj is independently hydrogen or -CH3; and each Rn is independently hydrogen, halogen, or -CH3. [00177] 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-; RS is optionally substituted C1-C2 alkyl, -ORj, or -N(Rj)2; each Rj is independently hydrogen or -CH3; and each Rn is independently hydrogen, halogen, or -CH3. [00178] 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-; RS is optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, optionally substituted C2-C5 alkynyl, -ORj, or -N(Rj)2; 58 WSGR Ref: 60134-709.601 each Rj is independently hydrogen or optionally substituted C1-C3 alkyl; or two Rj groups are optionally cyclized to form an optionally substituted C3-C7 carbocyclyl; or two Rj groups are optionally cyclized to form an optionally substituted 3 to 7-membered heterocyclyl; each Rn is independently hydrogen, halogen, or optionally substituted C1-C3 alkyl; or two Rn groups attached to the same carbon atom are optionally cyclized to form a C3-C6 carbocyclyl; or two Rn groups attached to the same carbon atom are optionally cyclized to form a 3 to 6- membered heterocyclyl. [00179] 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-; RS is optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, optionally substituted C2-C5 alkynyl, -ORj, or -N(Rj)2; each Rj is independently hydrogen or optionally substituted C1-C3 alkyl; or two Rj groups are optionally cyclized to form an optionally substituted C3-C7 carbocyclyl; or two Rj groups are optionally cyclized to form an optionally substituted 3 to 7-membered heterocyclyl; each Rn is independently hydrogen, halogen, or optionally substituted C1-C3 alkyl; or two Rn groups attached to the same carbon atom are optionally cyclized to form a C3-C6 carbocyclyl; or two Rn groups attached to the same carbon atom are optionally cyclized to form a 3 to 6- membered heterocyclyl. [00180] In some embodiments, B is substituted with one or more substituents selected from: alkyl, amino, cyano, halogen, and optionally substituted morpholinyl. [00181] In some embodiments, B is substituted with one or more substituents selected from: . 59 WSGR Ref: 60134-709.601 [00182] In some embodiments, B is substituted with one or more substituents selected , [00183] In some embodiments, B is substituted with one or more substituents selected [00184] In some embodiments, B is substituted with one or more substituents selected from: [00185] In some embodiments, B is substituted with one or more substituents selected from: . [00186] In some embodiments, B is substituted with one or more substituents selected from: . [00187] In some embodiments, B is substituted with one or more substituents selected from: . [00188] In some embodiments, B is substituted with one or more substituents selected from: ; L is -N(Rj)-, -C(Rn)2-, or -O-; RS is optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, optionally substituted C2-C5 alkynyl, -ORj, or -N(Rj)2; 60 WSGR Ref: 60134-709.601 each Rj is hydrogen or -CH3; and each Rn is independently hydrogen, -F, -Cl, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3. [00189] In some embodiments, B is substituted with one or more substituents selected from: ; RS is optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, or optionally substituted C2-C5 alkynyl; and each Rj is independently hydrogen or -CH3. [00190] In some embodiments, B is substituted with one or more substituents selected from: RS is optionally substituted C1-C3 alkyl; and each Rj is independently hydrogen or -CH3. [00191] In some embodiments, B is substituted with one or more substituents selected from: ; RS is -CH3, -CH2F, -CHF2, -CF3, -CH2OCH3, -CH2NH2, or -CH2CH2NH2; and Rj is hydrogen or -CH3. [00192] In some embodiments, B is substituted with one or more substituents selected from: RS is -CH3, -CH2F, -CHF2, -CF3, -CH2OCH3, -CH2NH2, or -CH2CH2NH2. In some embodiments RS is -CH3, -CH2F, -CHF2, or -CF3. [00193] In some embodiments, B is substituted with one or more substituents selected from: . [00194] In some embodiments, B is substituted with one or more substituents selected from: ; RS is -CH3, -CH2F, -CHF2, -CF3, -CH2OCH3, -CH2NH2, or -CH2CH2NH2. In some embodiments RS is -CH3, -CH2F, -CHF2, -CF3, or -CH2OCH3. In some embodiments, RS is -CH3, - 61 WSGR Ref: 60134-709.601 CH2F, -CHF2, or -CF3. In some embodiments, RS is -CH3. In some embodiments, RS is - CF3. In some embodiments, RS is -CHF2. In some embodiments, RS is -CH2F. [00195] In some embodiments, B is substituted with one or more substituents selected from: . In some embodiments, B is substituted with one or more substituents selected from: some embodiments, B is substituted with one or more substituents selected from: . [00196] In some embodiments, B is substituted with one or more substituents selected from: In some embodiments, B is substituted with one or more substituents selected from: [00197] In some embodiments, B is substituted with one or more substituents selected from: ; RS is optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, or optionally substituted C2-C5 alkynyl. In some embodiments RS is -CH3, -CH2F, -CHF2, -CF3, - CH2OCH3, -CH2NH2, or -CH2CH2NH2. [00198] In some embodiments, B is substituted with one or more substituents selected from: . 62 WSGR Ref: 60134-709.601 [00199] In some embodiments, B is substituted with one or more substituents selected from: ; RS is -ORj, or -N(Rj)2; each Rj is independently hydrogen or optionally substituted C1-C3 alkyl; or two Rj groups are optionally cyclized to form an optionally substituted 3 to 7- membered heterocyclyl. [00200] In some embodiments, B is substituted with one or more substituents selected from: ; RS is -ORj, or -N(Rj)2; each Rj is independently hydrogen or optionally substituted C1-C3 alkyl. [00201] In some embodiments, B is substituted with one or more substituents selected from: ; RS is -ORj, or -N(Rj)2; each Rj is independently hydrogen or -CH3. [00202] In some embodiments, B is substituted with one or more substituents selected from: . [00203] In some embodiments, B is substituted with one or more substituents selected from: ; RS is optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, or optionally substituted C2-C5 alkynyl. each Rn is independently hydrogen, -F, -Cl, or -CH3. [00204] In some embodiments, B is substituted with one or more substituents selected from: RS is -CH3, -CH2F, -CHF2, -CF3, -CH2OCH3, -CH2NH2, or -CH2CH2NH2. each Rn is independently hydrogen, -F, or -CH3. 63 WSGR Ref: 60134-709.601 [00205] In some embodiments, B is substituted with one or more substituents selected from: RS is -CH3, -CH2F, -CHF2, -CF3, -CH2OCH3, -CH2NH2, or -CH2CH2NH2. In some embodiments, RS is -CH3, -CH2F, -CHF2, or -CF3. [00206] In some embodiments, B is substituted with one or more substituents selected from: . [00207] In some embodiments, B is substituted with one or more substituents selected from: RS is -ORj, or -N(Rj)2; each Rn is independently hydrogen, -F, -Cl, or -CH3; each Rj is independently hydrogen or optionally substituted C1-C3 alkyl; or two Rj groups are optionally cyclized to form an optionally substituted 3 to 7- membered heterocyclyl. [00208] In some embodiments, B is substituted with one or more substituents selected from: RS is -ORj, or -N(Rj)2; each Rn is independently hydrogen, -F, -Cl, or -CH3; each Rj is independently hydrogen or optionally substituted C1-C3 alkyl. [00209] In some embodiments, B is substituted with one or more substituents selected from: RS is -ORj, or -N(Rj)2; each Rn is independently hydrogen, -F, or -CH3; each Rj is independently hydrogen or -CH3. [00210] In some embodiments, B is substituted with one or more substituents selected . 64 WSGR Ref: 60134-709.601 [00211] In some embodiments, B is substituted with one or more substituents selected from: L is -NH-, -N(CH3)-, -CH2-, or -O-; wherein each RP is independently optionally substituted C1-C3 alkyl; or two RP are taken together to form an optionally substituted 3 to 10-membered heterocyclyl. [00212] In some embodiments, B is substituted with one or more substituents selected from: ; L is -NH-, -N(CH3)-, or -CH2-; wherein each RP is independently optionally substituted C1-C3 alkyl; or two RP are taken together to form an optionally substituted 3 to 10-membered heterocyclyl. [00213] In some embodiments, B is substituted with one or more substituents selected from: L is -NH-, -N(CH3)-, or -CH2-; wherein each RP is independently optionally substituted C1-C3 alkyl. [00214] In some embodiments, B is substituted with one or more substituents selected . [00216] In some embodiments, B is substituted with one or more substituents selected from: 65 WSGR Ref: 60134-709.601 alkyl, amino, cyano, halogen, optionally substituted morpholinyl, optionally substituted 3-aminopyrrolidin-1-yl, and optionally substituted piperazin-1-yl. [00217] 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. [00218] 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. [00219] In some embodiments, B is substituted with one or more substituents selected from: aminopyrrolidin-1-yl, and optionally substituted piperazin-1-yl. 66 WSGR Ref: 60134-709.601 [00220] 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. [00221] In some embodiments, B is substituted with one or more substituents selected from: aminopyrrolidin-1-yl, and optionally substituted piperazin-1-yl. [00222] 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. [00223] 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. 67 WSGR Ref: 60134-709.601 [00224] In some embodiments, B is substituted with one or more substituents selected optionally 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. [00225] 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 Rj is independently hydrogen or optionally substituted C1-C3 alkyl; or two Rj groups are optionally cyclized to form an optionally substituted C3-C7 carbocyclyl; or two Rj groups are optionally cyclized to form an optionally substituted 3 to 7-membered heterocyclyl; and each Rk is independently hydrogen, halogen, optionally substituted C1-C3 alkyl, or -OH; or two Rk groups attached to the same carbon atom are optionally cyclized to form a C3-C6 carbocyclyl; or two Rk groups attached to the same carbon atom are optionally cyclized to form a 3 to 6- membered heterocyclyl. [00226] In some embodiments, B is substituted with one or more substituents selected from: 68 WSGR Ref: 60134-709.601 aminopyrrolidin-1-yl, and optionally substituted piperazin-1-yl; each Rj is independently hydrogen or optionally substituted C1-C3 alkyl; or two Rj groups are optionally cyclized to form an optionally substituted C3-C7 carbocyclyl; or two Rj groups are optionally cyclized to form an optionally substituted 3 to 7-membered heterocyclyl; and each Rk is independently hydrogen, halogen, optionally substituted C1-C3 alkyl, or -OH; or two Rk groups attached to the same carbon atom are optionally cyclized to form a C3-C6 carbocyclyl; or two Rk groups attached to the same carbon atom are optionally cyclized to form a 3 to 6- membered heterocyclyl. [00227] In some embodiments, B is substituted with one or more substituents selected from: alkyl, amino, cyano, halogen, and optionally substituted morpholinyl; each Rj is independently hydrogen or optionally substituted C1-C3 alkyl; and each Rk is independently hydrogen, halogen, optionally substituted C1-C3 alkyl, or -OH. [00228] In some embodiments, B is substituted with one or more substituents selected from: each Rj is independently hydrogen or optionally substituted C1-C3 alkyl; and each Rk is independently hydrogen, halogen, optionally substituted C1-C3 alkyl, or -OH. 69 WSGR Ref: 60134-709.601 [00229] In some embodiments, B is substituted with one or more substituents selected from: alkyl, amino, cyano, halogen, optionally substituted morpholinyl; each Rj is independently hydrogen, -CH3, -CH2F, -CHF2, or -CF3; and each Rk is independently hydrogen, -F, -Cl, -CH3, -CH2F, -CHF2, -CF3, or -OH. [00230] In some embodiments, B is substituted with one or more substituents selected from: each Rj is independently hydrogen, -CH3, -CH2F, -CHF2, or -CF3; and each Rk is independently hydrogen, -F, -Cl, -CH3, -CH2F, -CHF2, -CF3, or -OH. [00231] In some embodiments, B is substituted with one or more substituents selected from: alkyl, amino, cyano, halogen, and optionally substituted morpholinyl; each Rj is independently hydrogen or -CH3; and each Rk is independently hydrogen, -F, -CH3, or -OH. [00232] In some embodiments, B is substituted with one or more substituents selected from: 70 WSGR Ref: 60134-709.601 each Rj is independently hydrogen or -CH3; and each Rk is independently hydrogen, -F, -CH3, or -OH. [00233] In some embodiments, B is substituted with one or more substituents selected from: each Rj is independently hydrogen or -CH3. [00234] In some embodiments, B is substituted with one or more substituents selected from: . [00235] In some embodiments, B is substituted with one or more substituents selected from: . [00236] In some embodiments, B is substituted with one or more substituents selected from: . each Rk is independently hydrogen, -F, or -CH3. In some embodiments, each Rk is independently hydrogen or -CH3. In some embodiments, each Rk is independently hydrogen or -F. In some embodiments, each Rk is independently -F. In some embodiments, each Rk is independently -H. [00237] In some embodiments, B is substituted with one or more substituents selected from: . [00238] In some embodiments, B is substituted with one or more substituents selected from: each Rj is independently hydrogen or -CH3. [00239] In some embodiments, B is substituted with one or more substituents selected from: each Rj is independently hydrogen or -CH3. 71 WSGR Ref: 60134-709.601 [00240] In some embodiments, B is substituted with one or more substituents selected from: each Rj is independently hydrogen or -CH3. [00241] In some embodiments, B is substituted with one or more substituents selected from: each Rj is independently hydrogen or -CH3. [00242] In some embodiments, B is substituted with one or more substituents selected from: each Rj is independently hydrogen or -CH3; and each Rk is independently hydrogen, -F, -Cl, -CH3, or -OH. [00243] In some embodiments, B is substituted with one or more substituents selected from: ; each Rj is independently hydrogen or -CH3; and each Rk is independently hydrogen, -F, or -CH3. [00244] In some embodiments, B is substituted with one or more substituents selected from: . [00245] In some embodiments, B is substituted with one or more substituents selected from: optionally substituted 3-aminopyrrolidin-1-yl. [00246] 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. [00247] In some embodiments, B is substituted with one or more substituents selected from: . [00248] In some embodiments, B is substituted with one or more substituents selected from: optionally substituted piperazin-1-yl. 72 WSGR Ref: 60134-709.601 [00249] 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. [00250] In some embodiments, B is substituted with one or more substituents selected from: . [00251] In some embodiments, B is substituted with one or more substituents selected from: ; each Rm is independently optionally substituted C1-C3 alkyl; or two Rm groups are optionally cyclized to form an optionally substituted 3 to 6-membered heterocyclyl. [00252] In some embodiments, B is substituted with one or more substituents selected from: ; each Rm is independently optionally substituted C1-C3 alkyl. [00253] In some embodiments, B is substituted with one or more substituents selected each Rm is independently unsubstituted C1-C3 alkyl. [00254] In some embodiments, B is substituted with one or more substituents selected from: . [00255] In some embodiments, two adjacent atoms of B are substituted by the divalent group consisting each Rj is independently hydrogen or optionally substituted C1-C3 alkyl; or two Rj groups are optionally cyclized to form an optionally substituted C3-C7 carbocyclyl; or two Rj groups are optionally cyclized to form an optionally substituted 3 to 7-membered heterocyclyl. 73 WSGR Ref: 60134-709.601 [00256] In some embodiments, two adjacent atoms of B are substituted by the divalent group consisting each Rj is independently hydrogen or -CH3. [00257] In some embodiments, two adjacent atoms of B are substituted by the divalent group consisting each Rj is independently hydrogen or optionally substituted C1-C3 alkyl; or two Rj groups are optionally cyclized to form an optionally substituted C3-C7 carbocyclyl; or two Rj groups are optionally cyclized to form an optionally substituted 3 to 7-membered heterocyclyl. [00258] In some embodiments, two adjacent atoms of B are substituted by the divalent group consisting . [00259] In some embodiments, B is substituted with one or more substituents selected from: [00260] In some embodiments, B is substituted with one or more substituents selected from: 74 WSGR Ref: 60134-709.601 [00261] In some embodiments, B is substituted with one or more substituents selected [00262] In some embodiments, B is substituted with one or more substituents selected fro , 75 WSGR Ref: 60134-709.601 [00263] In some embodiments, B is substituted with one or more substituents selected [00264] In some embodiments, B is substituted with one or more substituents selected 76 WSGR Ref: 60134-709.601 [00265] In some embodiments, B is substituted with one or more substituents selected . [00266] In some embodiments, B is substituted with one or more substituents selected 77 WSGR Ref: 60134-709.601 [00267] In some embodiments, B is substituted with one or more substituents selected [00268] In some embodiments, B is substituted with one or more substituents selected [00269] In some embodiments, B is substituted with one or more substituents selected 78 WSGR Ref: 60134-709.601 [00270] In some embodiments, B is substituted with one or more substituents selected [00271] In some embodiments, B is substituted with one or more substituents selected [00272] In some embodiments, B is substituted with one or more substituents selected 79 WSGR Ref: 60134-709.601 [00274] In some embodiments, X is N. [00275] In some embodiments, X is C-R. 80 WSGR Ref: 60134-709.601 [00276] In some embodiments, Y is N. [00277] In some embodiments, Y is C-R. [00278] In some embodiments, Z is N. [00279] In some embodiments, Z is C-R. [00280] In some embodiments, X is CR; Y is CR; and Z is CR. [00281] In some embodiments, X is CH; Y is CH; and Z is CH. [00282] In some embodiments, X is N; Y is CR; and Z is CR. [00283] In some embodiments, X is N; Y is CH; and Z is CH. [00284] In some embodiments, each R is independently hydrogen, deuterium, halogen, - CN, or optionally substituted C1-2 alkyl. [00285] In some embodiments, each R is independently hydrogen, deuterium, halogen, - CN, or optionally substituted C1 alkyl. [00286] In some embodiments, each R is independently hydrogen, deuterium, halogen, - CN, or -CH3. [00287] In some embodiments, each R is independently hydrogen, deuterium, or halogen. [00288] In some embodiments, each R is independently hydrogen, deuterium, or -F. [00289] In some embodiments, each R is independently hydrogen or deuterium. [00290] In some embodiments, E is absent. [00291] In some embodiments, E is O or N-R1. [00292] In some embodiments, E is O. [00293] In some embodiments, E is N-R1. [00294] In some embodiments, E is O or absent. [00295] In some embodiments, E is N-R1 or absent. [00296] In some embodiments, R1 is hydrogen, optionally substituted C1-C5 alkyl, -OH, - CN, -C(O)R8, or -C(O)N(R9)2. [00297] In some embodiments, R1 is hydrogen, optionally substituted C1-C5 alkyl, -OH, - CN, -C(O)CH3, -C(O)NH2, -C(O)NH(CH3), or -C(O)N(CH3)2. [00298] In some embodiments, R1 is hydrogen, optionally substituted C1-C5 alkyl, -OH, - CN, -C(O)CH3, or -C(O)N(CH3)2. [00299] In some embodiments, R1 is hydrogen, -CH3, -CH2CO2H, -CH(CH3)CO2H, -OH, -CN, -C(O)CH3, or -C(O)N(CH3)2. [00300] In some embodiments, R1 is hydrogen, optionally substituted C1-C5 alkyl, -OH, or -CN. [00301] In some embodiments, R1 is hydrogen or optionally substituted C1-C5 alkyl. In some embodiments, R1 is hydrogen or optionally substituted C1-C4 alkyl. In some embodiments, 81 WSGR Ref: 60134-709.601 R1 is hydrogen or optionally substituted C1-C3 alkyl. In some embodiments, R1 is hydrogen or optionally substituted C1-C2 alkyl. In some embodiments, R1 is hydrogen or optionally substituted C1 alkyl. In some embodiments, R1 is hydrogen or -CH3. [00302] In some embodiments, R1 is hydrogen. [00303] In some embodiments, R1 is optionally substituted alkyl. In some embodiments, R1 is optionally substituted C1-C5 alkyl. In some embodiments, R1 is optionally substituted C1- C4 alkyl. In some embodiments, R1 is optionally substituted C1-C3 alkyl. In some embodiments, R1 is optionally substituted C1-C2 alkyl. In some embodiments, R1 is optionally substituted C1 alkyl. In some embodiments, R1 is C1-C5 alkyl substituted with one or more group selected from -CO2H. In some embodiments, R1 is -H, -CH2CO2H, or -CH(CH3)CO2H. In some embodiments, R1 is -CH2CO2H or -CH(CH3)CO2H. In some embodiments, R1 is -CH2CO2H. In some embodiments, R1 is -CH(CH3)CO2H. [00304] In some embodiments, R1 is -OH. [00305] In some embodiments, R1 is -C(O)R8. [00306] In some embodiments, R1 is -C(O)CH3. [00307] In some embodiments, R1 is -C(O)N(R9)2. [00308] In some embodiments, R1 is -C(O)N(CH3)2. [00309] In some embodiments, RL is 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-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. [00310] 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: 82 WSGR 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. [00311] 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 83 WSGR Ref: 60134-709.601 E is O or NH. [00312] 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. [00313] 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: 84 WSGR Ref: 60134-709.601 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; and E is O or NH. [00314] 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: 85 WSGR Ref: 60134-709.601 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; and E is O or NH. [00315] 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: 86 WSGR 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. [00316] 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 87 WSGR Ref: 60134-709.601 E is O or NH. [00317] 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. [00318] 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: 88 WSGR 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. [00319] 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 89 WSGR Ref: 60134-709.601 E is O or NH. [00320] 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-C6 alkyl); 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 Rv is independently hydrogen or C1-C6 alkyl; and E is O or NH. 90 WSGR Ref: 60134-709.601 [00321] In some embodiments, RL is 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-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, wherein RL is not 4-piperidinyl. [00322] In some embodiments, RL is 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-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 4- to 5-membered C-heterocyclyl. [00323] In some embodiments, RL is 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-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. [00324] In some embodiments, RL is 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-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. [00325] In some embodiments, RL is 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-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 4-membered C-heterocyclyl. [00326] In some embodiments, RL is 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-C12 alkenyl, optionally substituted C4-C12 alkynyl, optionally substituted 3- to 6-membered carbocyclyl, optionally substituted aralkyl, optionally 91 WSGR Ref: 60134-709.601 substituted heteroarylalkyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclylalkyl, or optionally substituted 4-membered C-heterocyclyl. [00327] In some embodiments, RL is 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-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. [00328] In some embodiments, RL is 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-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. [00329] In some embodiments, RL is 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-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. [00330] In some embodiments, RL is 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-C12 alkenyl, optionally substituted C4-C12 alkynyl, 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. [00331] In some embodiments, RL is 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-C12 alkenyl, optionally substituted C4-C12 alkynyl, 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. [00332] In some embodiments, RL is 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-C12 alkenyl, optionally substituted C4-C12 alkynyl, 92 WSGR Ref: 60134-709.601 optionally substituted carbocyclyl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted carbocyclylalkyl, or optionally substituted heterocyclylalkyl. [00333] In some embodiments, RL is optionally substituted C4-C12 alkyl, optionally substituted -(C1-C3 alkylene)-O-(C1-C10 alkyl), optionally substituted C4-C12 alkenyl, optionally substituted C4-C12 alkynyl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted carbocyclylalkyl, or optionally substituted heterocyclylalkyl. [00334] In some embodiments, RL is optionally substituted C4-C12 alkyl, optionally substituted -(C1-C3 alkylene)-O-(C1-C10 alkyl), optionally substituted C4-C12 alkenyl, optionally substituted C4-C12 alkynyl, optionally substituted aralkyl or optionally substituted carbocyclylalkyl. [00335] In some embodiments, RL is optionally substituted C4-C12 alkyl, optionally substituted -(C1-C3 alkylene)-O-(C1-C10 alkyl), optionally substituted C4-C12 alkenyl, optionally substituted C4-C12 alkynyl, or optionally substituted carbocyclylalkyl. [00336] In some embodiments, RL is optionally substituted C4-C12 alkyl, optionally substituted -(C1-C3 alkylene)-O-(C1-C10 alkyl), optionally substituted C4-C12 alkenyl, or optionally substituted C4-C12 alkynyl. [00337] In some embodiments, RL is optionally substituted C4-C12 alkyl or optionally substituted -(C1-C3 alkylene)-O-(C1-C10 alkyl). [00338] In some embodiments, RL is optionally substituted C4-C10 alkyl or optionally substituted -(C1-C3 alkylene)-O-(C1-C8 alkyl). [00339] In some embodiments, RL is 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-C12 alkenyl, optionally substituted C4-C12 alkynyl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted carbocyclylalkyl, or optionally substituted heterocyclylalkyl. [00340] In some embodiments, RL is 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-C12 alkenyl, optionally substituted C4-C12 alkynyl, optionally substituted carbocyclylalkyl, or optionally substituted heterocyclylalkyl. [00341] In some embodiments, RL is 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-C10 alkenyl, optionally substituted C5-C10 alkynyl, optionally substituted carbocyclyl, optionally substituted aralkyl, optionally substituted 93 WSGR Ref: 60134-709.601 heteroarylalkyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclylalkyl, or optionally substituted C-heterocyclyl. [00342] In some embodiments, RL is optionally substituted C4-C10 alkyl, 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. [00343] In some embodiments, RL is optionally substituted C5-C12 alkyl, optionally substituted -(C1-C3 alkylene)-O-(C1-C10 alkyl), optionally substituted -(C1-C3 alkylene)-N(C1-C3 alkyl)(heteroaryl), optionally substituted C5-C12 alkenyl, optionally substituted C5-C12 alkynyl, optionally substituted carbocyclyl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted carbocyclylalkyl, or optionally substituted heterocyclylalkyl. [00344] In some embodiments, RL is optionally substituted C4-C12 alkyl, optionally substituted -(C1-C3 alkylene)-O-(C1-C10 alkyl), optionally substituted C4-C12 alkenyl, or optionally substituted C4-C12 alkynyl. [00345] In some embodiments, RL is optionally substituted C4-C12 alkyl, optionally substituted C4-C12 alkenyl, or optionally substituted C4-C12 alkynyl. [00346] In some embodiments, RL is optionally substituted C5-C12 alkyl, optionally substituted C5-C12 alkenyl, or optionally substituted C5-C12 alkynyl. [00347] In some embodiments, RL is optionally substituted C6-C12 alkyl, optionally substituted C6-C12 alkenyl, or optionally substituted C6-C12 alkynyl. [00348] In some embodiments, RL is an optionally substituted C4-C12 alkyl. [00349] In some embodiments, RL is an optionally substituted C5-C12 alkyl. [00350] In some embodiments, RL is an optionally substituted, linear C4-C10 alkyl. [00351] In some embodiments, RL is an optionally substituted, linear C5-C10 alkyl. [00352] In some embodiments, RL is an optionally substituted C4-C12 alkenyl. [00353] In some embodiments, RL is an optionally substituted C4-C10 alkenyl. [00354] In some embodiments, RL is an optionally substituted C4-C12 alkynyl. [00355] In some embodiments, RL is an optionally substituted C4-C10 alkynyl. [00356] In some embodiments, RL is an optionally substituted carbocyclyl. [00357] In some embodiments, RL is an optionally substituted C3-C8 carbocyclyl. [00358] In some embodiments, RL is an optionally substituted C4-C8 carbocyclyl. [00359] In some embodiments, RL is an optionally substituted C5-C8 carbocyclyl. [00360] In some embodiments, RL is an optionally substituted C5-C7 carbocyclyl. 94 WSGR Ref: 60134-709.601 [00361] In some embodiments, RL is an optionally substituted C5-C6 carbocyclyl. [00362] In some embodiments, RL is an optionally substituted 4-membered carbocyclyl. [00363] In some embodiments, RL is an optionally substituted aralkyl. [00364] In some embodiments, RL is an optionally substituted heteroarylalkyl. [00365] In some embodiments, RL is an optionally substituted carbocyclylalkyl. [00366] In some embodiments, RL is an optionally substituted heterocyclylalkyl. [00367] In some embodiments, RL is an optionally substituted C-heterocyclyl. [00368] In some embodiments, RL is an optionally substituted 4 to 8-membered C- heterocyclyl. [00369] In some embodiments, RL is an optionally substituted 5 to 6-membered C- heterocyclyl. [00370] In some embodiments, RL is an optionally substituted 4 to 5-membered C- heterocyclyl. [00371] In some embodiments, RL is an optionally substituted 4 to 6-membered C- heterocyclyl. [00372] In some embodiments, RL is an optionally substituted 6 membered C- heterocyclyl. [00373] In some embodiments, RL is an optionally substituted C-pyperidinyl. [00374] In some embodiments, RL is a substituted C-pyperidinyl. [00375] In some embodiments, RL is an optionally substituted 5 membered C- heterocyclyl. [00376] In some embodiments, RL is an optionally substituted 4 membered C- heterocyclyl. [00377] In some embodiments, RL is an optionally substituted oxetanyl. [00378] In some embodiments, RL is an optionally substituted C-azetidinyl. [00379] In some embodiments, RL is optionally substituted -(C1-C3 alkylene)-N-(C1-C3 alkyl)(heteroaryl). [00380] In some embodiments, RL is optionally substituted -(C1-C3 alkylene)-N- (CH3)(heteroaryl). In some embodiments, RL is optionally substituted –(CH2)3-N- (CH3)(heteroaryl). In some embodiments, RL is optionally substituted –(CH2)2-N- (CH3)(heteroaryl). [00381] In some embodiments, RL is optionally substituted -(C1-C2 alkylene)-O-(C1-C10 alkyl). [00382] In some embodiments, RL is optionally substituted -(C1 alkylene)-O-(C1-C10 alkyl). 95 WSGR Ref: 60134-709.601 [00383] In some embodiments, RL is optionally substituted -CH2O(C1-C10 alkyl). [00384] In some embodiments, RL is selected from the group consisting of: [00385] In some embodiments, RL is selected from the group consisting of: [00386] In some embodiments, RL is selected from the group consisting of: 96 WSGR Ref: 60134-709.601 97 WSGR Ref: 60134-709.601 98 WSGR Ref: 60134-709.601 [00389] In some embodiments, RL is selected from the group consisting of: 99 WSGR Ref: 60134-709.601 [00390] In some embodiments, RL is selected from the group consisting of: 100 WSGR Ref: 60134-709.601 , , , [ 101 WSGR Ref: 60134-709.601 . [00392] In some embodiments, RL is selected from the group consisting of: 102 WSGR Ref: 60134-709.601 103 WSGR Ref: 60134-709.601 . [00394] 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)-. [00395] In some embodiments, RS is optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, optionally substituted C2-C5 alkynyl, -ORj, or -N 2. In some embodiments, RS is optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, -ORj, or -N(Rj)2. In some embodiments, RS is optionally substituted C1-C4 alkyl, -ORj, or -N 2. In some embodiments, RS is optionally substituted C1- C4 alkyl. In some embodiments, RS is optionally substituted C1-C3 alkyl. In some embodiments, RS is optionally substituted C1-C2 alkyl. In some embodiments, RS is optionally substituted C1 alkyl. In some embodiments, RS is unsubstituted C1-C3 alkyl. In some embodiments, RS is C1-C3 alkyl optionally substituted with -F. In some embodiments, RS is optionally substituted -ORj, or - N(Rj)2. In some embodiments, RS is optionally substituted -ORj. In some embodiments, RS is optionally substituted N(Rj)2. In some embodiments, RS is optionally substituted -OH, -OCH3, - OCH2CH3, --NH2, -NHCH3, or -N(CH3)2. [00396] In some embodiments, each RP is 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 RP is independently optionally substituted C1-C3 alkyl, -ORj, or -N(Rj)2. In some embodiments, each RP is independently optionally substituted C1-C3 alkyl. In some embodiments, each RP is independently C1-C3 alkyl optionally substituted by -F. In some embodiments, each RP is independently -CH3, -CH2CH3, -OCH3, -OCH2CH3, -NH2, - NHCH3, or -N(CH3)2. In some embodiments, each RP is independently -CH3, -CH2CH3, OCH3, or -OCH2CH3. In some embodiments, each RP is independently -CH3. In some embodiments, two RP are taken together to form an optionally substituted 3 to 10-membered heterocyclyl. In some embodiments, two RP are taken together to form an optionally substituted 4 to 10- 104 WSGR Ref: 60134-709.601 membered heterocyclyl. In some embodiments, two RP are taken together to form an optionally substituted 5 to 6-membered heterocyclyl. [00397] In some embodiments, each Rj is independently hydrogen or optionally substituted C1-C3 alkyl; or two Rj groups are optionally cyclized to form an optionally substituted C3-C7 carbocyclyl; or two Rj groups are optionally cyclized to form an optionally substituted 3 to 7-membered heterocyclyl. [00398] In some embodiments, each Rj is independently hydrogen or optionally substituted C1-C3 alkyl; or two Rj groups are optionally cyclized to form an optionally substituted C3-C7 carbocyclyl; or two Rj groups are optionally cyclized to form an optionally substituted 4 to 7-membered heterocyclyl. [00399] In some embodiments, each Rj is independently hydrogen or optionally substituted C1-C3 alkyl; or two Rj groups are optionally cyclized to form an optionally substituted C3-C6 carbocyclyl; or two Rj groups are optionally cyclized to form an optionally substituted 3 to 6-membered heterocyclyl. [00400] In some embodiments, each Rj is independently hydrogen or optionally substituted C1-C3 alkyl; or two Rj groups are optionally cyclized to form an optionally substituted C3-C5 carbocyclyl; or two Rj groups are optionally cyclized to form an optionally substituted 3 to 5-membered heterocyclyl. [00401] In some embodiments, each Rj is independently hydrogen or optionally substituted C1-C3 alkyl; or two Rj groups are optionally cyclized to form an optionally substituted C3-C4 carbocyclyl; or two Rj groups are optionally cyclized to form an optionally substituted 4-membered heterocyclyl. [00402] In some embodiments, each Rj is independently hydrogen or optionally substituted C1-C3 alkyl; or two Rj groups are optionally cyclized to form an optionally substituted C3-C4 carbocyclyl. [00403] In some embodiments, each Rj is independently hydrogen or optionally substituted C1-C3 alkyl; or two Rj groups are optionally cyclized to form an optionally substituted C3 carbocyclyl. [00404] In some embodiments, each Rj is independently hydrogen or optionally substituted C1-C3 alkyl. In some embodiments, each Rj is independently hydrogen or optionally 105 WSGR Ref: 60134-709.601 substituted C1-C2 alkyl. In some embodiments, each Rj is independently hydrogen or optionally substituted C1 alkyl. In some embodiments, each Rj is independently hydrogen or -CH3. [00405] In some embodiments, each Rk is independently hydrogen, halogen, optionally substituted C1-C3 alkyl, or -OH; or two Rk groups attached to the same carbon atom are optionally cyclized to form a C3-C6 carbocyclyl; or two Rk groups attached to the same carbon atom are optionally cyclized to form a 3 to 6- membered heterocyclyl. [00406] In some embodiments, each Rk is independently hydrogen, halogen, optionally substituted C1-C3 alkyl, or -OH; or two Rk groups attached to the same carbon atom are optionally cyclized to form a C3-C5 carbocyclyl; or two Rk groups attached to the same carbon atom are optionally cyclized to form a 3 to 5- membered heterocyclyl. [00407] In some embodiments, each Rk is independently hydrogen, halogen, optionally substituted C1-C3 alkyl, or -OH; or two Rk groups attached to the same carbon atom are optionally cyclized to form a C3-C4 carbocyclyl; or two Rk groups attached to the same carbon atom are optionally cyclized to form a 4- membered heterocyclyl. [00408] In some embodiments, each Rk is independently hydrogen, halogen, optionally substituted C1-C3 alkyl, or -OH; or two Rk groups attached to the same carbon atom are optionally cyclized to form a C3-C4 carbocyclyl. [00409] In some embodiments, each Rk is independently hydrogen, halogen, optionally substituted C1-C3 alkyl, or -OH; or two Rk groups attached to the same carbon atom are optionally cyclized to form a C3 carbocyclyl. [00410] In some embodiments, each Rk is independently hydrogen, halogen, optionally substituted C1-C3 alkyl, or -OH. In some embodiments, each Rk is independently hydrogen, halogen, optionally substituted C1-C2 alkyl, or -OH. In some embodiments, each Rk is independently hydrogen, halogen, optionally substituted C1 alkyl, or -OH. [00411] In some embodiments, each Rk is independently hydrogen, -F, -OH, or -CH3. In some embodiments, each Rk is independently hydrogen, -F, or -CH3. In some embodiments, 106 WSGR Ref: 60134-709.601 each Rk is independently hydrogen or -CH3.In some embodiments, each Rk is independently hydrogen. [00412] In some embodiments, each Rm is independently optionally substituted C1-C3 alkyl; or two Rm groups are optionally cyclized to form an optionally substituted 3 to 6-membered heterocyclyl. [00413] In some embodiments, each Rm is independently optionally substituted C1-C3 alkyl; [00414] or two Rm groups are optionally cyclized to form an optionally substituted 5 to 6-membered heterocyclyl. [00415] In some embodiments, each Rm is independently optionally substituted C1-C3 alkyl; or two Rm groups are optionally cyclized to form an optionally substituted 4-membered heterocyclyl. [00416] In some embodiments, each Rm is independently optionally substituted C1-C3 alkyl. In some embodiments, each Rm is independently optionally substituted C1-C2 alkyl. In some embodiments, each Rm is independently optionally substituted C1 alkyl. In some embodiments, each Rm is independently -CH3. [00417] In some embodiments, each Rn is independently hydrogen, halogen, or optionally substituted C1-C3 alkyl; or two Rn groups attached to the same carbon atom are optionally cyclized to form a C3-C6 carbocyclyl; or two Rn groups attached to the same carbon atom are optionally cyclized to form a 3 to 6- membered heterocyclyl. [00418] In some embodiments, each Rn is independently hydrogen, halogen, or optionally substituted C1-C3 alkyl; or two Rn groups attached to the same carbon atom are optionally cyclized to form a C3-C4 carbocyclyl; or two Rn groups attached to the same carbon atom are optionally cyclized to form a 4- membered heterocyclyl. [00419] In some embodiments, each Rn is independently hydrogen, halogen, or optionally substituted C1-C3 alkyl; or two Rn groups attached to the same carbon atom are optionally cyclized to form a C3-C4 carbocyclyl. 107 WSGR Ref: 60134-709.601 [00420] In some embodiments, each Rn is independently hydrogen, halogen, or optionally substituted C1-C3 alkyl. In some embodiments, each Rn is independently hydrogen, halogen, or optionally substituted C1-C2 alkyl. In some embodiments, each Rn is independently hydrogen, halogen, or optionally substituted C1 alkyl. In some embodiments, each Rn is independently hydrogen, -F, or -CH3. [00421] In some embodiments, R8 is optionally substituted C1-C5 alkyl. In some embodiments, R8 is optionally substituted C1-C4 alkyl. In some embodiments, R8 is optionally substituted C1-C3 alkyl. In some embodiments, R8 is optionally substituted C1-C2 alkyl. In some embodiments, R8 is optionally substituted C1-C1 alkyl. In some embodiments, R8 is -CH3. [00422] In some embodiments, each R9 is independently hydrogen or optionally substituted C1-C3 alkyl; or two R9 groups attached to the same atom are optionally cyclized to form a 3 to 6-membered heterocyclyl. [00423] In some embodiments, each R9 is independently hydrogen or optionally substituted C1-C3 alkyl; or two R9 groups attached to the same atom are optionally cyclized to form a 4 to 6-membered heterocyclyl. [00424] In some embodiments, each R9 is independently hydrogen or optionally substituted C1-C3 alkyl; or two R9 groups attached to the same atom are optionally cyclized to form a 5 to 6-membered heterocyclyl. [00425] In some embodiments, each R9 is independently hydrogen or optionally substituted C1-C3 alkyl. In some embodiments, each R9 is independently hydrogen or optionally substituted C1-C2 alkyl. In some embodiments, each R9 is independently hydrogen or optionally substituted C1 alkyl. In some embodiments, each R9 is independently hydrogen or -CH3. [00426] One embodiment provides a LpxH inhibitory compound, or a pharmaceutically acceptable salt or solvate thereof, having a structure presented in Table 1. Table 1 108 WSGR Ref: 60134-709.601 109 WSGR Ref: 60134-709.601 110 WSGR Ref: 60134-709.601 111 WSGR Ref: 60134-709.601 112 WSGR Ref: 60134-709.601 113 WSGR Ref: 60134-709.601 114 WSGR Ref: 60134-709.601 115 WSGR Ref: 60134-709.601 116 WSGR Ref: 60134-709.601 117 WSGR Ref: 60134-709.601 [00427] Another embodiment provides a LpxH inhibitory compound, or a pharmaceutically acceptable salt or solvate thereof, having a structure presented in Table 2. 118 WSGR Ref: 60134-709.601 119 WSGR Ref: 60134-709.601 120 WSGR Ref: 60134-709.601 121 WSGR Ref: 60134-709.601 122 WSGR Ref: 60134-709.601 Preparation of Compounds [00428] 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). [00429] 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 123 WSGR 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. [00430] 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 [00431] 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, 21st Ed. Mack Pub. Co., Easton, PA (2005)). [00432] 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. [00433] 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. [00434] Provided herein is a pharmaceutical composition comprising at least one LpxH inhibitory compound as described herein, or a stereoisomer, pharmaceutically acceptable salt, 124 WSGR 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. [00435] 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. [00436] 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. [00437] 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. [00438] 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. [00439] 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. [00440] 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. [00441] 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, 125 WSGR 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, 21st Ed. Mack Pub. Co., Easton, PA (2005)). [00442] 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. [00443] 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. [00444] 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. [00445] Oral doses typically range from about 1.0 mg to about 1000 mg, one to four times, or more, per day. Methods of Treatment [00446] 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. [00447] 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. 126 WSGR Ref: 60134-709.601 [00448] 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. [00449] 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. [00450] 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. [00451] 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. [00452] 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. [00453] 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. [00454] 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. [00455] 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 127 WSGR 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. [00456] 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. [00457] 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. [00458] 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. [00459] 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 128 WSGR 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. [00460] 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 [00461] 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 129 WSGR 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 [00462] Intermediate 1 130 WSGR Ref: 60134-709.601 Step 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 131 WSGR 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 100 oC 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 132 WSGR Ref: 60134-709.601 Rf = 0.3 [00463] Intermediate 2 Step 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 100 oC 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 0 oC. 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 = 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 133 WSGR 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 [00464] Intermediate 3 Step 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 [00465] Intermediate 4 Step 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 134 WSGR 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 [00466] Intermediate 5 Step 1: tert-butyl 2-chloro-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate To the solution of 2-chloro-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine (1.0 g, 5.2 mmol),TEA (1.1 g, 10.8 mmol), DMAP (64 mg, 0.5 mmol) and DCM (40 mL).Then Boc2O (2.3 g, 10.5 mmol) was added and the reaction solution was stirred at room temperature for 2 hours. After completion, the solvent was removed under reduced pressure and the resulting residue was purified by flash column chromatography on silica gel and eluted with EA: PE=10%~30% to afford product tert-butyl 2-chloro-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate (1.2 g, Y:92%) as a white solid. LCMS: RT = 1.676 min, [M+H]+ = 255.1. TLC: PE/EA = 3:1, UV Rf = 0.6 Step 2: 6-(tert-butyl) 2-methyl 5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-2,6-dicarboxylate 135 WSGR 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 [00467] Intermediate 6 Step :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 100 oC 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 136 WSGR 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 Na2SO4 then concentrated to give product 5-(heptylthio)indoline (150 mg, 93.1% yield) as a brown solid. TLC: DCM:MeOH = 10:1, UV Rf = 0.3 Step 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 = 0.3 137 WSGR 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 100 oC 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 138 WSGR 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 [00469] Intermediate 8 Step 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). [00470] Intermediate 9 139 WSGR Ref: 60134-709.601 Step 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 140 WSGR 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 [00471] Intermediate 10 Step 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 100 oC 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 0 oC. 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 Na2SO4 then 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 = 0.6 141 WSGR 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 [00472] Intermediate 11 Step 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 100 oC 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 [00473] Intermediate 12 Step 1: methyl 3-(2-((tert-butoxycarbonyl)amino)ethoxy)benzoate 142 WSGR 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 100 oC 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 [00474] Intermediate 13 Step 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 0 oC. The mixture was stirred at RT for 1 h. The reaction mixture was added water, extracted with EA, washed with brine and dried with Na2SO4 then 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 143 WSGR 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 [00475] Example 1: (5-(heptylsulfonyl)indolin-1-yl)(pyrazolo[1,5-a]pyrimidin-3- yl)methanone Step 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 = 0.2 1H 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, 144 WSGR 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. [00476] Example 2: (5-(heptylsulfonyl)indolin-1-yl)(3-(piperazin-1- yl)phenyl)methanone Step 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. 145 WSGR Ref: 60134-709.601 [00477] 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 120 oC 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 Na2SO4 then 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. [00478] Example 4: 2-(5-(heptylsulfonyl)indoline-1-carbonyl)benzoic acid 146 WSGR Ref: 60134-709.601 Step 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 = 0.3 1H 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. [00479] Example 5: N-(2-(5-((3-(cyanomethyl)azetidin-1-yl)sulfonyl)indoline-1- carbonyl)phenyl)-N-methylmethanesulfonamide Step 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. 147 WSGR 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. [00480] Example 6: N-(2-(5-((2-cyclobutylethyl)sulfonyl)indoline-1- carbonyl)phenyl)-N-methylmethanesulfonamide Step 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 148 WSGR 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. [00481] Example 7: N-methyl-N-(2-(5-(pentylsulfonyl)indoline-1- carbonyl)phenyl)methanesulfonamide Step 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 149 WSGR 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. [00482] Example 8: N-methyl- -(2-(5-((5-methylhexyl)sulfonyl)indoline-1- carbonyl)phenyl)methanesulfonamide Step 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 150 WSGR 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. [00483] Example 9: N-(2-(5-((2-cyclopropylethyl)sulfonyl)indoline-1- carbonyl)phenyl)-N-methylmethanesulfonamide Step 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 151 WSGR 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. [00484] Example 10: N-(2-(5-((3-cyclopentylpropyl)sulfonyl)indoline-1- carbonyl)phenyl)-N-methylmethanesulfonamide Step 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% 152 WSGR 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. [00485] 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- methylmethanesulfonamide Step 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 50 o C 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), 153 WSGR 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. [00486] Example 12: Heptyl (imino) (1-(3-(piperazin-1-yl) benzoyl) indolin-5-yl)-l6- sulfanone Step 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. 154 WSGR 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 100 oC 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. [00487] Example 13: N-(2-(5-((7-hydroxyheptyl)sulfonyl)indoline-1- carbonyl)phenyl)-N-methylmethanesulfonamide 155 WSGR Ref: 60134-709.601 Step 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, 156 WSGR 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. [00488] 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 157 WSGR 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. [00489] Example 15: N-methyl-N-(2-(5-((6-methylheptyl)sulfonyl)indoline-1- carbonyl)phenyl)methanesulfonamide Step 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 158 WSGR Ref: 60134-709.601 resulting mixture was stirred at 80 oC 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. [00490] Example 16: N-(2-(5-(heptylsulfonimidoyl) indoline-1-carbonyl) phenyl)-N- methylmethanesulfonamide 159 WSGR 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 85 oC 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. [00491] Example 17: N-(2-(5-((2-hydroxyhexyl) sulfonyl) indoline-1-carbonyl) phenyl)-N-methylmethanesulfonamide Step 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. 160 WSGR 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. [00492] Example 18: (6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)(5- (heptylsulfonyl)indolin-1-yl)methanone Step 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 161 WSGR 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 Na2SO4 then 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 = 0.3 1H 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. [00493] Example 19: N-(2-(5-((7-aminoheptyl)sulfonyl)indoline-1-carbonyl)phenyl)- N-methylmethanesulfonamide Step 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 ) 162 WSGR 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. [00494] Example 20: N-methyl-N-(2-(5-((6,6,6-trifluorohexyl)sulfonyl)indoline-1- carbonyl)phenyl)methanesulfonamide 163 WSGR Ref: 60134-709.601 Step 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 – 164 WSGR 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. [00495] Example 21: N-(2-(5-((3-cyclopropylpropyl)sulfonyl)indoline-1- carbonyl)phenyl)-N-methylmethanesulfonamide Step 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). 165 WSGR Ref: 60134-709.601 MS(ESI) calculated for: C23H28N2O5S2, 476.14; found, 477.2. [00496] Example 22: N-(4-chloro-2-(5-(heptylsulfonyl)indoline-1-carbonyl)-1H- pyrrol-1-yl)methanesulfonamide Step 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. 166 WSGR 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. [00497] Example 23: N-(5-(5-(heptylsulfonyl)indoline-1-carbonyl)-3-methyl-1H- pyrazol-1-yl)methanesulfonamide 167 WSGR Ref: 60134-709.601 Prepared 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. [00498] Example 24: N-(2-(3,3-difluoro-5-(heptylsulfonimidoyl)indoline-1- carbonyl)phenyl)methanesulfonamide Step 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 168 WSGR 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, 169 WSGR 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. [00499] Example 25: N-(5-(5-(heptylsulfonyl)indoline-1-carbonyl)-1H-imidazol-1- yl)methanesulfonamide Step 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 Na2SO4 then 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 170 WSGR 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 0 oC. 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, 469.2 1H 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). [00500] Example 26: N-(3-(5-(heptylsulfonyl)indoline-1-carbonyl)pyrazolo[1,5- a]pyrimidin-2-yl)methanesulfonamide Step 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. 171 WSGR 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 172 WSGR 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 [00501] Example 27: (R)-N-(2-(5-((5-methylheptyl)sulfonyl)indoline-1- carbonyl)phenyl)methanesulfonamide Prepared 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. [00502] Example 28: N-(2-(5-(heptylsulfonyl)indoline-1-carbonyl)-1H-pyrrol-1-yl)me thanesulfonamide Step 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 173 WSGR 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. [00503] Example 29: N-(3-methyl-5-(5-((5-methylhexyl)sulfonyl)indoline-1- carbonyl)-1H-pyrazol-1-yl)methanesulfonamide Step 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 174 WSGR 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 [00504] Example 30: N-(2-(5-(heptylsulfonyl)indoline-1-carbonyl)-4-(piperazin-1- yl)phenyl)methanesulfonamide Step 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. 175 WSGR 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 100 oC 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 50 oC 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 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 Na2SO4 then 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 = 0.3 176 WSGR 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 0 oC. 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 [00505] Example 31: N-(2-(5-(heptylsulfonimidoyl)indoline-1- carbonyl)phenyl)methanesulfonamide 177 WSGR Ref: 60134-709.601 Step 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 afford product (2.3 g, 85 %) as a white solid. LCMS: RT = 2.526 min, [M+H] + =295.1. Step 2: 5-(heptylthio)indoline To a solution of tert-butyl 4-(3-(5-bromoindoline-1-carbonyl)phenyl)piperazine-1-carboxylate (300 mg, 0.859 mmol) in DCM (5 mL) was added TFA (979 mg, 8.59 mmol). The mixture was stirred at r.t for 1 h .The reaction was concentrated and added NaHCO3 (aq), extracted with DCM for three times, the organic phase was concentrated to afford product (200 mg, 93%) as a white solid. LCMS: RT = 1.642 min, [M+H] + =250.2. Step 3: N-(2-(5-(heptylthio)indoline-1-carbonyl)phenyl)methanesulfonamide To a solution of 2-(methylsulfonamido)benzoic acid (103 mg, 0.481 mmol) in SOCl2 (2 mL) , the reaction was stirred at 80oC for 1 h.SOCl2 was concentrated, the resdual was dissolved in DCM, 5-(heptylthio)indoline (80 mg, 0.321 mmol) in DCM (2 mL) and TEA (96 mg, 0.962 mmol) was added. The mixture was stirred at r.t for 1 h. The reaction was purified by flash column chromatography (PE/EA =60/40) to afford product (120 mg, 67%) as a white solid. LCMS: RT = 2.173 min, [M+H] + =447.3 Step 4: N-(2-(5-(heptylsulfonimidoyl)indoline-1-carbonyl)phenyl)methanesulfonamide To a solution of N-(2-(5-(heptylthio)indoline-1-carbonyl)phenyl)methanesulfonamide (117 mg, 0.262 mmol) in MeOH (5 mL) was added phenyl-l3-iodanediyl diacetate (211 mg, 0.655 mmol) and ammonium carbomate (62 mg, 0.655 mmol). The mixture was stirred at r.t for 1 h. The reaction was purified by flash column chromatography (DCM/MeOH =96/4) and prep-HPLC to afford product (40 mg, 30%) as a white solid. 178 WSGR Ref: 60134-709.601 1H NMR (400 MHz, DMSO-d6) δ 9.51 (s, 1H), 8.24 (s, 1H), 7.75 (s, 2H), 7.50 (t, J = 6.6 Hz, 3H), 7.33 (dd, J = 11.1, 4.9 Hz, 1H), 4.05 (s, 1H), 3.92 (s, 2H), 3.19 – 3.03 (m, 4H), 3.00 (s, 3H), 1.49 (dd, J = 15.5, 7.9 Hz, 2H), 1.35 – 1.09 (m, 9H), 0.84 (t, J = 7.0 Hz, 3H). MS(ESI) calculated for: C23H31N3O4S2, 477.2; found [M+H]+, 478.2 [00506] Example 32: (6-(((2-aminoethyl)amino)methyl)pyrazolo[1,5-a]pyrimidin-3- yl)(5-(heptylsulfonyl)indolin-1-yl)methanone Step 1: 6-formylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid To a solution of 5-amino-1H-pyrazole-4-carboxylic acid (500 mg, 3.93 mmol) in EtOH (6 mL) and AcOH (1 mL) was added methanetricarbaldehyde (470 mg, 4.7 mmol), the mixture was stirred for 1h at 15℃ under Ar, then the mixture was heated to 70℃ and stirred for 15 hours. The mixture was added EtOH and filtered, the solid was washed with EtOH, the target product (500 mg, 66.6% yield) was collected as a grey solid. LCMS: RT =0.404 min, [M+1]+ =192.1 1H NMR (400 MHz, DMSO-d6) δ 12.71 (s, 1H), 10.07 (s, 1H), 9.93 (d, J = 2.0 Hz, 1H), 9.11 (d, J = 2.0 Hz, 1H), 8.79 (s, 1H). Step 2: 3-(5-(heptylthio)indoline-1-carbonyl)pyrazolo[1,5-a]pyrimidine-6-carbaldehyde To a solution of 6-formylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (248 mg, 1.3 mmol) in ACN (10 mL) were added 5-(heptylthio)indoline (249 mg, 1 mmol), TCFH (560 mg, 2 mmol) and NMI (246 mg, 3 mmol), the mixture was stirred 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 (EtAOc/PE=60/40) to give target product (112 mg, 26.5% yield) as a yellow solid. LCMS: RT =2.186 min, [M+1]+ =423.1 Step 3: tert-butyl (2-(((3-(5-(heptylthio)indoline-1-carbonyl)pyrazolo[1,5-a]pyrimidin-6- yl)methyl)amino)ethyl)carbamate To a solution of 3-(5-(heptylthio)indoline-1-carbonyl)pyrazolo[1,5-a]pyrimidine-6-carbaldehyde (150 mg, 0.355 mmol) in DCM (10 mL) were added tert-butyl (2-aminoethyl)carbamate (142 mg, 0.888 mmol) and AcOH (21 mg, 0.355 mmol) under Ar, the mixture was stirred for 1h at room temperature, then added NaBH(OAc)3 (225 mg, 1.065 mmol). The mixture was stirred 179 WSGR Ref: 60134-709.601 overnight under Ar. The mixture was added NaHCO3 (aq), extracted with DCM, combined the organic layer, dried over sodium sulfate, the filtrate was concentrated under reduced pressure, the residue was purified by silica gel chromatography (EtOAc/PE=30/70) to give target product (42 mg, 20.9% yield) as a yellow solid. LCMS: RT =1.760 min, [M+1]+ =567.1 Step 4: tert-butyl (2-((tert-butoxycarbonyl)amino)ethyl)((3-(5-(heptylthio)indoline-1- carbonyl)pyrazolo[1,5-a]pyrimidin-6-yl)methyl)carbamate To a solution of tert-butyl (2-(((3-(5-(heptylthio)indoline-1-carbonyl)pyrazolo[1,5-a]pyrimidin- 6-yl)methyl)amino)ethyl)carbamate (42 mg, 0.074 mmol) in EtOH (2 mL) was added (Boc)2O (108 mg, 0.675 mmol), the mixture was stirred for 30 min at room temperature. The mixture was concentrated under reduced pressure, the residue was purified by silica gel chromatography (EtOAc/PE=50/50) to give target product (32 mg, 65.3% yield) as a yellow solid. LCMS: RT =1.910 min, [M+1]+ =667.1 Step 5: tert-butyl (2-((tert-butoxycarbonyl)amino)ethyl)((3-(5-(heptylsulfonyl)indoline-1- carbonyl)pyrazolo[1,5-a]pyrimidin-6-yl)methyl)carbamate To a solution of tert-butyl (2-((tert-butoxycarbonyl)amino)ethyl)((3-(5-(heptylthio)indoline-1- carbonyl)pyrazolo[1,5-a]pyrimidin-6-yl)methyl)carbamate (56 mg, 0.084 mmol) in DCM (3 mL) was added m-CPBA (36 mg, 0.21 mmol) at 0℃, the mixture was stirred for 40 min at 0℃. The mixture was concentrated under reduced pressure, the residue was purified by silica gel chromatography (EtOAc/PE=40/60) to give target product (52 mg, 88.6% yield) as a white solid. LCMS: RT =2.039 min, [M+1-56]+ =643.1 Step 6: (6-(((2-aminoethyl)amino)methyl)pyrazolo[1,5-a]pyrimidin-3-yl)(5- (heptylsulfonyl)indolin-1-yl)methanone To a solution of tert-butyl (2-((tert-butoxycarbonyl)amino)ethyl)((3-(5-(heptylsulfonyl)indoline- 1-carbonyl)pyrazolo[1,5-a]pyrimidin-6-yl)methyl)carbamate (47 mg, 0.067 mmol) in DCM (2.5 mL) was added TFA (0.5 mL), the mixture was stirred for 1h at room temperature. The mixture was added NaHCO3 (aq), extracted with DCM, combined the organic layer, dried over sodium sulfate, the filtrate was concentrated under reduced pressure, the residue was purified by prep- HPLC(HCl) to give target product (10.4 mg, 31.5% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.03 (s, 2H), 9.52 (d, J = 1.7 Hz, 1H), 8.97 (d, J = 2.0 Hz, 1H), 8.70 (s, 1H), 8.21 (d, J = 24.7 Hz, 3H), 8.16 (s, 1H), 7.77 (s, 1H), 7.76 – 7.67 (m, 1H), 4.41 (s, 2H), 4.38 (d, J = 8.7 Hz, 2H), 3.24 (dd, J = 15.0, 6.8 Hz, 8H), 1.53 (dt, J = 15.2, 7.4 Hz, 2H), 1.34 – 1.27 (m, 2H), 1.27 – 1.15 (m, 6H), 0.84 (t, J = 6.9 Hz, 3H). MS(ESI) calculated for: C25H34N6O3S, 498.2; found [M+H]+, 499.2 180 WSGR Ref: 60134-709.601 [00507] Example 33: N-(2-(5-(1-(4-chlorothiazol-2-yl)piperidine-4- sulfonimidoyl)indoline-1-carbonyl)phenyl)-N-methylmethanesulfonamide Step 1: tert-butyl 4-((1-(2-(N-methylmethylsulfonamido)benzoyl)indolin-5-yl)thio)piperidine-1- carboxylate To a solution of N-(2-(5-bromoindoline-1-carbonyl)phenyl)-N-methylmethanesulfonamide (300 mg, 0.735 mmol) in dioxane(5 mL) was added tert-butyl 4-mercaptopiperidine-1-carboxylate (191 mg, 0.882 mmol) and Pd2(dba)3 (67 mg, 0.074 mmol) , Xant-phos(85 mg, 0.147 mmol), DIEA(284 mg , 2.205 mmol) under Ar. The mixture was stirred at 100oC for 4 h. The reaction was filtered and the filter was concentrated and purified by flash column chromatography (PE/EA =50/50) to afford product (350 mg, 77 %) as a white solid. LCMS: RT = 2.001 min, [M+H] + =490.1. Step 2: N-methyl-N-(2-(5-(piperidin-4-ylthio)indoline-1-carbonyl)phenyl)methanesulfonamide To a solution of tert-butyl 4-((1-(2-(N-methylmethylsulfonamido)benzoyl)indolin-5- yl)thio)piperidine-1-carboxylate (250 mg, 0.458 mmol) in DCM (3 mL) was added TFA (522 mg, 4.58 mmol). The mixture was stirred at r.t for 2 h. The reaction was concentrated to remove TFA, the mixture was adjust pH to 8 by NaHCO3 (aq) and extracted with DCM for three times, the organic phase was concentrated to afford product(196 mg, 100 %) as a white solid. LCMS: RT = 1.330 min, [M+H] + =446.1. Step 3: N-(2-(5-((1-(4-chlorothiazol-2-yl)piperidin-4-yl)thio)indoline-1-carbonyl)phenyl)-N- methylmethanesulfonamide To a solution of N-methyl-N-(2-(5-(piperidin-4-ylthio)indoline-1- carbonyl)phenyl)methanesulfonamide (252 mg, 0.566 mmol) in DMF (3 mL) was added Cs2CO3 (368 mg, 1.132 mmol) and 2-bromo-4-chlorothiazole (118 mg, 0.594 mmol). The mixture was stirred at 80oC overnight. The organic phase was extracted with EA and concentrated and purified by flash column chromatography (PE/EA = 50/50) to afford product (120 mg, 33%) as a white solid. LCMS: RT = 2.029 min, [M+H] + =563.1 181 WSGR Ref: 60134-709.601 Step 4: N-(2-(5-(1-(4-chlorothiazol-2-yl)piperidine-4-sulfonimidoyl)indoline-1- carbonyl)phenyl)-N-methylmethanesulfonamide To a solution of N-(2-(5-((1-(4-chlorothiazol-2-yl)piperidin-4-yl)thio)indoline-1- carbonyl)phenyl)-N-methylmethanesulfonamide (120 mg, 0.213 mmol) in MeOH (3 mL) was added phenyl-l3-iodanediyl diacetate (171 mg, 0.532 mmol) and ammonium carbomate (33 mg, 0.426 mmol). The mixture was stirred at r.t for 1 h. The organic phase was purified by prep- HPLC to afford product (33 mg, 26%) as a white solid 1H NMR (400 MHz, DMSO-d6) δ 8.28 (d, J = 8.4 Hz, 1H), 7.74 (d, J = 11.7 Hz, 2H), 7.65 (t, J = 7.8 Hz, 2H), 7.59 (t, J = 7.7 Hz, 1H), 7.50 (t, J = 8.0 Hz, 1H), 6.75 (s, 1H), 4.27 (s, 1H), 4.04 – 3.83 (m, 4H), 3.18 (s, 3H), 3.15 – 2.95 (m, 8H), 1.97 (d, J = 13.3 Hz, 2H), 1.54 (dd, J = 24.1, 10.5 Hz, 2H). LCMS: RT = 1.585 min, [M+H] + =594.1 MS(ESI) calculated for C25H28ClN5O4S3, 593.2; found, 594.1. [00508] Example 34: (7-(((2-aminoethyl)amino)methyl)pyrazolo[1,5-a]pyrimidin-3- yl)(5-(heptylsulfonyl)indolin-1-yl)methanone Step 1: ethyl 7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate The mixture of ethyl 5-amino-1H-pyrazole-4-carboxylate (5.0 g, 32.25 mmol) and 4,4-dimethoxybutan-2-one (3.86 g, 29.31 mmol) in HCl aqueous solution (8 mL) was stirred at ambient temperature for 1 h. 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. The organic phase was concentrated in vacuo and purified by flash chromatography eluted with PE/EA=1:1 to give the product ethyl 7- methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (170 mg,yield : 90.4% yield) as a colorless oil. LCMS: RT = 2.052 min, [M+H]+ =206.1. Step 2: ethyl 7-(bromomethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate 182 WSGR Ref: 60134-709.601 The solution of ethyl ethyl 7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (3.0 g, 14.63 mmol), BPO (353 mg, 1.46 mmol) and NBS (2.84 g, 16.09 mmol) in CCl4 (60 mL) was stirred at 80℃ overnight. After starting material was consumed completely, water was added, extracted with ethyl acetate, the combined organic layers were washed with brine and dried over sodium sulfate. The organic phase was concentrated in vacuo and purified by flash chromatography eluted with PE/EA=1:1 to give the product ethyl 7-(bromomethyl)pyrazolo[1,5-a]pyrimidine-3- carboxylate (800 mg, yield : 19.32% yield) as a colorless oil. LCMS: RT = 1.368 min, [M+H]+ =284.0. Step 3: ethyl 7-(((2-((tert-butoxycarbonyl)amino)ethyl)amino)methyl)pyrazolo[1,5- a]pyrimidine-3-carboxylate The solution of ethyl 7-(bromomethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (700 mg, 2.47 mmol) , tert-butyl (2-aminoethyl)carbamate (396 mg, 2.47 mmol) and K2CO3 (682 mg, 4.94 mmol ) in MeCN (12 mL) was stirred at RT for 2 h. After starting material was consumed completely, water was added, extracted with ethyl acetate, the combined organic layers were washed with brine and dried over sodium sulfate. The organic phase was concentrated in vacuo and purified by flash chromatography eluted with PE/EA=4:1 to give the product 7-(((2-((tert- butoxycarbonyl)amino)ethyl)amino)methyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (800 mg, yield : 89.28% yield) as a yellowish oil. LCMS: RT = 1.144 min, [M+H]+ =364.1. Step 4: ethyl 7-(((tert-butoxycarbonyl)(2-((tert- butoxycarbonyl)amino)ethyl)amino)methyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate The solution of ethyl 7-(((2-((tert-butoxycarbonyl)amino)ethyl)amino)methyl)pyrazolo[1,5- a]pyrimidine-3-carboxylate (800 mg, 2.20 mmol) , Boc2O (527mg, 2.42 mmol) in EtOH(10 mL) was stirred at 50℃ for 2 h. After starting material was consumed completely, water was added, extracted with ethyl acetate, the combined organic layers were washed with brine and dried over sodium sulfate. The organic phase was concentrated in vacuo and purified by flash chromatography eluted with PE/EA=1:1 to give the product ethyl 7-(((tert-butoxycarbonyl)(2- ((tert-butoxycarbonyl)amino)ethyl)amino)methyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (800 mg, yield:80.0% yield) as a yellowish oil. LCMS: RT = 1.760 min, [M+H]+ =464.1. Step 5: 7-(((tert-butoxycarbonyl)(2-((tert- butoxycarbonyl)amino)ethyl)amino)methyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid To a 100 mL bottom flask were added ethyl 7-(((tert-butoxycarbonyl)(2-((tert- butoxycarbonyl)amino)ethyl)amino)methyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (400 mg, 0.86 mmol), NaOH (138 mg, 3.45 mmol), THF (10 mL) and H2O (10 mL) at 0°C. Then the 183 WSGR Ref: 60134-709.601 reaction mixture was stirred at ambient temperature for 2 h. After the reaction was completed, the mixture was adjusted pH = 5~6 by 10% HCl aqueous solution and extracted with DCM. The combined organic extract was washed with brine, dried with Na2SO4, filtered and concentrated to give crude product 7-(((tert-butoxycarbonyl)(2-((tert- butoxycarbonyl)amino)ethyl)amino)methyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (275 mg) as a yellow solid. LCMS: RT = 1.485 min, [M+H-100]+ =336.1. Step 6: tert-butyl (2-((tert-butoxycarbonyl)amino)ethyl)((3-(5-(heptylthio)indoline-1- carbonyl)pyrazolo[1,5-a]pyrimidin-7-yl)methyl)carbamate To a solution of 7-(((tert-butoxycarbonyl)(2-((tert- butoxycarbonyl)amino)ethyl)amino)methyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (275 mg, 0.63 mmol) and 5-(heptylthio)indoline (157 mg, 0.63 mmol) in MeCN (4 mL) were added TCFH (266 mg, 0.95 mmol) and NMI (180 mg, 2.20 mmol). The reaction mixture was stirred at ambient temperature for 1 h. After starting material was consumed completely, water was added, extracted with ethyl acetate, the combined organic layers were washed with brine and dried over sodium sulfate. The organic phase was concentrated in vacuo and purified by flash chromatography eluted with PE/EA=1:2 to give the product tert-butyl (2-((tert- butoxycarbonyl)amino)ethyl)((3-(5-(heptylthio)indoline-1-carbonyl)pyrazolo[1,5-a]pyrimidin-7- yl)methyl)carbamate (338 mg, 80.6% yield) as white solid. LCMS: RT = 2.318 min, [M+H]+ =667.3. Step 7: tert-butyl (2-((tert-butoxycarbonyl)amino)ethyl)((3-(5-(heptylsulfonyl)indoline-1- carbonyl)pyrazolo[1,5-a]pyrimidin-7-yl)methyl)carbamate To the solution of tert-butyl (2-((tert-butoxycarbonyl)amino)ethyl)((3-(5-(heptylthio)indoline-1- carbonyl)pyrazolo[1,5-a]pyrimidin-7-yl)methyl)carbamate (338 mg, 0.50 mmol) in DCM (8 mL) was added m-CPBA (180 mg, 1.01 mmol) at 0°C and the solution was stirred at room temperature overnight. After starting material was consumed completely, water was added, extracted with ethyl acetate, the combined organic layers were washed with brine and dried over sodium sulfate. The organic phase was concentrated in vacuo and purified by flash chromatography eluted with PE/EA=1:1 to give the product tert-butyl (2-((tert- butoxycarbonyl)amino)ethyl)((3-(5-(heptylsulfonyl)indoline-1-carbonyl)pyrazolo[1,5- a]pyrimidin-7-yl)methyl)carbamate (300 mg, yield: 85.9%) as a white solid. LCMS: RT = 2.001 min, [M+H-56]+ =643.3. Step 8: (7-(((2-aminoethyl)amino)methyl)pyrazolo[1,5-a]pyrimidin-3-yl)(5- (heptylsulfonyl)indolin-1-yl)methanone 184 WSGR Ref: 60134-709.601 To the solution of tert-butyl (2-((tert-butoxycarbonyl)amino)ethyl)((3-(5- (heptylsulfonyl)indoline-1-carbonyl)pyrazolo[1,5-a]pyrimidin-7-yl)methyl)carbamate (300 mg, 0.42 mmol) in DCM (6 mL) was added TFA (2 mL). The mixture was stirred at room temperature for 3 h.The reaction mixture was concentrated in vacuo. Then the mixture was neutralized with NaHCO3 to pH>7. Then the residue was purified by prep-HPLC (base) to give product (7-(((2-aminoethyl)amino)methyl)pyrazolo[1,5-a]pyrimidin-3-yl)(5- (heptylsulfonyl)indolin-1-yl)methanone (55.9 mg, 26.7 % yield). 1H NMR (400 MHz, DMSO) δ 10.36 (s, 2H), 8.88 (d, J = 4.3 Hz, 1H), 8.73 (s, 1H), 8.29 (s, 3H), 8.14 (s, 1H), 7.77 (s, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.59 (d, J = 4.3 Hz, 1H), 4.88 (s, 2H), 4.38 (t, J = 8.5 Hz, 2H), 3.43 (s, 2H), 3.26 (dd, J = 14.8, 9.1 Hz, 6H), 1.52 (d, J = 7.4 Hz, 2H), 1.24 (ddd, J = 22.3, 15.9, 8.4 Hz, 8H), 0.84 (t, J = 6.9 Hz, 3H). MS(ESI) calculated for C25H34N6O3S, 498.24; found, 499.3. [00509] Example 35: N-(4-(2-aminoethoxy)-2-(5-(heptylsulfonyl)indoline-1- carbonyl)phenyl)methanesulfonamide Step 1: methyl 5-(2-((tert-butoxycarbonyl)amino)ethoxy)-2-nitrobenzoate To a stirred solution of tert-butyl (2-hydroxyethyl)carbamate (999 mg, 6.2 mmol) and NaH (372 mg, 9.3 mmol) in THF (20 mL) was added methyl 5-fluoro-2-nitrobenzoate (1000 mg, 6.2 mmol). The mixture was stirred at room temperature for 2 h. After quenching the reaction, the reaction mixture was poured into separatory funnel and separated. The aqueous layer was extracted with EA (3*50 mL). The combined organic phase was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure.The crude product was purified by flash chromatography eluted with PE: EA = 5:1 to give the product (1.0 g, yield: 47%) as a white solid. TLC: PE/EA = 5:1, UV Rf = 0.5 Step 2: methyl 2-amino-5-(2-((tert-butoxycarbonyl)amino)ethoxy)benzoate 185 WSGR Ref: 60134-709.601 To a stirred solution of methyl 5-(2-((tert-butoxycarbonyl)amino)ethoxy)-2-nitrobenzoate (1000 mg, 2.94 mmol) in MeOH (20 mL) was added Pd/C (156 mg). The mixture was stirred at room temperature for 2 h under H2 atmosphere. The precipitate was filtered off and washed with 10 mL of MeOH, dried in vacuum to give product (900 mg, yield: 88%) as a yellow solid.. TLC: PE/EA = 1:1, UV Rf = 0.5 Step 3: methyl 5-(2-((tert-butoxycarbonyl)amino)ethoxy)-2-(methylsulfonamido)benzoate To a stirred solution of methyl 2-amino-5-(2-((tert-butoxycarbonyl)amino)ethoxy)benzoate (900 mg, 2.9 mmol) and TEA (879 mg, 8.7 mmol) in DCM (20 mL) was added MsCl (499 mg, 4.355 mmol). The mixture was stirred at room temperature for 2 h. 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 vacuo. The resulting crude material was purified by silica gel chromatography eluted with PE: EA = 70: 30 to give the product (900 mg, yield: 80%) as a yellow solid. TLC: PE/EA = 5:1, UV Rf = 0.5 Step 4: 5-(2-((tert-butoxycarbonyl)amino)ethoxy)-2-(methylsulfonamido)benzoic acid To a solution of methyl 5-(2-((tert-butoxycarbonyl)amino)ethoxy)-2- (methylsulfonamido)benzoate (400 mg, 1.03 mmol) in 20 mL THF and 7 mL H2O was added NaOH (206 mg, 5.155 mmol). The mixture was stirred at room temperature for 4h. The mixture was acidified with 2N HCl until pH = 3. The resulting solution was extracted with EA (20 mL×3). After concentration, the crude product was used directly for the next step without purification (400 mg, yield: 99%) as a white solid. TLC: DCM/MeOH = 10:1, UV Rf = 0.2 Step 5: tert-butyl (2-(3-(5-(heptylthio)indoline-1-carbonyl)-4- (methylsulfonamido)phenoxy)ethyl)carbamate TCFH (224 mg, 0.8 mmol) and NMI (66 mg, 0.8 mmol) were dissolved into dry ACN (15 mL) solution of 5-(2-((tert-butoxycarbonyl)amino)ethoxy)-2-(methylsulfonamido)benzoic acid (150 mg, 0.4 mmol) and 5-(heptylthio)indoline (100 mg, 0.4 mmol). The reaction mixture was stirred 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 = 0-50% to give the product (170 mg, yield: 70%) as white oil. TLC: PE/EA = 1:1, UV Rf = 0.5 186 WSGR Ref: 60134-709.601 Step 6: tert-butyl (2-(3-(5-(heptylsulfonyl)indoline-1-carbonyl)-4- (methylsulfonamido)phenoxy)ethyl)carbamate m-cPBA (111 mg, 0.645 mmol) was added into (2-(3-(5-(heptylthio)indoline-1-carbonyl)-4- (methylsulfonamido)phenoxy)ethyl)carbamate(130 mg, 0.215 mmol) in 10 mL DCM. The reaction mixture was stirred 2 h at room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was purified by silica gel chromatography eluted with PE: EA = 0-50% to give the product (120 mg, yield: 88%) as a white solid. TLC: PE/EA = 1:1, UV Rf = 0.5 Step 7: N-(4-(2-aminoethoxy)-2-(5-(heptylsulfonyl)indoline-1- carbonyl)phenyl)methanesulfonamide TFA (0.4 mL) was added into tert-butyl (2-(3-(5-(heptylsulfonyl)indoline-1-carbonyl)-4- (methylsulfonamido)phenoxy)ethyl)carbamate(10 mg, 0.016 mmol) in 2 mL DCM. 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 to give the product (34.2 mg, yield: 37%) as a white solid. 1H NMR (400 MHz, DMSO) δ 8.28 (s, 1H), 7.75 (s, 2H), 7.34 (d, J = 9.2 Hz, 1H), 7.02 (d, J = 5.0 Hz, 2H), 5.09 (s, 2H), 3.95 (d, J = 5.2 Hz, 4H), 3.26 – 3.19 (m, 2H), 3.13 (t, J = 8.3 Hz, 2H), 2.90 (t, J = 5.6 Hz, 2H), 2.85 (s, 2H), 1.58 – 1.46 (m, 2H), 1.38 – 1.13 (m, 8H), 0.84 (t, J = 6.9 Hz, 3H). MS(ESI) calculated for C21H28N2O5S2, 537.20; found, 538.2. [00510] Example 36: (S)-N-(2-(5-((5-methylheptyl)sulfonyl)indoline-1- carbonyl)phenyl)methanesulfonamide Step 1: methyl (S)-5-methylheptanoate To the solution of methyl acrylate (1.1 g, 12.0 mmol), Zn(780 mg, 12.0 mmol) and NiCl2 (620 mg, 4.8 mmol) in Py (24 mL),the reaction mixture were stirred at 50℃ for 30 min. Then added (S)-1-bromo-2-methylbutane (1.8 g, 12.0 mmol), the reaction mixture were stirred at RT for 3 h 187 WSGR Ref: 60134-709.601 in Ar. After starting material was consumed completely, water was added, extracted with ethyl acetate, the combined organic layers were washed with brine and dried over sodium sulfate. It was concentrated under vacuum to give product methyl (S)-5-methylheptanoate (1.8 g, crude) as a colorless oil. Step 2: (S)-5-methylheptan-1-ol The solution of (S)-5-methylheptanoate (1.8 g, 11.39 mmol), LiAlH4 (9.1 mL, 22.78 mmol ) in THF(20 mL) was stirred at RT for 3 h. 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. The organic phase was concentrated in vacuo and purified by flash chromatography eluted with PE/EA=5:1 to give product (S)-5-methylheptan-1-ol (1.3 g, 87.8 % yield) as a colorless oil. Step 3: (S)-5-methylheptyl methanesulfonate The solution of (S)-5-methylheptan-1-ol (1.3 g,10.0 mmol), Cs2CO3 (6.5 g, 20.0 mmol) in DCM (20 mL) was stirred at 0℃ for 30 min. Then added MsCl (2.28 g, 20.0 mmol), the reaction mixture were stirred at RT overnight. After starting material was consumed completely, water was added, extracted with ethyl acetate, the combined organic layers were washed with brine and dried over sodium sulfate. The organic phase was concentrated in vacuo and purified by flash chromatography eluted with PE/EA=5:1 to give product (S)-5-methylheptyl methanesulfonate as a colorless oil (800 mg, 38.4% yield). Step 4: (S)-N-(2-(5-((5-methylheptyl)thio)indoline-1-carbonyl)phenyl)methanesulfonamide The solution of (S)-5-methylheptyl methanesulfonate (72 mg, 0.34 mmol), N-(2-(5- mercaptoindoline-1-carbonyl)phenyl)methanesulfonamide (60 mg, 0.17 mmol) and NaH (16 mg, 0.34 mmol ) in THF(5 mL) was stirred at RT for 2 h. After starting material was consumed completely, water was added, extracted with ethyl acetate, the combined organic layers were washed with brine and dried over sodium sulfate. The organic phase was concentrated in vacuo and purified by flash chromatography eluted with PE/EA=3:1 to give the product (S)-N-(2-(5- ((5-methylheptyl)thio)indoline-1-carbonyl)phenyl)methanesulfonamide (33 mg, yield:42.3% yield) as yellowish solid. Step 5: (S)-N-(2-(5-((5-methylheptyl)sulfonyl)indoline-1-carbonyl)phenyl)methanesulfonamide To the solution of (S)-N-(2-(5-((5-methylheptyl)thio)indoline-1- carbonyl)phenyl)methanesulfonamide (33 mg, 0.071 mmol) in DCM (4 mL) was added m- CPBA (25 mg, 0.142 mmol) at 0°C and the solution was stirred at room temperature overnight. It was extracted with ethyl acetate and water, the combined organic layers were washed with brine and dried over sodium sulfate and purified by flash chromatography to give crude product, then the residue was purified by prep-HPLC (base) to give product (S)-N-(2-(5-((5- 188 WSGR Ref: 60134-709.601 methylheptyl)sulfonyl)indoline-1-carbonyl)phenyl)methanesulfonamide (5.4 mg, yield: 16.8%) as a white solid. 1H NMR (400 MHz, DMSO) δ 9.48 (s, 1H), 8.30 (s, 1H), 7.72 (s, 2H), 7.38 (d, J = 8.0 Hz, 1H), 7.30 (s, 2H), 6.93 (s, 1H), 3.99 (s, 2H), 3.22 (s, 2H), 3.12 (s, 2H), 2.77 (s, 3H), 1.50 (d, J = 7.4 Hz, 2H), 1.32 – 1.22 (m, 5H), 1.09 – 1.00 (m, 2H), 0.80 (dd, J = 6.8, 3.6 Hz, 6H). MS(ESI) calculated for C24H32N2O5S2, 492.18; found, 493.1. [00511] Example 37: N-(2-(5-(heptylsulfonyl)indoline-1-carbonyl)-4- morpholinophenyl)methanesulfonamide Step 1: methyl 5-bromo-2-(N-(methylsulfonyl)methylsulfonamido)benzoate To a solution of ethyl methyl 2-amino-5-bromobenzoate (1.15 g, 5.0 mmol) and TEA (5.06 g,50.0 mmol) in DCM (50 mL) was added MsCl (3.84 g, 25.0 mmol). The resulting mixture was stirred at 25℃ for 3h. The mixture was quenched with water and extracted with EtOAc 3 times. The combined organic layers was washed with brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (EA/PE=50~70%) to give the title compound as a colorless oil, 1.6 g, yield: 83%. LCMS: RT = 1.92 min, [M+1]+ =386/388 Step 2: methyl 2-(methylsulfonamido)-5-morpholinobenzoate A solution of methyl 5-bromo-2-(N-(methylsulfonyl)methylsulfonamido)benzoate (600 mg,1.56 mmol), heptane-1-thiol (272 mg, 3.12 mmol), Cs2CO3 (1.52 g, 4.68 mmol), Pd2dba3(143 mg, 0.156 mmol) and xphos (149 mg, 0.312 mmol) in 1,4-dioxane (20 mL) was stirred at 100℃ for 16 h under Ar atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (MeOH / DCM=2:98) to give the title compound as a yellow solid (355 mg, yield: 72.5%). LCMS: RT =1.55 min, [M+1]+ =315 Step 3: 2-(methylsulfonamido)-5-morpholinobenzoic acid A solution of methyl 2-(methylsulfonamido)-5-morpholinobenzoate (355 mg, 1.13 mmol) and LiOH (271 mg, 11.3 mmol) in MeOH (10 mL) and water (1 mL) was stirred at 25℃ for 1h. The 189 WSGR Ref: 60134-709.601 reaction mixture was quenched with HCl (2N, 6 mL) and extracted with EtOAc 3 times. The combined organic layers was washed with brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound as a colorless oil (310 mg, yield: 91%). The residue was used directly in next step without further purification. LCMS: RT = 1.16 min, [M+1]+ =301 Step 4: N-(2-(5-(heptylthio)indoline-1-carbonyl)-4-morpholinophenyl)methanesulfonamide To a solution of 2-(methylsulfonamido)-5-morpholinobenzoic acid (180 mg, 0.6 mmol) and 4- (heptylthio)aniline (150mg, 0.6 mmol) in MeCN (10 mL) was added NMI (148 mg, 1.8 mmol) and TCFH (252 mg, 0.9 mmol). The resulting mixture was stirred at 80℃ for 1h. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (EA/PE=50:50) to give the title compound as a white solid, 233 mg, yield: 71.7%. LCMS: RT = 2.09 min, [M+1]+ =532 Step 5: N-(2-(5-(heptylsulfonyl)indoline-1-carbonyl)-4-morpholinophenyl)methanesulfonamide To a solution of N-(2-(5-(heptylthio)indoline-1-carbonyl)-4- morpholinophenyl)methanesulfonamide (133 mg, 0.25 mmol) in DCM (6 mL) was added m- CPBA (99 mg, 0.575 mmol). The resulting mixture was stirred at 25℃ for 1h. The mixture was quenched with Na2SO3(aq) and extracted with EtOAc 3 times. The combined organic layers was washed with brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue purified by prep-HPLC to give the title compound as a white solid, 16.0 mg, yield: 11%. 1H NMR (400 MHz, DMSO-d6) δ 9.16 (s, 1H), 8.29 (d, J = 7.8 Hz, 1H), 7.75 (s, 2H), 7.29 (d, J = 9.2 Hz, 1H), 7.05 (d, J = 7.3 Hz, 2H), 3.92 (s, 2H), 3.76 – 3.68 (m, 4H), 3.26 – 3.18 (m, 2H), 3.13 (d, J = 16.6 Hz, 6H), 2.91 (s, 3H), 1.58 – 1.45 (m, 2H), 1.30 (d, J = 7.6 Hz, 2H), 1.23 (dd, J = 12.6, 6.4 Hz, 6H), 0.84 (t, J = 6.9 Hz, 3H). MS(ESI) calculated for: C27H37N3O6S2, 563.21; found [M+H]+, 564.2 [00512] Example 38: 2-(5-(heptylsulfonimidoyl)indoline-1-carbonyl)benzoic acid Step 1: methyl 2-(5-(heptylthio)indoline-1-carbonyl)benzoate To a solution of 2-(methoxycarbonyl)benzoic acid (180 mg, 1 mmol) in ACN (4 mL) was added 5-(heptylthio)indoline (249 mg, 1 mmol), TCFH (420 mg, 1.5 mmol) and NMI (287 mg, 3.5 190 WSGR Ref: 60134-709.601 mmol), then the mixture was stirred at room for 3 hours. After removal of the solvent, the residue was purified by flash (EA/PE=1:4) to give the desired product. MS(ESI) calculated for: C24H29NO3S, 411.2; found [M+H]+, 412.1. Step 2: methyl 2-(5-(heptylsulfonimidoyl)indoline-1-carbonyl)benzoate The solution of methyl 2-(5-(heptylthio)indoline-1-carbonyl)benzoate (230 mg, 0.56 mmol) in MeOH (5 mL) were added ammonium carbomate (134.4 mg, 1.4 mmol) and phenyl-l3- iodanediyl diacetate (360.4 mg, 1.12 mmol), the mixture was stirred at room temperature for 2 hours. After removal of the solvent, water was added, extracted with EtOAc, the combined organic layer was dried over Na2SO4, after removal of the solvent, the residue was purified by column (DCM:MeOH=95:5) to give the desired product (240 mg, yield: 96.9%). MS(ESI) calculated for: C24H30N2O4S, 442.2; found [M+H]+, 443.3. Step 3: 2-(5-(heptylsulfonimidoyl)indoline-1-carbonyl)benzoic acid To a solution of methyl 2-(5-(heptylsulfonimidoyl)indoline-1-carbonyl)benzoate (240 mg, 0.54 mmol) in THF (9 mL) was added LiOH.H2O (68.4 mg, 1.63 mmol) and H2O (3 mL), then the mixture was stirred at room temperature for 1 hours. Then adjust pH to 3-4 with 1N HCl aqueous solution, extracted with EtOAc, the combined organic layer was dried over Na2SO4, after removal of the solvent, the residue was purified by prep-HPLC (acetonitrile and 0.1% FA in water) to get 102 mg product. 1H NMR (400 MHz, DMSO-d6) δ 8.20 (s, 1H), 8.01 (dd, J = 7.8, 0.9 Hz, 1H), 7.81 – 7.72 (m, 2H), 7.71 (d, J = 1.3 Hz, 1H), 7.61 (d, J = 6.9 Hz, 1H), 7.49 (d, J = 7.1 Hz, 1H), 3.83 (s, 2H), 3.16 (t, J = 8.5 Hz, 2H), 3.10 (d, J = 8.0 Hz, 2H), 1.57 (dd, J = 15.3, 7.7 Hz, 2H), 1.27 (ddd, J = 16.3, 12.4, 6.3 Hz, 8H), 0.87 (t, J = 7.0 Hz, 3H). MS(ESI) calculated for: C23H28N2O4S, 428.2; found [M+H]+, 429.2. [00513] Example 39: N-(4-(((3-aminopropyl)amino)methyl)-2-(5- (heptylsulfonyl)indoline-1-carbonyl)phenyl)methanesulfonamide Prepared N-(4-(((3-aminopropyl)amino)methyl)-2-(5-(heptylsulfonyl)indoline-1- carbonyl)phenyl)methanesulfonamide essentially as described in preparation Example 53. 1H NMR (400 MHz, DMSO-d6) δ 9.71 (s, 1H), 9.41 (s, 2H), 8.29 (s, 1H), 7.95 (s, 3H), 7.79 (s, 2H), 7.74 (s, 1H), 7.68 (d, J = 8.5 Hz, 1H), 7.55 (d, J = 8.4 Hz, 1H), 4.14 (d, J = 5.5 Hz, 2H), 4.01 (s, 2H), 3.27 – 3.21 (m, 2H), 3.18 (dd, J = 13.6, 5.1 Hz, 2H), 3.03 (s, 3H), 3.02 – 2.95 (m, 191 WSGR Ref: 60134-709.601 2H), 2.91 (d, J = 6.4 Hz, 2H), 2.05 – 1.93 (m, 2H), 1.59 – 1.47 (m, 2H), 1.39 – 1.27 (m, 2H), 1.26 – 1.09 (m, 6H), 0.84 (t, J = 6.9 Hz, 3H). MS(ESI) calculated for: C27H40N4O5S2, 564.2; found [M+H]+, 565.3. [00514] Example 40: N-(4-(((3-aminopropyl)amino)methyl)-2-(5- (heptylsulfonimidoyl)indoline-1-carbonyl)phenyl)methanesulfonamide Step 1: tert-butyl (3-((tert-butoxycarbonyl)amino)propyl)(3-(5-(heptylthio)indoline-1-carbonyl)- 4-(methylsulfonamido)benzyl)carbamate To a solution of 5-(((tert-butoxycarbonyl)(3-((tert- butoxycarbonyl)amino)propyl)amino)methyl)-2-(methylsulfonamido)benzoic acid (260 mg, 0.518mmol) in MeCN (5 mL) was added 5-(heptylthio)indoline (100 mg, 0.518 mmol), TCFH (167 mg, 0.777 mmol) and NMI (100 mg, 1.25 mmol). The mixture was stirred at r.t for 1 h. The reaction was concentrated and residue was purified by flash column chromatography (PE/EA =50/50) to afford product (150mg, 39 %) as a white solid. LCMS: RT = 1.864 min, [M+H] + =633.1. Step 2: tert-butyl (3-((tert-butoxycarbonyl)amino)propyl)(3-(5-(heptylsulfonimidoyl)indoline-1- carbonyl)-4-(methylsulfonamido)benzyl)carbamate To a solution of tert-butyl (3-((tert-butoxycarbonyl)amino)propyl)(3-(5-(heptylthio)indoline-1- carbonyl)-4-(methylsulfonamido)benzyl)carbamate (130 mg, 0.177 mmol) in MeOH (5 mL) was added phenyl-l3-iodanediyl diacetate (142 mg, 0.443 mmol) and ammonium carbomate (43 mg, 0.433 mmol). The mixture was stirred at r.t for 1 h. The reaction was purified by flash column chromatography (DCM/MeOH =96/4) to afford product (60 mg, 41 %) as a white solid. LCMS: RT = 1.724 min, [M+H] + =765.1. Step 3: N-(4-(((3-aminopropyl)amino)methyl)-2-(5-(heptylsulfonimidoyl)indoline-1- carbonyl)phenyl)methanesulfonamide To a solution of tert-butyl (3-((tert-butoxycarbonyl)amino)propyl)(3-(5- (heptylsulfonimidoyl)indoline-1-carbonyl)-4-(methylsulfonamido)benzyl)carbamate (60 mg, 0.078 mmol) in DCM(3 mL) was added TFA(60 mg, 0.52 mmol). The mixture was stirred at r.t 192 WSGR Ref: 60134-709.601 for 1 h. The reaction was concentrated and added NaHCO3 (aq), the water was extracted with DCM for three times, the organic phase was concentrated and purified by Prep-HPLC (H2O/MeCN) to afford product (11 mg, 20 %) as a white solid. LCMS: RT = 1.191 min, [M+H] + =564.1. 1H NMR (400 MHz, DMSO-d6) δ 8.25 (s, 1H), 7.70 (s, 2H), 7.29 (d, J = 8.2 Hz, 1H), 7.15 (d, J = 30.4 Hz, 2H), 4.00 (s, 3H), 3.61 (s, 2H), 3.17 – 2.96 (m, 5H), 2.82 (s, 2H), 2.67 (d, J = 3.8 Hz, 2H), 2.58 (s, 1H), 1.62 (s, 2H), 1.50 (s, 2H), 1.23 (dd, J = 17.0, 9.8 Hz, 8H), 0.84 (t, J = 7.0 Hz, 3H). MS(ESI) calculated for: C27H41N5O4S2, 563.2; found [M+H]+, 564.1. [00515] Example 41: N-(4-(5-(heptylsulfonyl)indoline-1-carbonyl)-1-methyl-1H- pyrazol-3-yl)methanesulfonamide Step 1: N-(4-(5-(heptylthio)indoline-1-carbonyl)-1-methyl-1H-pyrazol-3-yl)methanesulfonamide To a solution of 1-methyl-3-(methylsulfonamido)-1H-pyrazole-4-carboxylic acid (150 mg, 0.684 mmol) in MeCN (5 mL) were added 5-(heptylthio)indoline (188 mg, 0.753 mmol), TCFH (383 mg, 0.368 mmol) and NMI (168 mg, 2.052 mmol), the mixture was stirred 2 h at roomtemperature. The mixture was added water, and extracted with EtOAc, combined the organic layer, washed with brine, dried over sodium sulfate, the filtrate was concentrated under reduced pressure, the residue was purified by silica gel chromatography (EtOAc /PE=5:1) to give product (195 mg, 64% yield) as a white solid. LCMS: RT =1.86 min, [M+1]+ =451 Step 2: N-(4-(5-(heptylsulfonyl)indoline-1-carbonyl)-1-methyl-1H-pyrazol-3- yl)methanesulfonamide To a solution of N-(4-(5-(heptylthio)indoline-1-carbonyl)-1-methyl-1H-pyrazol-3- yl)methanesulfonamide (150 mg, 0.33 mmol) in DCM (10 mL) was added m-CPBA (172 mg, 0.99 mmol), the mixture was stirred 1 h at roomtemperature. The mixture was added Na2S2O3 (aq.), 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 Prep-HPLC (H2O/MeCN) to give product (43.5 mg, 50% yield) as a white solid. 1H NMR (401 MHz, DMSO) δ 9.60 (s, 1H), 8.29 (s, 1H), 8.22 (d, J = 8.5 Hz, 1H), 7.74 (s, 1H), 7.73 – 7.69 (m, 1H), 4.34 (t, J = 8.5 Hz, 2H), 3.83 (s, 3H), 3.26 (dd, J = 15.3, 8.0 Hz, 4H), 3.20 (s, 3H), 1.51 (dd, J = 15.4, 7.9 Hz, 2H), 1.32 – 1.18 (m, 8H), 0.83 (t, J = 7.0 Hz, 3H). MS(ESI) calculated for C21H30N4O5S2, 482.1, found, 483.1. 193 WSGR Ref: 60134-709.601 [00516] Example 42: 6-chloro-4-(5-(heptylsulfonyl)indoline-1-carbonyl)nicotinic acid Step 1: 3-(ethoxycarbonyl)isonicotinic acid To a solution of diethyl pyridine-3,4-dicarboxylate (5 g, 22.42 mmol) in H2O (60 mL) was added NaOH (900 mg, 22.42 mmol), then the mixture was stirred at room temperature for 2 days. The mixture was extracted with DCM, the aqueous layer was adjust pH to 1 with 1N HCl solution, after removal of the solvent, added THF, stirred at 50oC, filtered, the filate was concentrated, the residue was dissolve into MeOH, recrystallization to get 1.1 g desired product. MS(ESI) calculated for: C9H9NO4, 195.1; found [M+H]+, 196.1. Step 2: ethyl 4-(5-(heptylthio)indoline-1-carbonyl)nicotinate The solution of 3-(ethoxycarbonyl)isonicotinic acid (1 g, 5.13 mmol) in ACN (20 mL) was added 5-(heptylthio)indoline (1.15 g, 4.62 mmol), TCFH (2.15 g, 7.69 mmol) and NMI (1.47 g, 17.95 mmol), then the mixture was stirred at room temperature for 3 hours. After removal of the solvent, the residue was purified by column (PE:EA=7:3) to give the desired product (1.75 g, yield: 80.1%). MS(ESI) calculated for: C24H30N2O3S, 426.2; found [M+H]+, 427.2. Step 3: 3-(ethoxycarbonyl)-4-(5-(heptylsulfonyl)indoline-1-carbonyl)pyridine 1-oxide The solution of ethyl 4-(5-(heptylthio)indoline-1-carbonyl)nicotinate (1.75 g, 4.11 mmol) in DCM (15 mL) was added m-CPBA (4.25 g, 24.65 mmol), the mixture was stirred at room temperature overnight. After removal of the solvent, water was added, extracted with EtOAc, the combined organic layer was dried over Na2SO4, after removal of the solvent, the residue was purified by column (DCM:MeOH=98:2) to give the desired product (900 mg, yield: 46.2%). MS(ESI) calculated for: C24H30N2O3S, 426.2; found [M+H]+, 427.2. Step 4: ethyl 6-chloro-4-(5-(heptylsulfinyl)indoline-1-carbonyl)nicotinate The solution of 3-(ethoxycarbonyl)-4-(5-(heptylsulfonyl)indoline-1-carbonyl)pyridine 1-oxide (900 mg, 1.9 mmol) in POCl3 (6 mL) was stirred at 90oC overnight. After removal of the solvent, the residue was purified by column (PE:EA=4:1) to give the desired product (80 mg, yield: 8.6%) and another isomer (340 mg). MS(ESI) calculated for: C24H29ClN2O5S, 492.2; found [M+H]+, 493.2. 194 WSGR Ref: 60134-709.601 Step 5: 6-chloro-4-(5-(heptylsulfonyl)indoline-1-carbonyl)nicotinic acid To a solution of ethyl 6-chloro-4-(5-(heptylsulfinyl)indoline-1-carbonyl)nicotinate (60 mg, 0.12 mmol) in THF (3 mL) was added H2O (1 mL) and LiOH.H2O (25.6 mg, 0.61 mmol), the mixture was stirred at room temperature for 1h. The mixture was adjusted with 2 mol/L HCl aqueous pH of 3-4, extracted with EtOAc, the combined organic layer was dried over Na2SO4, after removal of the solvent, the residue was purified by prep-HPLC (acetonitrile and 0.1% FA in water) to get product (12.1 mg, yield: 21.4%). 1H NMR (400 MHz, DMSO-d6) δ 13.97 (s, 1H), 8.99 (d, J = 10.1 Hz, 1H), 8.34 – 8.20 (m, 1H), 7.86 (d, J = 17.3 Hz, 1H), 7.82 – 7.75 (m, 2H), 3.80 (t, J = 8.4 Hz, 2H), 3.26 – 3.13 (m, 4H), 1.53 (dd, J = 15.4, 7.9 Hz, 2H), 1.33 – 1.20 (m, 8H), 0.84 (t, J = 6.9 Hz, 3H). MS(ESI) calculated for: C22H25ClN2O5S, 464.1; found [M+H]+, 465.2. [00517] Example 43: 6-(5-(heptylsulfonyl)indoline-1-carbonyl)-3-methyl-3,4- dihydroquinazolin-2(1H)-one Step 1: 3-methyl-2-oxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid To a solution of methyl 3-methyl-2-oxo-1,2,3,4-tetrahydroquinazoline-6-carboxylate (220 mg, 1 mmol) in MeOH (5 mL) and H2O (1 mL) was added NaOH (400 mg, 10 mmol). The mixture was stirred at 50oC for 2 h. After cooling down, pH of the mixture was adjusted to ~3 with 3 N HCl solution and extracted with EtOAc (50 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered off, and concentrated in vacuo to afford product (150 mg, 72 %) as a white solid. LCMS: RT = 1.120 min, [M+H] + =207.1. Step 2: 6-(5-(heptylthio)indoline-1-carbonyl)-3-methyl-3,4-dihydroquinazolin-2(1H)-one To a solution of 3-methyl-2-oxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (117 mg, 0.567 mmol) and 5-(heptylthio)indoline (141 mg, 0.567 mmol) in MeCN (5 mL) was added TCFH (238 mg, 0.850 mmol) and NMI (139 mg, 1.701 mmol). The mixture was stirred at r.t for 1 h. The reaction was purified by flash column chromatography (DCM/MeOH =96/4) to afford product (150 mg, 57 %) as a white solid. LCMS: RT = 2.060 min, [M+H] + =438.2. Step 3: 6-(5-(heptylsulfonyl)indoline-1-carbonyl)-3-methyl-3,4-dihydroquinazolin-2(1H)-one To a solution of 6-(5-(heptylthio)indoline-1-carbonyl)-3-methyl-3,4-dihydroquinazolin-2(1H)- one (150 mg, 0.343 mmol) in DCM (5 mL) was added m-CPBA(147 mg, 0.858 mmol). The mixture was stirred at r.t for 1 h. The reaction was added H2O and extracted by EA, the organic 195 WSGR Ref: 60134-709.601 phase was purified by flash column chromatography (DCM/10 % MeOH in DCM =100/0- 60/40) and prep-HPLC to afford product (33 mg, 20 %) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.51 (s, 1H), 7.87 (s, 1H), 7.75 (s, 1H), 7.73 – 7.66 (m, 1H), 7.48 – 7.38 (m, 2H), 6.84 (d, J = 8.2 Hz, 1H), 4.46 (s, 3H), 4.14 (t, J = 8.4 Hz, 2H), 3.22 (dd, J = 15.5, 7.6 Hz, 2H), 3.16 (d, J = 8.4 Hz, 2H), 2.88 (s, 3H), 1.52 (dt, J = 15.3, 7.5 Hz, 2H), 1.29 (dd, J = 14.2, 6.4 Hz, 2H), 1.25 – 1.12 (m, 6H), 0.84 (t, J = 7.0 Hz, 3H). MS(ESI) calculated for: C25H31N3O4S, 464.1; found [M+H]+, 470.1. [00518] Example 44: N-(1-(3-aminopropyl)-4-(5-(heptylsulfonyl)indoline-1-carbonyl)- 1H-pyrazol-5-yl)methanesulfonamide Step 1: ethyl 5-amino-1-(3-((tert-butoxycarbonyl)amino)propyl)-1H-pyrazole-4-carboxylate To a solution of ethyl 3-amino-1H-pyrazole-4-carboxylate (1.55 g, 10.0 mmol) in THF (50 mL) was added NaH (800 mg, 20.0 mmol, 60%wt) at 0 ℃. The mixture was stirred at 0 ℃ for 10 minutes. Then tert-butyl (3-bromopropyl)carbamate (4.76 g, 20.0 mmol) was added to the mixture. The resulting mixture was stirred at 70 oC for 16h. The mixture was quenched with water and extracted with EtOAc 3 times. The combined organic layers was washed with brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (EA/PE=70:30) to give the title compound as a colorless oil, 940 mg, yield: 30.1% LCMS: RT = 1.46 min, [M+1]+ =313 Step 2: ethyl 1-(3-((tert-butoxycarbonyl)amino)propyl)-5-(methylsulfonamido)-1H-pyrazole-4- carboxylate To a solution of ethyl 5-amino-1-(3-((tert-butoxycarbonyl)amino)propyl)-1H-pyrazole-4- carboxylate (940 mg, 3.0 mmol) and TEA (910 mg, 9.0 mmol) in DCM (15 mL) was added MsCl (515mg, 4.5 mmol). The resulting mixture was stirred at room temperature for 2h. The 196 WSGR Ref: 60134-709.601 reaction mixture was concentrated under reduced pressure. The residue was used directly in next step without further purification. LCMS: RT = 1.54 min, [M+1-56]+ =335 Step 3: 1-(3-((tert-butoxycarbonyl)amino)propyl)-5-(methylsulfonamido)-1H-pyrazole-4- carboxylic acid A solution of ethyl 1-(3-((tert-butoxycarbonyl)amino)propyl)-5-(methylsulfonamido)-1H- pyrazole-4-carboxylate (1.15 g, 2.94 mmol) and NaOH (588 mg, 14.7 mmol) in EtOH (20 mL) and water (4 mL) was s stirred at 80 ℃ for 16h. The reaction mixture was quenched with HCl (2N, 8 mL) and extracted with EtOAc 3 times. The combined organic layers was washed with brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (MeOH / DCM=5/95) to give the title compound as a white solid, 670 mg, yield: 62.8%. LCMS: RT = 1.29 min, [M+1-56]+ =307 Step 4: tert-butyl (3-(4-(5-(heptylthio)indoline-1-carbonyl)-5-(methylsulfonamido)-1H-pyrazol- 1-yl)propyl)carbamate To a solution of 1-(3-((tert-butoxycarbonyl)amino)propyl)-5-(methylsulfonamido)-1H-pyrazole- 4-carboxylic acid (120 mg, 0.33 mmol) and 5-(heptylthio)indoline (82 mg, 0.33 mmol) in MeCN (5 mL) was added NMI (82 mg, 1.0 mmol) and TCFH (140 mg, 0.5 mmol). The resulting mixture was stirred at 25℃ for 1h. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (EA/PE=70:30) to give the title compound as a colorless oil, 183 mg, yield: 93%. LCMS: RT = 2.15 min, [M+1]+ =594 Step 5: tert-butyl (3-(4-(5-(heptylsulfonyl)indoline-1-carbonyl)-5-(methylsulfonamido)-1H- pyrazol-1-yl)propyl)carbamate To a solution of tert-butyl (3-(4-(5-(heptylthio)indoline-1-carbonyl)-5-(methylsulfonamido)-1H- pyrazol-1-yl)propyl)carbamate (180 mg, 0.3 mmol) in DCM (6 mL) was added m-CPBA (120 mg, 0.7 mmol). The resulting mixture was stirred at 25℃ for 1h. The mixture was quenched with Na2SO3 (aq) and extracted with EtOAc 3 times. The combined organic layer was washed with brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (MeOH / DCM=2:98) to give the title compound as a yellow solid, 157 mg, yield: 84%. LCMS: RT =1.88 min, [M+1]+ =625 Step 6: N-(1-(3-aminopropyl)-4-(5-(heptylsulfonyl)indoline-1-carbonyl)-1H-pyrazol-5- yl)methanesulfonamide 197 WSGR Ref: 60134-709.601 To a solution of tert-butyl (3-(4-(5-(heptylsulfonyl)indoline-1-carbonyl)-5-(methylsulfonamido)- 1H-pyrazol-1-yl)propyl)carbamate (157 mg, 0.25 mmol) in DCM (5 mL) was added TFA (1mL). The mixture was stirred at room temperature for 1h. The reaction mixture was concentrated under reduced pressure. The residue purified by prep-HPLC to give the title compound as a white solid, 69 mg, yield: 52%. 1H NMR (400 MHz, DMSO-d6) δ 8.14 (s, 1H), 8.47 – 7.71 (m, 3H), 7.69 – 7.62 (m, 2H), 7.48 (s, 1H), 4.23 (t, J = 8.6 Hz, 2H), 4.08 (t, J = 6.2 Hz, 2H), 3.20 (s, 2H), 3.13 (t, J = 8.5 Hz, 2H), 2.72 (t, J = 6.6 Hz, 2H), 2.63 (s, 3H), 1.99 (dd, J = 12.5, 6.2 Hz, 2H), 1.53 (dt, J = 15.3, 7.5 Hz, 2H), 1.34 – 1.16 (m, 8H), 0.84 (t, J = 6.9 Hz, 3H). MS(ESI) calculated for: C23H35N5O5S2, 525.21; found [M+H]+, 526.2 [00519] Example 45: N-(3-(5-(heptylsulfonyl)indoline-1-carbonyl)pyrazolo[1,5- a]pyrimidin-2-yl)-2-methoxyethane-1-sulfonamide Step 1: ethyl 2-((2-methoxyethyl)sulfonamido)pyrazolo[1,5-a]pyrimidine-3-carboxylate To a mixture of ethyl 2-aminopyrazolo[1,5-a]pyrimidine-3-carboxylate (500 mg, 2.425 mmol) in DCM (10 mL) were added TEA (613 mg, 6.063 mmol), DMAP (59 mg, 0.485 mmol) and 2- methoxyethane-1-sulfonyl chloride (461 mg, 2.91 mmol), the mixture was stirred for 1h at room temperature. The mixture was concentrated under reduced pressure, the residue was purified by silica gel chromatography (EtOAc/PE=50/50) to give target product (299 mg, 37.6% yield) as a yellowish solid. LCMS: RT =1.233 min, [M+1]+ =329.1 Step 2: 2-((2-methoxyethyl)sulfonamido)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid To a solution of ethyl 2-((2-methoxyethyl)sulfonamido)pyrazolo[1,5-a]pyrimidine-3-carboxylate (299 mg, 0.911 mmol) in MeOH (16 mL) was added a solution of LiOH.H2O (382 mg, 9.108 mmol) in H2O (4 mL), then the mixture was heated to 55℃ and stirred overnight. The mixture was concentrated under reduced pressure, the residue was added water, and neutralized with 2N HCl, the target product (245 mg, 89.5% yield) was collected by filtered. LCMS: RT =0.768 min, [M+1]+ =301.1 Step 3: N-(3-(5-(heptylthio)indoline-1-carbonyl)pyrazolo[1,5-a]pyrimidin-2-yl)-2- methoxyethane-1-sulfonamide 198 WSGR Ref: 60134-709.601 To a mixture of 2-((2-methoxyethyl)sulfonamido)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (245 mg, 0.816 mmol), 5-(heptylthio)indoline (224 mg, 0.897 mmol) and TCFH (457 mg, 1.632 mmol) in ACN (10 mL) was added NMI (201 mg, 2.448 mmol), the mixture was stirred for 1h 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=2/98) to give target product (250 mg, 57.6% yield) as a white solid. LCMS: RT =2.153 min, [M+1]+ =532.1 Step 4: N-(3-(5-(heptylsulfonyl)indoline-1-carbonyl)pyrazolo[1,5-a]pyrimidin-2-yl)-2- methoxyethane-1-sulfonamide To a mixture of N-(3-(5-(heptylthio)indoline-1-carbonyl)pyrazolo[1,5-a]pyrimidin-2-yl)-2- methoxyethane-1-sulfonamide (100 mg, 0.195 mmol) in DCM (5 mL) was added m-CPBA (84 mg, 0.487 mmol) at room temperature, the mixture was stirred for 30 min. The mixture was concentrated under reduced pressure, the residue was purified by silica gel chromatography (MeOH / DCM=2/98) and prep-HPLC (neutral) to give target product (55.2 mg, 50.2% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.44 (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), 7.76 (s, 1H), 7.72 (d, J = 8.5 Hz, 1H), 7.18 (dd, J = 6.9, 4.3 Hz, 1H), 4.25 (t, J = 8.6 Hz, 2H), 3.73 (s, 4H), 3.27 – 3.15 (m, 7H), 1.52 (dt, J = 15.3, 7.5 Hz, 2H), 1.32 – 1.12 (m, 8H), 0.84 (t, J = 7.0 Hz, 3H). MS(ESI) calculated for: C25H33N5O6S2, 563.2; found [M+H]+, 564.2 1H NMR (400 MHz, DMSO-d6) δ8.26 (d, J = 7.9 Hz, 1H), 7.70 (d, J = 11.5 Hz, 2H), 7.22 (d, J = 9.0 Hz, 1H), 6.79 (d, J = 7.3 Hz, 1H), 6.67 (s, 1H), 3.99 (s, 3H), 3.83 (dd, J = 13.6, 7.8 Hz, 2H), 3.12 – 3.03 (m, 4H), 2.81 (t, J = 5.6 Hz, 2H), 2.56 (s, 3H), 1.50 (s, 2H), 1.25 (d, J = 6.6 Hz, 2H), 1.19 (s, 6H), 0.84 (s, 3H). MS(ESI) calculated for C25H36N4O5S2, 536.2; found, 537.2 [00520] Example 46: N-(4-(2-aminoethoxy)-2-(5-(heptylsulfonimidoyl)indoline-1- carbonyl)phenyl)methanesulfonamide Prepared from N-(4-(2-aminoethoxy)-2-(5-(heptylsulfonimidoyl)indoline-1- carbonyl)phenyl)methanesulfonamide essentially as described in Example 45 using t tert-butyl (2-hydroxyethyl)carbamate to obtain the title compound. 199 WSGR Ref: 60134-709.601 [00521] Example 47: N-(2-(5-(heptylsulfonimidoyl)indoline-1-carbonyl)-4-(piperazin- 1-yl)phenyl)methanesulfonamide Step 1: tert-butyl 4-(3-(methoxycarbonyl)-4-nitrophenyl)piperazine-1-carboxylate To the solution of methyl 5-fluoro-2-nitrobenzoate (1 g, 5.02 mmol) in DMF (15 mL) was added tert-butyl piperazine-1-carboxylate (1.12 g, 6.03 mmol) and Cs2CO3 (3.26 g, 10.04 mmol). The mixture was stirred at RT for 2 h. The reaction mixture was quenched by H2O, extracted with EA, washed with brine, and dried with Na2SO4 then concentrated and purified by flash choromatography elute with PE/EA=4:1 to afford the title compound tert-butyl 4-(3- (methoxycarbonyl)-4-nitrophenyl)piperazine-1-carboxylate (1.7 g, 92.8% yield) as a yellow solid. MS(ESI) calculated for C17H23N3O6, 365.39; found, 366.1 TLC: PE:EA=5:1, UV, Rf = 0.3 Step 2: 5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-nitrobenzoic acid To the solution of tert-butyl 4-(3-(methoxycarbonyl)-4-nitrophenyl)piperazine-1-carboxylate (700 mg, 1.91 mmol) in MeOH(15 mL) and NaOH(611 mg, 15.28 mmol) in H2O(5 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 5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-nitrobenzoic acid (630 mg, 94.0% yield) as a white solid. MS(ESI) calculated for C16H21N3O6, 351.36; found, 352.1 TLC: DCM:MeOH=20:1, UV, Rf = 0.4 Step 3: tert-butyl 4-(4-nitro-3-(5-(N-(2,2,2-trifluoroacetyl)heptylsulfonimidoyl)indoline-1- carbonyl)phenyl)piperazine-1-carboxylate To the solution of 5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-nitrobenzoic acid (787 mg, 2.23 mmol) in Py(10 mL) and 2,2,2-trifluoro-N-(heptyl(indolin-5-yl)(oxo)-l6- sulfanylidene)acetamide (700 mg, 1.86 mmol)was added. Then POCl3 (571 mg, 3.71 mmol) was added slowly at 0 oC. The mixture was stirred at RT for 2 h. The reaction mixture was 200 WSGR Ref: 60134-709.601 neutralized with water, then extracted with EA, washed with brine, and dried with Na2SO4 then concentrated and purified by flash choromatography elute with PE/EA=1:1 to afford the title compound tert-butyl 4-(4-nitro-3-(5-(N-(2,2,2-trifluoroacetyl)heptylsulfonimidoyl)indoline-1- carbonyl)phenyl)piperazine-1-carboxylate (230 mg, 14.5% yield). MS(ESI) calculated for C33H42F3N5O7S, 709.78; found, 710.3 TLC: PE:EA=1:1, UV, Rf = 0.4 Step 4: tert-butyl 4-(4-amino-3-(5-(N-(2,2,2-trifluoroacetyl)heptylsulfonimidoyl)indoline-1- carbonyl)phenyl)piperazine-1-carboxylate To the solution of tert-butyl 4-(4-nitro-3-(5-(N-(2,2,2- trifluoroacetyl)heptylsulfonimidoyl)indoline-1-carbonyl)phenyl)piperazine-1-carboxylate (120 mg, 0.17 mmol) in MeOH(5 mL) and Pd/C(12 mg, 10 wt%) was added. The reaction mixture was flushed with H2 three times. The mixture was stirred at RT overnight. The reaction mixture was filtered through a Celite pad and the filtrate cake was washed with EA (10 mL, 3 times), then the organic phase was concentrated to afford the title compound tert-butyl 4-(4-amino-3-(5- (N-(2,2,2-trifluoroacetyl)heptylsulfonimidoyl)indoline-1-carbonyl)phenyl)piperazine-1- carboxylate (100 mg, 86.6% yield). MS(ESI) calculated for C33H44F3N5O7S, 679.3; found, 680.1 TLC: PE:EA=1:2, UV, Rf = 0.4 Step 5: tert-butyl 4-(4-(methylsulfonamido)-3-(5-(N-(2,2,2- trifluoroacetyl)heptylsulfonimidoyl)indoline-1-carbonyl)phenyl)piperazine-1-carboxylate To the solution of tert-butyl 4-(4-amino-3-(5-(N-(2,2,2- trifluoroacetyl)heptylsulfonimidoyl)indoline-1-carbonyl)phenyl)piperazine-1-carboxylate (80 mg, 0.118 mmol) in DCM (5 mL) was added Py(28 mg, 0.354 mmol) and MsCl (21 mg, 0.177 mmol). 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 Na2SO4 then concentrated and purified by flash choromatography elute with DCM/MeOH=50:1 to afford the title compound tert-butyl 4- (4-(methylsulfonamido)-3-(5-(N-(2,2,2-trifluoroacetyl)heptylsulfonimidoyl)indoline-1- carbonyl)phenyl)piperazine-1-carboxylate (70 mg, 78.4% yield) as a yellow solid. MS(ESI) calculated for C34H46F3N5O7S2, 757.89; found, 758.3 TLC: DCM:MeOH=20:1, UV, Rf = 0.4 Step 6: 2,2,2-trifluoro-N-(heptyl(1-(2-(methylsulfonamido)-5-(piperazin-1-yl)benzoyl)indolin-5- yl)(oxo)-l6-sulfanylidene)acetamide To the solution of tert-butyl 4-(4-(methylsulfonamido)-3-(5-(N-(2,2,2- trifluoroacetyl)heptylsulfonimidoyl)indoline-1-carbonyl)phenyl)piperazine-1-carboxylate (70 mg, 0.092 mmol) in DCM(5 mL) and TFA(1 mL) was added. The mixture was stirred at RTfor 201 WSGR Ref: 60134-709.601 2 h. The reaction mixture was neutralized with NaHCO3(aq) to pH=8, then extracted with EA, washed with brine, and dried with Na2SO4 then concentrated to afford the title compound 2,2,2- trifluoro-N-(heptyl(1-(2-(methylsulfonamido)-5-(piperazin-1-yl)benzoyl)indolin-5-yl)(oxo)-l6- sulfanylidene)acetamide (55 mg, 92.3% yield) as a yellow solid. MS(ESI) calculated for C29H38F3N5O5S2, 657.77; found, 658.2 TLC: DCM:MeOH=20:1, UV, Rf = 0.3 Step 7: N-(2-(5-(heptylsulfonimidoyl)indoline-1-carbonyl)-4-(piperazin-1- yl)phenyl)methanesulfonamide To the solution of 2,2,2-trifluoro-N-(heptyl(1-(2-(methylsulfonamido)-5-(piperazin-1- yl)benzoyl)indolin-5-yl)(oxo)-l6-sulfanylidene)acetamide (40 mg, 0.06 mmol) in MeOH(3 mL) and K2CO3(25 mg, 0.18 mmol)was added. The mixture was stirred at RT for 1 h. The reaction mixture was filtered 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-(heptylsulfonimidoyl)indoline-1-carbonyl)-4-(piperazin-1- yl)phenyl)methanesulfonamide (8.0 mg, 23.8% yield) as white solid. 1H NMR (400 MHz, DMSO-d6) δ8.25 (d, J = 8.7 Hz, 1H), 7.70 (s, 2H), 7.22 (d, J = 8.7 Hz, 1H), 6.88 (s, 1H), 6.75 (s, 1H), 4.00 (s, 3H), 3.08 (dd, J = 19.1, 10.9 Hz, 5H), 2.94 (s, 4H), 2.80 (s, 4H), 2.67 (d, J = 1.8 Hz, 3H), 1.49 (s, 2H), 1.26 (s, 2H), 1.23 – 1.15 (m, 6H), 0.84 (t, J = 7.0 Hz, 3H). MS(ESI) calculated for C27H39N5O4S2, 561.76; found, 562.2 [00522] Example 48: 6-(5-(heptylsulfonyl)indoline-1-carbonyl)-3-methyl-3,4-dihydro- 2H-benzo[e][1,3]oxazin-2-one Step 1: 6-(5-(heptylthio)indoline-1-carbonyl)-3-methyl-3,4-dihydro-2H-benzo[e][1,3]oxazin-2- one To a solution of 3-methyl-2-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazine-6-carboxylic acid(100 mg, 0.484 mmol) and 5-(heptylthio)indoline(180.8 mg, 0.726 mmol) in Pyridine (8 mL) was added POCl3(111.4 mg, 0.726 mmol). The mixture was stirred for 2h at room temperature. The mixture was added some NaHCO3, 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=1/99) to give product (135 mg, 74.1% yield) as a yellow solid. LCMS: RT =2.115 min, [M+1]+ =439.2 202 WSGR Ref: 60134-709.601 Step 2: 6-(5-(heptylsulfonyl)indoline-1-carbonyl)-4H-3l2-benzo[e][1,3]oxazin-2-one To a solution of 6-(5-(heptylthio)indoline-1-carbonyl)-3-methyl-3,4-dihydro-2H- benzo[e][1,3]oxazin-2-one(135 mg 0.308 mmol) in DCM (8 mL) were added m-CPBA (156.3 mg 0.770 mmol). The mixture was stirred for 2h at room temperature. The mixture was added NaHCO3 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 solid was purified by prep-HPLC to give product (30 mg, 26.8% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.96 (s, 1H), 7.77 (d, J = 1.8 Hz, 1H), 7.71 (dd, J = 8.5, 2.0 Hz, 1H), 7.58 (dd, J = 8.3, 2.0 Hz, 1H), 7.56 (d, J = 1.9 Hz, 1H), 7.14 (d, J = 8.3 Hz, 1H), 4.56 (s, 2H), 4.12 (t, J = 8.4 Hz, 2H), 3.26 – 3.21 (m, 2H), 3.18 (t, J = 8.4 Hz, 2H), 3.00 (s, 3H), 1.51 (ddd, J = 11.9, 9.7, 6.3 Hz, 2H), 1.34 – 1.16 (m, 8H), 0.84 (t, J = 6.9 Hz, 3H). MS(ESI) calculated for: C25H30N2O5S, 470.19; found [M+H]+, 471.2 [00523] Example 49: (6-(((3-aminopropyl)amino)methyl)pyrazolo[1,5-a]pyrimidin-3- yl)(5-(heptylsulfonyl)indolin-1-yl)methanone Step 1: ethyl 6-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate To the solution of ethyl 3-amino-1H-pyrazole-4-carboxylate (1.0 g, 6.22 mmol) in EtOH (10 mL ) were added 1,1,3,3-tetraethoxy-2-methylpropane(79.3 mg, 6.22mmol) and 1M HCl dioxane (4 ml). The mixture was stirred at 80℃ for overnight. The mixture was sodium chloride aqueous so lution (80 mL) and extracted with EA (50 mL*3), the organic phase was separated, washed with brine (30 mL*3) and dried with Na2SO4 then concentrated and purified by flash chromatography eluted with PE:EA=2:1 to afford the title compound methyl 5-methyl-2-(N-methylmethylsulfona mido)benzoate (500 mg, 100% yield) as a yellow oil. LCMS: RT =1.168min, [M+H]+ =206 Step 2: ethyl 6-(bromomethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate To the solution of methyl ethyl 6-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (500mg, 2.439 mmol) in CCl4 (20 mL) was added BPO (277.2mg, 0.73 mmol) at rt. Then NBS (564mg, 3.168 mmol) was added slowly. The mixture was stirred at 90 oC for 1h. The reaction mixture was extracted with EA (30mL*3), the organic phase was separated, washed with brine (30 mL*3) and dried with Na2SO4 then concentrated and purified by flash chromatography eluted with 203 WSGR Ref: 60134-709.601 PE:EA=7:3 to afford the title compound ethyl 6-(bromomethyl)pyrazolo[1,5-a]pyrimidine-3- carboxylate4 (370mg, 54% yield) as a yellow oil. LCMS: RT =1.340min, [M+H]+ =284,[M+2H]+ =286 Step 3: ethyl 6-(((3-((tert-butoxycarbonyl)amino)propyl)amino)methyl)pyrazolo[1,5-a]pyrimidin e-3-carboxylate To the solution of methyl ethyl 6-(bromomethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (370 mg, 1.307 mmol) in ACN (15 mL) was added tert-butyl (3-aminopropyl)carbamate (361mg, 2.0 72 mmol) and K2CO3 (250mg,1.811 mmol) slowly. The mixture was stirred at rt for 1 h. The mi xture was quenched with H2O (30 mL). The reaction mixture was extracted with EA (30 mL*3), the organic phase was separated, washed with brine (30 mL*3) and dried with Na2SO4 then conc entrated and purified by flash chromatography eluted with DCM:MeOH=30:1 to afford the title compound ethyl 6-(((3-((tert-butoxycarbonyl)amino)propyl)amino)methyl)pyrazolo[1,5-a]pyrim idine-3-carboxylate (290mg, 85.04% yield) as a yellow soild. LCMS: RT =1.174min, [M+H]+ =378 Step 4: ethyl 6-(((tert-butoxycarbonyl)(3-((tert-butoxycarbonyl)amino)propyl)amino)methyl)pyr azolo[1,5-a]pyrimidine-3-carboxylate To the solution of methyl ethyl 6-(((3-((tert-butoxycarbonyl)amino)propyl)amino)methyl)pyrazo lo[1,5-a]pyrimidine-3-carboxylate (270mg, 0.716mmol) in EtOH (16 mL) was added (Boc)2O (1 87mg, 0.858 mmol). The mixture was stirred at rt for 1.5 h. The reaction mixture was extracted with EA (30 mL*3), the organic phase was separated, washed with brine (30 mL*3) and dried w ith Na2SO4 then concentrated to afford the title compound ethyl 6-(((tert-butoxycarbonyl)(3-((ter t-butoxycarbonyl)amino)propyl)amino)methyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (290 m g, 85.04% yield) as a yellow solid. LCMS: RT =1.718min, [M+H]+ =478.3 Step 5: 6-(((tert-butoxycarbonyl)(3-((tert-butoxycarbonyl)amino)propyl)amino)methyl)pyrazolo[ 1,5-a]pyrimidine-3-carboxylic acid To the solution of 6-(((tert-butoxycarbonyl)(3-((tert-butoxycarbonyl)amino)propyl)amino)methy l)pyrazolo[1,5-a]pyrimidine-3-carboxylate ((290 mg, 0.608mmol) in THF(10 mL) was added th e solution of LiOH (206 mg,4.909mmol)in H2O(10 mL). The mixture was stirred at 70 oC for 6 h. The reaction mixture was adjusted PH=6 with 2N HCl and extracted with EA (30 mL*3), the organic phase was separated, washed with brine (20 mL*3) and dried with Na2SO4 then concentr ated to afford the title compound 6-(((tert-butoxycarbonyl)(3-((tert-butoxycarbonyl)amino)propy l)amino)methyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (244 mg, 88.97% % yield) as a white solid. LCMS: RT =1.495min, [M+H]+ =450.2 204 WSGR Ref: 60134-709.601 Step 6: tert-butyl (3-((tert-butoxycarbonyl)amino)propyl)((3-(5-(heptylthio)indoline-1-carbonyl) pyrazolo[1,5-a]pyrimidin-6-yl)methyl)carbamate To the solution of 6-(((tert-butoxycarbonyl)(3-((tert-butoxycarbonyl)amino)propyl)amino)methy l)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (244 mg, 0.543mmol) in ACN(10 mL) were adde d 5-(heptylthio)indoline (128 mg, 0.514 mmol), TCFH (216 mg, 0.769 mmol) and NMI(148 mg, 1.792 mmol). The mixture was stirred at room temperature for 2 h. The reaction mixture was co ncentrated and purified by flash chromatography eluted with PE:EA= 75:25 to afford the title co mpound tert-butyl (3-((tert-butoxycarbonyl)amino)propyl)((3-(5-(heptylthio)indoline-1-carbonyl )pyrazolo[1,5-a]pyrimidin-6-yl)methyl)carbamate (310 mg, 84.01% yield) as a yellow solid. LCMS: RT =2.316min, [M+H]+ =681.4 Step 7: tert-butyl (3-((tert-butoxycarbonyl)amino)propyl)((3-(5-(heptylsulfonyl)indoline-1-carbo nyl)pyrazolo[1,5-a]pyrimidin-6-yl)methyl)carbamate To a solution of tert-butyl (3-((tert-butoxycarbonyl)amino)propyl)((3-(5-(heptylthio)indoline-1-c arbonyl)pyrazolo[1,5-a]pyrimidin-6-yl)methyl)carbamate (290 mg, 0.426 mmol)in DCM (45 mL) was added m-CPBA (178 mg, 1.026 mmol) at 0oC, the 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 org anic layer was washed with brine, dried over sodium sulfate, concentrated under reduced pressur e, and the residue was purified by silica gel chromatography (MeOH/DCM=1/99) to give the des ired product compound tert-butyl (3-((tert-butoxycarbonyl)amino)propyl)((3-(5-(heptylsulfonyl) indoline-1-carbonyl)pyrazolo[1,5-a]pyrimidin-6-yl)methyl)carbamate (300mg, 99 % yield) as a white solid. LCMS: RT =1.997min, [M+H]+ =613 Step 8: (6-(((3-aminopropyl)amino)methyl)pyrazolo[1,5-a]pyrimidin-3-yl)(5-(heptylsulfonyl)ind olin-1-yl)methanone To the solution of (3-((tert-butoxycarbonyl)amino)propyl)((3-(5-(heptylsulfonyl)indoline-1-carb onyl)pyrazolo[1,5-a]pyrimidin-6-yl)methyl)carbamate (180 mg, 0.0281 mmol) in DCM (8 mL) was added TFA (2 mL). The mixture was stirred at rt for 2h. The reaction mixture was neutralize d with NaHCO3 (aq) to pH=8 and was extracted with EA (50 mL*3), the organic phase was sepa rated, washed with brine (30 mL*3) and dried with Na2SO4 then concentrated to purified by pre p-HPLC, after prep-HPLC purification, the eluent was concentrated to remove organic solvents. The residual aqueous solution was lyophilized to afford the title compound (6-(((3-aminopropyl) amino)methyl)pyrazolo[1,5-a]pyrimidin-3-yl)(5-(heptylsulfonyl)indolin-1-yl)methanone (93 mg , 72.1% yield) as a white solid. 205 WSGR Ref: 60134-709.601 1H NMR (400 MHz, DMSO-d6) δ 9.24 (s, 1H), 8.80 (d, J = 2.1 Hz, 1H), 8.63 (s, 1H), 8.14 (s, 1H), 7.78 – 7.69 (m, 2H), 4.39 (t, J = 8.6 Hz, 2H), 3.99 (s, 2H), 3.24 (q, J = 8.5, 7.9 Hz, 6H), 2.88 (t, J = 7.4 Hz, 5H), 2.33 (p, J = 1.9 Hz, 1H), 1.77 (s, 2H), 1.53 (s, 2H), 1.34 – 1.09 (m, 8H), 0.84 (t, J = 6.9 Hz, 3H). MS(ESI) calculated for C26H36N6O3S, 512.26; found, 513.2. [00524] Example 50: 7-(5-(heptylsulfonyl)indoline-1-carbonyl)-3,4-dimethyl-3,4- dihydroquinazolin-2(1H)-one Step 1: 7-(5-(heptylthio)indoline-1-carbonyl)-3,4-dimethyl-3,4-dihydroquinazolin-2(1H)-one To a solution of 3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (60 mg, 0.27 mmol) and 5-(heptylthio)indoline (68 mg, 0.27 mmol) in MeCN (5 mL) was added NMI (66 mg, 0.81 mmol) and TCFH (112 mg, 0.4 mmol). The resulting mixture was stirred at 25℃ for 1h. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (EA/PE=70:30) to give the title compound as a white solid, 90 mg, yield: 74%. LCMS: RT = 2.10 min, [M+1]+ =452 Step 2: 7-(5-(heptylsulfonyl)indoline-1-carbonyl)-3,4-dimethyl-3,4-dihydroquinazolin-2(1H)-one To a solution of 7-(5-(heptylthio)indoline-1-carbonyl)-3,4-dimethyl-3,4-dihydroquinazolin- 2(1H)-one (90 mg, 0.2 mmol) in DCM (6 mL) was added m-CPBA (79 mg, 0.46 mmol). The resulting mixture was stirred at 25℃ for 1h. The mixture was quenched with Na2SO3(aq) and extracted with EtOAc 3 times. The combined organic layer was washed with brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue purified by prep-HPLC to give the title compound as a white solid, 39.4 mg, yield:41% 1H NMR (400 MHz, DMSO-d6) δ 9.57 (s, 1H), 7.84 (s, 1H), 7.75 (s, 1H), 7.71 – 7.66 (m, 1H), 7.48 – 7.41 (m, 2H), 6.87 (d, J = 8.1 Hz, 1H), 4.59 (q, J = 6.5 Hz, 1H), 4.21 – 4.04 (m, 2H), 3.27 – 3.13 (m, 4H), 2.90 (s, 3H), 1.57 – 1.45 (m, 2H), 1.33 – 1.16 (m, 11H), 0.84 (t, J = 6.9 Hz, 3H). MS(ESI) calculated for: C26H33N3O4S, 483.22; found [M+H]+, 484.2 [00525] Example 51: N-(2-(5-(heptylsulfonyl)indoline-1- carbonyl)phenyl)methanesulfonamide 206 WSGR Ref: 60134-709.601 Step 1: N-(2-(5-(heptylsulfonyl)indoline-1-carbonyl)phenyl)methanesulfonamide To a solution of 2-(methylsulfonamido)benzoic acid (100 mg, 0.465 mmol) and 5- (heptylthio)indoline(115.8 mg, 0.465 mmol) in ACN (10 mL) were added TCFH(156.5 mg, 0.558 mmol) and NMI(0.5 ml) The mixture was stirred for 1h 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 (EA/PE=50/50) to give product (110 mg, 49.5% yield) as a yellow solid. LCMS: RT =2.118 min, [M+1]+ =447.2 Step 2: N-(2-(5-(heptylsulfonyl)indoline-1-carbonyl)phenyl)methanesulfonamide To a solution of N-(2-(5-(heptylthio)indoline-1-carbonyl)phenyl)methanesulfonamide (110 mg 0.247 mmol) in DCM(10 ml) were added m-CPBA(125.1 mg 0.617 mmol). The mixture was stirred for 2h at room temperature. The mixture was added some NaHCO3, 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 prep-HPLC to give product (31 mg, 41.5% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.52 (s, 1H), 8.28 (s, 1H), 7.76 (d, J = 1.7 Hz, 2H), 7.60 – 7.45 (m,3H), 7.38 – 7.30 (m, 1H), 3.93 (s, 2H), 3.27 – 3.20 (m, 2H), 3.15 (t, J = 8.4 Hz, 2H), 3.00 (s, 3H), 1.61– 1.46 (m, 2H), 1.31 (t, J = 7.6 Hz, 2H), 1.27 – 1.13 (m, 6H), 0.84 (t, J = 6.9 Hz, 3H). MS(ESI) calculated for: C23H30N2O5S2, 478.16; found [M+H]+, 479.2 [00526] Example 52: N-(2-(5-(heptylsulfonimidoyl)-2, 3-dihydro-1H-pyrrolo[3,2- b]pyridine-1-carbonyl)phenyl)methanesulfonamide Step 1: 5-(hexylthio)-2, 3-dihydro-1H-pyrrolo[3,2-b]pyridine To a solution of 5-bromo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine(240 mg, 1.205 mmol) in dioxane(5 mL) was added heptane-1-thiol(190 mg, 1.446 mmol) and Pd2(dba)3 (110 mg, 0.121 mmol) , Xant-phos(139 mg, 0.241 mmol), DIEA(466 mg , 3.61 mmol) under Ar. The mixture was stirred at 100oC for 4 h. The reaction was purified by flash column chromatography (PE/EA =90/10) to afford product (300 mg, 98 %) as a white solid. LCMS: RT = 1.842 min, [M+H] + =251.1. 207 WSGR Ref: 60134-709.601 Step 2: N-(2-(5-(heptylthio)-2, 3-dihydro-1H-pyrrolo[3,2-b]pyridine-1- carbonyl)phenyl)methanesulfonamide To a solution of 2-(methylsulfonamido)benzoic acid(300 mg, 1.4 mmol) in SOCl2(2 mL) , the reaction was stirred at 80oC for 1 h.SOCl2 was concentrated, the resdual was dissolved in DCM, N-(2-(5-(heptylthio)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1- carbonyl)phenyl)methanesulfonamide (270 mg, 1.08 mmol) in DCM(2 mL) and TEA(218 mg, 2.16 mmol) was added. The mixture was stirred at r.t for 1 h. The reaction was purified by flash column chromatography (PE/EA =60/40) to afford product (400 mg, 77 %) as a white solid. LCMS: RT = 2.012 min, [M+H] + =448.1. Step 3: N-(2-(5-(heptylsulfonimidoyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1- carbonyl)phenyl)methanesulfonamide To a solution of N-(2-(5-(heptylthio)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1- carbonyl)phenyl)methanesulfonamide (150 mg, 0.335 mmol) in MeOH(5 mL) was added phenyl-l3-iodanediyl diacetate (270 mg, 0.838 mmol) and ammonium carbomate (80 mg, 0.838 mmol). The mixture was stirred at r.t for 1 h. The reaction was purified by flash column chromatography (DCM/MeOH =96/4) and prep-HPLC to afford product (40 mg, 25 %) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.51 (d, J = 8.3 Hz, 1H), 7.93 (d, J = 8.3 Hz, 1H), 7.65 (dt, J = 21.0, 7.9 Hz, 3H), 7.53 (t, J = 7.4 Hz, 1H), 4.19 – 3.85 (m, 1H), 3.39 – 3.33 (m, 2H), 3.26 – 3.15 (m, 4H), 3.07 (s, 3H), 1.58 (dt, J = 15.0, 7.6 Hz, 2H), 1.40 – 1.29 (m, 3H), 1.28 – 1.12 (m, 8H), 0.84 (t, J = 7.0 Hz, 2H). MS(ESI) calculated for: C22H30N4O4S2, 478.16; found [M+H]+, 479.1 [00527] Example 53: 6-(5-(heptylsulfonimidoyl)indoline-1-carbonyl)-3-methyl-2-oxo- 1,2,3,4-tetrahydroquinazoline-7-carboxylic acid Step 1: 7-bromo-6-(5-(heptylthio)indoline-1-carbonyl)-3-methyl-3,4-dihydroquinazolin-2(1H)- one To a solution of 7-bromo-3-methyl-2-oxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid(410 mg, 1.439 mmol) and 5-(heptylthio)indoline(358.3 mg, 1.439 mmol) in ACN (10 mL) were added TCFH (605.6 mg, 2.159 mmol) and NMI (1 ml). The mixture was stirred for 1h at room 208 WSGR Ref: 60134-709.601 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 (EA/PE=0~50/50) to give product (560 mg, 75.5% yield) as a yellow solid. LCMS: RT =2.113 min, [M+1]+ =516.1/518.1 Step 2: 7-bromo-6-(5-(heptylsulfonimidoyl)indoline-1-carbonyl)-3-methyl-3,4- dihydroquinazolin-2(1H)-one To a solution of 7-bromo-6-(5-(heptylthio)indoline-1-carbonyl)-3-methyl-3,4- dihydroquinazolin-2(1H)-one (560 mg 1.085 mmol) in MeOH (20 mL) were added ammonium carbomate (260.4 mg 2.713 mmol) and (diacetoxyiodo)benzene (873.6 mg 2.713 mmol). The mixture was stirred for 1h at room temperature. The mixture was added some NaHCO3, 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=50/50) to give product (250 mg, 42.0% yield) as a yellow solid. LCMS: RT =1.750 min, [M+1]+ =547.1/549.1 Step 3: methyl 6-(5-(heptylsulfonimidoyl)indoline-1-carbonyl)-3-methyl-2-oxo-1,2,3,4- tetrahydroquinazoline-7-carboxylate To a solution of 7-bromo-6-(5-(heptylsulfonimidoyl)indoline-1-carbonyl)-3-methyl-3,4- dihydroquinazolin-2(1H)-one (250 mg, 0.456 mmol) in MeOH (10 mL) were added Pd(dppf)Cl2 (33.7 mg, 0.046 mmol) and DIEA (0.5 mL). The mixture was stirred at 100oC overnight. 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 concentrated under reduced pressure, the residue was purified silica gel chromatography (EA/PE=50/50) to give product (100 mg, 41.7% yield) as a yellow solid. LCMS: RT =1.441 min, [M+1]+ =528.2 Step 4: 6-(5-(heptylsulfonimidoyl)indoline-1-carbonyl)-3-methyl-2-oxo-1,2,3,4- tetrahydroquinazoline-7-carboxylic acid To a solution of methyl 6-(5-(heptylsulfonimidoyl)indoline-1-carbonyl)-3-methyl-2-oxo-1,2,3,4- tetrahydroquinazoline-7-carboxylate(100 mg, 0.190 mmol) in THF (5 mL) were added LiOH(23.9 mg, 0.570 mmol) The mixture was stirred for 3h at room temperature. The mixture was added some HCl, and extracted with EtOAc, combined the organic layer, washed with brine, dried over sodium sulfate, the filtrate was concentrated under reduced pressure, the solid was purified by prep-HPLC to give product (15 mg, 15.4% yield) as a white solid. 209 WSGR Ref: 60134-709.601 1H NMR (400 MHz, DMSO-d6) δ 9.41 (s, 1H), 8.25 (s, 1H), 7.75 (s, 3H), 6.75 (s, 1H), 4.51 (s, 2H), 3.76 (s, 2H), 3.24 (s, 2H), 3.01 (s, 2H), 2.90 (s, 3H), 1.57 (d, J = 10.4 Hz, 2H), 1.34 – 1.15 (m, 8H), 0.84 (t, J = 6.9 Hz, 3H). MS(ESI) calculated for: C26H32N4O5S, 512.63; found [M+H]+, 513.2 [00528] Example 54: N-(4-cyano-2-(5-(heptylsulfonyl)indoline-1-carbonyl)-1H- pyrrol-1-yl)methanesulfonamide Prepared N-(4-cyano-2-(5-(heptylsulfonyl)indoline-1-carbonyl)-1H-pyrrol-1- yl)methanesulfonamide essentially as described in preparation Example 24. 1H NMR (400 MHz, DMSO-d6) δ11.61 (s, 1H), 8.10 (s, 1H), 7.79 (s, 1H), 7.75 (d, J = 8.5 Hz, 1H), 7.18 (d, J = 4.6 Hz, 1H), 6.91 (d, J = 4.5 Hz, 1H), 4.26 (s, 2H), 3.23 (dt, J = 13.6, 8.1 Hz, 4H), 3.10 (s, 3H), 1.53 (dt, J = 15.4, 7.5 Hz, 2H), 1.33 – 1.17 (m, 8H), 0.84 (t, J = 7.0 Hz, 3H). MS(ESI) calculated for: C22H28N4O5S2, 492.2; found [M+H]+, 493.2. [00529] Example 55: N-(2-(5-((3-oxoheptyl)sulfonyl)indoline-1- carbonyl)phenyl)methanesulfonamide Step 1: hept-1-en-3-one To a solution of hept-1-en-3-ol (1 g, 8.772 mmol) in DCM (10 mL) were added DMP (3.72 g, 8.772 mmol) at room temperature. The mixture was stirred for 1h at room temperature. The mixture was added some NaHCO3, and extracted with DCM, combined the organic layer, washed with brine, dried over sodium sulfate, the filtrate was concentrated under reduced pressure, the residue was purified silica gel chromatography (EA /PE=10/90) to give product (800 mg, 81.6% yield) as a yellow oil. Step 2: 1-chloroheptan-3-one To a solution of hept-1-en-3-one (800 mg, 7.143 mmol) in TMSCl (10 mL) was added water (1 mL) at room temperature. The mixture was stirred for 1h at room temperature. The mixture was 210 WSGR Ref: 60134-709.601 added some NaHCO3, and extracted with EA, combined the organic layer, washed with brine, dried over sodium sulfate, the filtrate was concentrated under reduced pressure, the residue was purified silica gel chromatography (EA /PE=10/90) to give product (850 mg, 80.2% yield) as a yellow oil. Step 3: 1-(indolin-5-ylthio)heptan-3-one To a solution of 5-thiocyanatoindoline (300 mg, 1.705 mmol) in EtOH (7 mL) were added Na2S in water (5 mL) at room temperature. The mixture was stirred for 1h at 50℃. Then added 1- chloroheptan-3-one(253 mg, 1.705 mmol), The mixture was stirred for 2h at 50℃.The mixture was added some NaHCO3, and extracted with EA, combined the organic layer, washed with brine, dried over sodium sulfate, the filtrate was concentrated under reduced pressure, the residue was purified silica gel chromatography (EA /PE=10/90) to give product (260 mg, 58.1% yield) as a yellow oil. LCMS: RT =1.365 min, [M+1]+ =264.1 Step 4: N-(2-(5-((3,3-difluoroheptyl)thio)indoline-1-carbonyl)phenyl)methanesulfonamide To a solution of 1-(indolin-5-ylthio)heptan-3-one (260 mg, 0.989 mmol) in ACN (15 mL) were added 2-(methylsulfonamido)benzoic acid (215 mg, 0.989 mmol), TCFH (277.41 mg, 0.989 mmol) and NMI (0.5 mL) at room temperature. The mixture was stirred for 1h at room temperature. The mixture was added some NH4Cl, and extracted with EA, combined the organic layer, washed with brine, dried over sodium sulfate, the filtrate was concentrated under reduced pressure, the residue was purified silica gel chromatography (EA /PE=10/90) to give product (90 mg, 19.8% yield) as a yellow oil. LCMS: RT =1.689 min, [M+1]+ =461.1 Step 5: N-(2-(5-((3-oxoheptyl)sulfonyl)indoline-1-carbonyl)phenyl)methanesulfonamide To a solution of N-(2-(5-((3,3-difluoroheptyl)thio)indoline-1- carbonyl)phenyl)methanesulfonamide (90 mg, 0.196 mmol) in DCM (4 mL) was added m- CPBA (79.55 mg, 0.392 mmol) at 0℃. The mixture was stirred for 1h at room temperature. The mixture was added some NaHCO3, and extracted with EA, combined the organic layer, washed with brine, dried over sodium sulfate, the filtrate was concentrated under reduced pressure, the residue was purified by prep-HPLC to give product (25 mg, 38.4% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.52 (s, 1H), 8.27 (s, 1H), 7.77 (d, J = 1.8 Hz, 2H), 7.58 – 7.45 (m, 3H), 7.34 (td, J = 7.1, 1.9 Hz, 1H), 3.94 (s, 2H), 3.43 (t, J = 7.3 Hz, 2H), 3.15 (t, J = 8.5 Hz, 2H), 3.00 (s, 3H), 2.76 (t, J = 7.3 Hz, 2H), 2.45 (t, J = 7.3 Hz, 2H), 1.45 – 1.36 (m, 2H), 1.27 – 1.17 (m, 2H), 0.84 (t, J = 7.3 Hz, 3H). MS(ESI) calculated for: C23H28N2O6S2, 492.14; found [M+H]+, 493.1 211 WSGR Ref: 60134-709.601 [00530] Example 56: 7-amino-4-(5-(heptylsulfonyl)indoline-1-carbonyl)-2H- chromen-2-one Step 1: ethyl 7-amino-2-oxo-2H-chromene-4-carboxylate To a solution of 3-aminophenol (10.0 g, 91.74 mmol) and diethyl 2-oxosuccinate sodium salt (21.18 g, 100.9 mmol) in EtOH (80 mL). The reaction mixture was stirred at 80℃ overnight. After starting material was consumed completely, water was added, extracted with ethyl acetate, the combined organic layers were washed with brine and dried over sodium sulfate. The organic phase was concentrated in vacuo and purified by flash chromatography eluted with PE/EA=1:2 to give the product ethyl 7-amino-2-oxo-2H-chromene-4-carboxylate (2.1 g, yield :9.8% yield) as colorless oil. LCMS: RT = 1.483 min, [M+H]+ =234.1. Step 2: ethyl 7-(((benzyloxy)carbonyl)amino)-2-oxo-2H-chromene-4-carboxylate To a solution of ethyl 7-amino-2-oxo-2H-chromene-4-carboxylate (2.1 g, 9.01 mmol) and NaHCO3 (1.51 g, 18.02 mmol) in THF (20 mL) and H2O (20 mL) was added CbzCl (1.68 g, 9.9 mmol). The reaction mixture was stirred at ambient temperature for 1 h. After starting material was consumed completely, water was added, extracted with ethyl acetate, the combined organic layers were washed with brine and dried over sodium sulfate. The organic phase was concentrated in vacuo and purified by flash chromatography eluted with PE/EA=1:2 to give the product ethyl 7-(((benzyloxy)carbonyl)amino)-2-oxo-2H-chromene-4-carboxylate (1.0 g, yield:30.3% yield) as a white solid. LCMS: RT = 1.766 min, [M+H]+ =368.2. Step 3: 7-(((benzyloxy)carbonyl)amino)-2-oxo-2H-chromene-4-carboxylic acid To a 100 mL bottom flask were added ethyl 7-(((benzyloxy)carbonyl)amino)-2-oxo-2H- chromene-4-carboxylate (1.0 g, 2.72 mmol), NaOH (130 mg, 3.27 mmol), THF (10 mL) and H2O (10 mL) at 0°C. Then the reaction mixture was stirred at ambient temperature for 2 h. After the reaction was completed, the mixture was adjusted pH = 5~6 by 10%HCl and extracted with DCM. The combined organic extract was washed with brine, dried with Na2SO4, filtered and 212 WSGR Ref: 60134-709.601 concentrated to give crude product 7-(((benzyloxy)carbonyl)amino)-2-oxo-2H-chromene-4- carboxylic acid (840 mg) as a yellow solid. LCMS: RT = 1.365 min, [M+H]+ =340.1. Step 4: benzyl (4-(5-(heptylthio)indoline-1-carbonyl)-2-oxo-2H-chromen-7-yl)carbamate 7-(((benzyloxy)carbonyl)amino)-2-oxo-2H-chromene-4-carboxylic acid (840 mg, 2.47 mmol) was dissolved into SOCl2 (2 mL) in a 50 mL bottom flask, the mixture was heated to 80℃ and stirred for 1 hour. Then the mixture was concentrated under reduced pressure, the residue was added to a solution of 5-(heptylthio)indoline (615 mg, 2.47 mmol) and TEA (498 mg, 4.94 mmol) in DCM (10 mL), the mixture was stirred for 1 hours at room temperature. The mixture was concentrated under reduced pressure, the residue was purified by silica gel chromatography (EtOAc/PE=1:3) to give product benzyl (4-(5-(heptylthio)indoline-1-carbonyl)-2-oxo-2H- chromen-7-yl)carbamate (210 mg, 15.1% yield) as a white solid. LCMS: RT = 2.034 min, [M+1]+ = 571.2 Step 5: benzyl (4-(5-(heptylsulfonyl)indoline-1-carbonyl)-2-oxo-2H-chromen-7-yl)carbamate To the solution of benzyl (4-(5-(heptylthio)indoline-1-carbonyl)-2-oxo-2H-chromen-7- yl)carbamate (210 mg, 0.36 mmol) in DCM (4 mL) was added m-CPBA (190 mg, 1.08 mmol) at 0°C and the solution was stirred at room temperature overnight. After starting material was consumed completely, water was added, extracted with ethyl acetate, the combined organic layers were washed with brine and dried over sodium sulfate. The organic phase was concentrated in vacuo and purified by flash chromatography eluted with PE/EA=1:1 to give the product benzyl (4-(5-(heptylsulfonyl)indoline-1-carbonyl)-2-oxo-2H-chromen-7-yl)carbamate (140 mg, yield : 64.8%) as a white solid. LCMS: RT = 1.963 min, [M+H]+ =603.2. Step 6: 7-amino-4-(5-(heptylsulfonyl)indoline-1-carbonyl)-2H-chromen-2-one To the solution of benzyl (4-(5-(heptylsulfonyl)indoline-1-carbonyl)-2-oxo-2H-chromen-7- yl)carbamate (140 mg, 0.23 mmol) in MeOH (5 mL) was added Pd/C (14 mg). The mixture was stirred at room temperature for 3 h in H2. The mixture was concentrated under reduced pressure, the residue was added water and neutralized with H2O, then extracted with EtOAc, combined the organic layer, dried over sodium sulfate, the filtrate was concentrated under reduced pressure, the residue was purified by prep-HPLC (base) to give product 7-amino-4-(5- (heptylsulfonyl)indoline-1-carbonyl)-2H-chromen-2-one (59.0 mg, 55.14 % yield). 1H NMR (400 MHz, DMSO) δ 8.35 (d, J = 9.0 Hz, 1H), 7.82 (d, J = 5.3 Hz, 2H), 7.14 (d, J = 8.6 Hz, 1H), 6.57 (dd, J = 8.6, 2.0 Hz, 1H), 6.49 (d, J = 2.0 Hz, 1H), 6.39 (s, 2H), 6.21 (s, 1H), 4.03 (s, 2H), 3.25 (dd, J = 15.6, 7.6 Hz, 2H), 3.20 (t, J = 8.3 Hz, 2H), 1.60 – 1.45 (m, 2H), 1.38 – 1.18 (m, 8H), 0.85 (t, J = 6.9 Hz, 3H). 213 WSGR Ref: 60134-709.601 MS(ESI) calculated for C25H28N2O5S, 468.17; found, 469.3. [00531] Example 57: N-(2-fluoro-6-(5-(heptylsulfonyl)indoline-1- carbonyl)phenyl)methanesulfonamide Step 1. methyl 3-fluoro-2-methanesulfonamidobenzoate The methyl 2-amino-3-fluorobenzoate (1 g, 5.912 mmol, 1 equiv.) in pyridine (5 mL), a stir bar, were added to a 20.0 mL size reaction vessel. To the mixture was added methanesulfonyl chloride (744.84 mg, 6.503 mmol, 1.1 equiv.) at 0 ℃. Then it was stirred at 20 ℃ for 12 h. The reaction mixture was quenched by water at 0°C (10 mL), and extracted with DCM (30 mL x 3). The combined organic extracts were concentrated under reduced pressure. It was purified by silica gel column with EA/PE (10-30%) to afford the product methyl 3-fluoro-2- methanesulfonamidobenzoate (400 mg, 27.37% yield, 94% purity). LCMS (ES, m/z) calculated for C9H10FNO4S: 247.03, found: 248.90 [M+H]+, Rt 0.700 min. Step 2. N-{2-fluoro-6-[5-(heptane-1-sulfonyl)-2,3-dihydroindole-1- carbonyl]phenyl}methanesulfonamide The methyl 3-fluoro-2-methanesulfonamidobenzoate (200 mg, 0.809 mmol, 1 equiv.) in toluene (2 mL), Intermediate 6, 5-(heptane-1-sulfonyl)-2,3-dihydro-1H-indole (0.809 mmol, 1 equiv), a stir bar, were added to a 20.0 mL size reaction vessel. Then trimethylaluminium (0.81 mL, 1.618 mmol, 2 equiv.) was added at 0 ℃ under nitrogen atmosphere. The mixture was stirred at 80 ℃ for 2 h, diluted with water (20 mL) and extracted with DCM (50 mL x 3). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated. It was purified by C18 reverse column with H2O/ACN (0-30%) to afford the crude product. The crude product was purified by Prer- HPLC using a XBridge Prep OBD C18 Column, 30*150 mm, 5μm column (eluent: Water (10 mM NH4HCO3) and ACN, 39% to 59% (v/v)) to yield N-{2-fluoro-6-[5-(heptane-1-sulfonyl)-2,3-dihydroindole-1- carbonyl]phenyl}methanesulfonamide (44.5 mg, 11.08% yield, 99.6% purity) as an off-white solid. LCMS (ES, m/z) calculated for C23H29FN2O5S2: 496.15, found: 497.1 [M+H]+, Rt 1.620 min. 1H NMR (400 MHz, DMSO) δ 9.61 (s, 1H), 8.29 (d, J = 8.9 Hz, 1H), 7.78 (d, J = 7.3 Hz, 2H), 7.53 – 7.40 (m, 3H), 3.91 (t, J = 8.4 Hz, 2H), 3.25 (t, J = 7.9 Hz, 2H), 3.14 (t, J = 8.4 Hz, 2H), 3.00 (s, 3H), 1.53 (d, J = 6.7 Hz, 2H), 1.34 – 1.16 (m, 8H), 0.85 (t, J = 6.8 Hz, 3H). 214 WSGR Ref: 60134-709.601 [00532] Example 58: N-(5-(5-(heptylsulfonyl)indoline-1-carbonyl)-2-(piperazin-1- yl)pyrimidin-4-yl)methanesulfonamide Step 1. ethyl 4-amino-2-[4-(tert-butoxycarbonyl)piperazin-1-yl]pyrimidine-5-carboxylate The solution of ethyl 4-amino-2-chloropyrimidine-5-carboxylate (3 g, 14.880 mmol, 1 equiv) in ACN (100 mL) and tert-butyl piperazine-1-carboxylate (4.16 g, 22.320 mmol, 1.5 equiv) was added dropwise into the mixture. Then added K2CO3 (4.11 g, 29.760 mmol, 2 equiv) . The mixture was stirred at 80℃ for 2 h,diluted with water (100 mL) and extracted with EA (100 mL x 3). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated. The mixture was purified by silica gel column (PE/EA) to afford ethyl 4-amino-2-[4-(tert- butoxycarbonyl)piperazin-1-yl]pyrimidine-5-carboxylate (3.2 g, 61.20%yield, 98.562%purity) . LCMS (ES, m/z), calcd. for C16H25N5O4: 351.407 m/z, found 352.10 [M+H]+, Rt 0.805 min. Step 2. ethyl 2-[4-(tert-butoxycarbonyl)piperazin-1-yl]-4-methanesulfonamidopyrimidine-5- carboxylate To a stirred solution of ethyl 4-amino-2-[4-(tert-butoxycarbonyl)piperazin-1-yl]pyrimidine-5- carboxylate (1 g, 2.846 mmol, 1 equiv) in DMF (10 mL) and added NaH (0.14 g, 5.834 mmol, 2.05 equiv) 0 ℃ under N2. The reaction mixture was stirred at r.t for a period of 0.5h Then added MsCl (0.39 g, 3.415 mmol, 1.2 equiv) at 0 ℃. The reaction mixture was stirred at r.t for a period of 16h.diluted with water (100 mL) and extracted with EA (100 mL x 3). The mixture were dried over anhydrous sodium sulfate, filtered, and concentrated. The mixture was purified by silica gel column ( PE/EA ) to afford ethyl 2-[4-(tert-butoxycarbonyl)piperazin-1-yl]-4- methanesulfonamidopyrimidine-5-carboxylate (650 mg, 53.18%yield, 77.668%purity) . LCMS (ES, m/z), calcd. For C17H27N5O6S: 429.49 m/z, found 430.15 [M+H]+, Rt 0.612 min. Step 3. tert-butyl 4-{5-[5-(heptylsulfanyl)-2,3-dihydroindole-1-carbonyl]-4- methanesulfonamidopyrimidin-2-yl}piperazine-1-carboxylate To a stirred mixture of ethyl 2-[4-(tert-butoxycarbonyl)piperazin-1-yl]-4- methanesulfonamidopyrimidine-5-carboxylate (380 mg, 0.885 mmol, 1 equiv) and 5- 215 WSGR Ref: 60134-709.601 (heptylsulfanyl)-2,3-dihydro-1H-indole (331.02 mg, 1.328 mmol, 1.5 equiv) in toluene (10 mL, 2.655 mmol, 3 equiv). Then added Trimethylaluminium (127.56 mg, 1.770 mmol, 2 equiv) at 0 ℃ under N2. The resulting mixture was stirred at 100℃ for additional 16 h. The resulting mixture was concentrated under reduced pressure, then purified by C18 reversed column (H2O/ACN ) to afford tert-butyl 4-{5-[5-(heptylsulfanyl)-2,3-dihydroindole-1-carbonyl]-4- methanesulfonamidopyrimidin-2-yl}piperazine-1-carboxylate (280 mg, 50.01%yield, 71.061%purity) . LCMS (ES, m/z), calcd. For C30H44N6O5S2: 632.84 m/z, found 633.30 [M+H]+, Rt 1.179 min. Step 4. tert-butyl 4-{5-[5-(heptane-1-sulfonyl)-2,3-dihydroindole-1-carbonyl]-4- methanesulfonamidopyrimidin-2-yl}piperazine-1-carboxylate To a stirred mixture of tert-butyl 4-{5-[5-(heptylsulfanyl)-2,3-dihydroindole-1-carbonyl]-4- methanesulfonamidopyrimidin-2-yl}piperazine-1-carboxylate (270 mg, 0.427 mmol, 1 equiv) in DCM (5 mL) . Then added m-CPBA (220.87 mg, 1.281 mmol, 3 equiv) at 0℃ . The resulting mixture was stirred at RT for additional 2 h. The resulting mixture was concentrated under reduced pressure, then purified by C18 reversed column (H2O/ACN ) to afford tert-butyl 4-{5- [5-(heptane-1-sulfonyl)-2,3-dihydroindole-1-carbonyl]-4-methanesulfonamidopyrimidin-2- yl}piperazine-1-carboxylate (130 mg, 45.83%yield, 96.391%purity) . LCMS (ES, m/z), calcd. for C30H44N6O7S2: 664.84 m/z, found 663.20 [M-H]-, Rt 1.036 min. Step 5. N-{5-[5-(heptane-1-sulfonyl)-2,3-dihydroindole-1-carbonyl]-2-(piperazin-1- yl)pyrimidin-4-yl}methanesulfonamide To a stirred solution of tert-butyl 4-{5-[5-(heptane-1-sulfonyl)-2,3-dihydroindole-1-carbonyl]-4- methanesulfonamidopyrimidin-2-yl}piperazine-1-carboxylate (120 mg, 0.180 mmol, 1 equiv) in HFIP (5 mL) . Then added AlCl3 (48.13 mg, 0.360 mmol, 2 equiv). The reaction mixture was stirred at r.t for 1h under N2. The crude product was purified by Prer-HPLC using a XSelect CSH C18 OBD Prep Column 5 μm, 30 mm X 150 mm; Mobile Phase A (eluent: Water and ACN, 55% to 65% (v/v)) to get N-{5-[5-(heptane-1-sulfonyl)-2,3-dihydroindole-1-carbonyl]-2- (piperazin-1-yl)pyrimidin-4-yl}methanesulfonamide (54.5 mg, 53.47% yield, 98.3%purity). LCMS (ES, m/z), calcd. For C25H36N6O5S2: 564.72 m/z, found 565.25 [M-H]-, Rt 1.419 min. 1H NMR (300 MHz, CDCl3) δ 8.42 (s, 1H), 7.86 – 7.72 (m, 3H), 4.30 (t, J = 8.2 Hz, 2H), 4.08 (s, 4H), 3.42 (s, 3H), 3.25 (t, J = 8.2 Hz, 2H), 3.16 – 3.02 (m, 6H), 1.76 – 1.61 (m, 2H), 1.41 – 1.19 (m, 8H), 0.87 (t, J = 6.4 Hz, 3H). [00533] Example 59: N-(2-(5-(heptylsulfonyl)indoline-1-carbonyl)-5-(piperazin-1- yl)thiophen-3-yl)methanesulfonamide 216 WSGR Ref: 60134-709.601 Step 1. methyl 5-bromo-3-(methylsulfonamido)thiophene-2-carboxylate To a stirred solution of methyl 3-amino-5-bromothiophene-2-carboxylate (1 g, 4.236 mmol, 1 equiv) and pyridine (0.67 g, 8.472 mmol, 2 equiv) in DCM (20 mL). Then added MsCl (0.58 g, 5.083 mmol, 1.2 equiv) at 0℃. The reaction mixture was stirred at r.t for a period of 16h. diluted with water (100 mL) and extracted with EA (100 mL x 3). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated. The mixture was purified by silica gel column (PE/EA) to afford ethyl 2-[4-(tert-butoxycarbonyl)piperazin-1-yl]-4- methanesulfonamidopyrimidine-5-carboxylate (650 mg, 53.18%yield, 77.668%purity). LCMS (ES, m/z), calcd. For C7H8BrNO4S2: 313.90 m/z, found 313.90 [M-H]-, Rt 0.937 min. Step 2. tert-butyl 4-(5-(methoxycarbonyl)-4-(methylsulfonamido)thiophen-2-yl)piperazine-1- carboxylate To a stirred solution of methyl 5-bromo-3-methanesulfonamidothiophene-2-carboxylate (930 mg, 2.960 mmol, 1 equiv) and tert-butyl piperazine-1-carboxylate (827.02 mg, 4.440 mmol, 1.5 equiv) in Dioxane (10 mL) . Then added Cs2CO3 (1928.97 mg, 5.920 mmol, 2 equiv) and Ephos (158.31 mg, 0.296 mmol, 0.1 equiv) , EPhos Pd G4 (271.91 mg, 0.296 mmol, 0.1 equiv) . The reaction mixture was stirred at 100℃ for a period of 16h under N2. diluted with water (100 mL) and extracted with EA (100 mL x 3). The mixture were dried over anhydrous sodium sulfate, filtered, and concentrated. The mixture was purified by silica gel column ( PE/EA ) to afford tert-butyl 4-[4-methanesulfonamido-5-(methoxycarbonyl)thiophen-2-yl]piperazine-1- carboxylate (900 mg, 72.47%yield, 86.013%purity) . LCMS (ES, m/z), calcd. For C16H25N3O6S2: 419.51 m/z, found 420.15 [M+H]+, Rt 0.755 min.. Step 3. tert-butyl 4-(5-(5-(heptylsulfonyl)indoline-1-carbonyl)-4-(methylsulfonamido)thiophen- 2-yl)piperazine-1-carboxylate To a stirred solution of tert-butyl 4-[4-methanesulfonamido-5-(methoxycarbonyl)thiophen-2- yl]piperazine-1-carboxylate (300 mg, 0.715 mmol, 1 equiv) and Intermediate 6, 5-(heptane-1- sulfonyl)-2,3-dihydro-1H-indole (301.86 mg, 1.073 mmol, 1.5 equiv) in toluene (8 mL, 0.002 mmol) . Then added AlMe3 (103.10 mg, 1.430 mmol, 2 equiv) at 0℃ under N2. The reaction mixture was stirred at 100℃ for a period of 1h under N2, diluted with water (100 mL) and 217 WSGR Ref: 60134-709.601 extracted with EA (100 mL x 3). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated. The mixture was purified by C18 reverse column to afford tert-butyl 4-{5-[5- (heptane-1-sulfonyl)-2,3-dihydroindole-1-carbonyl]-4-methanesulfonamidothiophen-2- yl}piperazine-1-carboxylate (80 mg, 16.72%yield, 93.777%purity) . LCMS (ES, m/z), calcd. For C30H44N4O7S3: 668.88 m/z, found 669.25 [M+H]+, Rt 1.096 min. Step 4. N-(2-(5-(heptylsulfonyl)indoline-1-carbonyl)-5-(piperazin-1-yl)thiophen-3- yl)methanesulfonamide To a stirred solution of tert-butyl N-[(3R)-1-(5-{5-[4-(4-cyano-6-methylpyrimidin-2- yl)piperazin-1-ylsulfonyl]-2,3-dihydroindole-1-carbonyl}-1-methanesulfonamidopyrrol-3- yl)pyrrolidin-3-yl]carbamate (110 mg, 0.146 mmol, 1 equiv) in HFIP (5 mL). Then added AlCl3 (61.79 mg, 0.464 mmol, 2 equiv) . The reaction mixture was stirred at r.t for a period of 1h. The crude product was purified by Prer-HPLC using a XSelect CSH C18 OBD Prep Column 5 μm, 30 mm X 150 mm; Mobile Phase A (eluent: Water (0.1% FA) and ACN, 8% to 28% (v/v)) to get N-{2-[5-(heptane-1-sulfonyl)-2,3-dihydroindole-1-carbonyl]-5-(piperazin-1- yl)thiophen-3-yl}methanesulfonamide (53 mg, 40.21% yield, 95.1% purity). LCMS (ES, m/z), calcd. for C25H36N4O5S3: 568.77 m/z, found 569.20 [M+H]+, Rt 6.046 min.1H NMR (300 MHz, DMSO) δ 8.10 (d, J = 8.6 Hz, 1H), 7.75 – 7.62 (m, 2H), 6.34 (s, 1H), 4.46 (t, J = 8.4 Hz, 2H), 3.34 – 3.18 (m, 4H), 3.19 (s, 3H), 2.90 – 2.80 (m, 4H), 1.60 – 1.44 (m, 2H), 1.33 – 1.12 (m, 8H), 0.89 – 0.78 (m, 3H). II. Biological Evaluation Example 1 – Minimum Inhibitory Concentration (MIC) Determination [00534] Test Media Cation-adjusted Mueller-Hinton broth (CAMHB) was used for MIC testing of all organisms. [00535] Broth Microdilution MIC Methodology MIC values were determined using a broth microdilution procedure described by CLSI (1, 2). Automated liquid handlers (Multidrop 384, Labsystems, Helsinki, Finland; Biomek 2000 and Biomek FX, Beckman Coulter, Fullerton CA) were used to conduct serial dilutions and liquid transfers. [00536] To prepare the drug mother plates, which would provide the serial drug dilutions for the replicate daughter plates, the wells of columns 2 through 12 of standard 96-well microdilution plates (Costar 3795) were filled with 150 µl of the designated diluent for each row of drug. A 300 µL aliquot of each test article was dispensed into the appropriate wells in column 1. The Biomek 2000 was then used to make 2-fold serial dilutions in the mother plates from 218 WSGR Ref: 60134-709.601 column 1 through column 11. The wells of column 12 contained no drug and served as the organism growth control wells for the assay. [00537] The daughter plates were loaded with 190 µL per well of CAMHB using the Multidrop 384. The daughter plates were completed on the Biomek FX instrument which transferred 2 µL of drug solution from each well of a mother plate to the corresponding well of each daughter plate in a single step. [00538] A standardized inoculum of each test organism was prepared per CLSI methods (1). The inoculum for each organism was dispensed into sterile reservoirs divided by length (Beckman Coulter), and the Biomek 2000 was used to inoculate the plates. Daughter plates were placed on the Biomek 2000 work surface in reverse orientation so that inoculation took place from low to high drug concentration. The plates were then inoculated with 10 µL of the inoculum resulting in a final cell density of approximately 5 x 105 CFU/mL per well. [00539] Plates were stacked 3 to 4 high, covered with a sterile lid on the top plate, placed in plastic bags, and incubated at 35°C for 20 hrs. Following incubation, the microplates were removed from the incubator and viewed from the bottom using a plate viewer. An uninoculated solubility control plate was observed for sterility and evidence of drug precipitation. The MIC was read and recorded as the lowest concentration of drug that inhibited visible growth of the organism. Lastly the plates then had the OD600 determined on a Biotek Synergy 2 (Winooski, VT). The readings from the medium solubility plate were used as the blank to correct for background. Antibacterial activity (MIC, µg/mL) and cytotoxicity of select analogs is provided in Table 3. 1. CLSI. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard; 11th ed. CLSI standard M07. CLSI, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087 USA, 2018. 2. CLSI. Performance Standards for Antimicrobial Susceptibility Testing; 32nd ed. CLSI supplement M100. CLSI, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087 USA, 2022. Example 2 – LpxH Biochemical Assay – IC50 (nM) 219 WSGR Ref: 60134-709.601 220 WSGR Ref: 60134-709.601 221 WSGR Ref: 60134-709.601 Table 3 methylmethanesul fonamide 222 WSGR Ref: 60134-709.601 N- methylmethanesul fonamide 223 WSGR Ref: 60134-709.601 ethanesulfonamid e 224 WSGR Ref: 60134-709.601 ethanesulfonamid e 225 WSGR Ref: 60134-709.601 mide 226 WSGR Ref: 60134-709.601 sulfonamide 227 WSGR Ref: 60134-709.601 carbonyl)phenyl)m ethanesulfonamid e 228 WSGR Ref: 60134-709.601 carbonyl)phenyl)m ethanesulfonamid e 229 WSGR Ref: 60134-709.601 yl)-2- methoxyethane-1- sulfonamide 230 WSGR Ref: 60134-709.601 2(1H)-one 231 WSGR Ref: 60134-709.601 e 232 WSGR Ref: 60134-709.601 NT = not y tel)smteedth.anesulfona ATCC 25922 M mICide (µg/mL), ATCC 43816 MIC (µg/mL): 0-4 (*); >4-16 (**); >16-32 (***); >3264 (****). HN814 TolC:Tn10 MIC (µg/mL), RFM 795 MIC (µg/mL): <1 (*); 1-4 (**); >4-16 (***); >16 (****). LpxH biochemical IC50 (nM): < 20 (*); 20-100 (**); >100-500 (***); >500 (****). III. Preparation of Pharmaceutical Dosage Forms Example 1: Oral capsule 233 WSGR Ref: 60134-709.601 [00540] The active ingredient is a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof. A capsule for oral administration is prepared by mixing 1-1000 mg of active ingredient with starch or other suitable powder blend. The mixture is incorporated into an oral dosage unit such as a hard gelatin capsule, which is suitable for oral administration. Example 2: Solution for injection [00541] The active ingredient is a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, and is formulated as a solution in sesame oil at a concentration of 10-100 mg-eq/mL. [00542] The examples and embodiments described herein are for illustrative purposes only and various modifications or changes suggested to persons skilled in the art are to be included within the spirit and purview of this application and scope of the appended claims. Numbered Embodiments [00543] Some numbered examples of embodiments follow. embodiments follow. (1): A compound of Formula (I-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; R1 is hydrogen, optionally substituted alkyl, -OH, -CN, -C(O)R8, or -C(O)N(R9)2; R8 is optionally substituted C1-C5 alkyl; each R9 is independently hydrogen or optionally substituted C1-C3 alkyl; or two R9 groups attached to the same atom are optionally cyclized to form a 3 to 6-membered heterocyclyl; RL is 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-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 R4 is independently hydrogen, deuterium, or optionally substituted C1-C3 alkyl; or two R4 groups together form an oxo; or two R4 234 WSGR Ref: 60134-709.601 groups together form a 3- or 4-membered carbocyclyl; or two R4 groups together form a 4- membered heterocyclyl; each R5 is independently hydrogen, deuterium, halogen, or optionally substituted C1-C3 alkyl; or two R5 groups together form an oxo; or two R5 groups together form a 3- or 4-membered carbocyclyl; or two R5 groups together form 4- membered heterocyclyl; each R6 is independently hydrogen, deuterium, halogen, or optionally substituted C1-C3 alkyl; or two R6 groups together form an oxo; or two R6 groups together form a 3- or 4-membered carbocyclyl; or two R6 groups together form 4- membered heterocyclyl; each R7 is independently hydrogen, deuterium, or optionally substituted C1-C3 alkyl; or two R7 groups together form an oxo; or two R7 groups together form a 3- or 4-membered carbocyclyl; or two R7 groups together form 4- membered heterocyclyl; and R3 is hydrogen or optionally substituted C1-C3 alkyl; 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; 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; R1 is hydrogen, optionally substituted alkyl, -OH, -CN, -C(O)R8, or - C(O)N(R9)2; R8 is optionally substituted C1-C5 alkyl; each R9 is independently hydrogen or optionally substituted C1-C3 alkyl; or two R9 groups attached to the same atom are optionally cyclized to form a 3 to 6-membered heterocyclyl; RL is 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-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 R4 is independently hydrogen, deuterium, or optionally substituted C1-C3 alkyl; or two R4 groups together form an oxo; or two R4 groups together form a 3- or 4-membered carbocyclyl; 235 WSGR Ref: 60134-709.601 or two R4 groups together form a 4-membered heterocyclyl; each R5 is independently hydrogen, deuterium, halogen, or optionally substituted C1-C3 alkyl; or two R5 groups together form an oxo; or two R5 groups together form a 3- or 4-membered carbocyclyl; or two R5 groups together form 4-membered heterocyclyl; each R6 is independently hydrogen, deuterium, halogen, or optionally substituted C1-C3 alkyl; or two R6 groups together form an oxo; or two R6 groups together form a 3- or 4-membered carbocyclyl; or two R6 groups together form 4-membered heterocyclyl; each R7 is independently hydrogen, deuterium, or optionally substituted C1-C3 alkyl; or two R7 groups together form an oxo; or two R7 groups together form a 3- or 4-membered carbocyclyl; or two R7 groups together form 4-membered heterocyclyl; and R3 is hydrogen or optionally substituted C1-C3 alkyl. (3): A compound of Formula (I-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; R1 is hydrogen, optionally substituted alkyl, -OH, -CN, -C(O)R8, or -C(O)N(R9)2; R8 is optionally substituted C1-C5 alkyl; each R9 is independently hydrogen or optionally substituted C1-C3 alkyl; or two R9 groups attached to the same atom are optionally cyclized to form a 3 to 6- membered heterocyclyl; RL is 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-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-N(R3)-; where the * denotes the bond to N; each R4 is independently hydrogen, deuterium, or optionally substituted C1-C3 alkyl; or two R4 groups together form an oxo; or two R4 groups together form a 3- or 4-membered carbocyclyl; or two R4 groups together form a 4- membered heterocyclyl; each R5 is independently hydrogen, deuterium, halogen, or optionally substituted C1-C3 alkyl; or two R5 groups together form an oxo; or two R5 groups together form a 3- or 4-membered carbocyclyl; or two R5 groups together form 4- 236 WSGR Ref: 60134-709.601 membered heterocyclyl; each R6 is independently hydrogen, deuterium, halogen, or optionally substituted C1-C3 alkyl; or two R6 groups together form an oxo; or two R6 groups together form a 3- or 4-membered carbocyclyl; or two R6 groups together form 4- membered heterocyclyl; each R7 is independently hydrogen, deuterium, or optionally substituted C1-C3 alkyl; or two R7 groups together form an oxo; or two R7 groups together form a 3- or 4-membered carbocyclyl; or two R7 groups together form 4- membered heterocyclyl; and R3 is hydrogen or optionally substituted C1-C3 alkyl. (4): The compound of any one of embodiments 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. (5): The compound of any one of embodiments 1-4, or a pharmaceutically acceptable salt or solvate thereof, wherein G is *-CH2-C(R5)2-; where the * denotes the bond to N. (6): The compound of any one of embodiments 1-4, or a pharmaceutically acceptable salt or solvate thereof, wherein G is *- C(R4)2-CH2-; where the * denotes the bond to N. (7): The compound of any one of embodiments 1-6, or a pharmaceutically acceptable salt or solvate thereof, wherein G is -CH2-CH2-. (8): The compound of any one of embodiments 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. (9): The compound of any one of embodiments 1-3 or 8, 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. (10): The compound of any one of embodiments 1-3 or 8-9, or a pharmaceutically acceptable salt or solvate thereof, wherein G is -CH2-CH2-CH2-. (11): The compound of any one of embodiments 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. (12): The compound of any one of embodiments 1-3 or 11, or a pharmaceutically acceptable salt or solvate thereof, wherein G is *-CH2-CH2-O-; where the * denotes the bond to N. (13): The compound of any one of embodiments 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. (14): The compound of any one of embodiments 1-3 or 13, 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. (15): A compound of any one of embodiments 1-3, wherein the compound is a compound of Formula (II-c), pharmaceutically acceptable salt or solvate thereof, wherein, B is an optionally substituted aryl, optionally substituted heteroaryl, optionally 237 WSGR Ref: 60134-709.601 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; R1 is hydrogen, optionally substituted alkyl, -OH, -CN, -C(O)R8, or -C(O)N(R9)2; R8 is optionally substituted C1-C5 alkyl; each R9 is independently hydrogen or optionally substituted C1-C3 alkyl; or two R9 groups attached to the same atom are optionally cyclized to form a 3 to 6-membered heterocyclyl; RL is 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-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 R4 is independently hydrogen, deuterium, or optionally substituted C1-C3 alkyl; or two R4 groups together form an oxo; or two R4 groups together form a 3- or 4- membered carbocyclyl; or two R4 groups together form a 4-membered heterocyclyl; and each R5 is independently hydrogen, deuterium, halogen, or optionally substituted C1-C3 alkyl; or two R5 groups together form an oxo; or two R5 groups together form a 3- or 4-membered carbocyclyl; or two R5 groups together form 4-membered heterocyclyl. (16): The compound of embodiment 15, or a pharmaceutically acceptable salt or solvate thereof, wherein, each R4 is independently hydrogen, deuterium, or optionally substituted C1-C3 alkyl; and each R5 is independently hydrogen, deuterium, or optionally substituted C1-C3 alkyl. (17): The compound of embodiment 15 or 16, or a pharmaceutically acceptable salt or solvate thereof, wherein, each R4 is 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 R5 is independently hydrogen, deuterium, or C1-C3 alkyl, wherein the alkyl is optionally substituted with one or more halogen, hydroxy, methoxy, amino, -NHMe, or -NMe2. (18): The compound of embodiment 15 or 16, or a pharmaceutically acceptable salt or solvate thereof, wherein, each R4 is independently hydrogen, deuterium, or optionally substituted C1 alkyl; and each R5 is independently hydrogen, deuterium, or optionally substituted C1 alkyl. (19): The compound of embodiment 15 or 18, or a pharmaceutically acceptable salt or solvate thereof, wherein, each R4 is 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 R5 is 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. (20): The compound of any one of embodiments 15-19, or a pharmaceutically acceptable salt or solvate thereof, wherein, each R4 is 238 WSGR Ref: 60134-709.601 independently hydrogen or deuterium; and each R5 is independently hydrogen or deuterium. (21): The compound of any one of embodiments 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. (22): The compound of any one of embodiments 1-21, 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. (23): The compound of any one of embodiments 1-22, 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. (24): The compound of any one of embodiments 1- 22, 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. (25): The compound of any one of embodiments 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 C-heterocyclyl. (26): The compound of any one of embodiments 1-25, 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. (27): The compound of any one of embodiments 1-22, 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. (28): The compound of any one of embodiments 1-25, 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. (29): The compound of any one of embodiments 1-28, or a pharmaceutically acceptable salt or solvate thereof, wherein B is an optionally substituted aryl or optionally substituted heteroaryl. (30): The compound of any one of embodiments 1-2, or a pharmaceutically acceptable salt or solvate thereof, wherein B is an optionally substituted 4- to 8-membered carbocyclyl. (31): The compound of embodiment 30, or a pharmaceutically acceptable salt or solvate thereof, wherein B is an optionally substituted 5- to 8-membered carbocyclyl. (32): The compound of embodiment 30, or a pharmaceutically acceptable salt or solvate thereof, wherein B is an optionally substituted 5- to 6-membered carbocyclyl. (33): The compound of embodiment 30, or a pharmaceutically acceptable salt or solvate thereof, wherein B is an optionally substituted 4- 239 WSGR Ref: 60134-709.601 membered carbocyclyl. (34): The compound of embodiment 30, or a pharmaceutically acceptable salt or solvate thereof, wherein B is an optionally substituted 5-membered carbocyclyl. (35): The compound of embodiment 30, or a pharmaceutically acceptable salt or solvate thereof, wherein B is an optionally substituted 6-membered carbocyclyl. (36): The compound of any one of embodiments 1-20 or a pharmaceutically acceptable salt or solvate thereof, wherein B is an optionally substituted heterocyclyl. (37): The compound of embodiment 36, or a pharmaceutically acceptable salt or solvate thereof, wherein B is an optionally substituted 4 to 6-membered heterocyclyl. (38): The compound of embodiment 36, or a pharmaceutically acceptable salt or solvate thereof, wherein B is an optionally substituted 4- membered heterocyclyl. (39): The compound of embodiment 36, or a pharmaceutically acceptable salt or solvate thereof, wherein B is an optionally substituted 5-membered heterocyclyl. (40): The compound of embodiment 36, or a pharmaceutically acceptable salt or solvate thereof, wherein B is an optionally substituted 6-membered heterocyclyl. (41): The compound of embodiment 36 or a pharmaceutically acceptable salt or solvate thereof, wherein B is an optionally substituted C-heterocyclyl. (42): The compound of embodiment 41, or a pharmaceutically acceptable salt or solvate thereof, wherein B is an optionally substituted 4 to 6- membered C-heterocyclyl. (43): The compound of embodiment 41, or a pharmaceutically acceptable salt or solvate thereof, wherein B is an optionally substituted 4-membered C- heterocyclyl. (44): The compound of embodiment 41, or a pharmaceutically acceptable salt or solvate thereof, wherein B is an optionally substituted 5-membered C-heterocyclyl. (45): The compound of embodiment 41, or a pharmaceutically acceptable salt or solvate thereof, wherein B is an optionally substituted 6-membered C-heterocyclyl. (46): The compound of any one of embodiments 1-20, or a pharmaceutically acceptable salt or solvate thereof, wherein B is an optionally substituted heteroaryl. (47): The compound of any one of embodiments 1-20 or 46, or a pharmaceutically acceptable salt or solvate thereof, wherein B is an optionally substituted 5- to 10-membered heteroaryl. (48): The compound of any one of embodiments 1-20 or 46-47, or a pharmaceutically acceptable salt or solvate thereof, wherein B is an optionally substituted 5- to 6-membered heteroaryl. (49): The compound of any one of embodiments 1-20 or 46-48, or a pharmaceutically acceptable salt or solvate thereof, wherein B is an optionally substituted 5- membered heteroaryl. (50): The compound of any one of embodiments 1-20 or 46-48, or a pharmaceutically acceptable salt or solvate thereof, wherein B is an optionally substituted 6- membered heteroaryl. (51): The compound of any one of embodiments 1-20 or 46-47, or a pharmaceutically acceptable salt or solvate thereof, wherein B is an optionally substituted 9- membered heteroaryl. (52): The compound of any one of embodiments 1-20 or 46-47, or a pharmaceutically acceptable salt or solvate thereof, wherein B is an optionally substituted 10- 240 WSGR Ref: 60134-709.601 membered heteroaryl. (53): The compound of any one of embodiments 1-20, or a pharmaceutically acceptable salt or solvate thereof, wherein B is an optionally substituted aryl. (54): The compound of embodiment 53, or a pharmaceutically acceptable salt or solvate thereof, wherein B is an optionally substituted phenyl. (55): The compound of any one of embodiments 1-54, or a pharmaceutically acceptable salt or solvate thereof, wherein 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-; RS is optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, optionally substituted C2-C5 alkynyl, -ORj, or -N(Rj)2; each RP is independently optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, optionally substituted C2-C5 alkynyl, -ORj, or -N(Rj)2; or two RP are taken together to form an optionally substituted 3 to 10-membered heterocyclyl; each Rj is independently hydrogen or optionally substituted C1-C3 alkyl; or two Rj groups are optionally cyclized to form an optionally substituted C3-C7 carbocyclyl; or two Rj groups are optionally cyclized to form an optionally substituted 3 to 7- membered heterocyclyl; each Rk is independently hydrogen, halogen, optionally substituted C1- C3 alkyl, or -OH; or two Rk groups attached to the same carbon atom are optionally cyclized to form a C3-C6 carbocyclyl; or two Rk groups attached to the same carbon atom are optionally cyclized to form a 3 to 6-membered heterocyclyl; each Rm is independently optionally substituted C1-C3 alkyl; or two Rm groups are optionally cyclized to form an optionally substituted 3 to 6-membered heterocyclyl; each Rn is independently hydrogen, halogen, or optionally substituted C1-C3 alkyl; or two Rn groups attached to the same carbon atom are optionally cyclized to form a C3-C6 carbocyclyl; or two Rn groups attached to the same carbon atom are optionally cyclized to form a 3 to 6-membered heterocyclyl. (56): The compound of any one of embodiments 1-55, wherein B is substituted with one or more substituents selected from: . (57): The compound of any one of embodiments 1-55, or a pharmaceutically acceptable salt or solvate thereof, wherein B is substituted with one or more substituents selected 241 WSGR Ref: 60134-709.601 compound of any one of embodiments 1-55, wherein B is substituted with one or more substituents selected from: ; L is -N(Rj)-, -C(Rn)2-, or -O-; RS is optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, optionally substituted C2-C5 alkynyl, -ORj, or - N(Rj)2; each Rj is hydrogen or -CH3; each Rn is independently hydrogen, -F, -Cl, -CH3, - CH2CH3, -CH2F, -CHF2, -CF3. (59): The compound of any one of embodiments 1-55, wherein B is substituted with one or more substituents selected from: ; RS is optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, or optionally substituted C2-C5 alkynyl; each Rj is independently hydrogen or -CH3. (60): The compound of any one of embodiments 1-55, wherein B is substituted with one or more substituents selected from: ; RS is optionally substituted C1-C3 alkyl; and Rj is independently hydrogen or -CH3. (61): The compound of any one of embodiments 1-55, wherein B is substituted with one or more substituents selected from: ; RS is -CH3, -CH2F, -CHF2, -CF3, -CH2OCH3, -CH2NH2, or -CH2CH2NH2; and Rj is hydrogen or -CH3. (62): The compound of any one of embodiments 1-55, wherein B is substituted with one or more substituents selected from: ; RS is - CH3, -CH2F, -CHF2, -CF3, -CH2OCH3, -CH2NH2, or -CH2CH2NH2. (63): The compound of any one of embodiments 1-55, 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 embodiments 1-55, wherein B is substituted with one or more substituents selected from: 242 WSGR Ref: 60134-709.601 ; RS is -CH3, -CH2F, -CHF2, -CF3, -CH2OCH3, -CH2NH2, or -CH2CH2NH2. (65): The compound of any one of embodiments 1-55, 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 embodiments 1-55, 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 embodiments 1-55, wherein B is substituted with one or more substituents selected from: ; RS is optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, or optionally substituted C2-C5 alkynyl. (68): The compound of any one of embodiments 1-55, wherein B is substituted with one or more substituents selected from: The compound of any one of embodiments 1-55, 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 embodiments 1-55, wherein B is substituted with one or more substituents selected from: ; RS is -ORj, or -N(Rj)2; each Rj is independently hydrogen or optionally substituted C1-C3 alkyl; or two Rj groups are optionally cyclized to form an optionally substituted 3 to 7-membered heterocyclyl. (71): The compound of any one of embodiments 1-55, wherein B is substituted with one or more substituents selected from: 243 WSGR Ref: 60134-709.601 . (72): The compound of any one of embodiments 1-55, wherein B is substituted with one or more substituents selected from: ; RS is optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, or optionally substituted C2-C5 alkynyl; and each Rn is independently hydrogen, -F, -Cl, or -CH3. (73): The compound of any one of embodiments 1-55, wherein B is substituted with one or more substituents selected from: ; RS is -CH3, - CH2F, -CHF2, -CF3, -CH2OCH3, -CH2NH2, or -CH2CH2NH2; and each Rn is independently hydrogen, -F, or -CH3. (74): The compound of any one of embodiments 1-55, wherein B is substituted with one or more substituents selected from: ; RS is -CH3, -CH2F, -CHF2, - CF3, -CH2OCH3, -CH2NH2, or -CH2CH2NH2. (75): The compound of any one of embodiments 1-55, 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 embodiments 1- 55, wherein B is substituted with one or more substituents selected from: ; RS is - ORj, or -N(Rj)2; each Rn is independently hydrogen, -F, -Cl, or -CH3; each Rj is independently hydrogen or optionally substituted C1-C3 alkyl; or two Rj groups are optionally cyclized to form an optionally substituted 3 to 7-membered heterocyclyl. (77): The compound of any one of embodiments 1-55, or a pharmaceutically acceptable salt or solvate thereof, wherein B is substituted with one or more substituents selected from: . (78): The compound of any one of embodiments 1-55, 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 RP is independently optionally substituted C1-C3 alkyl; or two RP are taken together to form an optionally substituted 3 to 10-membered heterocyclyl. (79): The compound of any one of embodiments 1-55, or a pharmaceutically acceptable salt or solvate thereof, 244 WSGR Ref: 60134-709.601 wherein B is substituted with one or more substituents selected from: ; L is -NH-, - N(CH3)-, or -CH2-; wherein each RP is independently optionally substituted C1-C3 alkyl; or two RP are taken together to form an optionally substituted 3 to 10-membered heterocyclyl. (80): The compound of any one of embodiments 1-55, or a pharmaceutically acceptable salt or solvate thereof, wherein B is substituted with one or more substituents selected from: . (81): The compound of any one of embodiments 1-55, or a pharmaceutically acceptable salt or solvate thereof, wherein B is substituted with one or more substituents selected from: and The compound of any one of embodiments 1-55, 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. (83): The compound of any one of embodiments 1-55, or a pharmaceutically acceptable salt or solvate thereof, wherein B is substituted with one or more substituents selected from: ; each Rj is independently hydrogen or -CH3. (84): The compound of any one of embodiments 1-55, or a pharmaceutically acceptable salt or solvate thereof, wherein B is substituted with one or more substituents selected from: . (85): The compound of any one of embodiments 1-55, or a pharmaceutically acceptable salt or solvate thereof, wherein B is substituted with one or more substituents selected from: . (86): The compound of any one of embodiments 1-55, or a pharmaceutically acceptable salt or solvate thereof, wherein B is substituted with one or more substituents selected from: ; each Rk is independently hydrogen, -F, or -CH3. (87): The compound of any one of embodiments 1-55, or a pharmaceutically acceptable salt or 245 WSGR Ref: 60134-709.601 solvate thereof, wherein B is substituted with one or more substituents selected from: . (88): The compound of any one of embodiments 1-55, or a pharmaceutically acceptable salt or solvate thereof, wherein B is substituted with one or more substituents selected from: each Rj is independently hydrogen or -CH3. (89): The compound of any one of embodiments 1-55, or a pharmaceutically acceptable salt or solvate thereof, wherein B is substituted with one or more substituents selected from: each Rj is independently hydrogen or -CH3. each Rk is independently hydrogen, -F, -Cl, -CH3, or -OH. (90): The compound of any one of embodiments 1-55, 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 embodiments 1-55, 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. (92): The compound of any one of embodiments 1-55, 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 embodiments 1-55, or a pharmaceutically acceptable salt or solvate thereof, wherein B is substituted with one or more substituents selected from: optionally substituted piperazin-1-yl. (94): The compound of any one of embodiments 1-55, 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 embodiments 1-55, or a pharmaceutically acceptable salt or solvate thereof, wherein B is 246 WSGR Ref: 60134-709.601 substituted with one or more substituents selected from: ; each Rm is independently optionally substituted C1-C3 alkyl; or two Rm groups are optionally cyclized to form an optionally substituted 3 to 6-membered heterocyclyl. (96): The compound of any one of embodiments 1-55, 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 embodiments 1-55, or a pharmaceutically acceptable salt or solvate thereof, wherein two adjacent atoms of B are substituted by the divalent group consisting of ; each Rj is independently hydrogen or optionally substituted C1-C3 alkyl; or two Rj groups are optionally cyclized to form an optionally substituted C3-C7 carbocyclyl; or two Rj groups are optionally cyclized to form an optionally substituted 3 to 7-membered heterocyclyl. (98): The compound of any one of embodiments 1-55, or a pharmaceutically acceptable salt or solvate thereof, wherein two adjacent atoms of B are substituted by the divalent group consisting of ; each Rj is independently hydrogen or optionally substituted C1-C3 alkyl; or two Rj groups are optionally cyclized to form an optionally substituted C3-C7 carbocyclyl; or two Rj groups are optionally cyclized to form an optionally substituted 3 to 7-membered heterocyclyl. (99): The compound of any one of embodiments 1-55, or a pharmaceutically acceptable salt or solvate thereof, wherein two adjacent atoms of B are substituted by the divalent group consisting of . (100): The compound of any one of embodiments 1-55, or a pharmaceutically acceptable salt or solvate thereof, wherein B is substituted with one or more substituents selected 247 WSGR Ref: 60134-709.601 compound of any one of embodiments 1-55, or a pharmaceutically acceptable salt or solvate thereof, wherein B is substituted with one or more substituents selected from: , , , embodiments 1-101, or a pharmaceutically acceptable salt or solvate thereof, wherein X is N. (103): The compound of any one of embodiments 1-101, or a pharmaceutically acceptable salt or solvate thereof, wherein X is C-R. (104): The compound of any one of embodiments 1-103, or a pharmaceutically acceptable salt or solvate thereof, wherein Y is N. (105): The compound of any one of embodiments 1-103, or a pharmaceutically acceptable salt or solvate thereof, wherein Y is C-R. (106): The compound of any one of embodiments 1-105, or a pharmaceutically acceptable salt or solvate thereof, wherein Z is N. (107): The compound of any one of embodiments 1-105, or a pharmaceutically acceptable salt or solvate thereof, wherein Z is C-R. (108): The compound of any one of embodiments 1-101, or a pharmaceutically acceptable salt or solvate thereof, wherein: X is CR; Y is CR; and Z is CR. (109): The compound of any one of embodiment 1-101 or 108, or a pharmaceutically acceptable salt or solvate thereof, wherein: X is CH; Y is CH; and Z is CH. (110): The compound of any one of embodiments 1- 101, or a pharmaceutically acceptable salt or solvate thereof, wherein: X is N; Y is CR; and Z is CR. (111): The compound of any one of embodiments 1-101 or 110, or a pharmaceutically acceptable salt or solvate thereof, wherein: X is N; Y is CH; and Z is CH. (112): The compound 248 WSGR Ref: 60134-709.601 of any one of embodiments 1-108 or 110, or a pharmaceutically acceptable salt or solvate thereof, wherein each R is independently hydrogen, deuterium, halogen, -CN, or optionally substituted C1 alkyl. (113): The compound of any one of embodiments 1-108 or 110, or a pharmaceutically acceptable salt or solvate thereof, wherein each R is independently hydrogen, deuterium, halogen, -CN, or -CH3. (114): The compound of any one of embodiments 1-108 or 110, or a pharmaceutically acceptable salt or solvate thereof, wherein each R is independently hydrogen, deuterium, or halogen. (115): The compound of any one of embodiments 1-108 or 110, or a pharmaceutically acceptable salt or solvate thereof, wherein each R is independently hydrogen or deuterium. (116): The compound of any one of embodiments 1-115, or a pharmaceutically acceptable salt or solvate thereof, wherein E is absent. (117): The compound of any one of embodiments 1-115, or a pharmaceutically acceptable salt or solvate thereof, wherein E is O. (118): The compound of any one of embodiments 1-115, or a pharmaceutically acceptable salt or solvate thereof, wherein E is N-R1. (119): The compound of embodiment 118, or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is hydrogen. (120): The compound of embodiment 118, or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is optionally substituted alkyl. (121): The compound of embodiment 118, or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is C1-C5 alkyl substituted with one or more group selected from -CO2H. (122): The compound of embodiment 118, or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -H, -CH2CO2H, or - CH(CH3)CO2H. (123): The compound of embodiment 118, or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -CH2CO2H or -CH(CH3)CO2H. (124): The compound of embodiment 118, or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is - CH2CO2H. (125): The compound of embodiment 118, or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -CH(CH3)CO2H. (126): The compound of embodiment 118, or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -OH. (127): The compound of embodiment 118, or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is - C(O)R8. (128): The compound of embodiment 118 o 127, or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)CH3. (129): The compound of embodiment 118, or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)N(R9)2. (130): The compound of embodiment 118 or 129, or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)N(CH3)2. (131): The compound of any one of embodiments 1-130, or a pharmaceutically acceptable salt or solvate thereof, wherein RL is optionally substituted C4-C10 alkyl, optionally substituted -(C1-C3 alkylene)-O-(C1-C8 alkyl), optionally substituted -(C1-C3 alkylene)-N(C1-C3 alkyl)(heteroaryl), optionally substituted C4-C10 alkenyl, optionally substituted C4-C10 alkynyl, optionally substituted carbocyclyl, optionally substituted aralkyl, 249 WSGR Ref: 60134-709.601 optionally substituted heteroarylalkyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclylalkyl, or optionally substituted C-heterocyclyl. (132): The compound of any one of embodiments 1-130, or a pharmaceutically acceptable salt or solvate thereof, wherein RL is 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-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. (133): The compound of any one of embodiments 1-130, or a pharmaceutically acceptable salt or solvate thereof, wherein RL is optionally substituted C4-C10 alkyl, 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. (134): The compound of any one of embodiments 1-130, or a pharmaceutically acceptable salt or solvate thereof, wherein RL is optionally substituted C5-C12 alkyl, optionally substituted -(C1-C3 alkylene)-O-(C1-C10 alkyl), optionally substituted -(C1-C3 alkylene)-N(C1-C3 alkyl)(heteroaryl), optionally substituted C5-C12 alkenyl, optionally substituted C5-C12 alkynyl, optionally substituted carbocyclyl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted carbocyclylalkyl, or optionally substituted heterocyclylalkyl. (135): The compound of any one of embodiments 1-130, or a pharmaceutically acceptable salt or solvate thereof, wherein RL is optionally substituted C4-C12 alkyl, optionally substituted -(C1-C3 alkylene)-O- (C1-C10 alkyl), optionally substituted C4-C12 alkenyl, or optionally substituted C4-C12 alkynyl. (136): The compound of any one of embodiments 1-130, or a pharmaceutically acceptable salt or solvate thereof, wherein RL is optionally substituted C4-C12 alkyl, optionally substituted C4- C12 alkenyl, or optionally substituted C4-C12 alkynyl. (137): The compound of any one of embodiments 1-130, or a pharmaceutically acceptable salt or solvate thereof, wherein RL is optionally substituted C5-C12 alkyl, optionally substituted C5-C12 alkenyl, or optionally substituted C5-C12 alkynyl. (138): The compound of any one of embodiments 1-130, or a pharmaceutically acceptable salt or solvate thereof, wherein RL is optionally substituted C6-C12 alkyl, optionally substituted C6-C12 alkenyl, or optionally substituted C6-C12 alkynyl. (139): The compound of any one of embodiments 1-130, or a pharmaceutically acceptable salt or solvate thereof, wherein RL is an optionally substituted C4-C10 alkyl. (140): The compound of any one of embodiments 1-130 or a pharmaceutically acceptable salt or solvate thereof, wherein RL is an optionally substituted, linear C4-C10 alkyl. (141): The compound of any one of embodiments 1- 250 WSGR Ref: 60134-709.601 130, or a pharmaceutically acceptable salt or solvate thereof, wherein RL is an unsubstituted, linear C4-C10 alkyl. (142): The compound of any one of embodiments 1-130, or a pharmaceutically acceptable salt or solvate thereof, wherein RL is an optionally substituted C4- C12 alkenyl. (143): The compound of any one of embodiments 1-130, or a pharmaceutically acceptable salt or solvate thereof, wherein RL is an optionally substituted C4-C10 alkenyl. (144): The compound of any one of embodiments 1-130, or a pharmaceutically acceptable salt or solvate thereof, wherein RL is an optionally substituted C4-C12 alkynyl. (145): The compound of any one of embodiments 1-130, or a pharmaceutically acceptable salt or solvate thereof, wherein RL is an optionally substituted C4-C10 alkynyl. (146): The compound of any one of embodiments 1-130, or a pharmaceutically acceptable salt or solvate thereof, wherein RL is an optionally substituted carbocyclyl. (147): The compound of any one of embodiments 1-130, or a pharmaceutically acceptable salt or solvate thereof, wherein RL is an optionally substituted C3- C8 carbocyclyl. (148): The compound of any one of embodiments 1-130, or a pharmaceutically acceptable salt or solvate thereof, wherein RL is an optionally substituted C4-C8 carbocyclyl. (149): The compound of any one of embodiments 1-130, or a pharmaceutically acceptable salt or solvate thereof, wherein RL is an optionally substituted C5-C8 carbocyclyl. (150): The compound of any one of embodiments 1-130, or a pharmaceutically acceptable salt or solvate thereof, wherein RL is an optionally substituted 4-membered carbocyclyl. (151): The compound of any one of embodiments 1-130, or a pharmaceutically acceptable salt or solvate thereof, wherein RL is an optionally substituted aralkyl. (152): The compound of any one of embodiments 1-130, or a pharmaceutically acceptable salt or solvate thereof, wherein RL is an optionally substituted heteroarylalkyl. The compound of any one of embodiments 1-130, or a pharmaceutically acceptable salt or solvate thereof, wherein RL is an optionally substituted carbocyclylalkyl. The compound of any one of embodiments 1-130, or a pharmaceutically acceptable salt or solvate thereof, wherein RL is an optionally substituted heterocyclylalkyl. (153): The compound of any one of embodiments 1-130, or a pharmaceutically acceptable salt or solvate thereof, wherein RL is an optionally substituted C-heterocyclyl. (154): The compound of any one of embodiments 1-130, or a pharmaceutically acceptable salt or solvate thereof, wherein RL is an optionally substituted 4 to 8-membered C-heterocyclyl. (155): The compound of any one of embodiments 1-130, or a pharmaceutically acceptable salt or solvate thereof, wherein RL is an optionally substituted 5 to 6-membered C-heterocyclyl. (156): The compound of any one of embodiments 1-130, or a pharmaceutically acceptable salt or solvate thereof, wherein RL is an optionally substituted 4 to 5-membered C-heterocyclyl. (157): The compound of any one of embodiments 1-130, or a pharmaceutically acceptable salt or solvate thereof, wherein RL is an optionally substituted 4 to 6-membered C-heterocyclyl. (158): The compound 251 WSGR Ref: 60134-709.601 of any one of embodiments 1-130, or a pharmaceutically acceptable salt or solvate thereof, wherein RL is an optionally substituted 5 membered C-heterocyclyl. (159): The compound of any one of embodiments 1-130, or a pharmaceutically acceptable salt or solvate thereof, wherein RL is an optionally substituted oxetanyl. (160): The compound of any one of embodiments 1- 130, or a pharmaceutically acceptable salt or solvate thereof, wherein RL is an optionally substituted C-azetidinyl. (161): The compound of any one of embodiments 1-130, or a pharmaceutically acceptable salt or solvate thereof, wherein RL is optionally substituted -(C1-C3 alkylene)-N-(C1-C3 alkyl)(heteroaryl). (162): The compound of any one of embodiments 1-130, or a pharmaceutically acceptable salt or solvate thereof, wherein RL is optionally substituted - (C1-C2 alkylene)-O-(C1-C10 alkyl). (163): The compound of any one of embodiments 1-130, or a pharmaceutically acceptable salt or solvate thereof, wherein RL is optionally substituted -(C1 alkylene)-O-(C1-C10 alkyl). (164): The compound of any one of embodiments 1-130, or a pharmaceutically acceptable salt or solvate thereof, wherein RL is optionally substituted - CH2O(C1-C10 alkyl). (165): The compound of any one of embodiments 1-130, or a pharmaceutically acceptable salt or solvate thereof, wherein RL is selected from the group , compound of any one of embodiments 1-130, or a pharmaceutically acceptable salt or solvate thereof, wherein RL is selected from the group consisting of: , , , 252 WSGR Ref: 60134-709.601 embodiments 1-130, or a pharmaceutically acceptable salt or solvate thereof, wherein RL is selected from the group consisting of: , , , 253 WSGR Ref: 60134-709.601 embodiment 1, or pharmaceutically acceptable salt or solvate thereof, as provided in Table 1 or 2. (169): A compound, or pharmaceutically acceptable salt or solvate thereof, as provided in Table 1. (170): A compound, or pharmaceutically acceptable salt or solvate thereof, as provided in Table 2. (171): A pharmaceutical composition comprising a compound, or pharmaceutically acceptable salt or solvate thereof, as described in any one of embodiments 1-172 and a pharmaceutically acceptable excipient. (172): A method of preparing a pharmaceutical composition comprising mixing a compound, or pharmaceutically acceptable salt or solvate thereof, of any one of embodiments 1-172, and a pharmaceutically acceptable carrier. (173): A compound of any one of embodiments 1-172, or pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body. (174): A compound of any one of embodiments 1-172, or pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of infection by at least one Gram-negative pathogen. (175): Use of a compound of any one of embodiments 1-172, 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. (176): 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 embodiments 1-172, or pharmaceutically acceptable salt or 254 WSGR Ref: 60134-709.601 solvate thereof. (177): 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 embodiments 1-172, or pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient. (178): The use of embodiment 176 or 177, or the method of embodiment 178 or 179, 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. (179): The use of embodiment 176 or 177, or the method of embodiment 178 or 179, 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. (180): A method of inhibiting LpxH enzyme comprising contacting the enzyme with a compound of any one of embodiments 1-172 wherein the LpxH enzyme is contacted in an in vitro setting. (181): A method of inhibiting LpxH enzyme comprising contacting the enzyme with a compound of any one of embodiments 1-172, wherein the LpxH enzyme is contacted in an in vivo setting. 255

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; R1 is hydrogen, optionally substituted alkyl, -OH, -CN, -C(O)R8, or -C(O)N(R9)2; R8 is optionally substituted C1-C5 alkyl; each R9 is independently hydrogen or optionally substituted C1-C3 alkyl; or two R9 groups attached to the same atom are optionally cyclized to form a 3 to 6-membered heterocyclyl; RL is 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-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: 256 WSGR Ref: 60134-709.601 *-C(R4)2-C(R5)2-N(R3)-; where the * denotes the bond to N; each R4 is independently hydrogen, deuterium, or optionally substituted C1-C3 alkyl; or two R4 groups together form an oxo; or two R4 groups together form a 3- or 4-membered carbocyclyl; or two R4 groups together form a 4-membered heterocyclyl; each R5 is independently hydrogen, deuterium, halogen, or optionally substituted C1- C3 alkyl; or two R5 groups together form an oxo; or two R5 groups together form a 3- or 4-membered carbocyclyl; or two R5 groups together form 4-membered heterocyclyl; each R6 is independently hydrogen, deuterium, halogen, or optionally substituted C1- C3 alkyl; or two R6 groups together form an oxo; or two R6 groups together form a 3- or 4-membered carbocyclyl; or two R6 groups together form 4-membered heterocyclyl; each R7 is independently hydrogen, deuterium, or optionally substituted C1-C3 alkyl; or two R7 groups together form an oxo; or two R7 groups together form a 3- or 4-membered carbocyclyl; or two R7 groups together form 4-membered heterocyclyl; and R3 is hydrogen or optionally substituted C1-C3 alkyl; 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; 257 WSGR Ref: 60134-709.601 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; R1 is hydrogen, optionally substituted alkyl, -OH, -CN, -C(O)R8, or -C(O)N(R9)2; R8 is optionally substituted C1-C5 alkyl; each R9 is independently hydrogen or optionally substituted C1-C3 alkyl; or two R9 groups attached to the same atom are optionally cyclized to form a 3 to 6-membered heterocyclyl; RL is 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-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 R4 is independently hydrogen, deuterium, or optionally substituted C1-C3 alkyl; or two R4 groups together form an oxo; or two R4 groups together form a 3- or 4-membered carbocyclyl; or two R4 groups together form a 4-membered heterocyclyl; each R5 is independently hydrogen, deuterium, halogen, or optionally substituted C1- C3 alkyl; or two R5 groups together form an oxo; or two R5 groups together form a 3- or 4-membered carbocyclyl; or two R5 groups together form 4-membered heterocyclyl; each R6 is independently hydrogen, deuterium, halogen, or optionally substituted C1- C3 alkyl; or two R6 groups together form an oxo; or two R6 groups together form a 3- or 4-membered carbocyclyl; or two R6 groups together form 4-membered heterocyclyl; each R7 is independently hydrogen, deuterium, or optionally substituted C1-C3 alkyl; 258 WSGR Ref: 60134-709.601 or two R7 groups together form an oxo; or two R7 groups together form a 3- or 4-membered carbocyclyl; or two R7 groups together form 4-membered heterocyclyl; and R3 is 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; R1 is hydrogen, optionally substituted alkyl, -OH, -CN, -C(O)R8, or -C(O)N(R9)2; R8 is optionally substituted C1-C5 alkyl; each R9 is independently hydrogen or optionally substituted C1-C3 alkyl; or two R9 groups attached to the same atom are optionally cyclized to form a 3 to 6-membered heterocyclyl; RL is 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-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: 259 WSGR Ref: 60134-709.601 the * denotes the bond to N; each R4 is independently hydrogen, deuterium, or optionally substituted C1-C3 alkyl; or two R4 groups together form an oxo; or two R4 groups together form a 3- or 4-membered carbocyclyl; or two R4 groups together form a 4-membered heterocyclyl; each R5 is independently hydrogen, deuterium, halogen, or optionally substituted C1- C3 alkyl; or two R5 groups together form an oxo; or two R5 groups together form a 3- or 4-membered carbocyclyl; or two R5 groups together form 4-membered heterocyclyl; each R6 is independently hydrogen, deuterium, halogen, or optionally substituted C1- C3 alkyl; or two R6 groups together form an oxo; or two R6 groups together form a 3- or 4-membered carbocyclyl; or two R6 groups together form 4-membered heterocyclyl; each R7 is independently hydrogen, deuterium, or optionally substituted C1-C3 alkyl; or two R7 groups together form an oxo; or two R7 groups together form a 3- or 4-membered carbocyclyl; or two R7 groups together form 4-membered heterocyclyl; and R3 is 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. 260 WSGR 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; R1 is hydrogen, optionally substituted alkyl, -OH, -CN, -C(O)R8, or -C(O)N(R9)2; R8 is optionally substituted C1-C5 alkyl; each R9 is independently hydrogen or optionally substituted C1-C3 alkyl; 261 WSGR Ref: 60134-709.601 or two R9 groups attached to the same atom are optionally cyclized to form a 3 to 6-membered heterocyclyl; RL is 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-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 R4 is independently hydrogen, deuterium, or optionally substituted C1-C3 alkyl; or two R4 groups together form an oxo; or two R4 groups together form a 3- or 4-membered carbocyclyl; or two R4 groups together form a 4-membered heterocyclyl; and each R5 is independently hydrogen, deuterium, halogen, or optionally substituted C1-C3 alkyl; or two R5 groups together form an oxo; or two R5 groups together form a 3- or 4-membered carbocyclyl; or two R5 groups together form 4-membered heterocyclyl. 17. The compound of claim 16, or a pharmaceutically acceptable salt or solvate thereof, wherein, each R4 is independently hydrogen, deuterium, or optionally substituted C1-C3 alkyl; and each R5 is 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 R4 is 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 R5 is independently hydrogen, deuterium, or C1-C3 alkyl, 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 R4 is independently hydrogen, deuterium, or optionally substituted C1 alkyl; and each R5 is independently hydrogen, deuterium, or optionally substituted C1 alkyl. 20. The compound of claim 16 or 19, or a pharmaceutically acceptable salt or solvate thereof, wherein, 262 WSGR Ref: 60134-709.601 each R4 is 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 R5 is 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 R4 is independently hydrogen or deuterium; and each R5 is 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 R4 is independently hydrogen or deuterium; and each R5 is 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. 263 WSGR 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. 264 WSGR 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. 265 WSGR 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 of C1-C6 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 of L is -N(Rj)-, -C(Rn)2-, or -O-; RS is optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, optionally substituted C2-C5 alkynyl, -ORj, or -N(Rj)2; each RP is independently optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, optionally substituted C2-C5 alkynyl, -ORj, or -N(Rj)2; or two RP are taken together to form an optionally substituted 3 to 10-membered heterocyclyl; each Rj is independently hydrogen or optionally substituted C1-C3 alkyl; or two Rj groups are optionally cyclized to form an optionally substituted C3-C7 carbocyclyl; or two Rj groups are optionally cyclized to form an optionally substituted 3 to 7- membered heterocyclyl; each Rk is independently hydrogen, halogen, optionally substituted C1-C3 alkyl, or -OH; or two Rk groups attached to the same carbon atom are optionally cyclized to form a C3- C6 carbocyclyl; or two Rk groups attached to the same carbon atom are optionally cyclized to form a 3 to 6-membered heterocyclyl; each Rm is independently optionally substituted C1-C3 alkyl; 266 WSGR Ref: 60134-709.601 or two Rm groups are optionally cyclized to form an optionally substituted 3 to 6- membered heterocyclyl; each Rn is independently hydrogen, halogen, or optionally substituted C1-C3 alkyl; or two Rn groups attached to the same carbon atom are optionally cyclized to form a C3- C6 carbocyclyl; or two Rn groups 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 of 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-; RS is optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, optionally substituted C2-C5 alkynyl, -ORj, or -N(Rj)2; each RP is independently optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, optionally substituted C2-C5 alkynyl, -ORj, or -N(Rj)2; or two RP are taken together to form an optionally substituted 3 to 10-membered heterocyclyl; each Rj is independently hydrogen or optionally substituted C1-C3 alkyl; or two Rj groups are optionally cyclized to form an optionally substituted C3-C7 carbocyclyl; or two Rj groups are optionally cyclized to form an optionally substituted 3 to 7- membered heterocyclyl; each Rk is independently hydrogen, halogen, optionally substituted C1-C3 alkyl, or -OH; 267 WSGR Ref: 60134-709.601 or two Rk groups attached to the same carbon atom are optionally cyclized to form a C3- C6 carbocyclyl; or two Rk groups attached to the same carbon atom are optionally cyclized to form a 3 to 6-membered heterocyclyl; each Rm is independently optionally substituted C1-C3 alkyl; or two Rm groups are optionally cyclized to form an optionally substituted 3 to 6- membered heterocyclyl; each Rn is independently hydrogen, halogen, or optionally substituted C1-C3 alkyl; or two Rn groups attached to the same carbon atom are optionally cyclized to form a C3- C6 carbocyclyl; or two Rn groups 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-; RS is optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, optionally substituted C2-C5 alkynyl, -ORj, or -N(Rj)2; each Rj is hydrogen or -CH3; each Rn is independently hydrogen, -F, -Cl, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3. 268 WSGR 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: ; RS is optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, or optionally substituted C2-C5 alkynyl; each Rj is 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: ; RS is optionally substituted C1-C3 alkyl; and Rj is 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: ; RS is -CH3, -CH2F, -CHF2, -CF3, -CH2OCH3, -CH2NH2, or -CH2CH2NH2; and Rj is hydrogen or -CH3. 68. The compound of any one of claims 1-61, wherein B is substituted with one or more substituents selected from: ; RS is -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: ; RS is -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: 269 WSGR 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: ; RS is optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, or optionally substituted C2-C5 alkynyl. 74. The compound of any one of claims 1-61, wherein B is substituted with one or more substituents selected from: ; RS is -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: ; RS is -ORj, or -N(Rj)2; each Rj is independently hydrogen or optionally substituted C1-C3 alkyl; or two Rj groups are optionally cyclized to form an optionally substituted 3 to 7- membered heterocyclyl. 270 WSGR 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: ; RS is optionally substituted C1-C5 alkyl, optionally substituted C2-C5 alkenyl, or optionally substituted C2-C5 alkynyl; and each Rn is 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: ; RS is -CH3, -CH2F, -CHF2, -CF3, -CH2OCH3, -CH2NH2, or -CH2CH2NH2; and each Rn is 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: ; RS is -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: ; RS is -ORj, or -N(Rj)2; each Rn is independently hydrogen, -F, -Cl, or -CH3; each Rj is independently hydrogen or optionally substituted C1-C3 alkyl; or two Rj groups are optionally cyclized to form an optionally substituted 3 to 7- membered heterocyclyl. 271 WSGR 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 RP is independently optionally substituted C1-C3 alkyl; or two RP are 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 RP is independently optionally substituted C1-C3 alkyl; or two RP are 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: 272 WSGR Ref: 60134-709.601 alkyl, 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 Rj is 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 Rk is independently hydrogen, -F, or -CH3. 273 WSGR 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 Rj is independently hydrogen or -CH3. 274 WSGR 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 Rj is independently hydrogen or -CH3. each Rk is 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: . 275 WSGR 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 Rm is independently optionally substituted C1-C3 alkyl; or two Rm groups 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 each Rj is independently hydrogen or optionally substituted C1-C3 alkyl; or two Rj groups are optionally cyclized to form an optionally substituted C3-C7 carbocyclyl; or two Rj groups 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 each Rj is independently hydrogen or optionally substituted C1-C3 alkyl; or two Rj groups are optionally cyclized to form an optionally substituted C3-C7 carbocyclyl; or two Rj groups 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 . 276 WSGR 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: , 277 WSGR Ref: 60134-709.601 114. 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 , , 278 WSGR Ref: 60134-709.601 116. 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. 279 WSGR 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 C1 alkyl. 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. 280 WSGR 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 R1 is hydrogen. 134. The compound of claim 132, or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is optionally substituted alkyl. 135. The compound of claim 132, or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is 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 R1 is -H, -CH2CO2H, or -CH(CH3)CO2H. 137. The compound of claim 132, or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -CH2CO2H or -CH(CH3)CO2H. 138. The compound of claim 132, or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -CH2CO2H. 139. The compound of claim 132, or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -CH(CH3)CO2H. 140. The compound of claim 132, or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -OH. 141. The compound of claim 132, or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R8. 142. The compound of claim 132, or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)CH3. 143. The compound of claim 132, or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)N(R9)2. 144. The compound of claim 132 or 143, or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)N(CH3)2. 145. The compound of any one of claims 1-144, or a pharmaceutically acceptable salt or solvate thereof, wherein RL is optionally substituted C4-C10 alkyl, optionally substituted - (C1-C3 alkylene)-O-(C1-C8 alkyl), optionally substituted -(C1-C3 alkylene)-N(C1-C3 281 WSGR 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 RL is 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-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 RL is optionally substituted C4-C10 alkyl, 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 RL is optionally substituted C5-C12 alkyl, optionally substituted - (C1-C3 alkylene)-O-(C1-C10 alkyl), optionally substituted -(C1-C3 alkylene)-N(C1-C3 alkyl)(heteroaryl), optionally substituted 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 RL is optionally substituted C4-C12 alkyl, optionally substituted - (C1-C3 alkylene)-O-(C1-C10 alkyl), optionally substituted C4-C12 alkenyl, 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 RL is optionally substituted C4-C12 alkyl, 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 RL is optionally substituted C5-C12 alkyl, optionally substituted C5-C12 alkenyl, or optionally substituted C5-C12 alkynyl. 282 WSGR Ref: 60134-709.601 152. The compound of any one of claims 1-144, or a pharmaceutically acceptable salt or solvate thereof, wherein RL is optionally substituted C6-C12 alkyl, optionally substituted C6-C12 alkenyl, or optionally substituted C6-C12 alkynyl. 153. The compound of any one of claims 1-144, or a pharmaceutically acceptable salt or solvate thereof, wherein RL is 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 RL is 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 RL is an unsubstituted, linear C4-C10 alkyl. 156. The compound of any one of claims 1-144, or a pharmaceutically acceptable salt or solvate thereof, wherein RL is 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 RL is an optionally substituted C4-C10 alkenyl. 158. The compound of any one of claims 1-144, or a pharmaceutically acceptable salt or solvate thereof, wherein RL is 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 RL is 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 RL is an optionally substituted carbocyclyl. 161. The compound of any one of claims 1-144, or a pharmaceutically acceptable salt or solvate thereof, wherein RL is 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 RL is an optionally substituted C4-C8 carbocyclyl. 163. The compound of any one of claims 1-144, or a pharmaceutically acceptable salt or solvate thereof, wherein RL is 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 RL is 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 RL is an optionally substituted aralkyl. 166. The compound of any one of claims 1-144, or a pharmaceutically acceptable salt or solvate thereof, wherein RL is an optionally substituted heteroarylalkyl. 167. The compound of any one of claims 1-144, or a pharmaceutically acceptable salt or solvate thereof, wherein RL is an optionally substituted carbocyclylalkyl. 168. The compound of any one of claims 1-144, or a pharmaceutically acceptable salt or solvate thereof, wherein RL is an optionally substituted heterocyclylalkyl. 283 WSGR Ref: 60134-709.601 169. The compound of any one of claims 1-144, or a pharmaceutically acceptable salt or solvate thereof, wherein RL is an optionally substituted C-heterocyclyl. 170. The compound of any one of claims 1-144, or a pharmaceutically acceptable salt or solvate thereof, wherein RL is 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 RL is 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 RL is 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 RL is 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 RL is 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 RL is an optionally substituted C-pyperidinyl. 176. The compound of any one of claims 1-144, or a pharmaceutically acceptable salt or solvate thereof, wherein RL is 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 RL is an optionally substituted oxetanyl. 178. The compound of any one of claims 1-144, or a pharmaceutically acceptable salt or solvate thereof, wherein RL is an optionally substituted C-azetidinyl. 179. The compound of any one of claims 1-144, or a pharmaceutically acceptable salt or solvate thereof, wherein RL is optionally substituted -(C1-C3 alkylene)-N-(C1-C3 alkyl)(heteroaryl). 180. The compound of any one of claims 1-144, or a pharmaceutically acceptable salt or solvate thereof, wherein RL is 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 RL is optionally substituted -(C1 alkylene)-O-(C1-C10 alkyl). 182. The compound of any one of claims 1-144, or a pharmaceutically acceptable salt or solvate thereof, wherein RL is optionally substituted -CH2O(C1-C10 alkyl). 183. The compound of any one of claims 1-144, or a pharmaceutically acceptable salt or solvate thereof, wherein RL is selected from the group consisting of: , , 284 WSGR Ref: 60134-709.601 184. The compound of any one of claims 1-144, or a pharmaceutically acceptable salt or solvate thereof, wherein RL is 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 RL is 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 RL is selected from the group consisting of: , 285 WSGR Ref: 60134-709.601 286 WSGR Ref: 60134-709.601 . 187. The compound of any one of claims 1-144, or a pharmaceutically acceptable salt or solvate thereof, wherein RL is selected from the group consisting of: , 287 WSGR Ref: 60134-709.601 . 188. The compound of any one of claims 1-144, or a pharmaceutically acceptable salt or solvate thereof, wherein RL is selected from the group consisting of: , 288 WSGR Ref: 60134-709.601 189. 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. 289 WSGR 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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WO2022220725A1 (en) * 2021-04-16 2022-10-20 Edouard Zamaratski Lpxh inhibitors as anti-infective agents
WO2023166103A1 (en) * 2022-03-04 2023-09-07 F. Hoffmann-La Roche Ag Benzamide compounds for treatment of bacterial infections

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022220725A1 (en) * 2021-04-16 2022-10-20 Edouard Zamaratski Lpxh inhibitors as anti-infective agents
WO2023166103A1 (en) * 2022-03-04 2023-09-07 F. Hoffmann-La Roche Ag Benzamide compounds for treatment of bacterial infections

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