WO2025207665A1 - Composés de quinolinone et leurs utilisations - Google Patents

Composés de quinolinone et leurs utilisations

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Publication number
WO2025207665A1
WO2025207665A1 PCT/US2025/021387 US2025021387W WO2025207665A1 WO 2025207665 A1 WO2025207665 A1 WO 2025207665A1 US 2025021387 W US2025021387 W US 2025021387W WO 2025207665 A1 WO2025207665 A1 WO 2025207665A1
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Prior art keywords
alkyl
independently selected
carbocycle
optionally substituted
substituents independently
Prior art date
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Pending
Application number
PCT/US2025/021387
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English (en)
Inventor
Natalie Anne Hawryluk
Stephen Thomas Schlachter
Kevin Koch
Michael Joseph Luzzio
Alan James Russell
Marc Justin Evanchik
Christina Elizabeth WONG
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Edgewise Therapeutics Inc
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Edgewise Therapeutics Inc
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Publication of WO2025207665A1 publication Critical patent/WO2025207665A1/fr
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
    • 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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • 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
    • C07D401/12—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 chain containing hetero atoms as chain links
    • 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
    • C07D401/14—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 three or more hetero rings
    • 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
    • C07D405/14—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 three or more hetero rings
    • 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
    • C07D487/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/08—Bridged systems

Definitions

  • Obesity is a medical condition involving excess body fat accumulated to such an extent that it can potentially have negative effects on health.
  • Obesity is a major cause of disability and is correlated with various diseases and conditions, particularly cardiovascular diseases, type 2 diabetes, obstructive sleep apnea, certain types of cancer, and osteoarthritis.
  • Obesity is a leading preventable cause of death worldwide, with increasing rates in adults and children. In 2022, over 1 billion people were obese worldwide. Excess body fat underlies 64% of cases of diabetes in men and 77% of cases in women.
  • the present disclosure provides a compound represented by Formulas (I), (I-A), (II), (II-A), (III), (IV), or (V).
  • R 1 is selected from: hydrogen
  • R 1 together with R 2 form a C3-10 cycloalkyl, C5-10 cycloalkenyl, 3- to 10- membered heterocycloalkyl, or 5- to 10-membered heterocycloalkenyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -0R 8a , -SR 8a , -N(R 8a ) 2 , -C(0)R 8a , -C(O)N(R 8a ) 2 , -N(R 8a )C(O)R 8a , - N(R 8a )C(O)N(R 8a ) 2 , -OC(O)N(R 8a ) 2 , -N(R 8a )C(O)OR 8a , -C(0)0R 8a , -0C(0)R 8a , - S(O)R 8a , -S(O) 2 R 8a , -N0
  • R 1 together with R 2 form a C3-10 cycloalkyl, C5-10 cycloalkenyl, 3- to 10- membered heterocycloalkyl, or 5- to 10-membered heterocycloalkenyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -0R 8a , -SR 8a , -N(R 8a ) 2 , -C(0)R 8a , -C(O)N(R 8a ) 2 , -N(R 8a )C(O)R 8a , - N(R 8a )C(O)N(R 8a ) 2 , -OC(O)N(R 8a ) 2 , -N(R 8a )C(O)OR 8a , -C(0)0R 8a , -0C(0)R 8a , - S(O)R 8a , -S(O) 2 R 8a , -NO2,
  • Ci-6 alkyl optionally substituted with one or more substituents independently selected from R 7c ; or
  • R 4 is selected from: halogen, -0R 8d , -SR 8d , -N(R 8d ) 2 , -N0 2 , and -CN;
  • C1-6 alkyl substituted with one or more substituents independently selected from - Cl, -Br, -0R 8d , -SR 8d , -N(R 8d ) 2 , -N0 2 , and -CN, C3-10 carbocycle, and 3- to 10-membered heterocycle, wherein each C3-10 carbocycle and 3- to 10-membered heterocycleis optionally substituted with one or more substituents independently selected from R 7d ; and
  • C1-6 alkyl optionally substituted with one or more substituents independently selected from-Cl, -Br, -0R 8e , -SR 8e , -N(R 8e ) 2 , -N0 2 , and -CN, C3-10 carbocycle, and 3- to 10-membered heterocycle, wherein the C3-10 carbocycle, and 3- to 10-membered heterocycle, are each optionally substituted with one or more substituents independently selected from R 7e ; or R 4 and R 4a together form a C4-10 carbocycle, or 3- to 10-membered heterocycle, wherein the C3-10 carbocycle, or 3- to 10-membered heterocycle, is optionally substituted with one or more substituents independently selected from R 7e ;
  • R 6 is selected from: hydrogen;
  • each R 7 , R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , and R 7g is independently selected from: hydrogen, halogen, -CN, -OH, -SH, -NO2, -NH2, -O-C1-6 alkyl, -S-C1-6 alkyl, - N(CI-6 alkyl)2, and -NH(CI-6 alkyl); and
  • C x -y or “C x -C y ” (e.g., when used in conjunction with a chemical moiety, such as alkyl, alkenyl, or alkynyl) is meant to include groups that comprise a number of carbon atoms greater than or equal to x carbon atoms and less than or equal to y carbon atoms in the chemical moiety, subject to the following.
  • the term “C x.y ” or “C x -C y ” is not meant to limit the number of carbon atoms which may be attached to the chemical moiety when the chemical moiety is substituted with a second chemical moiety.
  • C1-6 alkyl or “Ci to Ce alkyl” refers to saturated, substituted or unsubstituted, hydrocarbon groups, including straight-chain alkyl groups (e.g., linear alkyl groups) and branched alkyl groups that contain 1, 2, 3, 4, 5, or 6 carbon atoms, plus however many carbon atoms may be present in any substituents of the C1-6 alkyl.
  • a C1-6 alkyl is optionally substituted with a second chemical moiety comprising two carbon atoms, then it will be understood that the Ci-6 alkyl can include between 1 and 8 carbon atoms.
  • C x -yalkenyl and C x -yalkynyl refer to substituted or unsubstituted unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond, respectively.
  • Amino refers to the -NH2 moiety.
  • Cyano refers to the -CN moiety.
  • Niro refers to the -NO2 moiety.
  • Oxa refers to the -O- moiety.
  • Alkyl refers to a straight (e.g., linear) or branched (e.g., nonlinear) hydrocarbon moiety consisting solely of carbon and hydrogen atoms, fully saturated.
  • “alkyl” comprises 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 one to eight carbon atoms (e.g., Ci-Cs alkyl).
  • an alkyl comprises one to six carbon atoms (e.g., Ci-Ce alkyl).
  • 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., Ci alkyl, e.g., methyl).
  • an alkyl comprises five to fifteen carbon atoms (e.g., C5-C15 alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (e.g., Cs-Cs 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).
  • the alkyl group is selected from methyl, ethyl, 1 -propyl (//-propyl), 1 -methylethyl (2- propyl, /.w-propyl), 1 -butyl (//-butyl), 1 -methylpropyl (.scc-butyl), 2-methylpropyl (/.w-butyl), 1,1 -dimethylethyl (tert-butyl), and 1 -pentyl (//-pentyl).
  • the alkyl is attached to the rest of the molecule by a single bond.
  • Aminoalkyl refers to a moiety bonded through a nitrogen atom of the form -N(H)(alkyl) or N(alkyl)(alkyl), wherein when the moiety is N(alkyl)(alkyl), the two alkyl groups bonded to nitrogen can be the same alkyl groups or different alkyl groups.
  • Alkoxy refers to a moiety bonded through an oxygen atom of the formula -O-alkyl, where alkyl is an alkyl chain as defined above.
  • alkenyl refers to a straight (e.g., linear) or branched (e.g., nonlinear) hydrocarbon moiety consisting solely of carbon and hydrogen atoms, the moiety comprising at least one carbon-carbon double bond.
  • an alkenyl comprises two to twelve carbon atoms.
  • an alkenyl comprises two to eight carbon atoms.
  • an alkenyl comprises two to four carbon atoms.
  • alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (e.g., vinyl), prop-l-enyl (e.g., allyl), but-l-enyl, pent-l-enyl, penta- 1,4-dienyl, and the like.
  • ethenyl e.g., vinyl
  • prop-l-enyl e.g., allyl
  • but-l-enyl e.g., pent-l-enyl, penta- 1,4-dienyl, and the like.
  • Alkylene or “alkylene chain” refers to a linear (e.g., straight), or branched (e.g., nonlinear), divalent, hydrocarbon moiety.
  • An “alkylene” or “alkylene chain” can link a portion of the molecule to a second moiety.
  • An “alkylene” or “alkylene chain” consists solely of carbon and hydrogen atoms (substitution of an alkylene with one or more substituents comprising atoms other than hydrogen, such as N, O, and S, may be specified).
  • An “alkylene” or “alkylene chain” can contain no unsaturation (notwithstanding the points of attachment of an alkylene to the rest of the molecule).
  • the “alkylene” or “alkylene chain” comprises one to twelve carbon atoms, for example, methylene, ethylene, propylene, ⁇ -butylene, and the like.
  • the alkylene chain can be attached to the portion of the molecule through a single bond and to the second moiety through a single bond.
  • the points of attachment of an alkylene chain to the rest of the molecule and to the second moiety can be through one carbon atom in the alkylene chain or can be through any two carbon atoms within the alkylene.
  • an alkylene comprises one to eight carbon atoms (e.g., Ci-Cs alkylene).
  • 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., Ci alkylene). In other embodiments, an alkylene comprises five to eight carbon atoms (e.g., Cs-Cs 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).
  • an "alkenylene” or “alkenylene chain” comprises from two to twelve carbon atoms.
  • the alkenylene chain can be attached to the portion of the molecule through a single bond and to the second moiety through a single bond.
  • the points of attachment of an alkenylene chain to the rest of the molecule and to the second moiety can be through one carbon atom in the alkenylene chain or through any two carbon atoms within the alkenylene chain.
  • an alkenylene comprises two to eight carbon atoms (e.g., C2-C8 alkenylene).
  • an alkenylene comprises two to five carbon atoms (e.g.,
  • an alkenylene comprises two to four carbon atoms (e.g.,
  • an alkenylene comprises two to three carbon atoms (e.g.,
  • an alkenylene comprises two to five carbon atoms (e.g.,
  • an alkenylene comprises three to five carbon atoms (e.g., C3-C5 alkenylene).
  • Alkynylene or “alkynylene chain” refers to a linear (e.g., straight), or branched, divalent, hydrocarbon moiety.
  • An “alkynylene” or “alkynylene chain” can link a portion of the molecule to a second moiety.
  • An “alkynylene” or “alkynylene chain” consists solely of carbon and hydrogen (substitution of an alkynylene with one or more substituents comprising atoms other than hydrogen, such as N, O, and S, may be specified).
  • An “alkynylene” or “alkynylene chain” comprises at least one carbon-carbon triple bond.
  • 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., Cs-Cs alkynylene). In other embodiments, an alkynylene comprises three to five carbon atoms e.g., C3- C5 alkynylene).
  • carrier refers to a saturated or unsaturated (e.g., aromatic or nonaromatic unsaturated) ring or ring system in which each atom of the ring is carbon.
  • the term “carbocycle” comprises “aryls,” “cycloalkenyls,” and “cycloalkyls.”
  • the term “carbocycle” includes 3- to 12-membered monocyclic rings (e.g., 3- to 10- membered monocyclic rings) and 4- to 20-membered polycyclic ring systems (e.g., 5- to 15-membered spiro polycyclic ring systems, 5- to 15-membered bridged polycyclic ring systems, or 4- to 15-membered fused polycyclic ring systems).
  • carbocycle includes ring systems that are both fused and bridged; ring systems that are both fused and spiro; ring systems that are both bridged and spiro; and ring systems that are both fused and bridged and are also spiro.
  • Each ring of a polycyclic carbocycle may be selected from saturated and unsaturated (e.g., aromatic or nonaromatic unsaturated) rings.
  • an aromatic ring (e.g., phenyl) of a polycyclic carbocycle may be fused to a saturated or unsaturated ring (e.g., cyclohexane, cyclopentane, cyclohexene, or phenyl).
  • a polycyclic carbocycle includes any combination of saturated and unsaturated (e.g., aromatic or nonaromatic unsaturated) rings, as valence permits.
  • polycyclic carbocycles can be spiro bicyclic rings, such as spiropentane.
  • Exemplary carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, naphthyl, traw -bicyclo[4.4.0]decane, cis- bicylo[4.4.0]decane, spiro[3.4]octane, fluoranthene, and bicyclo[l. l.l]pentanyl.
  • a carbocycle may be bridged, fused, spiro, or any combination thereof.
  • a carbocycle is a bridged carbocycle.
  • a carbocycle is a fused carbocycle.
  • a carbocycle is a spiro carbocycle. In some embodiments, a carbocycle is a bridged and fused carbocycle. In some embodiments, a carbocycle is a bridged and spiro carbocycle. In some embodiments, a carbocycle is a fused and spiro carbocycle. In some embodiments, a carbocycle is a bridged, fused and spiro carbocycle.
  • aryl refers to an aromatic monocyclic or aromatic polycyclic hydrocarbon ring system comprising at least one cyclic, delocalized (4n+2) ⁇ -electronic system, wherein n is an integer greater than or equal to 0, in accordance with Huckel theory.
  • the aromatic monocyclic or aromatic polycyclic hydrocarbon ring system comprises only hydrogen atoms and carbon atoms.
  • the aromatic monocyclic or polycyclic system contains from three to twenty carbon atoms.
  • at least one of the rings in the polycyclic aromatic ring system is aromatic.
  • the aryl substituent bears no net charge and is not zwitterionic. In some embodiments, none of the carbon atoms of the aryl substituent are charged. In some embodiments, none of the carbon atoms of the aryl substituent are charged.
  • cycloalkyl refers to a saturated ring in which each atom of the ring is carbon.
  • Cycloalkyl may include monocyclic and polycyclic rings such as 3- to 10-membered monocyclic rings, 5- to 12-membered bicyclic rings, 5- to 12-membered spiro bicycles, and 5- to 12-membered bridged rings.
  • a cycloalkyl comprises three to ten carbon atoms.
  • a cycloalkyl comprises three to seven carbon atoms.
  • a cycloalkyl comprises five to seven carbon atoms.
  • the cycloalkyl may be attached to the rest of the molecule by a single bond.
  • Examples of monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Examples of polycyclic cycloalkyls include, but are not limited to, adamantyl, spiropentane, norbornyl (e.g., bicyclo[2.2.1]heptanyl), decalinyl, 7,7 dimethyl bicyclo[2.2.1]heptanyl, bicyclofl. l.l]pentanyl, spiropentane, and the like.
  • cycloalkenyl refers to a saturated ring in which each atom of the ring is carbon and there is at least one double bond between two ring carbon atoms.
  • Cycloalkenyl may include monocyclic and polycyclic rings, such as 3- to 10-membered monocyclic rings and 4- to 12- membered bicyclic rings (e.g., 5- to 12-membered bridged bicyclic rings, fused 4- to 12-membered bicyclic rings, and spiro 5- to 12-membered bicyclic rings).
  • a cycloalkenyl comprises five to seven carbon atoms.
  • the cycloalkenyl may be attached to the rest of the molecule by a single bond. Examples of monocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.
  • halo or, alternatively, “halogen” or “halide,” means fluoro, chloro, bromo or iodo. In some embodiments, a halo is fluoro, chloro, or bromo. In some embodiments, a halo is a fluoro or a chloro. In some embodiments, a halo is a fluoro. In some embodiments, a halo is a chloro.
  • haloalkyl refers to an alkyl, as defined above, that is substituted by one or more halogens, for example, trifluoromethyl, dichloromethyl, bromomethyl, 2,2,2-trifluoroethyl, l-chloromethyl-2-fluoroethyl, and the like.
  • the alkyl part of the haloalkyl is optionally further substituted as described herein.
  • a heterocycle is a bridged and fused heterocycle.
  • a heterocycle is a bridged and spiro heterocycle.
  • a heterocycle is a fused and spiro heterocycle.
  • a heterocycle is a bridged, fused and spiro heterocycle.
  • heterocycles include 4- to 20-membered bicyclic ring systems (e.g., 4- to 15-membered fused bicyclic ring systems, 5- to 15-membered spiro bicyclic ring systems, and 5- to 15-membered bridged bicyclic ring systems).
  • heterocycle includes tricyclic ring systems, which may be bridged, fused, spiro, or a combination thereof.
  • heterocycle includes tetracyclic ring systems, which may be bridged, fused, spiro, or a combination thereof.
  • heterocycle includes ring systems that are both fused and bridged; ring systems that are both fused and spiro; ring systems that are both bridged and spiro; and ring systems that are both fused and bridged and are also spiro.
  • Each ring of a polycyclic heterocycle may be selected from saturated and unsaturated (e.g., aromatic or nonaromatic unsaturated) rings.
  • a polycyclic heterocycle includes any combination of saturated, and unsaturated (e.g., aromatic or nonaromatic unsaturated) rings, as valence permits.
  • an aromatic ring e.g., pyridyl or phenyl
  • a polycyclic heterocycle includes any combination of ring sizes such as 3-3 spiro, 4-5 fused ring systems, 5-5 fused ring systems, 5-6 fused ring systems, 6-6 fused ring systems, 5-7 fused ring systems, 6-7 fused ring systems, 5-8 fused ring systems, and 6-8 fused ring systems.
  • a bicyclic heterocycle further includes spiro bicyclic rings, e.g., 5 to 12-membered spiro bicycles, such as 2-oxa-6-azaspiro[3.3]heptane.
  • a heterocycle comprises multiple heteroatoms.
  • a heterocycle comprises an atom selected from nitrogen, oxygen, and sulfur.
  • a heterocycle comprises multiple atoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a heterocycle comprises one or more atom(s) selected from nitrogen, oxygen, and sulfur. In some embodiments, a heterocycle comprises one or more atom(s) selected from nitrogen and oxygen. In some embodiments, a heterocycle comprises one or more atom(s) selected from nitrogen and sulfur. In some embodiments, a heterocycle comprises one or more atom(s) selected from oxygen and sulfur. In some embodiments, a heterocycle comprises one or more atom(s) selected from nitrogen. In some embodiments, a heterocycle comprises one or more atom(s) selected from oxygen. In some embodiments, a heterocycle comprises one or more atom(s) selected from sulfur.
  • a heterocycle does not comprise Boron in the ring. In some embodiments, a heterocycle does not comprise Phosphorus in the ring. In some embodiments, a heterocycle does not comprise Sulfur in the ring. In some embodiments, a heterocycle does not comprise Oxygen in the ring. In some embodiments, a heterocycle does not comprise Nitrogen in the ring. In some embodiments, a heterocycle comprises only heteroatoms selected from nitrogen, oxygen, and sulfur in the ring, and the heterocycle comprises no other heteroatoms in the ring.
  • heterocycles include azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzoxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[Z>][l,4]dioxepinyl, benzo[b][l,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodi oxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotri azolyl, benzo[4,6]imidazo[l,2-a]pyridin
  • a heterocycle comprises a moiety selected from a heteroaryl, a heterocycloalkyl, and a heterocycloalkenyl.
  • the heterocycle is a heteroaryl.
  • the heterocycle is a heterocycloalkyl.
  • the heterocycle is a heterocycloalkenyl.
  • a heterocycle comprises an atom selected from nitrogen and oxygen. In some embodiments, a heterocycle comprises an atom selected from nitrogen and sulfur. In some embodiments, a heterocycle comprises an atom selected from oxygen and sulfur. In some embodiments, a heterocycle comprises an atom selected from nitrogen. In some embodiments, a heterocycle comprises an atom selected from oxygen. In some embodiments, a heterocycle comprises an atom selected from sulfur.
  • a heterocycle comprises 1 to 8 heteroatoms. In some embodiments, the heterocycle comprises 1 to 5 heteroatoms. In some embodiments, the heterocycle comprises 1 to 3 heteroatoms. In some embodiments, the heterocycle comprises 1 to 2 heteroatoms. In some embodiments, the heterocycle comprises 1 heteroatom. In some embodiments, the heterocycle comprises 2 heteroatoms. In some embodiments, the heterocycle comprises 3 heteroatoms. In some embodiments, the heterocycle comprises 4 heteroatoms. In some embodiments, the heterocycle comprises 5 heteroatoms. In some embodiments, the heterocycle comprises 6 heteroatoms.
  • a heterocycle comprises a 3-memberd ring, 4-membered ring, 5- membered ring, 6-membered ring, 7-membered ring, 8-membered ring, 9-membered ring, 10- membered ring, 11 -membered ring, 12-membered ring, 13 -membered ring, 14-membered ring, or 15-20 membered ring.
  • a heterocycle is 3- to 10-membered.
  • a heterocycle is 3- to 6-membered.
  • a heterocycle is 5- to 6- membered.
  • a heterocycle is 9- to 10-membered.
  • a heterocycle is 9- to 11 -membered. In some embodiments, a heterocycle is 9- to 15-membered. [0040] In some embodiments, the heterocycle is monosubstituted, di substituted, tri substituted, tetrasubstituted, or pentasubstituted (e.g., with further substituents in addition to the point of attachment). In some embodiments, the total number of substituents (e.g., atoms other than hydrogen) on the heterocycle (e.g., bonded to the ring of the heterocycle) is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more.
  • one or more nitrogen atoms in the molecule or moiety (e.g., in a heterocycle), can be optionally quaternized.
  • the heterocycle substituent is positively charged, some embodiments, the heterocycle moiety is neutral. In some embodiments, the heterocycle substituent is zwitterionic. Alternatively, or in addition, in some embodiments, the heterocycle substituent is not charged. In some embodiments, the heterocycle substituent bears no charges. In some embodiments, the heterocycle substituent bears no net charge. In some embodiments, no atoms within the heterocycle substituent bear any net charge. In some embodiments, the heterocycle substituent bears no net charge and is not zwitterionic.
  • heteroaryl refers to a moiety derived from an aromatic monocyclic or aromatic polycyclic ring system, in which one or more heteroatom(s) is(are) member(s) of the ring system, and the ring system comprises at least one cyclic, delocalized (4n+2) ⁇ -electronic system, wherein n is an integer greater than or equal to 0, in accordance with Huckel theory.
  • one or more heteroatom(s) is(are) member(s) of the ring system comprising the cyclic, delocalized (4n+2) ⁇ -electronic system (e.g., the ring with aromaticity).
  • Exemplary heteroatoms include N, O, Si, P, B, and S atoms.
  • the heteroaryl moiety is a monocyclic or polycyclic (e.g., bicyclic, tricyclic or tetracyclic) ring system, wherein at least one of the rings in the ring system is aromatic, e.g., it contains a cyclic, delocalized (4n+2) 7t-electron system in accordance with the Hiickel theory.
  • Heteroaryl includes fused, bridged, and spiro ring systems.
  • the heteroatom(s) in the heteroaryl moiety is(are) optionally oxidized.
  • One or more nitrogen atom(s), if present, is(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[Z>][l,4]dioxepinyl, benzo[b][l,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotri azolyl, benzo[4,6]imidazo[l,2-a]pyridinyl,
  • heteroaryl examples include 5, 6,7,8- tetrahydroquinoline; l,2,3,4-tetrahydro-l,8-naphthyridine; 6,7-dihydro-5H-cyclopenta[b]pyridine; 2,3-dihydro-lH-pyrrolo[2,3-b]pyridine; 4,5,6,7-tetrahydrobenzofuran; 4,5,6,7-tetrahydrofuro[2,3- b]pyridine; 5,6-dihydro-4H-cyclopenta[b]furan; 4,5-dihydrothieno[2,3-b]furan.
  • the heteroaryl substituent is positively or negatively charged. In some embodiments, the heteroaryl substituent is neutral. In some embodiments, the heteroaryl substituent is zwitterionic; alternatively, or in addition, in some embodiments, the heteroaryl substituent is not charged. In some embodiments, the heteroaryl substituent bears no charges. In some embodiments, the heteroaryl substituent bears no net charge. In some embodiments, the heteroaryl substituent bears no net charge and is not zwitterionic.
  • heterocycle comprises “heteroaryls,” “heterocycloalkenyls,” and “heterocycloalkyls.”
  • a heterocycloalkyl may be covalently bound to one or more carbocycle(s) or heterocycle(s).
  • exemplary heteroatoms include N, O, Si, P, B, and S atoms.
  • Heterocycloalkyl may include monocyclic and polycyclic rings such as 3- to 10-membered monocyclic rings, 6- to 12- membered bicyclic rings, 5- to 12-membered spiro bicycles, or 5- to 12-membered bridged rings.
  • the heteroatoms in the heterocycloalkyl radical are optionally oxidized.
  • One or more nitrogen atoms, if present, are optionally quatemized.
  • heterocycloalkyl is attached to the rest of the molecule through any atom of the heterocycloalkyl, valence permitting, such as any carbon or nitrogen atoms of the heterocycloalkyl.
  • heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl,
  • a heterocycloalkyl comprises one heteroatom. In some embodiments, a heterocycloalkyl comprises one heteroatom selected from N, O, and S. In some embodiments, a heterocycloalkyl comprises multiple heteroatoms. In some embodiments, a heterocycloalkyl comprises multiple heteroatoms selected from N, O, and S.
  • heterocycloalkenyl refers to a moiety comprising an unsaturated ring (e.g., a ring with either single bonds or double bonds connecting the members of the ring): wherein the unsaturated ring comprises carbon atoms and one or more heteroatom(s); wherein the unsaturated ring may be optionally fused, bridged with, or spiro to an additional ring, wherein the additional ring may comprise only carbon atoms as members of the additional ring or wherein the additional ring may comprise one or more heteroatom(s) as member(s) of the additional ring; and wherein there is at least one double bond between two ringcarbon atoms (e.g., carbon atoms that are members of the unsaturated ring).
  • unsaturated ring e.g., a ring with either single bonds or double bonds connecting the members of the ring
  • Heterocycloalkenyl does not include heteroaryl rings.
  • Exemplary heteroatoms include N, O, Si, P, B, and S atoms.
  • Heterocycloalkenyl may include monocyclic and polycyclic rings such as 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and 5- to 12-membered bridged rings.
  • a heterocycloalkenyl comprises five to seven ring atoms.
  • the heterocycloalkenyl may be attached to the rest of the molecule by a single bond.
  • Examples of monocyclic cycloalkenyls include, e.g., pyrroline (dihydropyrrole), pyrazoline (dihydropyrazole), imidazoline (dihydroimidazole), triazoline (dihydrotriazole), dihydrofuran, dihydrothiophene, oxazoline (dihydrooxazole), isoxazoline (dihydroisoxazole), thiazoline (dihydrothiazole), isothiazoline (dihydroisothiazole), oxadiazoline (dihydrooxadiazole), thiadiazoline (dihydrothiadiazole), dihydropyridine, tetrahydropyridine, dihydropyridazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyrazine,
  • a “spirocyclic” moiety e.g., a “spiro” moiety
  • a spirocyclic heterocycle e.g., a spirocyclic heterocycloalkenyl, a spirocyclic carbocycle, a spirocyclic heterocycloalkyl, a spirocyclic cycloalkenyl, or a spirocyclic cycloalkyl
  • a polycyclic system e.g., bicyclic, tricyclic, tetracyclic
  • spirocyclic moieties include, but are [0046]
  • a spirocyclic heterocycle comprises a spirocyclic moiety that comprises at least one heteroatom in the ring system of the spirocyclic moiety.
  • Examples of spirocyclic heterocycles include, but are [0046]
  • the design of a prodrug increases the lipophilicity of the pharmaceutical agent. In some embodiments, the design of a prodrug increases the effective water solubility. See, e.g., Fedorak et al., Am. J. Physiol., 269:G210-218 (1995); McLoed c/ a/., Gastroenterol, 106:405-413 (1994); Hochhaus et al., Biomed. Chrom., 6:283-286 (1992); J. Larsen and H. Bundgaard, Int. J. Pharmaceutics, 37, 87 (1987); J. Larsen et al., Int. J.
  • the present disclosure provides methods of producing the above-defined compounds.
  • the compounds may be synthesized using conventional techniques.
  • these compounds are conveniently synthesized from readily available starting materials.
  • X 1 , X 2 , X 3 , and X 4 are independently selected from C(R°) and N; each R° is independently selected from: hydrogen, halogen, -NO 2 , -CN, -N 3 , -OR 8 , -SR 8 , -N(R 8 ) 2 , -C(O)R 8 , -C(O)N(R 8 ) 2 , -N(R 8 )C(O)R 8 , -N(R 8 )C(O)N(R 8 ) 2 , -OC(O)N(R 8 ) 2 , -N(R 8 )C(O)OR 8 , -C(O)OR 8 , -C(O)OR 8 , - OC(O)R 8 , -S(O)R 8 , and -S(O) 2 R 8 ;
  • R 2 is selected from: hydrogen
  • R 1 together with R 2 form a C3-10 cycloalkyl, C5-10 cycloalkenyl, 3- to 10- membered heterocycloalkyl, or 5- to 10-membered heterocycloalkenyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -0R 8a , -SR 8a , -N(R 8a ) 2 , -C(0)R 8a , -C(O)N(R 8a ) 2 , -N(R 8a )C(O)R 8a , - N(R 8a )C(O)N(R 8a ) 2 , -OC(O)N(R 8a ) 2 , -N(R 8a )C(O)OR 8a , -C(0)0R 8a , -0C(0)R 8a , - S(O)R 8a , -S(O) 2 R 8a , -N0
  • R 3 is selected from: hydrogen;
  • R 4 is selected from: halogen, -0R 8d , -SR 8d , -N(R 8d ) 2 , -N0 2 , and -CN;
  • R 4 and R 4a together form a C4-10 carbocycle, or 3- to 10-membered heterocycle, wherein the C3-10 carbocycle, or 3- to 10-membered heterocycle, is optionally substituted with one or more substituents independently selected from R 7e ;
  • C1-6 alkyl optionally substituted with one or more substituents independently selected from-Cl, -Br, -OR 8e , -SR 8e , -N(R 8e )2, -NO2, and -CN, C3-10 carbocycle, and 3- to 10-membered heterocycle, wherein the C3-10 carbocycle, and 3- to 10-membered heterocycle, are each optionally substituted with one or more substituents independently selected from R 7e ; or R 4 and R 4a together form a C4-10 carbocycle, or 3- to 10-membered heterocycle, wherein the C3-10 carbocycle, or 3- to 10-membered heterocycle, is optionally substituted with one or more substituents independently selected from R 7e ;
  • X 1 , X 2 , X 3 , and X 4 are independently selected from C(R°) and N; each R° is independently selected from: hydrogen, halogen, -NO 2 , -CN, -N3, -OR 8 , -SR 8 , -N(R 8 ) 2 , -C(0)R 8 , -C(O)N(R 8 ) 2 , -N(R 8 )C(O)R 8 , -N(R 8 )C(O)N(R 8 ) 2 , -OC(O)N(R 8 ) 2 , -N(R 8 )C(O)OR 8 , -C(0)0R 8 , - 0C(0)R 8 , -S(O)R 8 , and -S(O) 2 R 8 ;
  • R 1 is selected from: hydrogen
  • R 1 together with R 2 form a C 3 -io cycloalkyl, C5-10 cycloalkenyl, 3- to 10- membered heterocycloalkyl, or 5- to 10-membered heterocycloalkenyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 8a , -SR 8a , -N(R 8a ) 2 , -C(0)R 8a , -C(O)N(R 8a ) 2 , -N(R 8a )C(O)R 8a , - N(R 8a )C(O)N(R 8a ) 2 , -OC(O)N(R 8a ) 2 , -N(R 8a )C(O)OR 8a , -C(0)0R 8a , -0C(0)R 8a , - S(O)R 8a , -S(O) 2 R 8a , -
  • R 1 together with R 2 form a C3-10 cycloalkyl, C5-10 cycloalkenyl, 3- to 10- membered heterocycloalkyl, or 5- to 10-membered heterocycloalkenyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -0R 8a , -SR 8a , -N(R 8a ) 2 , -C(0)R 8a , -C(O)N(R 8a ) 2 , -N(R 8a )C(O)R 8a , - N(R 8a )C(O)N(R 8a ) 2 , -OC(O)N(R 8a ) 2 , -N(R 8a )C(O)OR 8a , -C(0)0R 8a , -0C(0)R 8a , - S(O)R 8a , -S(O) 2 R 8a , -NO2,
  • R 3 is selected from: hydrogen; and Ci-6 alkyl optionally substituted with one or more substituents independently selected from R 7c ; or
  • R 4 is selected from:
  • C1-6 alkyl optionally substituted with one or more substituents independently selected from -Cl, -Br, -0R 8e , -SR 8e , -N(R 8e ) 2 , -N0 2 , and -CN, C3-10 carbocycle, and 3- to 10-membered heterocycle, wherein the C3-10 carbocycle, and 3- to 10-membered heterocycle, are each optionally substituted with one or more substituents independently selected from R 7e ; or R 4 and R 4a together form a C4-10 carbocycle, or 3- to 10-membered heterocycle, wherein the C3-10 carbocycle, or 3- to 10-membered heterocycle, is optionally substituted with one or more substituents independently selected from R 7e ;
  • R 5 is selected from: hydrogen, halogen, -OR 8f , -SR 8f , -N(R 8f )2, -NO2, -CN, C1-6 alkyl, C3-10 carbocycle, and
  • X 1 , X 2 , X 3 , and X 4 are each independently selected from C(R°). In some embodiments, X 1 , X 2 , X 3 , and X 4 are independently selected from C(R°) and N. In some embodiments, X 1 is selected from C(R°) and N. In some embodiments, X 2 is selected from C(R°) and N. In some embodiments, X 3 is selected from C(R°) and N. In some embodiments, X 4 is selected from C(R°) and N. In some embodiments, X 1 is selected from C(R°) and N.
  • X 3 is selected from C(R°) and N. In some embodiments, X 4 is selected from C(R°) and N. In some embodiments, X 1 is selected from C(H), C(halogen) and N. In some embodiments, X 2 is selected from C(H), C(halogen) and N. In some embodiments, X 3 is selected from C(H), C(halogen) and N. In some embodiments, X 4 is selected from C(H), C(halogen) and N. In some embodiments, X 1 is selected from C(H) and C(halogen). In some embodiments, X 2 is selected from C(H) and C(halogen).
  • X 3 is selected from C(H) and C(halogen). In some embodiments, X 4 is selected from C(H) and C(halogen). In some embodiments, X 1 is selected from C(H) and C(F). In some embodiments, X 2 is selected from C(H) and C(F). In some embodiments, X 3 is selected from C(H) and C(F). In some embodiments, X 4 is selected from C(H) and C(F). In some embodiments, X 1 is selected from C(H) and N. In some embodiments, X 2 is selected from C(H) and N. In some embodiments, X 3 is selected from C(H) and N.
  • X 3 is selected from C(H), and X 4 is selected from C(H).
  • X 1 is selected from C(F), and X 2 is selected from C(F).
  • X 1 is selected from C(H), and X 2 is selected from C(H).
  • X 1 is selected from C(F), and X 2 is selected from C(H).
  • X 1 is selected from C(H), and X 2 is selected from C(F).
  • X 1 is selected from N, and X 2 is selected from C(H).
  • X 1 is selected from C(H), and X 2 is selected from N.
  • X 1 is selected from C(F), and X 2 is selected from N.
  • at least one of X 1 , X 2 , X 3 , and X 4 need not be N.
  • X 1 , X 2 , X 3 , and X 4 are each independently selected from C(R°) and N. In some embodiments, at least one of X 1 , X 2 , X 3 , and X 4 is N. In some embodiments, at least two of X 1 , X 2 , X 3 , and X 4 are N. In some embodiments, X 1 is N. In some embodiments, X 2 is N. In some embodiments, X 3 is N. In some embodiments, X 4 is N.
  • X 1 , X 2 , X 3 , and X 4 are each independently selected from: C(H), C(halogen), and N. In some embodiments, X 1 , X 2 , X 3 , and X 4 are each independently selected from: C(H), C(F), and N. In some embodiments, X 1 , X 2 , X 3 , and X 4 are each independently selected from: C(H) and C(F).
  • each R° is independently selected from: hydrogen, halogen, -NO 2 , -CN, -N 3 , -OR 8 , -SR 8 , -N(R 8 ) 2 , -C(O)R 8 , -C(O)N(R 8 ) 2 , -N(R 8 )C(O)R 8 , -N(R 8 )C(O)N(R 8 ) 2 , -OC(O)N(R 8 ) 2 , -N(R 8 )C(O)OR 8 , -C(O)OR 8 , -OC(O)R 8 , -S(O)R 8 , and - S(O) 2 R 8 ;
  • each R° is independently selected from: hydrogen, halogen, -NO2, -CN, -N3, -OR 8 , -SR 8 , and -N(R 8 )2;
  • each R° is independently selected from: hydrogen, -F, -Cl, -Br, -I, -NO2, -CN, -N3, -OR 8 , -SR 8 , -
  • each R° is independently selected from: hydrogen, -F, -Cl, -Br, -CN, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl.
  • each R° is independently selected from: methyl, ethyl, w-propyl, and isopropyl. In some embodiments, each R° is hydrogen. In some embodiments, each R° is selected from -H and halogen. In some embodiments, each R° is selected from -H and -F.In some embodiments, for a compound or salt of Formula (I), or Formula (I-A) R 1 is selected from: hydrogen;
  • R 1 is selected from: hydrogen;
  • R 1 together with R 2 form a C3-10 carbocycle, or 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 8a , -N(R 8a ) 2 , -C(O)R 8a , -C(O)N(R 8a ) 2 , - N(R 8a )C(O)R 8a , -C(O)OR 8a , -OC(O)R 8a , -CN, Ci- 6 alkyl, C 2.6 alkenyl, and C 2.6 alkynyl, wherein Ci-6 alkyl, C 2 -6 alkenyl, and C 2 -6 alkynyl are each optionally substituted with one or more substituents independently selected from R 7a .
  • R 1 is selected from: hydrogen; Ci-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 8a , - N(R 8a ) 2 , -C(O)R 8a , -C(O)N(R 8a ) 2 , -N(R 8a )C(O)R 8a , -C(O)OR 8a , -OC(O)R 8a , -CN, C3-6 carbocycle, and 3- to 6-membered heterocycle, wherein the C3-6 carbocycle, and 3- to 6- membered heterocycle, are each optionally substituted with one or more substituents independently selected from R 7a ; and
  • R 1 together with R 2 form a C3-6 carbocycle, or 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 8a , -
  • R 2 is selected from: phenyl, pyridyl, pyrimidyl, pyridazinyl, pyrimidinyl, and pyrazinyl, wherein each phenyl, pyridyl, pyrimidyl, pyridazinyl, pyrimidinyl, and pyrazinyl is optionally substituted with one or more substituents independently selected from halogen, -CN, and C1-6 alkyl, wherein C1-6 alkyl is optionally substituted with one or more R 8b .
  • R 2 is selected from: phenyl, pyridyl, and pyrimidinyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, and C1-6 alkyl, wherein C1-6 alkyl is optionally substituted with one or more R 8b .
  • R 2 is selected from: phenyl, pyridyl, and pyrimidinyl, each of which is optionally substituted with one or more substituents independently selected from fluoro and -CN.
  • R 2 is selected from:
  • R 3 is selected from: hydrogen; and Ci-6 alkyl optionally substituted with one or more substituents independently selected from R 7c .
  • R 3 is selected from hydrogen, methyl, ethyl, w-propyl, and isopropyl. In some embodiments, R 3 is hydrogen.
  • R 2 together with R 3 form a C3-10 carbocycle, or 3- to 15-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 8a , -SR 8a , - N(R 8a ) 2 , -C(O)R 8a , -C(O)N(R 8a ) 2 , -N(R 8a )C(O)R 8a , -N(R 8a )C(O)N(R 8a ) 2 , -OC(O)N(R 8a ) 2 , - N(R 8a )C(O)OR 8a , -C(O)OR 8a , -OC(O)R 8a , -S(O)R 8a , -S(O) 2 R 8a , -NO 2 ,
  • R 2 together with R 3 form an optionally substituted 3- to 15-membered heterocycle. In some embodiments, R 2 together with R 3 form an optionally substituted bridged 3- to 15-membered heterocycle. In some embodiments, the carbocycle or heterocycle formed from R 2 together with R 3 is bridged. In some embodiments, the carbocycle or heterocycle formed from R 2 together with R 3 is fused. In some embodiments, the carbocycle or heterocycle formed from R 2 together with R 3 is fused bridged.
  • R 2 together with R 3 form a heterocycle optionally substituted with one or more substituents independently selected from: halogen, -CN, -N0 2 , -OH, -0(Ci-6 alkyl), -0(Ci-6 haloalkyl), -SH, - S(Ci-6 alkyl), -NH 2 , -NH(CI-6 alkyl), -N(CI-6 alkyl) 2 , C1-6 alkyl, and C1-6 haloalkyl.
  • substituents independently selected from: halogen, -CN, -N0 2 , -OH, -0(Ci-6 alkyl), -0(Ci-6 haloalkyl), -SH, - S(Ci-6 alkyl), -NH 2 , -NH(CI-6 alkyl), -N(CI-6 alkyl) 2 , C1-6 alkyl, and C1-6 haloalkyl.
  • R 2 together with R 3 form a heterocycle optionally substituted with one or more substituents independently selected from: -CN, -F, -Cl, -OH, -0(CH , -0(CF3), -NH 2 , -NH(CH , - N(CH 3 ) 2 , -SH, -S(CH 3 ), -CH 3 , and -CF 3 .
  • R 2 together with R 3 form a heterocycle selected from: that is optionally substituted (e.g., optionally substituted with one or more substituents independently selected from: halogen, -CN, -NO 2 , -OH, - O(Ci- 6 alkyl), -O(Ci- 6 haloalkyl), -SH, -S(Ci- 6 alkyl), -NH 2 , -NH(CI- 6 alkyl), -N(CI- 6 alkyl) 2 , Ci- 6 alkyl, and Ci-6 haloalkyl; or optionally substituted with one or more substituents independently selected from: -CN, -F, -Cl, -OH, -O(CH 3 ), -O(CF 3 ), -NH 2 , -NH(CH 3 ), -N(CH 3 ) 2 , -SH,
  • R 4 is selected from: halogen, -OR 8d , -SR 8d , -N(R 8d ) 2 , -NO 2 , and -CN;
  • Ci alkyl, C 2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, and Ce alkyl wherein each Ci alkyl, C 2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, and Ce alkyl is optionally substituted with one or more substituents independently selected from R 7d ;
  • R 4 is selected from: halogen, -OR 8d , -SR 8d , -N(R 8d ) 2 , -NO 2 , and -CN;
  • R 5 is selected from: hydrogen, halogen, -OR 8f , C1-6 alkyl, C3-10 carbocycle, and 3- to 10-membered heterocycle. In some embodiments, R 5 is selected from: hydrogen, halogen, C1-6 alkyl, C3-10 carbocycle, and 3- to 10- membered heterocycle. In some embodiments, R 5 is selected from: methyl, ethyl, n- propyl, and isopropyl. In some embodiments, R 5 is selected from: -OH and -O(Ci-6 alkyl). In some embodiments, R 5 is -OH. In some embodiments, R 5 is -O(Ci-6 alkyl). In some embodiments, R 5 is -OCH3.
  • each R 7 is independently selected from halogen, -CN, - N0 2 , -OH, -O(Ci- 6 alkyl), -O(Ci- 6 haloalkyl), -SH, -S(Ci- 6 alkyl), -NH 2 , -NH(CI- 6 alkyl), -N(CI-6 alkyl)2, C1-6 alkyl, C1-6 haloalkyl, C3-10 carbocycle and 3- to 10-membered heterocycle.
  • each R 7 is independently selected from -F, -Cl, -CN, -NO2, -OH, -0(Ci-6 alkyl), -0(Ci-6 haloalkyl), -SH, -S(Ci-6 alkyl), -NH2, -NH(CI-6 alkyl), and -N(CI-6 alkyl)2.
  • each R 7 is independently selected from -CN, -F, -Cl, -OH, -0(CH3), -0(CF3), -NH2, - NH(CH 3 ), -N(CH 3 ) 2 , -SH, -S(CH 3 ), -CH 3 , and -CF 3 .
  • each R 7a is independently selected from halogen, -CN, -NO2, -OH, -0(Ci-6 alkyl), - 0(Ci-6 haloalkyl), -SH, -S(Ci-6 alkyl), -NH2, -NH(CI-6 alkyl), -N(CI-6 alkyl)2, C1-6 alkyl, C1-6 haloalkyl, C3-10 carbocycle and 3- to 10-membered heterocycle.
  • each R 7a is independently selected from halogen, -CN, -NO2, -OH, -0(Ci-6 alkyl), -0(Ci-6 haloalkyl), -SH, - S(Ci-6 alkyl), -NH2, -NH(CI-6 alkyl), -N(CI-6 alkyl)2, C1-6 alkyl, and C1-6 haloalkyl.
  • each R 7a is independently selected from -CN, -F, -Cl, -OH, -0(CH3), -0(CF3), -NH2, -NH(CH 3 ), -N(CH 3 ) 2 , -SH, -S(CH 3 ), -CH 3 , and -CF 3 .
  • each R 7b is independently selected from halogen, -CN, -NO2, -OH, -0(Ci-6 alkyl), - 0(Ci-6 haloalkyl), -SH, -S(Ci-6 alkyl), -NH2, -NH(CI-6 alkyl), -N(CI-6 alkyl)2, Ci-6 alkyl, Ci-6 haloalkyl, C3-10 carbocycle and 3- to 10-membered heterocycle.
  • each R 7b is independently selected from halogen, -CN, -NO2, -OH, -0(Ci-6 alkyl), -0(Ci-6 haloalkyl), -SH, - S(Ci-6 alkyl), -NH2, -NH(CI-6 alkyl), -N(CI-6 alkyl)2, Ci-6 alkyl, and Ci-6 haloalkyl.
  • each R 7b is independently selected from -F, -Cl, -CN, -NO2, -OH, -0(Ci-6 alkyl), - 0(Ci-6 haloalkyl), -SH, -S(Ci-6 alkyl), -NH2, -NH(CI-6 alkyl), and -N(CI-6 alkyl)2.
  • each R 7c is independently selected from -F, -Cl, -CN, -NO2, -OH, -0(Ci-6 alkyl), - 0(Ci-6 haloalkyl), -SH, -S(Ci-6 alkyl), -NH2, -NH(CI-6 alkyl), and -N(CI-6 alkyl)2.
  • each R 7c is independently selected from -CN, -F, -Cl, -OH, -0(CH3), -0(CF3), -NH2, -NH(CH 3 ), -N(CH 3 ) 2 , -SH, -S(CH 3 ), -CH 3 , and -CF 3 .
  • each R 7d is independently selected from halogen, -CN, -NO2, -OH, -0(Ci-6 alkyl), -0(Ci-6 haloalkyl), -SH, - S(Ci-6 alkyl), -NH2, -NH(CI-6 alkyl), -N(CI-6 alkyl)2, Ci-6 alkyl, and Ci-6 haloalkyl.
  • each R 7d is independently selected from -F, -Cl, -CN, -NO2, -OH, -0(Ci-6 alkyl), - 0(Ci-6 haloalkyl), -SH, -S(Ci-6 alkyl), -NH2, -NH(CI-6 alkyl), and -N(CI-6 alkyl)2.
  • each R 7e is independently selected from halogen, -CN, -NO2, -OH, -0(Ci-6 alkyl), - 0(Ci-6 haloalkyl), -SH, -S(Ci-6 alkyl), -NH2, -NH(CI-6 alkyl), -N(CI-6 alkyl)2, C1-6 alkyl, C1-6 haloalkyl, C3-10 carbocycle and 3- to 10-membered heterocycle.
  • each R 7e is independently selected from halogen, -CN, -NO2, -OH, -0(Ci-6 alkyl), -0(Ci-6 haloalkyl), -SH, - S(Ci-6 alkyl), -NH2, -NH(CI-6 alkyl), -N(CI-6 alkyl)2, C1-6 alkyl, and C1-6 haloalkyl.
  • each R 7e is independently selected from -F, -Cl, -CN, -NO2, -OH, -0(Ci-6 alkyl), - 0(Ci-6 haloalkyl), -SH, -S(Ci-6 alkyl), -NH2, -NH(CI-6 alkyl), and -N(CI-6 alkyl)2.
  • each R 7e is independently selected from -CN, -F, -Cl, -OH, -0(CH3), -0(CF3), -NH2, -NH(CH 3 ), -N(CH 3 ) 2 , -SH, -S(CH 3 ), -CH 3 , and -CF 3 .
  • each R 7f is independently selected from halogen, -CN, -NO2, -OH, -0(Ci-6 alkyl), - 0(Ci-6 haloalkyl), -SH, -S(Ci-6 alkyl), -NH2, -NH(CI-6 alkyl), -N(CI-6 alkyl)2, Ci-6 alkyl, Ci-6 haloalkyl, C3-10 carbocycle and 3- to 10-membered heterocycle.
  • each R 7f is independently selected from halogen, -CN, -NO2, -OH, -0(Ci-6 alkyl), -0(Ci-6 haloalkyl), -SH, - S(Ci-6 alkyl), -NH2, -NH(CI-6 alkyl), -N(CI-6 alkyl)2, Ci-6 alkyl, and Ci-6 haloalkyl.
  • each R 7f is independently selected from -CN, -F, -Cl, -OH, -O(CH3), -O(CF3), -NH2, -NH(CH 3 ), -N(CH 3 ) 2 , -SH, -S(CH 3 ), -CH 3 , and -CF 3 .
  • each R 7g is independently selected from halogen, -CN, -N0 2 , -OH, -0(Ci-6 alkyl), - 0(Ci-6 haloalkyl), -SH, -S(Ci-6 alkyl), -NH 2 , -NH(CI-6 alkyl), -N(CI-6 alkyl) 2 , C1-6 alkyl, C1-6 haloalkyl, C3-10 carbocycle and 3- to 10-membered heterocycle.
  • each R 7g is independently selected from halogen, -CN, -N0 2 , -OH, -0(Ci-6 alkyl), -0(Ci-6 haloalkyl), -SH, - S(Ci-6 alkyl), -NH 2 , -NH(CI-6 alkyl), -N(CI-6 alkyl) 2 , C1-6 alkyl, and C1-6 haloalkyl.
  • each R 7g is independently selected from -CN, -F, -Cl, -OH, -0(CH , -0(CF3), -NH 2 , -NH(CH 3 ), -N(CH 3 ) 2 , -SH, -S(CH 3 ), -CH 3 , and -CF 3 .
  • each R 8 is independently selected from: hydrogen; C1-6 alkyl, optionally substituted with one or more substituents independently selected from halogen, - CN, -NO2, -OH, -O(Ci- 6 alkyl), -O(Ci- 6 haloalkyl), -SH, -S(Ci- 6 alkyl), -NH 2 , -NH(CI- 6 alkyl), - N(CI-6 alkyl) 2 , C3-10 carbocycle and 3-10 membered heterocycle; and C3-10 carbocycle and 3- to 10- membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -N0 2 , -OH, -0(Ci-6 alkyl), -0(Ci-6 haloalkyl), -SH, - S(Ci-6 alkyl), -NH2, -NH(CI-6 alkyl), -N(CI-6 al
  • each R 8 is independently selected from: hydrogen; C1-6 alkyl, optionally substituted with one or more substituents independently selected from -CN, -F, -Cl, -OH, -0(CH , -0(CF3), - NH 2 , -NH(CH 3 ), -N(CH 3 ) 2 , -SH, -S(CH 3 ), -CH 3 , and -CF 3 ; and C3-10 carbocycle and 3- to 10- membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from -CN, -F, -Cl, -OH, -0(CH 3 ), -O(CF 3 ), -NH 2 , -NH(CH 3 ), -N(CH 3 ) 2 , - SH, -S(CH3), -CH3, and -CF3.
  • each R 8 is independently selected from: hydrogen; C1-6 alkyl; C1-6 haloalkyl; and C3-10 carbocycle and 3- to 10-membered heterocycle. In some embodiments, each R 8 is independently selected from: hydrogen; C1-6 alkyl; and C1-6 haloalkyl (e.g., fluoroalkyl). In some embodiments, each R 8 is independently selected from: hydrogen; and Ci-6 alkyl. In some embodiments, each R 8 is independently selected from: hydrogen; and Ci-6 alkyl; and C3-10 carbocycle. In some embodiments, each R 8 is independently selected from: hydrogen; and C1-6 alkyl; and C3-10 carbocycle, wherein the C3-10 carbocycle is [l.l.
  • each R 8 is independently selected from: hydrogen; and C1-5 alkyl. In some embodiments, each R 8 is independently selected from: hydrogen; and C1-4 alkyl. In some embodiments, each R 8 is independently selected from: hydrogen; and C1-3 alkyl. In some embodiments, each R 8 is independently selected from: hydrogen; and C1-2 alkyl. In some embodiments, each R 8 is independently selected from: hydrogen; and Ci alkyl. In some embodiments, each R 8 is independently selected from: hydrogen. In some embodiments, each R 8 is independently selected from: Ci alkyl.
  • each R 8a is independently selected from: hydrogen; C1-6 alkyl, optionally substituted with one or more substituents independently selected from halogen, - CN, -NO2, -OH, -O(Ci- 6 alkyl), -O(Ci- 6 haloalkyl), -SH, -S(Ci- 6 alkyl), -NH 2 , -NH(CI- 6 alkyl), - N(CI-6 alkyl) 2 , C3-10 carbocycle and 3-10 membered heterocycle; and C3-10 carbocycle and 3- to 10- membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -N0 2 , -OH, -0(Ci-6 alkyl), -0(Ci-6 haloalkyl), -SH, - S(Ci-6 alkyl), -NH2, -NH(CI-6 alkyl), -N(CI-6
  • each R 8a is independently selected from: hydrogen; C1-6 alkyl; C1-6 haloalkyl; and C3-10 carbocycle and 3- to 10-membered heterocycle. In some embodiments, each R 8a is independently selected from: hydrogen; C1-6 alkyl; and C1-6 haloalkyl (e.g., fluoroalkyl). In some embodiments, each R 8a is independently selected from: hydrogen; and C1-6 alkyl. In some embodiments, each R 8a is independently selected from: hydrogen; and C1-6 alkyl; and C3-10 carbocycle. In some embodiments, each R 8a is independently selected from: hydrogen; and C1-6 alkyl; and C3-10 carbocycle, wherein the C3-10 carbocycle is [l.
  • each R 8a is independently selected from: hydrogen; and C1-5 alkyl. In some embodiments, each R 8a is independently selected from: hydrogen; and C1-4 alkyl. In some embodiments, each R 8a is independently selected from: hydrogen; and C1-3 alkyl. In some embodiments, each R 8a is independently selected from: hydrogen; and C1-2 alkyl. In some embodiments, each R 8a is independently selected from: hydrogen; and Ci alkyl. In some embodiments, each R 8a is independently selected from: hydrogen. In some embodiments, each R 8a is independently selected from: Ci alkyl.
  • each R 8b is independently selected from: hydrogen; C1-6 alkyl, optionally substituted with one or more substituents independently selected from -CN, -F, -Cl, -OH, -O(CH , -O(CF3), - NH 2 , -NH(CH 3 ), -N(CH 3 ) 2 , -SH, -S(CH 3 ), -CH 3 , and -CF 3 ; and C3-10 carbocycle and 3- to 10- membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from -CN, -F, -Cl, -OH, -O(CH 3 ), -O(CF 3 ), -NH 2 , -NH(CH 3 ), -N(CH 3 ) 2 , - SH, -S(CH3), -CH3, and -CF3.
  • each R 8b is independently selected from: hydrogen; C1-6 alkyl; C1-6 haloalkyl; and C3-10 carbocycle and 3- to 10-membered heterocycle. In some embodiments, each R 8b is independently selected from: hydrogen; C1-6 alkyl; and C1-6 haloalkyl (e.g., fluoroalkyl). In some embodiments, each R 8b is independently selected from: hydrogen; and C1-6 alkyl. In some embodiments, each R 8b is independently selected from: hydrogen; and C1-6 alkyl; and C3-10 carbocycle. In some embodiments, each R 8b is independently selected from: hydrogen; and C1-6 alkyl; and C3-10 carbocycle, wherein the C3-10 carbocycle is [l.l.
  • each R 8b is independently selected from: hydrogen; and C1-5 alkyl. In some embodiments, each R 8b is independently selected from: hydrogen; and C1-4 alkyl. In some embodiments, each R 8b is independently selected from: hydrogen; and C1-3 alkyl. In some embodiments, each R 8b is independently selected from: hydrogen; and C1-2 alkyl. In some embodiments, each R 8b is independently selected from: hydrogen; and Ci alkyl. In some embodiments, each R 8b is independently selected from: hydrogen. In some embodiments, each R 8b is independently selected from: Ci alkyl.
  • each R 8c is independently selected from: hydrogen; C1-6 alkyl, optionally substituted with one or more substituents independently selected from halogen, - CN, -NO2, -OH, -O(Ci- 6 alkyl), -O(Ci- 6 haloalkyl), -SH, -S(Ci- 6 alkyl), -NH 2 , -NH(CI- 6 alkyl), - N(CI-6 alkyl)2, C3-10 carbocycle and 3-10 membered heterocycle; and C3-10 carbocycle and 3- to 10- membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, -OH, -0(Ci-6 alkyl), -0(Ci-6 haloalkyl), -SH, - S(Ci-6 alkyl), -NH2, -NH(CI-6 alkyl), -N(CI-6 alkyl)2,
  • each R 8c is independently selected from: hydrogen; C1-6 alkyl, optionally substituted with one or more substituents independently selected from -CN, -F, -Cl, -OH, -O(CH 3 ), -O(CF 3 ), -
  • each R 8c is independently selected from: hydrogen; C1-6 alkyl; C1-6 haloalkyl; and C 3 -io carbocycle and 3- to 10-membered heterocycle. In some embodiments, each R 8c is independently selected from: hydrogen; C1-6 alkyl; and C1-6 haloalkyl (e.g., fluoroalkyl). In some embodiments, each R 8c is independently selected from: hydrogen; and C1-6 alkyl. In some embodiments, each R 8c is independently selected from: hydrogen; and C1-6 alkyl; and C 3 -io carbocycle.
  • each R 8c is independently selected from: hydrogen; and Ci-6 alkyl; and C 3 -io carbocycle, wherein the C 3 -io carbocycle is [l.l. l]bicyclopentyl or cyclobutyl.
  • each R 8c is independently selected from: hydrogen; and C1-5 alkyl.
  • each R 8c is independently selected from hydrogen; and C1-4 alkyl.
  • each R 8c is independently selected from hydrogen; and Ci- 3 alkyl.
  • each R 8c is independently selected from hydrogen; and C1-2 alkyl.
  • each R 8c is independently selected from hydrogen; and Ci alkyl.
  • each R 8c is independently selected from: hydrogen.
  • each R 8c is independently selected from: Ci alkyl.
  • each R 8d is independently selected from: hydrogen; C1-6 alkyl, optionally substituted with one or more substituents independently selected from halogen, - CN, -N0 2 , -OH, -O(CI- 6 alkyl), -O(Ci- 6 haloalkyl), -SH, -S(Ci- 6 alkyl), -NH 2 , -NH(CI- 6 alkyl), - N(CI-6 alkyl) 2 , C3-10 carbocycle and 3-10 membered heterocycle; and C3-10 carbocycle and 3- to 10- membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -N0 2 , -OH, -0(Ci-6 alkyl), -0(Ci-6 haloalkyl), -SH, - S(Ci-6 alkyl), -NH 2 , -NH(CI-6 alkyl), --NH(CI
  • each R 8d is independently selected from: hydrogen; C1-6 alkyl, optionally substituted with one or more substituents independently selected from -CN, -F, -Cl, -OH, -0(CH , -0(CF3), - NH 2 , -NH(CH 3 ), -N(CH 3 ) 2 , -SH, -S(CH 3 ), -CH 3 , and -CF 3 ; and C3-10 carbocycle and 3- to 10- membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from -CN, -F, -Cl, -OH, -0(CH 3 ), -O(CF 3 ), -NH 2 , -NH(CH 3 ), -N(CH 3 ) 2 , - SH, -S(CH3), -CH3, and -CF3.
  • each R 8d is independently selected from: hydrogen; C1-6 alkyl; C1-6 haloalkyl; and C3-10 carbocycle and 3- to 10-membered heterocycle. In some embodiments, each R 8d is independently selected from: hydrogen; C1-6 alkyl; and C1-6 haloalkyl (e.g., fluoroalkyl). In some embodiments, each R 8d is independently selected from: hydrogen; and C1-6 alkyl. In some embodiments, each R 8d is independently selected from: hydrogen; and C1-6 alkyl; and C3-10 carbocycle. In some embodiments, each R 8d is independently selected from: hydrogen; and Ci-6 alkyl; and C3-10 carbocycle, wherein the C3-10 carbocycle is
  • each R 8d is independently selected from: Ci alkyl.
  • each R 8e is independently selected from: hydrogen; C1-6 alkyl; C1-6 haloalkyl; and C3-10 carbocycle and 3- to 10-membered heterocycle. In some embodiments, each R 8e is independently selected from: hydrogen; C1-6 alkyl; and C1-6 haloalkyl (e.g., fluoroalkyl). In some embodiments, each R 8e is independently selected from: hydrogen; and C1-6 alkyl. In some embodiments, each R 8e is independently selected from: hydrogen; and C1-6 alkyl; and C3-10 carbocycle. In some embodiments, each R 8e is independently selected from: hydrogen; and C1-6 alkyl; and C3-10 carbocycle, wherein the C3-10 carbocycle is [1.1.
  • each R 8e is independently selected from: hydrogen; and C1-5 alkyl. In some embodiments, each R 8e is independently selected from: hydrogen; and C1-4 alkyl. In some embodiments, each R 8e is independently selected from: hydrogen; and C1-3 alkyl. In some embodiments, each R 8e is independently selected from: hydrogen; and C1-2 alkyl. In some embodiments, each R 8e is independently selected from: hydrogen; and Ci alkyl. In some embodiments, each R 8e is independently selected from: hydrogen. In some embodiments, each R 8e is independently selected from: Ci alkyl.
  • each R 8g is independently selected from: hydrogen; Cn 6 alkyl, optionally substituted with one or more substituents independently selected from halogen, - CN, -NO2, -OH, -O(Ci- 6 alkyl), -O(Ci- 6 haloalkyl), -SH, -S(Ci- 6 alkyl), -NH 2 , -NH(CI- 6 alkyl), - N(CI-6 alkyl)2, C3-10 carbocycle and 3-10 membered heterocycle; and C3-10 carbocycle and 3- to 10- membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, -OH, -0(Ci-6 alkyl), -0(Ci-6 haloalkyl), -SH, - S(Ci-6 alkyl), -NH2, -NH(CI-6 alkyl), -N(CI-6 alkyl)
  • each R 8g is independently selected from: hydrogen; C1-6 alkyl, optionally substituted with one or more substituents independently selected from -CN, -F, -Cl, -OH, -0(CH , -O(CF 3 ), -NH 2 , -NH(CH 3 ), -N(CH 3 ) 2 , -SH, -S(CH 3 ), -CH 3 , and -CF 3 ; and C3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from -CN, -F, -Cl, -OH, -O(CH 3 ), -O(CF 3 ), -NH 2 , -NH(CH 3 ), -N(CH 3 ) 2 , - SH, -S(CH 3 ), -CH 3 , and -CF 3 .
  • the compound is not:
  • the present disclosure provides a compound represented by Formula (II): or a salt thereof, wherein:
  • X 11 , X 12 , X 13 , and X 14 are independently selected from C(R 10 ) and N; each R 10 is independently selected from: hydrogen, halogen, -NO2, -CN, -N3, -OR 18 , -SR 18 , -N(R 18 )2, -C(O)R 18 , - C(O)N(R 18 ) 2 , -N(R 18 )C(O)R 18 , -N(R 18 )C(O)N(R 18 ) 2 , -OC(O)N(R 18 ) 2 , - N(R 18 )C(O)OR 18 , -C(O)OR 18 , -OC(O)R 18 , -S(O)R 18 , and -S(O) 2 R 18 ;
  • R 11 is selected from: hydrogen
  • R 14a is selected from: hydrogen;
  • R 15 is selected from: C4-6 alkyl, C3-10 heterocycloalkyl, and 4- to 10-membered heterocycle, wherein the C4-6 alkyl, C3-10 heterocycloalkyl, and 4- to 10- membered heterocycle are each optionally substituted with one or more substituents independently selected from R 17e ;
  • R 16 is selected from: hydrogen;
  • each R 17 , R 17a , R 17b , R 17c , R 17d , R 17e , and R 17f is independently selected from: hydrogen, halogen, -CN, -OH, -SH, -NO2, -NH2, -O-C1-6 alkyl, -S-C1-6 alkyl, - N(CI-6 alkyl)2, and -NH(CI-6 alkyl); and
  • each R 18 , R 18a , R 18b , R 18c , and R 18d is independently selected from: hydrogen, halogen, -CN, -OH, -SH, -NO2, -NH2, -O-C1-6 alkyl, -S-C1-6 alkyl, - N(CI-6 alkyl)
  • the present disclosure provides a compound represented by Formula (II-A): or a salt thereof, wherein:
  • X 11 , X 12 , X 13 , and X 14 are independently selected from C(R 10 ), and N; wherein no more than two of X 11 , X 12 , X 13 , and X 14 are N; wherein no more than three of X 11 , X 12 , X 13 , and X 14 are C(H); each R 10 is independently selected from: hydrogen, halogen, -NO2, -CN, -N3, -OR 18 , -SR 18 , -N(R 18 )2, -C(O)R 18 , - C(O)N(R 18 ) 2 , -N(R 18 )C(O)R 18 , -N(R 18 )C(O)N(R 18 ) 2 , -OC(O)N(R 18 ) 2 , - N(R 18 )C(O)OR 18 , -C(O)OR 18 , -C(O)OR 18 , -
  • R 11 is selected from: hydrogen
  • R 12 is selected from:
  • R 13 is selected from: hydrogen;
  • Ci-6 alkyl optionally substituted with one or more substituents independently selected from R 17c ;
  • R 14 is selected from: hydrogen;
  • R 14a is selected from: hydrogen, halogen, -OR 18e , -SR 18e , -N(R 18e )2, -NO2, and -CN; and
  • each R 10 is independently selected from: hydrogen, halogen, - CN, -NO2, -OH, -O(Ci- 6 alkyl), -O(Ci- 6 haloalkyl), -SH, -S(Ci- 6 alkyl), -NH 2 , -NH(CI- 6 alkyl), and - N(CI-6 alkyl)2; C1-6 alkyl, and C1-6 haloalkyl each of which is optionally substituted with one or more substituents independently selected from -F, -Cl, -OH, -0(CH , -O(CF3), -NH2, -NH(CH3), - N(CHs)2, -SH, -S(CH3), -CH3, and -CF3; and C3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from - F, -Cl, -OH, -
  • each R 10 is independently selected from: hydrogen, halogen, -CN, -NO2, -OH, -O(Cn 6 alkyl), -O(Ci-6 haloalkyl), -SH, -S(Ci-6 alkyl), -NH2, -NH(CI-6 alkyl), and -N(CI-6 alkyl)2; C1-6 alkyl, and C1-6 haloalkyl; and C3-10 carbocycle and 3- to 10-membered heterocycle.
  • each R 10 is independently selected from: hydrogen, halogen, -CN, -NO2, -OH, -O(Ci- 6 alkyl), -O(Ci-6 haloalkyl), -SH, -S(Ci-6 alkyl), -NH2, -NH(CI-6 alkyl), and -N(CI-6 alkyl)2; C1-6 alkyl, and C1-6 haloalkyl.
  • each R 10 is independently selected from: hydrogen, -CN, -F, -Cl, -OH, -O(CH 3 ), -O(CF 3 ), -NH 2 , -NH(CH 3 ), -N(CH 3 ) 2 , -SH, -S(CH 3 ), -CH 3 , and -CF 3 .
  • each R 10 is independently selected from: hydrogen, -CN, -F, -Cl, -OH, - O(CH 3 ), and -O(CF 3 ).
  • each R 10 is independently selected from: hydrogen, - CN, -F, and -Cl.
  • each R 10 is independently selected from: hydrogen, -CN, and -F.
  • each R 10 is independently selected from: hydrogen, and -F.
  • each R 10 is independently selected from: hydrogen.
  • each R 10 is independently selected from: hydrogen, -F, -Cl, -Br, -CN, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl. In some embodiments, R 10 is selected from: methyl, ethyl, w-propyl, and isopropyl. In some embodiments, each R 10 is independently selected from hydrogen. In some embodiments, each R 10 is independently selected from -H and halogen. In some embodiments, each R 10 is independently selected from -H and -F. In some embodiments, each R 10 is independently selected from -F. In some embodiments, for a compound or salt of Formula (II), or Formula (II-A), R 11 is independently selected from: hydrogen;
  • C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 18a , -N(R 18a )2, -C(O)R 18a , - C(O)N(R 18a ) 2 , -N(R 18a )C(O)R 18a , -C(O)OR 18a , -OC(O)R 18a , -CN, C 3 -no carbocycle, and 3- to 110-membered heterocycle, wherein the C 3 -no carbocycle, and 3- to 110-membered heterocycle, are each optionally substituted with one or more substituents independently selected from R 17a ; and
  • R 11 together with R 12 form a C3-6 carbocycle, or 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 18a , - N(R 18a ) 2 , -C(O)R 18a , -C(O)N(R 18a ) 2 , -N(R 18a )C(O)R 18a , -C(O)OR 18a , -OC(O)R 18a , -CN, Cn- 6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, wherein Cn-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with one or more substituents independently selected from R 17a .
  • R 11 is independently selected from: methyl, ethyl, w-propyl, and isopropyl. In some embodiments, R 11 is hydrogen. In some embodiments, R 11 is methyl. In some embodiments, for a compound or salt of Formula (II-A), R 12 is selected from:
  • R 12 is selected from:
  • R 12 is selected from: hydrogen;
  • a compound or salt are each optionally substituted with
  • heterocycloalkyl e.g., 5- to 20-membered heterocycle
  • 5- to 20-membered heterocycloalkenyl e.g., 5- to 10-membered heterocycloalkenyl
  • R 12 together with R 13 form a 3- to 20-membered heterocycloalkyl or a 5- to 20-membered heterocycloalkenyl , each of which is optionally substituted with Ci-6 alkyl optionally substituted with one or more substituents independently selected from R 17b .
  • R 12 together with R 13 form a 3- to 20-membered heterocycloalkyl or a 5- to 20-membered heterocycloalkenyl , each of which is optionally substituted with C3-10 carbocycle optionally substituted with one or more substituents independently selected from R 17b .
  • R 12 together with R 13 form a 3- to 20-membered heterocycloalkyl or a 5- to 20-membered heterocycloalkenyl, each of which is optionally substituted with a C3-10 carbocycle or 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from R 17b .
  • R 12 together with R 13 form a 3- to 20-membered heterocycloalkyl or a 5- to 20-membered heterocycloalkenyl, each of which is optionally substituted with a C3-10 carbocycle or 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -NO 2 , -OH, -O(Ci- 6 alkyl), -O(Ci- 6 haloalkyl), -SH, -S(Ci- 6 alkyl), -NH 2 , -NH(CI- 6 alkyl), -N(CI-6 alkyl) 2 , C1-6 alkyl and C1-6 haloalkyl.
  • R 12 together with R 13 form a 3- to 20-membered heterocycloalkyl or a 5- to 20-membered heterocycloalkenyl, each of which is optionally substituted with a C3-10 carbocycle or 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from -CN, -F, - Cl, -OH, -O(CH 3 ), -O(CF 3 ), -NH 2 , -NH(CH 3 ), -N(CH 3 ) 2 , -SH, -S(CH 3 ), -CH 3 , and -CF 3 .
  • R 12 together with R 13 form a 3- to 20-membered heterocycloalkyl or a 5- to 20-membered heterocycloalkenyl, each of which is optionally substituted with a C3-10 carbocycle or 3- to 10- membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from -F, and -CH3.
  • R 12 together with R 13 form an optionally substituted 3- to 20-membered heterocycloalkyl or a 5- to 20- membered heterocycloalkenyl.
  • R 12 together with R 13 form an optionally substituted 3- to 20-membered heterocycloalkyl or a 5- to 20-membered heterocycloalkenyl
  • R 14 is selected from: hydrogen; and Ci alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, and Ce alkyl, wherein each Ci alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, and Ce alkyl is substituted with one or more substituents independently selected from halogen, -OR 18d , -SR 18d , -N(R 18d )2, -NO2, and -CN, C3-10 carbocycle, and 3- to 10-membered heterocycle, wherein each C3-10 carbocycle, and 3- to 10-membered heterocycle is optionally substituted with one or more substituents independently selected from R 17d ; and C3-10 carbocycle, and 3- to 10-membered heterocycle, wherein each C3-10 carbocycle, and 3- to 10-membered heterocycle, is optionally substituted with one or more substituents independently selected from R 17d ; or R 14 and R
  • R 14 is selected from: hydrogen; and C1-6 alkyl substituted with one or more substituents independently selected from halogen, -OR 18d , -SR 18d , -N(R 18d )2, -NO2, and -CN, C3-10 carbocycle, and 3- to 10-membered heterocycle, wherein the C3-10 carbocycle, and 3- to 10- membered heterocycle, are each optionally substituted with one or more substituents independently selected from R 17d .
  • R 14 is selected from: hydrogen; and Ci-6 alkyl substituted with one or more substituents independently selected from halogen, -OR 18d , -SR 18d , -N(R 18d )2, -NO2, and -CN, C3-10 carbocycle, and 3- to 10-membered heterocycle, wherein the C3-10 carbocycle, and 3- to 10- membered heterocycle, are each optionally substituted with one or more substituents independently selected from R 17d .
  • R 14 is hydrogen.
  • R 14a is selected from: hydrogen, halogen, -OR 18e , -SR 8e , -N(R 18e )2, -NO2, and -CN; and
  • Ci alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, and Ce alkyl wherein each Ci alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, and Ce alkyl is optionally substituted with one or more substituents independently selected from halogen, -OR 18d , -SR 18d , -N(R 18d )2, -NO2, and -CN, C3-10 carbocycle, and 3- to 10-membered heterocycle, wherein the C3-10 carbocycle, and 3- to 10- membered heterocycle, are each optionally substituted with one or more substituents independently selected from R 17d ; or
  • R 14 and R 14a together form a C3-10 carbocycle, or 3- to 10-membered heterocycle, wherein the C3-10 carbocycle, or 3- to 10-membered heterocycle, is optionally substituted with one or more substituents independently selected from R 17d .
  • R 14a is selected from: hydrogen, halogen, -OR 18e , -SR 8e , -N(R 18e )2, -NO2, and -CN; and
  • R 14a is selected from: hydrogen, halogen, -OR 18e , -SR 8e , -N(R 18e )2; and C1-6 alkyl substituted with one or more substituents independently selected from halogen, - OR 18d , C 3 -10 carbocycle, and 3- to 10-membered heterocycle, wherein the C3-10 carbocycle, and 3- to 10-membered heterocycle, are each optionally substituted with one or more substituents independently selected from R 17d .
  • R 14a is selected from: hydrogen, , -OR 18e , - N(R 18e )2; and C1-6 alkyl substituted with one or more substituents independently selected from halogen, -OR 18d , C3 -10 carbocycle, and 3- to 10-membered heterocycle, wherein the C3-10 carbocycle, and 3- to 10-membered heterocycle, are each optionally substituted with one or more substituents independently selected from R 17d .
  • R 14a is selected from: hydrogen, , -OR 18e , -N(R 18e )2; and Ci-6 alkyl substituted with one or more substituents independently selected from halogen, -OR 18d , C3-10 carbocycle, and 3- to 10-membered heterocycle, wherein the C3-10 carbocycle, and 3- to 10-membered heterocycle.
  • R 14a is selected from: hydrogen, , -OR 18e , -N(R 18e )2; and C1-6 alkyl.
  • R 14a is selected from: hydrogen and C1-6 alkyl.
  • R 14a is selected from: hydrogen and Ci alkyl.
  • R 15 is selected from: C1-3 alkyl substituted with one or more substituents independently selected from R 17e ; C4-6 alkyl, optionally substituted with one or more substituents independently selected from R 17e ; and C3-10 carbocycle, and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from R 17e .
  • R 15 is selected from: C1-4 alkyl substituted with one or more substituents independently selected from R 17e ; C5-6 alkyl, optionally substituted with one or more substituents independently selected from R 17e ; and C3-10 carbocycle, and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from R 17e .
  • R 15 is selected from: C3-10 carbocycle, and 3- to 10- membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from R 17e .
  • R 15 is selected from C3-10 carbocycle, optionally substituted with one or more substituents independently selected from R 17e .
  • R 15 is selected from 3- to 10-membered heterocycle, optionally substituted with one or more substituents independently selected from R 17e . In some embodiments, R 15 is selected from 3- to 6-membered heterocycle, optionally substituted with one or more substituents independently selected from R 17e . In some embodiments, R 15 is selected from azetidine and oxetane, optionally substituted with one or more substituents independently selected from R 17e . In some embodiments, R 15 is selected from methyl. In some embodiments, R 15 is selected from -F.
  • R 15 is ,
  • R 14 and R 14a together form a C3-10 carbocycle, or 3- to 10-membered heterocycle, wherein the C3-10 carbocycle, or 3- to 10-membered heterocycle, is optionally substituted with one or more substituents independently selected from halogen, -CN, -NO 2 , -OH, -O(Ci- 6 alkyl), -O(Ci- 6 haloalkyl), -SH, -S(Ci- 6 alkyl), -NH 2 , -NH(CI- 6 alkyl), -N(CI-6 alkyl) 2 , C1-6 allkyl and C1-6 haloalkyl.
  • substituents independently selected from halogen, -CN, -NO 2 , -OH, -O(Ci- 6 alkyl), -O(Ci- 6 haloalkyl), -SH, -S(Ci- 6 alkyl), -NH 2 , -NH(CI- 6 alkyl),
  • R 14 and R 14a together form a C3-10 carbocycle, or 3- to 10-membered heterocycle, wherein the C3-10 carbocycle, or 3- to 10-membered heterocycle, is optionally substituted with one or more substituents independently selected from -CN, -F, -Cl, -OH, -O(CH 3 ), -O(CF 3 ), -NH 2 , -NH(CH 3 ), -N(CH 3 ) 2 , -SH, -S(CH 3 ), - CH 3 , and -CF 3 .
  • R 16 is selected from: hydrogen; and C1-6 alkyl optionally substituted with one or more substituents independently selected from R 17f .
  • R 16 is selected from hydrogen, methyl, ethyl, w-propyl, and isopropyl. In some embodiments, R 16 is hydrogen.
  • each R 17b is independently selected from: hydrogen, -F, -O-C1-6 alkyl; and C1-6 alkyl optionally substituted with one or more substituents independently selected from C3-10 carbocycle, and 3- to 10-membered heterocycle.
  • each R 17c is independently selected from: hydrogen, -F, -O-C1-6 alkyl; and Ci-6 alkyl optionally substituted with one or more substituents independently selected from C3-10 carbocycle, and 3- to 10-membered heterocycle.
  • each R 17d is independently selected from: hydrogen, -F, -O-C1-6 alkyl; and Ci-6 alkyl optionally substituted with one or more substituents independently selected from C3-10 carbocycle, and 3- to 10-membered heterocycle.
  • each R 17e is independently selected from: hydrogen, -F, -O-C1-6 alkyl; and C1-6 alkyl optionally substituted with one or more substituents independently selected from C3-10 carbocycle, and 3- to 10-membered heterocycle.
  • each R 17f is independently selected from: hydrogen, -F, -O-C1-6 alkyl; and Ci-6 alkyl optionally substituted with one or more substituents independently selected from C3-10 carbocycle, and 3- to 10-membered heterocycle.
  • each R 17g is independently selected from: hydrogen, -F, -O-C1-6 alkyl; and Ci-6 alkyl optionally substituted with one or more substituents independently selected from C3-10 carbocycle, and 3- to 10-membered heterocycle.
  • each R 18a is independently selected from: hydrogen; C1-6 alkyl, optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, -OH, - O(Ci- 6 alkyl), -O(Ci- 6 haloalkyl), -SH, -S(Ci- 6 alkyl), -NH 2 , -NH(CI- 6 alkyl), -N(CI- 6 alkyl) 2 , C3-10 carbocycle and 3-10 membered heterocycle; and C3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, -OH, -0(Ci-6 alkyl), -0(Ci-6 haloalkyl), -SH, -S(Ci-6 alkyl), - NH2, -NH(CI-6 alkyl), -N(CI-6 alky
  • each R 18a is independently selected from: hydrogen; C1-6 alkyl, optionally substituted with one or more substituents independently selected from -CN, -F, -Cl, -OH, -0(CH , -0(CF3), -NH2, -NH(CH3), - N(CHs)2, -SH, -S(CH3), -CH3, and -CF3; and C3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from - CN, -F, -Cl, -OH, -0(CH 3 ), -O(CF 3 ), -NH 2 , -NH(CH 3 ), -N(CH 3 ) 2 , -SH, -S(CH 3 ), -CH 3 , and -CF 3 .
  • each R 18a is independently selected from: hydrogen; and C1-5 alkyl. In some embodiments, each R 18a is independently selected from: hydrogen; and C1-4 alkyl. In some embodiments, each R 18a is independently selected from: hydrogen; and C1-3 alkyl. In some embodiments, each R 18a is independently selected from: hydrogen; and C1-2 alkyl. In some embodiments, each R 18a is independently selected from: hydrogen; and Ci alkyl. In some embodiments, each R 18a is independently selected from: hydrogen. In some embodiments, each R 18a is independently selected from: Ci alkyl.
  • each R 18b is independently selected from: hydrogen; C1-6 alkyl; C1-6 haloalkyl; and C3-10 carbocycle and 3- to 10-membered heterocycle. In some embodiments, each R 18b is independently selected from: hydrogen; C1-6 alkyl; and C1-6 haloalkyl (e.g., fluoroalkyl). In some embodiments, each R 18b is independently selected from: hydrogen; and C1-6 alkyl. In some embodiments, each R 18b is independently selected from: hydrogen; and C1-6 alkyl; and C3-10 carbocycle. In some embodiments, each R 18b is independently selected from: hydrogen; and C1-6 alkyl; and C3-10 carbocycle, wherein the C3-10 carbocycle is [l.l.
  • each R 18c is independently selected from: hydrogen; C1-6 alkyl, optionally substituted with one or more substituents independently selected from halogen, - CN, -NO2, -OH, -O(Ci- 6 alkyl), -O(Ci- 6 haloalkyl), -SH, -S(Ci- 6 alkyl), -NH 2 , -NH(CI- 6 alkyl), - N(CI-6 alkyl)2, C3-10 carbocycle and 3-10 membered heterocycle; and C3-10 carbocycle and 3- to 10- membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, -OH, -0(Ci-6 alkyl), -0(Ci-6 haloalkyl), -SH, - S(Ci-6 alkyl), -NH2, -NH(CI-6 alkyl), -N(CI-6 alkyl)2,
  • each R 18c is independently selected from: hydrogen; C1-6 alkyl, optionally substituted with one or more substituents independently selected from -CN, -F, -Cl, -OH, -0(CH , -0(CF3), - NH 2 , -NH(CH 3 ), -N(CH 3 ) 2 , -SH, -S(CH 3 ), -CH 3 , and -CF 3 ; and C3-10 carbocycle and 3- to 10- membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from -CN, -F, -Cl, -OH, -0(CH 3 ), -O(CF 3 ), -NH 2 , -NH(CH 3 ), -N(CH 3 ) 2 , - SH, -S(CH3), -CH3, and -CF3.
  • each R 18c is independently selected from: hydrogen; C1-6 alkyl; C1-6 haloalkyl; and C3-10 carbocycle and 3- to 10-membered heterocycle. In some embodiments, each R 18c is independently selected from: hydrogen; C1-6 alkyl; and C1-6 haloalkyl (e.g., fluoroalkyl). In some embodiments, each R 18c is independently selected from: hydrogen; and C1-6 alkyl. In some embodiments, each R 18c is independently selected from: hydrogen; and C1-6 alkyl; and C3-10 carbocycle. In some embodiments, each R 18c is independently selected from: hydrogen; and C1-6 alkyl; and C3-10 carbocycle, wherein the C3-10 carbocycle is [l.l.
  • each R 18c is independently selected from: hydrogen; and C1-5 alkyl. In some embodiments, each R 18c is independently selected from: hydrogen; and C1-4 alkyl. In some embodiments, each R 18c is independently selected from: hydrogen; and C1-3 alkyl. In some embodiments, each R 18c is independently selected from: hydrogen; and C1-2 alkyl. In some embodiments, each R 18c is independently selected from: hydrogen; and Ci alkyl. In some embodiments, each R 18c is independently selected from: hydrogen. In some embodiments, each R 18c is independently selected from: Ci alkyl.
  • each R 18d is independently selected from: hydrogen; C1-6 alkyl, optionally substituted with one or more substituents independently selected from halogen, - CN, -NO2, -OH, -O(Ci- 6 alkyl), -O(Ci- 6 haloalkyl), -SH, -S(Ci- 6 alkyl), -NH 2 , -NH(CI- 6 alkyl), - N(CI-6 alkyl)2, C3-10 carbocycle and 3-10 membered heterocycle; and C3-10 carbocycle and 3- to 10- membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, -OH, -0(Ci-6 alkyl), -0(Ci-6 haloalkyl), -SH, - S(Ci-6 alkyl), -NH2, -NH(CI-6 alkyl), -N(CI-6 alkyl)2,
  • each R 18d is independently selected from: hydrogen; C1-6 alkyl, optionally substituted with one or more substituents independently selected from -CN, -F, -Cl, -OH, -0(CH , -0(CF3), - NH 2 , -NH(CH 3 ), -N(CH 3 ) 2 , -SH, -S(CH 3 ), -CH 3 , and -CF 3 ; and C3-10 carbocycle and 3- to 10- membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from -CN, -F, -Cl, -OH, -0(CH 3 ), -O(CF 3 ), -NH 2 , -NH(CH 3 ), -N(CH 3 ) 2 , - SH, -S(CH3), -CH3, and -CF3.
  • each R 18d is independently selected from: hydrogen; and C1-5 alkyl. In some embodiments, each R 18d is independently selected from: hydrogen; and C1-4 alkyl. In some embodiments, each R 18d is independently selected from: hydrogen; and C1-3 alkyl. In some embodiments, each R 18d is independently selected from: hydrogen; and C1-2 alkyl. In some embodiments, each R 18d is independently selected from: hydrogen; and Ci alkyl. In some embodiments, each R 18d is independently selected from: hydrogen. In some embodiments, each R 18d is independently selected from: Ci alkyl.
  • each R 18e is independently selected from: hydrogen; C1-6 alkyl, optionally substituted with one or more substituents independently selected from halogen, - CN, -NO2, -OH, -O(Ci- 6 alkyl), -O(Ci- 6 haloalkyl), -SH, -S(Ci- 6 alkyl), -NH 2 , -NH(CI- 6 alkyl), - N(CI-6 alkyl)2, C3-10 carbocycle and 3-10 membered heterocycle; and C3-10 carbocycle and 3- to 10- membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, -OH, -O(Ci-6 alkyl), -O(Ci-6 haloalkyl), -SH, - S(Ci-6 alkyl), -NH2, -NH(CI-6 alkyl), -N(CI-6 alkyl)2,
  • each R 18e is independently selected from: hydrogen; C1-6 alkyl, optionally substituted with one or more substituents independently selected from -CN, -F, -Cl, -OH, -0(CH , -O(CF3), - NH 2 , -NH(CH 3 ), -N(CH 3 ) 2 , -SH, -S(CH 3 ), -CH 3 , and -CF 3 ; and C3-10 carbocycle and 3- to 10- membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from -CN, -F, -Cl, -OH, -O(CH 3 ), -O(CF 3 ), -NH 2 , -NH(CH 3 ), -N(CH 3 ) 2 , - SH, -S(CH3), -CH3, and -CF3.
  • each R 18e is independently selected from: hydrogen; C1-6 alkyl; C1-6 haloalkyl; and C3-10 carbocycle and 3- to 10-membered heterocycle. In some embodiments, each R 18e is independently selected from: hydrogen; C1-6 alkyl; and C1-6 haloalkyl (e.g., fluoroalkyl). In some embodiments, each R 18e is independently selected from: hydrogen; and C1-6 alkyl. In some embodiments, each R 18e is independently selected from: hydrogen; and C1-6 alkyl; and C3-10 carbocycle. In some embodiments, each R 18e is independently selected from: hydrogen; and C1-6 alkyl; and C3-10 carbocycle, wherein the C3-10 carbocycle is [l.l.
  • each R 18e is independently selected from: hydrogen; and C1-5 alkyl. In some embodiments, each R 18e is independently selected from: hydrogen; and C1-4 alkyl. In some embodiments, each R 18e is independently selected from: hydrogen; and C1-3 alkyl. In some embodiments, each R 18e is independently selected from: hydrogen; and C1-2 alkyl. In some embodiments, each R 18e is independently selected from: hydrogen; and Ci alkyl. In some embodiments, each R 18e is independently selected from: hydrogen. In some embodiments, each R 18e is independently selected from: Ci alkyl.
  • each R 18f is independently selected from: hydrogen; C1-6 alkyl, optionally substituted with one or more substituents independently selected from halogen, - CN, -NO2, -OH, -O(Ci- 6 alkyl), -O(Ci- 6 haloalkyl), -SH, -S(Ci- 6 alkyl), -NH 2 , -NH(CI- 6 alkyl), - N(CI-6 alkyl)2, C3-10 carbocycle and 3-10 membered heterocycle; and C3-10 carbocycle and 3- to 10- membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, -OH, -O(Ci-6 alkyl), -O(Ci-6 haloalkyl), -SH, - S(Ci-6 alkyl), -NH2, -NH(CI-6 alkyl), -N(CI-6 alkyl)2,
  • each R 18f is independently selected from: hydrogen; C1-6 alkyl, optionally substituted with one or more substituents independently selected from -CN, -F, -Cl, -OH, -O(CH 3 ), -O(CF3), - NH 2 , -NH(CH 3 ), -N(CH 3 ) 2 , -SH, -S(CH 3 ), -CH 3 , and -CF 3 ; and C 3 -io carbocycle and 3- to 10- membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from -CN, -F, -Cl, -OH, -O(CH 3 ), -O(CF 3 ), -NH 2 , -NH(CH 3 ), -N(CH 3 ) 2 , - SH, -S(CH 3 ), -CH 3 , and -CF 3 .
  • each R 18f is independently selected from: hydrogen; C1-6 alkyl; C1-6 haloalkyl; and C 3 -io carbocycle and 3- to 10-membered heterocycle. In some embodiments, each R 18f is independently selected from: hydrogen; C1-6 alkyl; and C1-6 haloalkyl (e.g., fluoroalkyl). In some embodiments, each R 18f is independently selected from: hydrogen; and C1-6 alkyl. In some embodiments, each R 18f is independently selected from: hydrogen; and C1-6 alkyl; and C 3 -io carbocycle.
  • each R 18f is independently selected from: hydrogen; and C1-6 alkyl; and C 3 -io carbocycle, wherein the C 3 -io carbocycle is [l.l. l]bicyclopentyl or cyclobutyl.
  • each R 18f is independently selected from: hydrogen; and C1-5 alkyl.
  • each R 18f is independently selected from: hydrogen; and C1-4 alkyl.
  • each R 18f is independently selected from: hydrogen; and Ci- 3 alkyl.
  • each R 18f is independently selected from: hydrogen; and C1-2 alkyl.
  • each R 18f is independently selected from: hydrogen; and Ci alkyl.
  • each R 18f is independently selected from: hydrogen.
  • each R 18f is independently selected from: Ci alkyl.
  • each R 18g is independently selected from: hydrogen; C1-6 alkyl, optionally substituted with one or more substituents independently selected from halogen, - CN, -NO2, -OH, -O(Ci- 6 alkyl), -O(Ci- 6 haloalkyl), -SH, -S(Ci- 6 alkyl), -NH 2 , -NH(CI- 6 alkyl), - N(CI-6 alkyl)2, C3-10 carbocycle and 3-10 membered heterocycle; and C3-10 carbocycle and 3- to 10- membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, -OH, -0(Ci-6 alkyl), -0(Ci-6 haloalkyl), -SH, - S(Ci-6 alkyl), -NH2, -NH(CI-6 alkyl), -N(CI-6 alkyl)2,
  • each R 18g is independently selected from: hydrogen; and C1-5 alkyl. In some embodiments, each R 18g is independently selected from: hydrogen; and C1-4 alkyl. In some embodiments, each R 18g is independently selected from: hydrogen; and C1-3 alkyl. In some embodiments, each R 18g is independently selected from: hydrogen; and C1-2 alkyl. In some embodiments, each R 18g is independently selected from: hydrogen; and Ci alkyl. In some embodiments, each R 18g is independently selected from: hydrogen. In some embodiments, each R 18g is independently selected from: Ci alkyl.
  • R 24 is independently selected from: hydrogen, halogen, -OR 28d , -SR 28d , -N(R 28d ) 2 , -N0 2 , and -CN; and Ci-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR 28d , -SR 28d , -N(R 28d )2, -NO2, and -CN, C3-10 carbocycle, and 3- to 10-membered heterocycle, wherein the C3-10 carbocycle, and 3- to 10-membered heterocycle, are each optionally substituted with one or more R 27d ; or
  • R 25 is selected from: hydrogen, halogen, -OR 28f , -SR 28f , -N(R 28f )2, -NO2, and -CN;
  • R 26 is selected from: hydrogen;
  • each R 27 , R 27a , R 27b , R 27c , R 27d , R 27e , R 27f , R 27g is independently selected from: hydrogen, halogen, -CN, -OH, -SH, -NO2, -NH2, -O-C1-6 alkyl, -S-C1-6 alkyl, - N(CI-6 alkyl)2, and -NH(CI-6 alkyl); and
  • each R 28 , R 28a , R 28b , R 28c , R 28d , R 28e , and R 28f is independently selected from: hydrogen, halogen, -CN, -OH, -SH, -NO2, -NH2, -O-C1-6 alkyl, -S-C1-6 alkyl,
  • n is selected from: 0, 1, and 2. In some embodiments, n is selected from 0 and 1. In some embodiments, n is selected from 1 and 2. In some embodiments, for a compound or salt of Formula (III), n is 0. In some embodiments, n is 1. In some embodiments, n is 2.
  • each R 20 is independently selected from: hydrogen;
  • Ci-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 28 , - N(R 28 ) 2 , -C(O)R 28 , -C(O)N(R 28 ) 2 , -N(R 28 )C(O)R 28 -C(O)OR 28 , -OC(O)R 28 , -S(O) 2 R 28 , - NO2, 0, -CN, C3-10 carbocycle and 3- to 10-membered heterocycle, wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents independently selected from R 27 ; and
  • each R 20 is independently selected from: C1-6 alkyl optionally substituted with one or more substituents independently selected from -F, -Cl, -Br, -OR 28 , -N(R 28 )2, -C(O)R 28 ; and C3-6 carbocycle and 3- to 6-membered heterocycle optionally substituted with one or more substituents independently selected from -F, -Cl, -Br, - OR 28 , -N(R 28 ) 2 , -C(O)R 28 .
  • R 21 is independently selected from: hydrogen;
  • C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 28a , - N(R 28a ) 2 , -C(O)R 28a , -C(O)N(R 28a ) 2 , -N(R 28a )C(O)R 28a , -C(O)OR 28a , -OC(O)R 28a , -CN, C3-6 carbocycle, and 3- to 6-membered heterocycle, wherein the C3-6 carbocycle, and 3- to 6-membered heterocycle, are each optionally substituted with one or more substituents independently selected from R 27a ; and
  • R 21 together with R 22 form a C3-6 carbocycle, or 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 28a , -N(R 28a )2, -C(O)R 28a , - C(O)N(R 28a ) 2 , -N(R 28a )C(O)R 28a , -C(O)OR 28a , -OC(O)R 28a , -CN, C21-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, wherein C21-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with one or more substituents independently selected from R 27a .
  • R 21 is independently selected from: methyl, ethyl, w-propyl, and isopropyl. In some embodiments, R 21 is hydrogen. In some embodiments, R 21 is methyl.
  • R 22 is independently selected from: hydrogen;
  • R 12 is selected from: phenyl, pyridyl, pyrimidyl, pyridazinyl, pyrimidinyl, and pyrazinyl, wherein each phenyl, pyridyl, pyrimidyl, pyridazinyl, pyrimidinyl, and pyrazinyl is optionally substituted with one or more substituents independently selected from halogen, -CN, and C1-6 alkyl.
  • R 22 is pyrimidyl.
  • R 12 is pyridyl.
  • R 12 is phenyl.
  • R 22 is selected from: T
  • R 23 is selected from: hydrogen; and C1-6 alkyl optionally substituted with one or more substituents independently selected from R 27C .
  • R 23 is selected from hydrogen, methyl, ethyl, w-propyl, and isopropyl. In some embodiments, R 23 is hydrogen.
  • R 24 is selected from: hydrogen, C1-6 alkyl, C3-10 carbocycle, and 3- to 10-membered heterocycle. In some embodiments, R 24 is selected from: methyl, ethyl, w-propyl, and isopropyl. In some embodiments, R 24 is hydrogen.
  • R 24a is selected from: hydrogen, C1-6 alkyl, C3-10 carbocycle, and 3- to 10-membered heterocycle. In some embodiments, R 24a is selected from: methyl, ethyl, w-propyl, and isopropyl. In some embodiments, R 24a is hydrogen.
  • R 25 is selected from: hydrogen, C1-6 alkyl, C3-10 carbocycle, and 3- to 10-membered heterocycle, wherein the C1-6 alkyl, C3-10 carbocycle, and 3- to 10- membered heterocycle are each optionally substituted with one or more substituents independently selected from R 27f .
  • R 25 is selected from hydrogen, methyl, ethyl, w-propyl, isopropyl, C3-6 carbocycle, and 3- to 6-membered heterocycle. In some embodiments, R 25 is methyl. In some embodiments, R 25 is hydrogen.
  • R 26 is selected from: hydrogen, methyl, ethyl, w-propyl, and isopropyl. In some embodiments, R 26 is methyl. In some embodiments, R 26 is hydrogen. [0180] In some embodiments, for a compound or salt of Formula (III), the compound is selected from:
  • each R 27 is independently selected from halogen, -CN, -NO2, -OH, -0(Ci-6 alkyl), -0(Ci-6 haloalkyl), -SH, -S(Ci-6 alkyl), - NH2, -NH(CI-6 alkyl), -N(CI-6 alkyl)2, C1-6 alkyl, and C1-6 haloalkyl.
  • each R 27 is independently selected from -F, -Cl, -CN, -NO2, -OH, -0(Ci-6 alkyl), -0(Ci-6 haloalkyl), -SH, -S(Ci-6 alkyl), -NH2, -NH(CI-6 alkyl), and -N(CI-6 alkyl)2.
  • each R 27 is independently selected from -CN, -F, -Cl, -OH, -0(CH 3 ), -O(CF 3 ), -NH 2 , -NH(CH 3 ), -N(CH 3 ) 2 , - SH, -S(CH 3 ), -CH 3 , and -CF 3 .
  • each R 27a is independently selected from halogen, -CN, -NO2, -OH, -0(Ci-6 alkyl), -0(Ci-6 haloalkyl), -SH, -S(Ci-6 alkyl), -NH2, -NH(CI-6 alkyl), -N(CI-6 alkyl)2, C1-6 alkyl, C1-6 haloalkyl, C3- 10 carbocycle and 3- to 10-membered heterocycle.
  • each R 27aa is independently selected from halogen, -CN, -NO2, -OH, -0(Ci-6 alkyl), -0(Ci-6 haloalkyl), -SH, - S(Ci-6 alkyl), -NH2, -NH(CI-6 alkyl), -N(CI-6 alkyl)2, C1-6 alkyl, and C1-6 haloalkyl.
  • each R 27a is independently selected from -F, -Cl, -CN, -NO2, -OH, -0(Ci-6 alkyl), - 0(Ci-6 haloalkyl), -SH, -S(Ci-6 alkyl), -NH2, -NH(CI-6 alkyl), and -N(CI-6 alkyl)2.
  • each R 27a is independently selected from -CN, -F, -Cl, -OH, -0(CH3), -0(CF3), -NH2, -NH(CH 3 ), -N(CH 3 ) 2 , -SH, -S(CH 3 ), -CH 3 , and -CF 3 .
  • each R 27b is independently selected from halogen, -CN, -NO2, -OH, -0(Ci-6 alkyl), -0(Ci-6 haloalkyl), -SH, -S(Ci-6 alkyl), -NH2, -NH(CI-6 alkyl), -N(CI-6 alkyl)2, C1-6 alkyl, C1-6 haloalkyl, C3- 10 carbocycle and 3- to 10-membered heterocycle.
  • each R 27b is independently selected from halogen, -CN, -NO2, -OH, -0(Ci-6 alkyl), -0(Ci-6 haloalkyl), -SH, -S(Ci-6 alkyl), - NH2, -NH(CI-6 alkyl), -N(CI-6 alkyl)2, C1-6 alkyl, and C1-6 haloalkyl.
  • each R 27b is independently selected from -F, -Cl, -CN, -NO2, -OH, -0(Ci-6 alkyl), -0(Ci-6 haloalkyl), - SH, -S(Ci-6 alkyl), -NH2, -NH(CI-6 alkyl), and -N(CI-6 alkyl)2.
  • each R 27b is independently selected from -CN, -F, -Cl, -OH, -0(CH 3 ), -O(CF 3 ), -NH 2 , -NH(CH 3 ), -N(CH 3 ) 2 , - SH, -S(CH 3 ), -CH 3 , and -CF 3 .
  • each R 27C is independently selected from halogen, -CN, -NO2, -OH, -0(Ci-6 alkyl), -0(Ci-6 haloalkyl), -SH, -S(Ci-6 alkyl), -NH2, -NH(CI-6 alkyl), -N(CI-6 alkyl)2, C1-6 alkyl, C1-6 haloalkyl, C3- 10 carbocycle and 3- to 10-membered heterocycle.
  • each R 27c is independently selected from halogen, -CN, -NO2, -OH, -0(Ci-6 alkyl), -0(Ci-6 haloalkyl), -SH, -S(Ci-6 alkyl), - NH2, -NH(CI-6 alkyl), -N(CI-6 alkyl)2, C1-6 alkyl, and C1-6 haloalkyl.
  • each R 27C is independently selected from -F, -Cl, -CN, -NO2, -OH, -0(Ci-6 alkyl), -0(Ci-6 haloalkyl), - SH, -S(Ci-6 alkyl), -NH2, -NH(CI-6 alkyl), and -N(CI-6 alkyl)2.
  • each R 27c is independently selected from -CN, -F, -Cl, -OH, -0(CH 3 ), -O(CF 3 ), -NH 2 , -NH(CH 3 ), -N(CH 3 ) 2 , - SH, -S(CH 3 ), -CH 3 , and -CF 3 .
  • each R 27d is independently selected from halogen, -CN, -NO2, -OH, -0(Ci-6 alkyl), -0(Ci-6 haloalkyl), -SH, -S(Ci-6 alkyl), - NH2, -NH(CI-6 alkyl), -N(CI-6 alkyl)2, C1-6 alkyl, and C1-6 haloalkyl.
  • each R 27d is independently selected from -F, -Cl, -CN, -NO2, -OH, -0(Ci-6 alkyl), -0(Ci-6 haloalkyl), - SH, -S(Ci-6 alkyl), -NH2, -NH(CI-6 alkyl), and -N(CI-6 alkyl)2.
  • each R 27d is independently selected from -CN, -F, -Cl, -OH, -0(CH 3 ), -O(CF 3 ), -NH 2 , -NH(CH 3 ), -N(CH 3 ) 2 , - SH, -S(CH 3 ), -CH 3 , and -CF 3 .
  • each R 27e is independently selected from halogen, -CN, -NO2, -OH, -0(Ci-6 alkyl), -0(Ci-6 haloalkyl), -SH, -S(Ci-6 alkyl), -NH2, -NH(CI-6 alkyl), -N(CI-6 alkyl)2, C1-6 alkyl, C1-6 haloalkyl, C3- 10 carbocycle and 3- to 10-membered heterocycle.
  • each R 27e is independently selected from halogen, -CN, -NO2, -OH, -0(Ci-6 alkyl), -0(Ci-6 haloalkyl), -SH, -S(Ci-6 alkyl), - NH2, -NH(CI-6 alkyl), -N(CI-6 alkyl)2, C1-6 alkyl, and C1-6 haloalkyl.
  • each R 27e is independently selected from -F, -Cl, -CN, -NO2, -OH, -0(Ci-6 alkyl), -0(Ci-6 haloalkyl), - SH, -S(Ci-6 alkyl), -NH2, -NH(CI-6 alkyl), and -N(CI-6 alkyl)2.
  • each R 27e is independently selected from -CN, -F, -Cl, -OH, -0(CH 3 ), -O(CF 3 ), -NH 2 , -NH(CH 3 ), -N(CH 3 ) 2 , - SH, -S(CH 3 ), -CH 3 , and -CF 3 .
  • each R 27f is independently selected from halogen, -CN, -NO2, -OH, -0(Ci-6 alkyl), -0(Ci-6 haloalkyl), -SH, -S(Ci-6 alkyl), - NH2, -NH(CI-6 alkyl), -N(CI-6 alkyl)2, C1-6 alkyl, and C1-6 haloalkyl.
  • each R 27f is independently selected from -F, -Cl, -CN, -NO2, -OH, -0(Ci-6 alkyl), -0(Ci-6 haloalkyl), - SH, -S(Ci-6 alkyl), -NH2, -NH(CI-6 alkyl), and -N(CI-6 alkyl)2.
  • each R 27f is independently selected from -CN, -F, -Cl, -OH, -0(CH 3 ), -O(CF 3 ), -NH 2 , -NH(CH 3 ), -N(CH 3 ) 2 , - SH, -S(CH 3 ), -CH 3 , and -CF 3 .
  • each R 27g is independently selected from halogen, -CN, -NO2, -OH, -0(Ci-6 alkyl), -0(Ci-6 haloalkyl), -SH, -S(Ci-6 alkyl), -NH2, -NH(CI-6 alkyl), -N(CI-6 alkyl)2, C1-6 alkyl, C1-6 haloalkyl, C3- 10 carbocycle and 3- to 10-membered heterocycle.
  • each R 27g is independently selected from -F, -Cl, -CN, -NO2, -OH, -0(Ci-6 alkyl), -0(Ci-6 haloalkyl), - SH, -S(Ci-6 alkyl), -NH2, -NH(CI-6 alkyl), and -N(CI-6 alkyl)2.
  • each R 28 is independently selected from: hydrogen; C1-6 alkyl, optionally substituted with one or more substituents independently selected from -CN, -F, -Cl, -OH, -0(CH , -0(CF3), -NH2, -NH(CH3), - N(CHS)2, -SH, -S(CH3), -CH3, and -CF3; and C3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from - CN, -F, -Cl, -OH, -0(CH 3 ), -O(CF 3 ), -NH 2 , -NH(CH 3 ), -N(CH 3 ) 2 , -SH, -S(CH 3 ), -CH 3 , and -CF 3 .
  • each R 28 is independently selected from: hydrogen; C1-6 alkyl; C1-6 haloalkyl; and C3-10 carbocycle and 3- to 10-membered heterocycle. In some embodiments, each R 28 is independently selected from: hydrogen; C1-6 alkyl; and C1-6 haloalkyl (e.g., fluoroalkyl). In some embodiments, each R 28 is independently selected from: hydrogen; and C1-6 alkyl. In some embodiments, each R 28 is independently selected from: hydrogen; and C1-6 alkyl; and C3-10 carbocycle. In some embodiments, each R 28 is independently selected from: hydrogen; and Ci-6 alkyl; and C3-10 carbocycle, wherein the C3-10 carbocycle is [l.
  • each R 28b is independently selected from: hydrogen; C1-6 alkyl, optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, -OH, - O(Ci- 6 alkyl), -O(Ci- 6 haloalkyl), -SH, -S(Ci- 6 alkyl), -NH 2 , -NH(CI- 6 alkyl), -N(CI- 6 alkyl) 2 , C3-10 carbocycle and 3-10 membered heterocycle; and C3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, -OH, -0(Ci-6 alkyl), -0(Ci-6 haloalkyl), -SH, -S(Ci-6 alkyl), - NH2, -NH(CI-6 alkyl), -N(CI-6 alky
  • each R 28b is independently selected from: hydrogen; C1-6 alkyl, optionally substituted with one or more substituents independently selected from -CN, -F, -Cl, -OH, -0(CH , -0(CF3), -NH2, -NH(CH3), - N(CHS)2, -SH, -S(CH3), -CH3, and -CF3; and C3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from - CN, -F, -Cl, -OH, -0(CH 3 ), -O(CF 3 ), -NH 2 , -NH(CH 3 ), -N(CH 3 ) 2 , -SH, -S(CH 3 ), -CH 3 , and -CF 3 .
  • each R 28b is independently selected from: hydrogen; C1-6 alkyl; C1-6 haloalkyl; and C3-10 carbocycle and 3- to 10-membered heterocycle. In some embodiments, each R 28b is independently selected from: hydrogen; C1-6 alkyl; and C1-6 haloalkyl (e.g., fluoroalkyl). In some embodiments, each R 28b is independently selected from: hydrogen; and C1-6 alkyl. In some embodiments, each R 28b is independently selected from: hydrogen; and C1-6 alkyl; and C3-10 carbocycle. In some embodiments, each R 28b is independently selected from: hydrogen; and Ci-6 alkyl; and C3-10 carbocycle, wherein the C3-10 carbocycle is [l.
  • each R 28b is independently selected from: hydrogen; and C1-5 alkyl. In some embodiments, each R 28b is independently selected from: hydrogen; and C1-4 alkyl. In some embodiments, each R 28b is independently selected from: hydrogen; and C1-3 alkyl. In some embodiments, each R 28b is independently selected from: hydrogen; and C1-2 alkyl. In some embodiments, each R 28b is independently selected from: hydrogen; and Ci alkyl. In some embodiments, each R 28b is independently selected from: hydrogen. In some embodiments, each R 28b is independently selected from: Ci alkyl.
  • each R 28c is independently selected from: hydrogen; C1-6 alkyl, optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, -OH, - O(Ci- 6 alkyl), -O(Ci- 6 haloalkyl), -SH, -S(Ci- 6 alkyl), -NH 2 , -NH(CI- 6 alkyl), -N(CI- 6 alkyl) 2 , C3-10 carbocycle and 3-10 membered heterocycle; and C3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, -OH, -O(Ci-6 alkyl), -O(Ci-6 haloalkyl), -SH, -S(Ci-6 alkyl), - NH2, -NH(CI-6 alkyl), -N(CI-6 alkyl
  • each R 28c is independently selected from: hydrogen; C1-6 alkyl, optionally substituted with one or more substituents independently selected from -CN, -F, -Cl, -OH, -0(CH , -O(CF3), -NH2, -NH(CH3), - N(CHs)2, -SH, -S(CH3), -CH3, and -CF3; and C3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from - CN, -F, -Cl, -OH, -0(CH 3 ), -O(CF 3 ), -NH 2 , -NH(CH 3 ), -N(CH 3 ) 2 , -SH, -S(CH 3 ), -CH 3 , and -CF 3 .
  • each R 28c is independently selected from: hydrogen; C1-6 alkyl; C1-6 haloalkyl; and C3-10 carbocycle and 3- to 10-membered heterocycle. In some embodiments, each R 28c is independently selected from: hydrogen; C1-6 alkyl; and C1-6 haloalkyl (e.g., fluoroalkyl). In some embodiments, each R 28c is independently selected from: hydrogen; and C1-6 alkyl. In some embodiments, each R 28c is independently selected from: hydrogen; and C1-6 alkyl; and C3-10 carbocycle. In some embodiments, each R 28c is independently selected from: hydrogen; and C1-6 alkyl; and C3-10 carbocycle, wherein the C3-10 carbocycle is [l.
  • each R 28c is independently selected from: hydrogen; and C1-5 alkyl. In some embodiments, each R 28c is independently selected from: hydrogen; and C1-4 alkyl. In some embodiments, each R 28c is independently selected from: hydrogen; and C1-3 alkyl. In some embodiments, each R 28c is independently selected from: hydrogen; and C1-2 alkyl. In some embodiments, each R 28c is independently selected from: hydrogen; and Ci alkyl. In some embodiments, each R 28c is independently selected from: hydrogen. In some embodiments, each R 28c is independently selected from: Ci alkyl.
  • each R 28d is independently selected from: hydrogen; C1-6 alkyl, optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, -OH, - O(Ci- 6 alkyl), -O(Ci- 6 haloalkyl), -SH, -S(Ci- 6 alkyl), -NH 2 , -NH(CI- 6 alkyl), -N(CI- 6 alkyl) 2 , C3-10 carbocycle and 3-10 membered heterocycle; and C3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, -OH, -O(Ci-6 alkyl), -O(Ci-6 haloalkyl), -SH, -S(Ci-6 alkyl), - NH 2 , -NH(CI-6 alkyl), -N(CI-6
  • each R 28d is independently selected from: hydrogen; C1-6 alkyl, optionally substituted with one or more substituents independently selected from -CN, -F, -Cl, -OH, -O(CH , -O(CF3), -NH 2 , -NH(CH , - N(CHS) 2 , -SH, -S(CH3), -CH3, and -CF3; and C3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from - CN, -F, -Cl, -OH, -O(CH 3 ), -O(CF 3 ), -NH 2 , -NH(CH 3 ), -N(CH 3 ) 2 , -SH, -S(CH 3 ), -CH 3 , and -CF 3 .
  • each R 28d is independently selected from: hydrogen; C1-6 alkyl; C1-6 haloalkyl; and C3-10 carbocycle and 3- to 10-membered heterocycle. In some embodiments, each R 28d is independently selected from: hydrogen; C1-6 alkyl; and C1-6 haloalkyl (e.g., fluoroalkyl). In some embodiments, each R 28d is independently selected from: hydrogen; and C1-6 alkyl. In some embodiments, each R 28d is independently selected from: hydrogen; and C1-6 alkyl; and C3-10 carbocycle. In some embodiments, each R 28d is independently selected from: hydrogen; and C1-6 alkyl; and C3-10 carbocycle, wherein the C3-10 carbocycle is [l.
  • each R 28d is independently selected from: hydrogen; and C1-5 alkyl. In some embodiments, each R 28d is independently selected from: hydrogen; and C1-4 alkyl. In some embodiments, each R 28d is independently selected from: hydrogen; and C1-3 alkyl. In some embodiments, each R 28d is independently selected from: hydrogen; and C1-2 alkyl. In some embodiments, each R 28d is independently selected from: hydrogen; and Ci alkyl. In some embodiments, each R 28d is independently selected from: hydrogen. In some embodiments, each R 28d is independently selected from: Ci alkyl.
  • each R 28e is independently selected from: hydrogen; C1-6 alkyl, optionally substituted with one or more substituents independently selected from -CN, -F, -Cl, -OH, -0(CH , -0(CF3), -NH2, -NH(CH3), - N(CH?)2, -SH, -S(CH3), -CH3, and -CF3; and C3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from - CN, -F, -Cl, -OH, -O(CH 3 ), -O(CF 3 ), -NH 2 , -NH(CH 3 ), -N(CH 3 ) 2 , -SH, -S(CH 3 ), -CH 3 , and -CF 3 .
  • each R 28e is independently selected from: hydrogen; Ci-6 alkyl; Ci-6 haloalkyl; and C 3 -io carbocycle and 3- to 10-membered heterocycle. In some embodiments, each R 28e is independently selected from: hydrogen; Ci-6 alkyl; and Ci-6 haloalkyl (e.g., fluoroalkyl). In some embodiments, each R 28e is independently selected from: hydrogen; and Ci-6 alkyl. In some embodiments, each R 28e is independently selected from: hydrogen; and Ci-6 alkyl; and C 3 -io carbocycle.
  • Y is independently selected from O, N-OH, N(CI-6 alkyl), and N-O(CI-6 alkyl). In some embodiments, Y is O. In some embodiments, Y is N-OH.
  • Ring A is independently selected from:
  • Ring A is independently selected from: C3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from -CN, -OH, -O-C1-6 alkyl, - N(CI-6 alkyl)2, -NH(CI-6 alkyl), C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl.
  • each R 30 , R 30a , andR 30b is independently selected from: C1-6 alkyl optionally substituted with one or more substituents independently selected from -F, -Cl, -Br, - OR 38 , -N(R 38 ) 2 , -C(O)R 38 ; and C3-6 carbocycle and 3- to 6-membered heterocycle optionally substituted with one or more substituents independently selected from -F, -Cl, -Br, -OR 38 , - N(R 38 ) 2 , -C(O)R 38 .
  • R 32 is independently selected from: methyl, ethyl, w-propyl, and isopropyl. In some embodiments, R 32 is hydrogen. In some embodiments, R 32 is methyl.
  • R 34 is selected from: hydrogen, C1-6 alkyl, C3-10 carbocycle, and 3- to 10-membered heterocycle. In some embodiments, R 34 is selected from: methyl, ethyl, w-propyl, and isopropyl. In some embodiments, R 34 is hydrogen.
  • R 34a is selected from: hydrogen, C1-6 alkyl, C3-10 carbocycle, and 3- to 10-membered heterocycle. In some embodiments, R 34a is selected from: methyl, ethyl, w-propyl, and isopropyl. In some embodiments, R 34a is hydrogen.
  • each R 37 is independently selected from: hydrogen; C1-6 alkyl, optionally substituted with one or more substituents independently selected from halogen, -CN, -N0 2 , -OH, - O(Ci- 6 alkyl), -O(Ci- 6 haloalkyl), -SH, -S(Ci- 6 alkyl), -NH 2 , -NH(CI- 6 alkyl), -N(CI- 6 alkyl) 2 , C3-10 carbocycle and 3-10 membered heterocycle; and C3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -NO 2 , -OH, -O(Ci-6 alkyl), -O(Ci-6 haloalkyl), -SH, -S(Ci-6 alkyl), - NH 2 , -NH(CI-6 alkyl), -
  • each R 37c is independently selected from: hydrogen; C1-6 alkyl, optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, -OH, - O(Ci- 6 alkyl), -O(Ci- 6 haloalkyl), -SH, -S(Ci- 6 alkyl), -NH 2 , -NH(CI- 6 alkyl), -N(CI- 6 alkyl) 2 , C3-10 carbocycle and 3-10 membered heterocycle; and C3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, -OH, -0(Ci-6 alkyl), -0(Ci-6 haloalkyl), -SH, -S(Ci-6 alkyl), - NH2, -NH(CI-6 alkyl), -N(CI-6 alky
  • each R 37c is independently selected from: hydrogen; C1-6 alkyl, optionally substituted with one or more substituents independently selected from -CN, -F, -Cl, -OH, -0(CH , -0(CF3), -NH2, -NH(CH3), - N(CHs)2, -SH, -S(CH3), -CH3, and -CF3; and C3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from - CN, -F, -Cl, -OH, -0(CH 3 ), -O(CF 3 ), -NH 2 , -NH(CH 3 ), -N(CH 3 ) 2 , -SH, -S(CH 3 ), -CH 3 , and -CF 3 .
  • each R 37d is independently selected from: hydrogen; C1-6 alkyl, optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, -OH, - O(Ci- 6 alkyl), -O(Ci- 6 haloalkyl), -SH, -S(Ci- 6 alkyl), -NH 2 , -NH(CI- 6 alkyl), -N(CI- 6 alkyl) 2 , C3-10 carbocycle and 3-10 membered heterocycle; and C3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, -OH, -O(Ci-6 alkyl), -O(Ci-6 haloalkyl), -SH, -S(Ci-6 alkyl), - NH 2 , -NH(CI-6 alkyl), -N(CI-6
  • each R 37d is independently selected from: hydrogen; C1-6 alkyl; C1-6 haloalkyl; and C3-10 carbocycle and 3- to 10-membered heterocycle. In some embodiments, each R 37d is independently selected from: hydrogen; C1-6 alkyl; and C1-6 haloalkyl (e.g., fluoroalkyl). In some embodiments, each R 37d is independently selected from: hydrogen; and C1-6 alkyl. In some embodiments, each R 37d is independently selected from: hydrogen; and C1-6 alkyl; and C3-10 carbocycle. In some embodiments, each R 37d is independently selected from: hydrogen; and C1-6 alkyl; and C3-10 carbocycle, wherein the C3-10 carbocycle is [l.
  • each R 37d is independently selected from: hydrogen; and C1-5 alkyl. In some embodiments, each R 37d is independently selected from: hydrogen; and C1-4 alkyl. In some embodiments, each R 37d is independently selected from: hydrogen; and C1-3 alkyl. In some embodiments, each R 37d is independently selected from: hydrogen; and C1-2 alkyl. In some embodiments, each R 37d is independently selected from: hydrogen; and Ci alkyl. In some embodiments, each R 37d is independently selected from: hydrogen. In some embodiments, each R 37d is independently selected from: Ci alkyl.
  • each R 37e is independently selected from: hydrogen; C1-6 alkyl, optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, -OH, - O(Ci- 6 alkyl), -O(Ci- 6 haloalkyl), -SH, -S(Ci- 6 alkyl), -NH 2 , -NH(CI- 6 alkyl), -N(CI- 6 alkyl) 2 , C3-10 carbocycle and 3-10 membered heterocycle; and C3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, -OH, -0(Ci-6 alkyl), -0(Ci-6 haloalkyl), -SH, -S(Ci-6 alkyl), - NH2, -NH(CI-6 alkyl), -N(CI-6 alky
  • each R 37e is independently selected from: hydrogen; C1-6 alkyl, optionally substituted with one or more substituents independently selected from -CN, -F, -Cl, -OH, -O(CH3), -O(CF3), -NH2, -NH(CH3), - N(CH3)2, -SH, -S(CH3), -CH3, and -CF3; and C3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from - CN, -F, -Cl, -OH, -O(CH 3 ), -O(CF 3 ), -NH 2 , -NH(CH 3 ), -N(CH 3 ) 2 , -SH, -S(CH 3 ), -CH 3 , and -CF 3 .
  • each R 37e is independently selected from: hydrogen; C1-6 alkyl; C1-6 haloalkyl; and C3-10 carbocycle and 3- to 10-membered heterocycle. In some embodiments, each R 37e is independently selected from: hydrogen; C1-6 alkyl; and C1-6 haloalkyl (e.g., fluoroalkyl). In some embodiments, each R 37e is independently selected from: hydrogen; and C1-6 alkyl. In some embodiments, each R 37e is independently selected from: hydrogen; and C1-6 alkyl; and C3-10 carbocycle. In some embodiments, each R 37e is independently selected from: hydrogen; and C1-6 alkyl; and C3-10 carbocycle, wherein the C3-10 carbocycle is [l.
  • each R 37e is independently selected from: hydrogen; and C1-5 alkyl. In some embodiments, each R 37e is independently selected from: hydrogen; and C1-4 alkyl. In some embodiments, each R 37e is independently selected from: hydrogen; and C1-3 alkyl. In some embodiments, each R 37e is independently selected from: hydrogen; and C1-2 alkyl. In some embodiments, each R 37e is independently selected from: hydrogen; and Ci alkyl. In some embodiments, each R 37e is independently selected from: hydrogen. In some embodiments, each R 37e is independently selected from: Ci alkyl.
  • each R 37f is independently selected from: hydrogen; C1-6 alkyl, optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, -OH, - O(Ci- 6 alkyl), -O(Ci- 6 haloalkyl), -SH, -S(Ci- 6 alkyl), -NH 2 , -NH(CI- 6 alkyl), -N(CI- 6 alkyl) 2 , C3-10 carbocycle and 3-10 membered heterocycle; and C3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, -OH, -0(Ci-6 alkyl), -0(Ci-6 haloalkyl), -SH, -S(Ci-6 alkyl), - NH2, -NH(CI-6 alkyl), -N(CI-6 alky
  • each R 37f is independently selected from: hydrogen; C1-6 alkyl, optionally substituted with one or more substituents independently selected from -CN, -F, -Cl, -OH, -0(CH , -0(CF3), -NH2, -NH(CH3), - N(CHS)2, -SH, -S(CH3), -CH3, and -CF3; and C3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from - CN, -F, -Cl, -OH, -0(CH 3 ), -O(CF 3 ), -NH 2 , -NH(CH 3 ), -N(CH 3 ) 2 , -SH, -S(CH 3 ), -CH 3 , and -CF 3 .
  • each R 37f is independently selected from: hydrogen; C1-6 alkyl; C1-6 haloalkyl; and C3-10 carbocycle and 3- to 10-membered heterocycle. In some embodiments, each R 37f is independently selected from: hydrogen; C1-6 alkyl; and C1-6 haloalkyl (e.g., fluoroalkyl). In some embodiments, each R 37f is independently selected from: hydrogen; and C1-6 alkyl. In some embodiments, each R 37f is independently selected from: hydrogen; and C1-6 alkyl; and C3-10 carbocycle. In some embodiments, each R 37f is independently selected from: hydrogen; and Ci-6 alkyl; and C3-10 carbocycle, wherein the C3-10 carbocycle is [l.
  • each R 37f is independently selected from: hydrogen; and C1-5 alkyl. In some embodiments, each R 37f is independently selected from: hydrogen; and C1-4 alkyl. In some embodiments, each R 37f is independently selected from: hydrogen; and C1-3 alkyl. In some embodiments, each R 37f is independently selected from: hydrogen; and C1-2 alkyl. In some embodiments, each R 37f is independently selected from: hydrogen; and Ci alkyl. In some embodiments, each R 37f is independently selected from: hydrogen. In some embodiments, each R 37f is independently selected from: Ci alkyl.
  • each R 37g is independently selected from: hydrogen; C1-6 alkyl, optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, -OH, - O(Ci- 6 alkyl), -O(Ci- 6 haloalkyl), -SH, -S(Ci- 6 alkyl), -NH 2 , -NH(CI- 6 alkyl), -N(CI- 6 alkyl) 2 , C3-10 carbocycle and 3-10 membered heterocycle; and C3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, -OH, -0(Ci-6 alkyl), -0(Ci-6 haloalkyl), -SH, -S(Ci-6 alkyl), - NH2, -NH(CI-6 alkyl), -N(CI-6 alky
  • each R 37g is independently selected from: hydrogen; C1-6 alkyl, optionally substituted with one or more substituents independently selected from -CN, -F, -Cl, -OH, -0(CH , -0(CF3), -NH2, -NH(CH3), - N(CHs)2, -SH, -S(CH3), -CH3, and -CF3; and C3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from - CN, -F, -Cl, -OH, -0(CH 3 ), -O(CF 3 ), -NH 2 , -NH(CH 3 ), -N(CH 3 ) 2 , -SH, -S(CH 3 ), -CH 3 , and -CF 3 .
  • each R 37g is independently selected from: hydrogen; and C1-5 alkyl. In some embodiments, each R 37g is independently selected from: hydrogen; and C1-4 alkyl. In some embodiments, each R 37g is independently selected from: hydrogen; and C1-3 alkyl. In some embodiments, each R 37g is independently selected from: hydrogen; and C1-2 alkyl. In some embodiments, each R 37g is independently selected from: hydrogen; and Ci alkyl. In some embodiments, each R 37g is independently selected from: hydrogen. In some embodiments, each R 37g is independently selected from: Ci alkyl.
  • each R 38 is independently selected from: hydrogen; C1-6 alkyl, optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, -OH, - O(Ci- 6 alkyl), -O(Ci- 6 haloalkyl), -SH, -S(Ci- 6 alkyl), -NH 2 , -NH(CI- 6 alkyl), -N(CI- 6 alkyl) 2 , C3-10 carbocycle and 3-10 membered heterocycle; and C3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, -OH, -O(Ci-6 alkyl), -O(Ci-6 haloalkyl), -SH, -S(Ci-6 alkyl), - NH 2 , -NH(CI-6 alkyl), -N(CI-6 al
  • each R 38 is independently selected from: hydrogen; C1-6 alkyl, optionally substituted with one or more substituents independently selected from -CN, -F, -Cl, -OH, -O(CH , -O(CF3), -NH 2 , -NH(CH , - N(CHS) 2 , -SH, -S(CH3), -CH3, and -CF3; and C3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from - CN, -F, -Cl, -OH, -O(CH 3 ), -O(CF 3 ), -NH 2 , -NH(CH 3 ), -N(CH 3 ) 2 , -SH, -S(CH 3 ), -CH 3 , and -CF 3 .
  • each R 38 is independently selected from: hydrogen; and C1-5 alkyl. In some embodiments, each R 38 is independently selected from: hydrogen; and C1-4 alkyl. In some embodiments, each R 38 is independently selected from: hydrogen; and C1-3 alkyl. In some embodiments, each R 38 is independently selected from: hydrogen; and C1-2 alkyl. In some embodiments, each R 38 is independently selected from: hydrogen; and Ci alkyl. In some embodiments, each R 38 is independently selected from: hydrogen. In some embodiments, each R 38 is independently selected from: Ci alkyl.
  • each R 38a is independently selected from: hydrogen; C1-6 alkyl, optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, -OH, - O(Ci- 6 alkyl), -O(Ci- 6 haloalkyl), -SH, -S(Ci- 6 alkyl), -NH 2 , -NH(CI- 6 alkyl), -N(CI- 6 alkyl) 2 , C3-10 carbocycle and 3-10 membered heterocycle; and C3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, -OH, -0(Ci-6 alkyl), -0(Ci-6 haloalkyl), -SH, -S(Ci-6 alkyl), - NH2, -NH(CI-6 alkyl), -N(CI-6 alky
  • each R 38a is independently selected from: hydrogen; C1-6 alkyl, optionally substituted with one or more substituents independently selected from -CN, -F, -Cl, -OH, -0(CH , -0(CF3), -NH2, -NH(CH3), - N(CH?)2, -SH, -S(CH3), -CH3, and -CF3; and C3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from - CN, -F, -Cl, -OH, -O(CH 3 ), -O(CF 3 ), -NH 2 , -NH(CH 3 ), -N(CH 3 ) 2 , -SH, -S(CH 3 ), -CH 3 , and -CF 3 .
  • each R 38a is independently selected from: hydrogen; Ci-6 alkyl; Ci-6 haloalkyl; and C 3 -io carbocycle and 3- to 10-membered heterocycle. In some embodiments, each R 38a is independently selected from: hydrogen; Ci-6 alkyl; and Ci-6 haloalkyl (e.g., fluoroalkyl). In some embodiments, each R 38a is independently selected from: hydrogen; and Ci-6 alkyl. In some embodiments, each R 38a is independently selected from: hydrogen; and Ci-6 alkyl; and C 3 -io carbocycle.
  • each R 38a is independently selected from: hydrogen; and Ci-6 alkyl; and C 3 -io carbocycle, wherein the C 3 -io carbocycle is [l. l.l]bicyclopentyl or cyclobutyl.
  • each R 38a is independently selected from: hydrogen; and C1-5 alkyl.
  • each R 38a is independently selected from: hydrogen; and C1-4 alkyl.
  • each R 38a is independently selected from: hydrogen; and Ci- 3 alkyl.
  • each R 38a is independently selected from: hydrogen; and Ci- 2 alkyl.
  • each R 38a is independently selected from: hydrogen; and Ci alkyl.
  • each R 38a is independently selected from: hydrogen.
  • each R 38a is independently selected from: Ci alkyl.
  • each R 38b is independently selected from: hydrogen; C1-6 alkyl, optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, -OH, - O(Ci- 6 alkyl), -O(Ci- 6 haloalkyl), -SH, -S(Ci- 6 alkyl), -NH 2 , -NH(CI- 6 alkyl), -N(CI- 6 alkyl) 2 , C3-10 carbocycle and 3-10 membered heterocycle; and C3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, -OH, -0(Ci-6 alkyl), -0(Ci-6 haloalkyl), -SH, -S(Ci-6 alkyl), - NH2, -NH(CI-6 alkyl), -N(CI-6 alky
  • each R 38b is independently selected from: hydrogen; C1-6 alkyl, optionally substituted with one or more substituents independently selected from -CN, -F, -Cl, -OH, -0(CH , -0(CF3), -NH2, -NH(CH3), - N(CHS)2, -SH, -S(CH3), -CH3, and -CF3; and C3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from - CN, -F, -Cl, -OH, -0(CH 3 ), -O(CF 3 ), -NH 2 , -NH(CH 3 ), -N(CH 3 ) 2 , -SH, -S(CH 3 ), -CH 3 , and -CF 3 .
  • each R 38b is independently selected from: hydrogen; C1-6 alkyl; C1-6 haloalkyl; and C3-10 carbocycle and 3- to 10-membered heterocycle. In some embodiments, each R 38b is independently selected from: hydrogen; C1-6 alkyl; and C1-6 haloalkyl (e.g., fluoroalkyl). In some embodiments, each R 38b is independently selected from: hydrogen; and C1-6 alkyl. In some embodiments, each R 38b is independently selected from: hydrogen; and C1-6 alkyl; and C3-10 carbocycle. In some embodiments, each R 38b is independently selected from: hydrogen; and C1-6 alkyl; and C3-10 carbocycle, wherein the C3-10 carbocycle is [l.
  • each R 38c is independently selected from: hydrogen; C1-6 alkyl, optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, -OH, - O(Ci- 6 alkyl), -O(Ci- 6 haloalkyl), -SH, -S(Ci- 6 alkyl), -NH 2 , -NH(CI- 6 alkyl), -N(CI- 6 alkyl) 2 , C3-10 carbocycle and 3-10 membered heterocycle; and C3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, -OH, -0(Ci-6 alkyl), -0(Ci-6 haloalkyl), -SH, -S(Ci-6 alkyl), - NH2, -NH(CI-6 alkyl), -N(CI-6 alky
  • each R 38c is independently selected from: hydrogen; C1-6 alkyl; C1-6 haloalkyl; and C3-10 carbocycle and 3- to 10-membered heterocycle. In some embodiments, each R 38c is independently selected from: hydrogen; C1-6 alkyl; and C1-6 haloalkyl (e.g., fluoroalkyl). In some embodiments, each R 38c is independently selected from: hydrogen; and C1-6 alkyl. In some embodiments, each R 38c is independently selected from: hydrogen; and C1-6 alkyl; and C3-10 carbocycle. In some embodiments, each R 38c is independently selected from: hydrogen; and C1-6 alkyl; and C3-10 carbocycle, wherein the C3-10 carbocycle is [l.
  • each R 38c is independently selected from: hydrogen; and C1-5 alkyl. In some embodiments, each R 38c is independently selected from: hydrogen; and C1-4 alkyl. In some embodiments, each R 38c is independently selected from: hydrogen; and C1-3 alkyl. In some embodiments, each R 38c is independently selected from: hydrogen; and C1-2 alkyl. In some embodiments, each R 38c is independently selected from: hydrogen; and Ci alkyl. In some embodiments, each R 38c is independently selected from: hydrogen. In some embodiments, each R 38c is independently selected from: Ci alkyl.
  • each R 38d is independently selected from: hydrogen; C1-6 alkyl; C1-6 haloalkyl; and C3-10 carbocycle and 3- to 10-membered heterocycle. In some embodiments, each R 38d is independently selected from: hydrogen; C1-6 alkyl; and C1-6 haloalkyl (e.g., fluoroalkyl). In some embodiments, each R 38d is independently selected from: hydrogen; and C1-6 alkyl. In some embodiments, each R 38d is independently selected from: hydrogen; and C1-6 alkyl; and C3-10 carbocycle. In some embodiments, each R 38d is independently selected from: hydrogen; and C1-6 alkyl; and C3-10 carbocycle, wherein the C3-10 carbocycle is [l.
  • each R 38d is independently selected from: hydrogen; and C1-5 alkyl. In some embodiments, each R 38d is independently selected from: hydrogen; and C1-4 alkyl. In some embodiments, each R 38d is independently selected from: hydrogen; and C1-3 alkyl. In some embodiments, each R 38d is independently selected from: hydrogen; and C1-2 alkyl. In some embodiments, each R 38d is independently selected from: hydrogen; and Ci alkyl. In some embodiments, each R 38d is independently selected from: hydrogen. In some embodiments, each R 38d is independently selected from: Ci alkyl.
  • each R 38e is independently selected from: hydrogen; C1-6 alkyl, optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, -OH, - O(Ci- 6 alkyl), -O(Ci- 6 haloalkyl), -SH, -S(Ci- 6 alkyl), -NH 2 , -NH(CI- 6 alkyl), -N(CI- 6 alkyl) 2 , C3-10 carbocycle and 3-10 membered heterocycle; and C3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, -OH, -0(Ci-6 alkyl), -0(Ci-6 haloalkyl), -SH, -S(Ci-6 alkyl), - NH2, -NH(CI-6 alkyl), -N(CI-6 alky
  • each R 38e is independently selected from: hydrogen; C1-6 alkyl; C1-6 haloalkyl; and C3-10 carbocycle and 3- to 10-membered heterocycle. In some embodiments, each R 38e is independently selected from: hydrogen; Ci-6 alkyl; and Ci-6 haloalkyl (e.g., fluoroalkyl). In some embodiments, each R 38e is independently selected from: hydrogen; and Ci-6 alkyl. In some embodiments, each R 38e is independently selected from: hydrogen; and Ci-6 alkyl; and C3-10 carbocycle. In some embodiments, each R 38e is independently selected from: hydrogen; and C1-6 alkyl; and C3-10 carbocycle, wherein the C3-10 carbocycle is [l.
  • R Oa is independently selected from: hydrogen, halogen, -N0 2 , -CN, -N3, -OR 8 , -SR 8 , -N(R 8 ) 2 , -C(0)R 8 , -C(O)N(R 8 ) 2 , -N(R 8 )C(O)R 8 , -N(R 8 )C(O)N(R 8 ) 2 , -OC(O)N(R 8 ) 2 , -N(R 8 )C(O)OR 8 , -C(0)0R 8 , -0C(0)R 8 , -S(O)R 8 , and -S(O) 2 R 8 ;
  • R Oc is independently selected from: hydrogen, halogen, -N0 2 , -CN, -N3, -OH, -0(Ci-6 haloalkyl), -SR 8 , -N(R 8 ) 2 , -C(0)R 8 , - C(O)N(R 8 ) 2 , -N(R 8 )C(O)R 8 , -N(R 8 )C(O)N(R 8 ) 2 , -OC(O)N(R 8 ) 2 , - N(R 8 )C(O)OR 8 , -C(0)0R 8 , -0C(0)R 8 , -S(O)R 8 , and -S(O) 2 R 8 ;
  • R od is independently selected from: hydrogen, halogen, -NO 2 , -CN, -N3, -OR 8 , -SR 8 , -N(R 8 ) 2 , -C(O)R 8 , -C(O)N(R 8 ) 2 , -N(R 8 )C(O)R 8 , -N(R 8 )C(O)N(R 8 ) 2 , -OC(O)N(R 8 ) 2 , -N(R 8 )C(O)OR 8 , -C(O)OR 8 , -OC(O)R 8 , -S(O)R 8 , and -S(O) 2 R 8 ;
  • R 4 is selected from: hydrogen, halogen, -0R 8d , -SR 8d , -N(R 8d ) 2 , -N0 2 , and -CN; and
  • C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -0R 8d , -SR 8d , -N(R 8d ) 2 , -N0 2 , and -CN, C3-10 carbocycle, and 3- to 10- membered heterocycle, wherein the C3-10 carbocycle, and 3- to 10-membered heterocycle, are each optionally substituted with one or more substituents independently selected from R 7d ; or R 4 and R 4a together form a C4-10 carbocycle, or 3- to 10-membered heterocycle, wherein the C3- 10 carbocycle, or 3- to 10-membered heterocycle, is optionally substituted with one or more substituents independently selected from R 7e ;
  • R 4a is selected from: hydrogen, halogen, -OR 8e , -SR 8e , -N(R 8e )2, -NO2, and -CN;
  • C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR 8e , -SR 8e , -N(R 8e )2, -NO2, and -CN, C3-10 carbocycle, and 3- to 10- membered heterocycle, wherein the C3-10 carbocycle, and 3- to 10-membered heterocycle, are each optionally substituted with one or more substituents independently selected from R 7e ; or
  • R 4 and R 4a together form a C4-10 carbocycle, or 3- to 10-membered heterocycle, wherein the C3- 10 carbocycle, or 3- to 10-membered heterocycle, is optionally substituted with one or more substituents independently selected from R 7e ;
  • R 5 is selected from: hydrogen, halogen, -OR 8f , -SR 8f , -N(R 8f )2, -NO2, -CN, C1-6 alkyl, C3-10 carbocycle, and 3- to 10- membered heterocycle, wherein the C1-6 alkyl, C3-10 carbocycle, and 3- to 10- membered heterocycle are each optionally substituted with one or more substituents independently selected from R 7f ;
  • R 6 is selected from: hydrogen;
  • each R 7 , R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , and R 7g is independently selected from: halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , -O-C1-6 alkyl, -S-C1-6 alkyl, -N(CI- 6 alkyl) 2 , and -NH(CI- 6 alkyl); and
  • X 1 is independently selected from C(R Oa ), N, and N + (-0 );
  • X 2 is independently selected from C(R ob ), N, and N + (-0 );
  • X 3 is independently selected from C(R Oc ), N, and N + (-0 );
  • X 4 is independently selected from C(R od ), N, and N + (-0 ); wherein no more than three of X 1 , X 2 , X 3 , and X 4 are C(H).
  • X 1 is C(R Oa ); X 2 is C(R ob ); X 3 is C(R Oc ); and X 4 is C(R od ).
  • X 1 is independently selected from C(R Oa ), N, and N + (-O );
  • X 2 is independently selected from C(R ob ), N, and N + (-O );
  • X 3 is independently selected from C(R Oc ), N, and N + (-O ); and
  • X 4 is independently selected from C(R od ), N, and N + (-O ).
  • X 1 is independently selected from N and N + (-O );
  • X 2 is independently selected from C(R ob ), N, and N + (-O );
  • X 3 is independently selected from C(R Oc ), N, and N + (-O );
  • X 4 is independently selected from C(R od ), N, and N + (-O ).
  • X 1 is independently selected from C(R Oa ), N, and N + (-O );
  • X 2 is independently selected from N, and N + (-O );
  • X 3 is independently selected from C(R Oc ), N, and N + (-O ); and
  • X 4 is independently selected from C(R od ), N, and N + (-O ).
  • X 1 is independently selected from C(R Oa ), N, and N + (-O );
  • X 2 is independently selected from C(R ob ), N, and N + (-O );
  • X 3 is independently selected from N, and N + (-O );
  • X 4 is independently selected from C(R od ), N, and N + (-O ).
  • X 1 is independently selected from C(R Oa ), N, and N + (-O );
  • X 2 is independently selected from C(R ob ), N, and N + (-O );
  • X 3 is independently selected from C(R Oc ), N, and N + (-O ); and
  • X 4 is independently selected from N, and N + (-O ).
  • X 1 is independently selected from C(R Oa ), N, and N + (-O );
  • X 2 is independently selected from C(R Oa ), N, and N + (-O );
  • X 3 is C(H), and
  • X 4 is C(H).
  • X 1 is C(R Oa );
  • X 2 is C(R ob );
  • X 3 is C(H), and
  • X 4 is C(H).
  • X 1 is C(R Oa ); X 2 is N;
  • X 3 is C(H), and X 4 is C(H).
  • X 1 is C(F) or C(H); X 2 is C(F); X 3 is C(H); and X 4 is C(H).
  • X 1 , X 2 , X 3 , and X 4 are independently selected from C(R°) and N.
  • X 1 is selected from C(R°) and N.
  • X 2 is selected from C(R°) and N.
  • X 3 is selected from C(R°) and N.
  • X 4 is selected from C(R°) and N.
  • X 1 is selected from C(R°) and N.
  • X 3 is selected from C(R°) and N. In some embodiments, X 4 is selected from C(R°) and N. In some embodiments, X 1 is selected from C(H), C(halogen) and N. In some embodiments, X 2 is selected from C(H), C(halogen) and N. In some embodiments, X 3 is selected from C(H), C(halogen) and N. In some embodiments, X 4 is selected from C(H), C(halogen) and N. In some embodiments, X 1 is selected from C(H) and C(halogen). In some embodiments, X 2 is selected from C(H) and C(halogen).
  • X 3 is selected from C(H) and C(halogen). In some embodiments, X 4 is selected from C(H) and C(halogen). In some embodiments, X 1 is selected from C(H) and C(F). In some embodiments, X 2 is selected from C(H) and C(F). In some embodiments, X 3 is selected from C(H) and C(F). In some embodiments, X 4 is selected from C(H) and C(F). In some embodiments, X 1 is selected from C(H). In some embodiments, X 2 is selected from C(H). In some embodiments, X 3 is selected from C(H). In some embodiments, X 4 is selected from C(H).
  • X 1 is selected from C(F). In some embodiments, X 2 is selected from C(F). In some embodiments, X 3 is selected from C(F). In some embodiments, X 4 is selected from C(F). In some embodiments, X 3 is selected from C(H), and X 4 is selected from C(H). In some embodiments, X 1 is selected from C(F), and X 2 is selected from C(F). In some embodiments, X 1 is selected from C(H), and X 2 is selected from C(H). In some embodiments, X 1 is selected from C(F), and X 2 is selected from C(H). In some embodiments, X 1 is selected from C(H), and X 2 is selected from C(H). In some embodiments, X 1 is selected from C(H), and X 2 is selected from C(F).
  • R Oa is independently selected from: hydrogen, halogen, -NO 2 , -CN, -N 3 , -OR 8 , -SR 8 , -N(R 8 ) 2 , -C(O)R 8 , -C(O)N(R 8 ) 2 , -N(R 8 )C(O)R 8 , -N(R 8 )C(O)N(R 8 ) 2 , -OC(O)N(R 8 ) 2 , -N(R 8 )C(O)OR 8 , -C(O)OR 8 , -OC(O)R 8 , -S(O)R 8 , and -S(O) 2 R 8 ;
  • R Oa is independently selected from hydrogen, halogen, -NO 2 , -CN, -N3, -OR 8 , -SR 8 , -N(R 8 ) 2 , -C(O)R 8 , -C(O)N(R 8 ) 2 , - N(R 8 )C(O)R 8 -N(R 8 )C(O)N(R 8 ) 2 , -OC(O)N(R 8 ) 2 , -N(R 8 )C(O)OR 8 , -C(O)OR 8 , -OC(O)R 8 , -S(O)R 8 , and -S(O) 2 R 8 .
  • R Oa is independently selected from hydrogen, and halogen.
  • R Oa is hydrogen.
  • R Oa is halogen.
  • R Oa is fluorine.
  • R ob is independently selected from: hydrogen, halogen, -NO 2 , -CN, -N3, -OR 8 , -SR 8 , -N(R 8 ) 2 , -C(O)R 8 , -C(O)N(R 8 ) 2 , -N(R 8 )C(O)R 8 , -N(R 8 )C(O)N(R 8 ) 2 , -OC(O)N(R 8 ) 2 , -N(R 8 )C(O)OR 8 , -C(O)OR 8 , -OC(O)R 8 , -S(O)R 8 , and -S(O) 2 R 8 ;
  • R ob is selected from hydrogen, halogen, -NO 2 , -CN, -N 3 , -OR 8 , -SR 8 , -N(R 8 ) 2 , -C(O)R 8 , -C(O)N(R 8 ) 2 , -N(R 8 )C(O)R 8 , - N(R 8 )C(O)N(R 8 ) 2 , -OC(O)N(R 8 ) 2 , -N(R 8 )C(O)OR 8 , -C(O)OR 8 , -OC(O)R 8 , -S(O)R 8 , and -S(O) 2 R 8 .
  • R ob is selected from: halogen, - CN, -NO 2 , -OH, -O(CI- 6 alkyl), -O(Ci- 6 haloalkyl), -NH 2 , -NH(CI- 6 alkyl), -N(CI- 6 alkyl) 2 , -SH, - S(Ci-6 alkyl), C1-6 alkyl, and C1-6 haloalkyl.
  • R ob is selected from: -F, -Cl, - CN, -NO 2 , -OH, -O(CH 3 ), -O(CH 3 ), -NH 2 , -NH(CH 3 ), -N(CH 3 ) 2 , -SH, -S(CH 3 ), CH 3 , and CF 3 .
  • R ob is independently selected from hydrogen, and halogen. In some embodiments, R ob is hydrogen. In some embodiments, R ob is halogen. In some embodiments, R ob is fluorine.
  • R Oc is independently selected from: hydrogen, halogen, -NO 2 , -CN, -N 3 , -OH, -O(Ci-6 haloalkyl), -SR 8 , -N(R 8 ) 2 , -C(O)R 8 , - C(O)N(R 8 ) 2 , -N(R 8 )C(O)R 8 , -N(R 8 )C(O)N(R 8 ) 2 , -OC(O)N(R 8 ) 2 , - N(R 8 )C(O)OR 8 , -C(O)OR 8 , -OC(O)R 8 , -S(O)R 8 , and -S(O) 2 R 8 ;
  • R Oc is independently selected from hydrogen, halogen, -NO2, -CN, -N3, -OH, -O(Ci-6 haloalkyl), -SR 8 , -N(R 8 )2, -C(O)R 8 , - C(O)N(R 8 ) 2 , -N(R 8 )C(O)R 8 , -N(R 8 )C(O)N(R 8 ) 2 , -OC(O)N(R 8 ) 2 , -N(R 8 )C(O)OR 8 , -C(O)OR 8 , -C(O)OR 8 , - OC(O)R 8 , -S(O)R 8 , and -S(O)2R 8 .
  • R od is independently selected from: hydrogen, halogen, -NO 2 , -CN, -N3, -OR 8 , -SR 8 , -N(R 8 ) 2 , -C(O)R 8 , -C(O)N(R 8 ) 2 , -N(R 8 )C(O)R 8 , -N(R 8 )C(O)N(R 8 ) 2 , -OC(O)N(R 8 ) 2 , -N(R 8 )C(O)OR 8 , -C(O)OR 8 , -OC(O)R 8 , -S(O)R 8 , and -S(O) 2 R 8 ;
  • R od is independently selected from hydrogen, halogen, -NO2, -CN, -N3, -OR 8 , -SR 8 , -N(R 8 )2, -C(O)R 8 , -C(O)N(R 8 )2, - N(R 8 )C(O)R 8 -N(R 8 )C(O)N(R 8 ) 2 , -OC(O)N(R 8 ) 2 , -N(R 8 )C(O)OR 8 , -C(O)OR 8 , -OC(O)R 8 , -S(O)R 8 , and -S(O)2R 8 .
  • R od is hydrogen.
  • R 4 is selected from: hydrogen, halogen, -OR 8d , -SR 8d , -N(R 8d )2, -NO2, and -CN; and
  • C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR 8d , -SR 8d , -N(R 8d )2, -NO2, and -CN, C3-10 carbocycle, and 3- to 10- membered heterocycle, wherein the C3-10 carbocycle, and 3- to 10-membered heterocycle, are each optionally substituted with one or more substituents independently selected from R 7d ; or
  • R 4 and R 4a together form a C4-10 carbocycle, or 3- to 10-membered heterocycle, wherein the C3- 10 carbocycle, or 3- to 10-membered heterocycle, is optionally substituted with one or more substituents independently selected from R 7e .
  • R 4 is selected from: hydrogen, halogen, and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen and C3-10 carbocycle, and 3- to 10-membered heterocycle, wherein the C3-10 carbocycle, and 3- to 10-membered heterocycle, are each optionally substituted with one or more substituents independently selected from R 7d .
  • R 4 is selected from hydrogen, halogen, -OR 8d , -SR 8d , -N(R 8d )2, -NO2, and -CN. In some embodiments, R 4 is hydrogen. [0245] In some embodiments, for a compound or salt of Formula (V), R 4a is selected from: hydrogen, halogen, -OR 8e , -SR 8e , -N(R 8e )2, -NO2, and -CN; and
  • C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR 8e , -SR 8e , -N(R 8e )2, -NO2, and -CN, C3-10 carbocycle, and 3- to 10- membered heterocycle, wherein the C3-10 carbocycle, and 3- to 10-membered heterocycle, are each optionally substituted with one or more substituents independently selected from R 7e ; or R 4 and R 4a together form a C4-10 carbocycle, or 3- to 10-membered heterocycle, wherein the C3-10 carbocycle, or 3- to 10-membered heterocycle, is optionally substituted with one or more substituents independently selected from R 7e .
  • R 4a is selected from: hydrogen, halogen, -OR 8e , -SR 8e , -N(R 8e )2, -NO2, and -CN. In some embodiments, R 4a is selected from: hydrogen, -F, -Cl, -Br, -I. In some embodiments, R 4a is selected from hydrogen and -F. In some embodiments, R 4a is hydrogen.
  • R 4 and R 4a together form a C4-6 carbocycle, or 3- to 6-membered heterocycle, wherein the C3-6 carbocycle, or 3- to 6-membered heterocycle, is optionally substituted with one or more substituents independently selected from R 7e .
  • R 4 and R 4a together form a C4-10 carbocycle, or 3- to 10-membered heterocycle.
  • R 4 and R 4a together form a C4-10 carbocycle.
  • R 4 and R 4a together form a cyclobutane.
  • R 5 is selected from hydrogen, halogen, -OR 8f , -SR 8f , -N(R 8f )2, -NO2, -CN, C1-6 alkyl, C3-10 carbocycle, and 3- to 10-membered heterocycle, wherein the C1-6 alkyl, C3-10 carbocycle, and 3- to 10- membered heterocycle are each optionally substituted with one or more substituents independently selected from R 7f .
  • R 5 is selected from hydrogen, -F, -Cl, -Br, I.
  • R 5 is selected from hydrogen, and -F.
  • R 5 is hydrogen.
  • R 5 is selected from -OR 8f and C1-6 alkyl optionally substituted with one or more substituents independently selected from R 7f . In some embodiments, R 5 is -OR 8f . In some embodiments, R 5 is selected from - O(Ci-6alkyl). In some embodiments, R 5 is -OH. In some embodiments, R 5 is -OCH3. In some embodiments, R 5 is C1-6 alkyl optionally substituted with one or more substituents independently selected from R 7f . In some embodiments, R 5 is -CH3.
  • R 6 is selected from: hydrogen;
  • R 6 is hydrogen.
  • each R 7 , R 7a , R 713 , R 7c , R 7d , R 7e , R 7f , and R 7g is independently selected from: halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , -O-C1-6 alkyl, -S-C1-6 alkyl, -N(CI- 6 alkyl) 2 , and -NH(CI- 6 alkyl); and
  • each R 7 , R 7a , R 713 , R 7c , R 7d , R 7e , R 7f , and R 7g is independently selected from: halogen, -CN, -OH, -SH, -NO2, -NH2, -O-C1-6 alkyl, -S-C1-6 alkyl, -N(CI-6 alkyl)2, and -NH(CI-6 alkyl), C1-6 alkyl, C3-10 carbocycle, and 3- to 10- membered heterocycle.
  • each R 7 , R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , and R 7g is independently selected from: halogen, -CN, -OH, -NH2, and -CH3.
  • each R 8 , R 8a , R 8b , R 8c , R 8d , R 8e , and R 8f is independently selected from: hydrogen;
  • each R 8 , R 8a , R 8b , R 8c , R 8d , R 8e , and R 8f is C1-6 alkyl.
  • R 8a is CH3.
  • each R 7 is independently selected from halogen, -CN, -NO2, -OH, -O(Ci-6 alkyl), -O(Ci-6 haloalkyl), -SH, -S(Ci-6 alkyl), - NH2, -NH(CI-6 alkyl), -N(CI-6 alkyl)2, C1-6 alkyl, C1-6 haloalkyl, C3-10 carbocycle and 3- to 10- membered heterocycle.
  • each R 7 is independently selected from halogen, - CN, -NO2, -OH, -O(Ci- 6 alkyl), -O(Ci- 6 haloalkyl), -SH, -S(Ci- 6 alkyl), -NH 2 , -NH(CI- 6 alkyl), - N(CI-6 alkyl)2, C1-6 alkyl, and C1-6 haloalkyl.
  • each R 7 is independently selected from -F, -Cl, -CN, -NO2, -OH, -O(Ci-6 alkyl), -O(Ci-6 haloalkyl), -SH, -S(Ci-6 alkyl), -NH2, -NH(CI-6 alkyl), and -N(CI-6 alkyl)2.
  • each R 7 is independently selected from -CN, -F, -Cl, -OH, -0(CH 3 ), -O(CF 3 ), -NH 2 , -NH(CH 3 ), -N(CH 3 ) 2 , -SH, -S(CH 3 ), -CH 3 , and -CF 3 .
  • each R 7a is independently selected from halogen, -CN, -NO2, -OH, -O(Ci-6 alkyl), -O(Ci-6 haloalkyl), -SH, -S(Ci-6 alkyl), - NH2, -NH(CI-6 alkyl), -N(CI-6 alkyl)2, C1-6 alkyl, C1-6 haloalkyl, C3-10 carbocycle and 3- to 10- membered heterocycle.
  • each R 7a is independently selected from halogen, - CN, -NO 2 , -OH, -O(Ci-6 alkyl), -O(Ci- 6 haloalkyl), -SH, -S(Ci- 6 alkyl), -NH 2 , -NH(CI- 6 alkyl), - N(CI-6 alkyl) 2 , C1-6 alkyl, and C1-6 haloalkyl.
  • each R 7a is independently selected from -F, -Cl, -CN, -NO 2 , -OH, -O(Ci-6 alkyl), -O(Ci-6 haloalkyl), -SH, -S(Ci-6 alkyl), -NH 2 , -NH(CI-6 alkyl), and -N(CI-6 alkyl) 2 .
  • each R 7a is independently selected from -CN, -F, -Cl, -OH, -O(CH 3 ), -O(CF 3 ), -NH 2 , -NH(CH 3 ), -N(CH 3 ) 2 , -SH, -S(CH 3 ), -CH 3 , and -CF 3 .
  • each R 7b is independently selected from halogen, -CN, -NO 2 , -OH, -O(Ci-6 alkyl), -O(Ci-6 haloalkyl), -SH, -S(Ci-6 alkyl), - NH 2 , -NH(CI-6 alkyl), -N(CI-6 alkyl) 2 , C1-6 alkyl, C1-6 haloalkyl, C 3 -io carbocycle and 3- to 10- membered heterocycle.
  • each R 7b is independently selected from halogen, - CN, -NO 2 , -OH, -O(CI- 6 alkyl), -O(Ci- 6 haloalkyl), -SH, -S(Ci- 6 alkyl), -NH 2 , -NH(CI- 6 alkyl), - N(CI-6 alkyl) 2 , C1-6 alkyl, and C1-6 haloalkyl.
  • each R 7b is independently selected from -F, -Cl, -CN, -NO 2 , -OH, -O(Ci-6 alkyl), -O(Ci-6 haloalkyl), -SH, -S(Ci-6 alkyl), -NH 2 , -NH(CI-6 alkyl), and -N(CI-6 alkyl) 2 .
  • each R 7b is independently selected from -CN, -F, -Cl, -OH, -O(CH 3 ), -O(CF 3 ), -NH 2 , -NH(CH 3 ), -N(CH 3 ) 2 , -SH, -S(CH 3 ), -CH 3 , and -CF 3 .
  • each R 7c is independently selected from halogen, -CN, -NO 2 , -OH, -O(Ci-6 alkyl), -O(Ci-6 haloalkyl), -SH, -S(Ci-6 alkyl), - NH 2 , -NH(CI-6 alkyl), -N(CI-6 alkyl) 2 , C1-6 alkyl, C1-6 haloalkyl, C 3 -io carbocycle and 3- to 10- membered heterocycle.
  • each R 7c is independently selected from halogen, - CN, -NO 2 , -OH, -O(CI- 6 alkyl), -O(Ci- 6 haloalkyl), -SH, -S(Ci- 6 alkyl), -NH 2 , -NH(CI- 6 alkyl), - N(CI-6 alkyl) 2 , C1-6 alkyl, and C1-6 haloalkyl.
  • each R 7c is independently selected from -F, -Cl, -CN, -NO 2 , -OH, -O(Ci-6 alkyl), -O(Ci-6 haloalkyl), -SH, -S(Ci-6 alkyl), -NH 2 , -NH(CI-6 alkyl), and -N(CI-6 alkyl) 2 .
  • each R 7c is independently selected from -CN, -F, -Cl, -OH, -O(CH 3 ), -O(CF 3 ), -NH 2 , -NH(CH 3 ), -N(CH 3 ) 2 , -SH, -S(CH 3 ), -CH 3 , and -CF 3 .
  • each R 7d is independently selected from halogen, -CN, -NO 2 , -OH, -O(Ci-6 alkyl), -O(Ci-6 haloalkyl), -SH, -S(Ci-6 alkyl), - NH 2 , -NH(CI-6 alkyl), -N(CI-6 alkyl) 2 , C1-6 alkyl, C1-6 haloalkyl, C 3 -io carbocycle and 3- to 10- membered heterocycle.
  • each R 7d is independently selected from halogen, - CN, -NO 2 , -OH, -O(CI- 6 alkyl), -O(Ci- 6 haloalkyl), -SH, -S(Ci- 6 alkyl), -NH 2 , -NH(CI- 6 alkyl), - N(CI-6 alkyl) 2 , C1-6 alkyl, and C1-6 haloalkyl.
  • each R 7d is independently selected from -F, -Cl, -CN, -NO 2 , -OH, -O(Ci-6 alkyl), -O(Ci-6 haloalkyl), -SH, -S(Ci-6 alkyl), -NH 2 , -NH(CI-6 alkyl), and -N(CI-6 alkyl) 2 .

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Abstract

L'invention concerne des composés de quinolinone pour moduler la myosine musculaire pour traiter l'obésité et des troubles apparentés tels que des maladies cardiovasculaires, le diabète de type 2, l'apnée obstructive du sommeil, le cancer et l'arthrose.
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