WO2021202720A1 - Use of triterpenoid nrf2 inhibitors - Google Patents

Use of triterpenoid nrf2 inhibitors Download PDF

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WO2021202720A1
WO2021202720A1 PCT/US2021/025158 US2021025158W WO2021202720A1 WO 2021202720 A1 WO2021202720 A1 WO 2021202720A1 US 2021025158 W US2021025158 W US 2021025158W WO 2021202720 A1 WO2021202720 A1 WO 2021202720A1
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alkyl
heterocycloalkyl
cycloalkyl
independently
alkynyl
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PCT/US2021/025158
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French (fr)
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Bohan Jin
Qing Dong
Gene Hung
Stephen W. Kaldor
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Fronthera U.S. Pharmaceuticals Llc
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Priority to CN202180026671.3A priority Critical patent/CN115697319A/en
Publication of WO2021202720A1 publication Critical patent/WO2021202720A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/661—Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/275—Nitriles; Isonitriles
    • A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4166—1,3-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/69—Boron compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys

Definitions

  • Kidney diseases are highly prevalent worldwide, and significantly reduce the quality of life of patients, creating an urgent need for effective therapeutic modalities. Despite this significant unmet medical need, none of the drugs launched to date have demonstrated promising potential to cure kidney diseases. This is likely due to the structural complexity of the kidney as well as difficulties in setting appropriate endpoints for clinical trials and identifying appropriate therapeutic targets.
  • Kelch-like ECH-associated protein 1-nuclear factor erythroid 2-related factor 2 (Keap1-Nrf2) system has drawn much attention in recent years for its anti-oxidative and anti- inflammatory properties, and its pharmacological potential for treatment of kidney diseases is being widely investigated in both clinical and non-clinical studies. [0003] A number of reports have described the association between Nrf2 and kidney diseases. Additionally, a review by Nezu et al. discusses the role of Nrf2 in genetically modified animals (Nrf2 knockout [KO], Keap1 knockdown [KD], and Keap1 conditional KO [cKO]) (Nezu, M., Suzuki, N., Yamamoto, M., 2017.
  • Nrf2-KO renin-like nephritis
  • streptozotocin-induced renal disease including renal function
  • ferric nitrilotriacetate-induced nephrotoxicity ischemia-reperfusion (IRI)-induced kidney injury.
  • IRI ischemia-reperfusion
  • the Keap1-KD mutation is associated with reduced IRI-induced tubular injury and reduced unilateral ureteral obstruction-induced renal fibrosis.
  • Nrf2 activators such as sulforaphane, curcumin, and synthetic triterpenoids (CDDO) such as bardoxolone methyl [CDDO-Me]
  • CDDO synthetic triterpenoids
  • a disease that is systemic lupus nephritis, diabetic chronic kidney disease (CDK), Alport syndrome, focal segmental glomerulosclerosis (FSGS), pulmonary hypertension, Friedreich's ataxia, autosomal dominant polycystic kidney disease (ADPKD), or IgA nephropathy
  • FIG.1A displays the spleen weight to body weight following treatment with compound 26 in an imiquimod-induced systemic lupus nephritis mouse model.
  • FIG.1B displays the fold of spleen mRNA expression following treatment with compound 26 in an imiquimod-induced systemic lupus nephritis mouse model.
  • FIG.2A displays the serum BUN (blood urea nitrogen) levels following treatment with compound 26 in an imiquimod-induced systemic lupus nephritis mouse model.
  • FIG.2B displays urine protein levels following treatment with compound 26 in an imiquimod- induced systemic lupus nephritis mouse model.
  • FIG.3A displays the kidney weight to body weight following treatment with compound 26 in an imiquimod-induced systemic lupus nephritis mouse model.
  • FIG.3B displays the renal histopathologic score following treatment with compound 26 in an imiquimod-induced systemic lupus nephritis mouse model.
  • FIG.3C displays the expression of NGAL in the kidney following treatment with compound 26 in an imiquimod-induced systemic lupus nephritis mouse model.
  • FIG.3D displays the expression of CD11b in the kidney following treatment with compound 26 in an imiquimod-induced systemic lupus nephritis mouse model.
  • an agent includes a plurality of such agents
  • the cell includes reference to one or more cells (or to a plurality of cells) and equivalents thereof known to those skilled in the art, and so forth.
  • ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included.
  • the term “about” when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range, in some instances, will vary between 1% and 15% of the stated number or numerical range.
  • Aliphatic chain refers to a linear chemical moiety that is composed of only carbons and hydrogens. In some embodiments, the aliphatic chain is saturated. In some embodiments, the aliphatic chain is unsaturated.
  • the unsaturated aliphatic chain contains one unsaturation. In some embodiments, the unsaturated aliphatic chain contains more than one unsaturation. In some embodiments, the unsaturated aliphatic chain contains two unsaturations. In some embodiments, the unsaturated aliphatic chain contains one double bond. In some embodiments, the unsaturated aliphatic chain contains two double bonds.
  • Alkyl refers to an optionally substituted straight-chain, or optionally substituted branched- chain saturated hydrocarbon monoradical having from one to about ten carbon atoms, or from one to six carbon atoms, wherein an sp 3 -hybridized carbon of the alkyl residue is attached to the rest of the molecule by a single bond.
  • Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2- dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3- methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl, and hexyl, and longer alkyl groups, such as heptyl, octyl
  • C 1 -C 6 alkyl means that the alkyl group consists of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated.
  • the alkyl is a C 1 -C 10 alkyl, a C 1 - C 9 alkyl, a C 1 -C 8 alkyl, a C 1 -C 7 alkyl, a C 1 -C 6 alkyl, a C 1 -C 5 alkyl, a C 1 -C 4 alkyl, a C 1 -C 3 alkyl, a C 1 -C 2 alkyl, or a C 1 alkyl.
  • an alkyl group is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the alkyl is optionally substituted with oxo, halogen, -CN, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • the alkyl is optionally substituted with oxo, halogen, -CN, -CF 3 , -OH, or -OMe.
  • alkyl is optionally substituted with halogen.
  • Alkenyl refers to an optionally substituted straight-chain, or optionally substituted branched- chain hydrocarbon monoradical having one or more carbon-carbon double-bonds and having from two to about ten carbon atoms, more preferably two to about six carbon atoms, wherein an sp 2 -hybridized carbon of the alkenyl residue is attached to the rest of the molecule by a single bond.
  • the group may be in either the cis or trans conformation about the double bond(s), and should be understood to include both isomers.
  • a numerical range such as “C 2 -C 6 alkenyl” means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkenyl” where no numerical range is designated.
  • the alkenyl is a C 2 -C 10 alkenyl, a C 2 -C 9 alkenyl, a C 2 -C 8 alkenyl, a C 2 -C 7 alkenyl, a C 2 -C 6 alkenyl, a C 2 -C 5 alkenyl, a C 2 -C 4 alkenyl, a C 2 -C 3 alkenyl, or a C 2 alkenyl.
  • an alkenyl group is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • an alkenyl is optionally substituted with oxo, halogen, -CN, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • an alkenyl is optionally substituted with oxo, halogen, -CN, -CF 3 , -OH, or -OMe.
  • alkenyl is optionally substituted with halogen.
  • Alkynyl refers to an optionally substituted straight-chain or optionally substituted branched- chain hydrocarbon monoradical having one or more carbon-carbon triple-bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, and the like.
  • C 2 -C 6 alkynyl means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkynyl” where no numerical range is designated.
  • the alkynyl is a C 2 -C 10 alkynyl, a C 2 -C 9 alkynyl, a C 2 -C 8 alkynyl, a C 2 -C 7 alkynyl, a C 2 -C 6 alkynyl, a C 2 -C 5 alkynyl, a C 2 -C 4 alkynyl, a C 2 -C 3 alkynyl, or a C 2 alkynyl.
  • an alkynyl group is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • an alkynyl is optionally substituted with oxo, halogen, -CN, - CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • an alkynyl is optionally substituted with oxo, halogen, -CN, -CF 3 , -OH, or -OMe.
  • alkynyl is optionally substituted with halogen.
  • Alkylene refers to a straight or branched divalent hydrocarbon chain. Unless stated otherwise specifically in the specification, an alkylene group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkylene is optionally substituted with oxo, halogen, - CN, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • an alkylene is optionally substituted with oxo, halogen, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the alkylene is optionally substituted with halogen.
  • Alkoxy refers to a radical of the formula -OR a where R a is an alkyl radical as defined. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • an alkoxy is optionally substituted with oxo, halogen, -CN, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 . In some embodiments, an alkoxy is optionally substituted with oxo, halogen, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the alkoxy is optionally substituted with halogen. [0024] “Aminoalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more amines. In some embodiments, the alkyl is substituted with one amine.
  • the alkyl is substituted with one, two, or three amines.
  • Hydroxyalkyl include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the hydroxyalkyl is aminomethyl.
  • Aryl refers to a radical derived from a hydrocarbon ring system comprising hydrogen, 6 to 30 carbon atoms, and at least one aromatic ring.
  • the aryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through an aromatic ring atom) or bridged ring systems.
  • the aryl is a 6- to 10-membered aryl. In some embodiments, the aryl is a 6-membered aryl.
  • Aryl radicals include, but are not limited to, aryl radicals derived from the hydrocarbon ring systems of anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as- indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene.
  • the aryl is phenyl.
  • an aryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • an aryl is optionally substituted with halogen, methyl, ethyl, -CN, - CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • an aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the aryl is optionally substituted with halogen.
  • Cycloalkyl refers to a stable, partially or fully saturated, monocyclic or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or a heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom), bridged, or spiro ring systems.
  • Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (C 3 -C 15 cycloalkyl), from three to ten carbon atoms (C 3 -C 10 cycloalkyl), from three to eight carbon atoms (C 3 -C 8 cycloalkyl), from three to six carbon atoms (C 3 -C 6 cycloalkyl), from three to five carbon atoms (C 3 -C 5 cycloalkyl), or three to four carbon atoms (C 3 -C 4 cycloalkyl).
  • the cycloalkyl is a 3- to 6- membered cycloalkyl.
  • the cycloalkyl is a 5- to 6-membered cycloalkyl.
  • Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Polycyclic cycloalkyls or carbocycles include, for example, adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl.
  • Partially saturated cycloalkyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless stated otherwise specifically in the specification, a cycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe.
  • the cycloalkyl is optionally substituted with halogen.
  • “Deuteroalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more deuteriums.
  • the alkyl is substituted with one deuterium. In some embodiments, the alkyl is substituted with one, two, or three deuteriums. In some embodiments, the alkyl is substituted with one, two, three, four, five, or six deuteriums.
  • Deuteroalkyl include, for example, CD 3 , CH 2 D, CHD 2 , CH 2 CD 3 , CD 2 CD 3 , CHDCD 3 , CH 2 CH 2 D, or CH 2 CHD 2 . In some embodiments, the deuteroalkyl is CD 3 . [0028] “Haloalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more halogens.
  • the alkyl is substituted with one, two, or three halogens. In some embodiments, the alkyl is substituted with one, two, three, four, five, or six halogens.
  • Haloalkyl include, for example, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like. In some embodiments, the haloalkyl is trifluoromethyl.
  • Halo or “halogen” refers to bromo, chloro, fluoro, or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.
  • Heteroalkyl refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, or combinations thereof. A heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
  • a heteroalkyl is a C 1 -C 6 heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen (e.g. -NH-, -N(alkyl)- ), sulfur, or combinations thereof wherein the heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
  • heteroalkyl are, for example, -CH 2 OCH 3 , - CH 2 CH 2 OCH 3 , -CH 2 CH 2 OCH 2 CH 2 OCH 3 , or -CH(CH 3 )OCH 3 .
  • a heteroalkyl is optionally substituted for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, - CN, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the heteroalkyl is optionally substituted with halogen.
  • “Hydroxyalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more hydroxyls. In some embodiments, the alkyl is substituted with one hydroxyl. In some embodiments, the alkyl is substituted with one, two, or three hydroxyls.
  • Hydroxyalkyl include, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.
  • Heterocycloalkyl refers to a stable 3- to 24-membered partially or fully saturated ring radical comprising 2 to 23 carbon atoms and from one to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, and sulfur.
  • the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom) or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized.
  • heterocycloalkyls include, but are not limited to, heterocycloalkyls having from two to fifteen carbon atoms (C 2 -C 15 heterocycloalkyl), from two to ten carbon atoms (C 2 -C 10 heterocycloalkyl), from two to eight carbon atoms (C 2 -C 8 heterocycloalkyl), from two to six carbon atoms (C 2 -C 6 heterocycloalkyl), from two to five carbon atoms (C 2 -C 5 heterocycloalkyl), or two to four carbon atoms (C 2 -C 4 heterocycloalkyl).
  • the heterocycloalkyl is a 3- to 6- membered heterocycloalkyl.
  • the cycloalkyl is a 5- to 6-membered heterocycloalkyl.
  • heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, t
  • heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to, the monosaccharides, the disaccharides, and the oligosaccharides. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e. skeletal atoms of the heterocycloalkyl ring).
  • a heterocycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • a heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • a heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, - CF 3 , -OH, or -OMe. In some embodiments, the heterocycloalkyl is optionally substituted with halogen.
  • Heteroaryl refers to a 5- to 14-membered ring system radical comprising hydrogen atoms, one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, and sulfur, and at least one aromatic ring.
  • the heteroaryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded through an aromatic ring atom) or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized.
  • the heteroaryl is a 5- to 10-membered heteroaryl.
  • the heteroaryl is a 5- to 6-membered heteroaryl.
  • Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furany
  • a heteroaryl is optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • a heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, - CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • a heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the heteroaryl is optionally substituted with halogen.
  • the terms “treat,” “prevent,” “ameliorate,” and “inhibit,” as well as words stemming therefrom, as used herein, do not necessarily imply 100% or complete treatment, prevention, amelioration, or inhibition. Rather, there are varying degrees of treatment, prevention, amelioration, and inhibition of which one of ordinary skill in the art recognizes as having a potential benefit or therapeutic effect.
  • the disclosed methods can provide any amount of any level of treatment, prevention, amelioration, or inhibition of the disorder in a mammal.
  • a disorder, including symptoms or conditions thereof may be reduced by, for example, about 100%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, or about 10%.
  • the treatment, prevention, amelioration, or inhibition provided by the methods disclosed herein can include treatment, prevention, amelioration, or inhibition of one or more conditions or symptoms of the disorder, e.g., cancer or an inflammatory disease.
  • “treatment,” “prevention,” “amelioration,” or “inhibition” encompass delaying the onset of the disorder, or a symptom or condition thereof.
  • an “effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of a compound disclosed herein being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated, e.g., cancer or an inflammatory disease. In some embodiments, the result is a reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
  • an “effective amount” for therapeutic uses is the amount of the composition comprising a compound disclosed herein required to provide a clinically significant decrease in disease symptoms.
  • an appropriate “effective” amount in any individual case is determined using techniques, such as a dose escalation study.
  • Ring A is a cycloalkyl or a heterocycloalkyl
  • R 1 is -CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (I), R 1 is -CN or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (I), R 1 is C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (I), R 1 is -CN. [0039] In some embodiments of a compound of Formula (I), R 8 is hydrogen or deuterium. In some embodiments of a compound of Formula (I), R 8 is hydrogen.
  • R 9 is C 1 -C 6 alkyl or C 2 -C 6 alkynyl. In some embodiments of a compound of Formula (I), R 9 is C 1 -C 6 alkyl. [0041] In some embodiments of a compound of Formula (I), R 10 is C 1 -C 6 alkyl or C 2 -C 6 alkynyl. In some embodiments of a compound of Formula (I), R 10 is C 1 -C 6 alkyl. [0042] In some embodiments of a compound of Formula (I), R 9 is C 1 -C 6 alkyl and R 10 is C 2 -C 6 alkynyl.
  • R 10 is C 1 -C 6 alkyl and R 9 is C 2 -C 6 alkynyl.
  • R 11 is hydrogen, halogen, or -OH.
  • R 11 is hydrogen or -OH.
  • R 11 is hydrogen.
  • R 12 and R 13 are independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 deuteroalkyl.
  • R 12 and R 13 are independently hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I), R 12 and R 13 are independently hydrogen or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (I), R 12 and R 13 are independently C 1 -C 6 alkyl. [0046] In some embodiments of a compound of Formula (I), R 12 and R 13 are taken together to form a cycloalkyl. In some embodiments of a compound of Formula (I), R 12 and R 13 are taken together to form a cycloalkyl substituted with 1-4 deuterium.
  • R 12 and R 13 are taken together to form a cycloalkyl substituted with 1 or 2 deuterium. In some embodiments of a compound of Formula (I), R 12 and R 13 are taken together to form a cycloalkyl substituted with 2-4 deuteriums. [0047] In some embodiments of a compound of Formula (I), R 12 and R 13 are taken together to form a heterocycloalkyl. In some embodiments of a compound of Formula (I), R 12 and R 13 are taken together to form a heterocycloalkyl substituted with 1-4 deuterium.
  • R 12 and R 13 are taken together to form a heterocycloalkyl substituted with 1 or 2 deuterium. In some embodiments of a compound of Formula (I), R 12 and R 13 are taken together to form a heterocycloalkyl substituted with 2-4 deuteriums.
  • R 3 is C 1 -C 6 alkyl optionally substituted with one, two, or three R 3a .
  • each R 3b is independently deuterium, halogen, -CN, -OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl.
  • each R 3b is independently deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl.
  • each R 4 is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one, two, or three R 4a .
  • each R 4 is independently C 1 - C 6 alkyl or cycloalkyl; wherein the alkyl and cycloalkyl are independently optionally substituted with one, two, or three R 4a . In some embodiments of a compound of Formula (I), each R 4 is independently C 1 - C 6 alkyl optionally substituted with one, two, or three R 4a . In some embodiments of a compound of Formula (I), each R 4 is independently C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I), each R 4 is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl.
  • each R 4a is independently oxo, deuterium, halogen, -CN, -OR b , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl, or heterocycloalkyl.
  • each R 4a is independently deuterium or halogen.
  • each R 4a is independently halogen.
  • each R 5 is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one, two, or three R 5a .
  • each R 5 is independently hydrogen, C 1 -C 6 alkyl, or cycloalkyl; wherein the alkyl and cycloalkyl are independently optionally substituted with one, two, or three R 5a .
  • each R 5 is independently hydrogen or C 1 - C 6 alkyl optionally substituted with one, two, or three R 5a . In some embodiments of a compound of Formula (I), each R 5 is independently C 1 -C 6 alkyl optionally substituted with one, two, or three R 5a . In some embodiments of a compound of Formula (I), each R 5 is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I), each R 5 is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl.
  • each R 5a is independently oxo, deuterium, halogen, -CN, -OR b , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl, or heterocycloalkyl.
  • each R 5a is independently deuterium or halogen.
  • each R 5a is independently halogen.
  • each R 6 and R 7 is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one, two, or three R 6a .
  • each R 6 and R 7 is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one, two, or three R 6a .
  • each R 6 and R 7 is independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; wherein the alkyl is independently optionally substituted with one, two, or three R 6a .
  • each R 6 and R 7 is independently hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I), each R 6 and R 7 is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. [0060] In some embodiments of a compound of Formula (I), each R 6a is independently oxo, deuterium, halogen, -CN, -OR b , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl, or heterocycloalkyl.
  • R 6 and R 7 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R 6b .
  • each R 6b is independently oxo, deuterium, halogen, -CN, -OR b , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, cycloalkyl, or heterocycloalkyl.
  • each R 6b is independently C 1 -C 6 alkyl or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (I), each R 6b is independently C 1 -C 6 alkyl.
  • R x is hydrogen, -NO 2 , or -CN. In some embodiments of a compound of Formula (I), R x is -NO 2 or -CN. In some embodiments of a compound of Formula (I), R x is -CN.
  • Ring A is a cycloalkyl.
  • Ring A is a heterocycloalkyl.
  • each R 2 is independently deuterium, halogen, -CN, -OR b , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (I), each R 2 is deuterium.
  • n is 0. In some embodiments of a compound of Formula (I), n is 1. In some embodiments of a compound of Formula (I), n is 2. In some embodiments of a compound of Formula (I), n is 3.
  • n is 4. In some embodiments of a compound of Formula (I), n is 5. In some embodiments of a compound of Formula (I), n is 6. In some embodiments of a compound of Formula (I), n is 1-4. In some embodiments of a compound of Formula (I), n is 1 or 2. In some embodiments of a compound of Formula (I), n is 2-4.
  • R 1 is -CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (II), R 1 is -CN or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (II), R 1 is C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (II), R 1 is -CN. [0069] In some embodiments of a compound of Formula (II), R 8 is hydrogen or deuterium.
  • R 8 is hydrogen.
  • R 9 is C 1 -C 6 alkyl or C 2 -C 6 alkynyl. In some embodiments of a compound of Formula (II), R 9 is C 1 -C 6 alkyl.
  • R 10 is C 1 -C 6 alkyl or C 2 -C 6 alkynyl. In some embodiments of a compound of Formula (II), R 10 is C 1 -C 6 alkyl.
  • R 9 is C 1 -C 6 alkyl and R 10 is C 2 -C 6 alkynyl. In some embodiments of a compound of Formula (II), R 10 is C 1 -C 6 alkyl and R 9 is C 2 -C 6 alkynyl.
  • R 11 is hydrogen, halogen, or -OH. In some embodiments of a compound of Formula (II), R 11 is hydrogen or -OH.
  • R 11 is hydrogen.
  • R 15 and R 16 are independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (II), R 15 and R 16 are independently hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II), R 15 and R 16 are independently hydrogen or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (II), R 15 and R 16 are independently C 1 -C 6 alkyl.
  • R 15 and R 16 are taken together to form a cycloalkyl. In some embodiments of a compound of Formula (II), R 15 and R 16 are taken together to form a cycloalkyl substituted with 1-4 deuterium. In some embodiments of a compound of Formula (II), R 15 and R 16 are taken together to form a cycloalkyl substituted with 1 or 2 deuterium. In some embodiments of a compound of Formula (II), R 15 and R 16 are taken together to form a cycloalkyl substituted with 2-4 deuteriums.
  • R 15 and R 16 are taken together to form a heterocycloalkyl. In some embodiments of a compound of Formula (II), R 15 and R 16 are taken together to form a heterocycloalkyl substituted with 1-4 deuterium. In some embodiments of a compound of Formula (II), R 15 and R 16 are taken together to form a heterocycloalkyl substituted with 1 or 2 deuterium. In some embodiments of a compound of Formula (II), R 15 and R 16 are taken together to form a heterocycloalkyl substituted with 2-4 deuteriums.
  • each R 3b is independently deuterium, halogen, -CN, -OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl.
  • each R 3b is independently deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl.
  • each R 4 is independently C 1 -C 6 alkyl, C 2 - C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one, two, or three R 4a .
  • each R 4 is independently C 1 -C 6 alkyl or cycloalkyl; wherein the alkyl and cycloalkyl are independently optionally substituted with one, two, or three R 4a . In some embodiments of a compound of Formula (II), each R 4 is independently C 1 -C 6 alkyl optionally substituted with one, two, or three R 4a . In some embodiments of a compound of Formula (II), each R 4 is independently C 1 -C 6 alkyl.
  • each R 4 is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl.
  • each R 4a is independently oxo, deuterium, halogen, -CN, -OR b , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl, or heterocycloalkyl.
  • each R 4a is independently deuterium or halogen.
  • each R 4a is independently halogen.
  • each R 5 is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one, two, or three R 5a .
  • each R 5 is independently hydrogen, C 1 -C 6 alkyl, or cycloalkyl; wherein the alkyl and cycloalkyl are independently optionally substituted with one, two, or three R 5a .
  • each R 5 is independently hydrogen or C 1 -C 6 alkyl optionally substituted with one, two, or three R 5a .
  • each R 5 is independently C 1 -C 6 alkyl optionally substituted with one, two, or three R 5a .
  • each R 5 is hydrogen or C 1 -C 6 alkyl.
  • each R 5 is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl.
  • two R 5 are taken together to form an optionally substituted heterocycloalkyl.
  • each R 5a is independently oxo, deuterium, halogen, -CN, -OR b , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl, or heterocycloalkyl.
  • each R 6 and R 7 is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one, two, or three R 6a .
  • each R 6 and R 7 is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one, two, or three R 6a .
  • each R 6 and R 7 is independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; wherein the alkyl are independently optionally substituted with one, two, or three R 6a .
  • each R 6 and R 7 is independently hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II), each R 6 and R 7 is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. [0090] In some embodiments of a compound of Formula (II), each R 6a is independently oxo, deuterium, halogen, -CN, -OR b , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl, or heterocycloalkyl.
  • R 6 and R 7 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R 6b .
  • each R 6b is independently oxo, deuterium, halogen, -CN, -OR b , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, cycloalkyl, or heterocycloalkyl.
  • each R 6b is independently C 1 -C 6 alkyl or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (II), each R 6b is independently C 1 -C 6 alkyl.
  • R x is hydrogen, -NO 2 , or -CN. In some embodiments of a compound of Formula (II), R x is -NO 2 or -CN. In some embodiments of a compound of Formula (II), R x is -CN.
  • Ring B is a cycloalkyl.
  • Ring B is a heterocycloalkyl.
  • each R 14 is independently deuterium, halogen, -CN, -OR b , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (II), each R 14 is deuterium.
  • m is 0. In some embodiments of a compound of Formula (II), m is 1. In some embodiments of a compound of Formula (II), m is 2. In some embodiments of a compound of Formula (II), m is 3.
  • m is 4. In some embodiments of a compound of Formula (II), m is 5. In some embodiments of a compound of Formula (II), m is 6. In some embodiments of a compound of Formula (II), m is 1-4. In some embodiments of a compound of Formula (II), m is 1 or 2. In some embodiments of a compound of Formula (II), m is 2-4.
  • R 1 is -CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (III), R 1 is -CN or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (III), R 1 is C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (III), R 1 is -CN. [0099] In some embodiments of a compound of Formula (III), R 8 is hydrogen or deuterium. In some embodiments of a compound of Formula (III), R 8 is hydrogen.
  • R 9 is C 1 -C 6 alkyl or C 2 -C 6 alkynyl. In some embodiments of a compound of Formula (III), R 9 is C 1 -C 6 alkyl. [00101] In some embodiments of a compound of Formula (III), R 10 is C 1 -C 6 alkyl or C 2 -C 6 alkynyl. In some embodiments of a compound of Formula (III), R 10 is C 1 -C 6 alkyl. [00102] In some embodiments of a compound of Formula (III), R 9 is C 1 -C 6 alkyl and R 10 is C 2 -C 6 alkynyl.
  • R 10 is C 1 -C 6 alkyl and R 9 is C 2 -C 6 alkynyl.
  • R 11 is hydrogen, halogen, or -OH.
  • R 11 is hydrogen or -OH.
  • R 11 is hydrogen.
  • R 12 and R 13 are independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (III), R 12 and R 13 are independently hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (III), R 12 and R 13 are independently hydrogen or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (III), R 12 and R 13 are independently C 1 -C 6 alkyl. [00106] In some embodiments of a compound of Formula (III), R 12 and R 13 are taken together to form a cycloalkyl.
  • R 12 and R 13 are taken together to form a cycloalkyl substituted with 1-4 deuterium. In some embodiments of a compound of Formula (III), R 12 and R 13 are taken together to form a cycloalkyl substituted with 1 or 2 deuterium. In some embodiments of a compound of Formula (III), R 12 and R 13 are taken together to form a cycloalkyl substituted with 2-4 deuteriums. [00107] In some embodiments of a compound of Formula (III), R 12 and R 13 are taken together to form a heterocycloalkyl.
  • R 12 and R 13 are taken together to form a heterocycloalkyl substituted with 1-4 deuterium. In some embodiments of a compound of Formula (III), R 12 and R 13 are taken together to form a heterocycloalkyl substituted with 1 or 2 deuterium. In some embodiments of a compound of Formula (III), R 12 and R 13 are taken together to form a heterocycloalkyl substituted with 2-4 deuteriums. [00108] In some embodiments of a compound of Formula (III), R 15 and R 16 are independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 deuteroalkyl.
  • R 15 and R 16 are independently hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (III), R 15 and R 16 are independently hydrogen or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (III), R 15 and R 16 are independently C 1 -C 6 alkyl. [00109] In some embodiments of a compound of Formula (III), R 15 and R 16 are taken together to form a cycloalkyl. In some embodiments of a compound of Formula (III), R 15 and R 16 are taken together to form a cycloalkyl substituted with 1-4 deuterium.
  • R 15 and R 16 are taken together to form a cycloalkyl substituted with 1 or 2 deuterium. In some embodiments of a compound of Formula (III), R 15 and R 16 are taken together to form a cycloalkyl substituted with 2-4 deuteriums. [00110] In some embodiments of a compound of Formula (III), R 15 and R 16 are taken together to form a heterocycloalkyl. In some embodiments of a compound of Formula (III), R 15 and R 16 are taken together to form a heterocycloalkyl substituted with 1-4 deuterium.
  • R 15 and R 16 are taken together to form a heterocycloalkyl substituted with 1 or 2 deuterium. In some embodiments of a compound of Formula (III), R 15 and R 16 are taken together to form a heterocycloalkyl substituted with 2-4 deuteriums.
  • R 3 is -B(OR 5 ) 2 or -Y(C 1 -C 6 alkylene)B(OR 5 ) 2 .
  • R 3 is N-linked heterocycloalkyl or N-linked heteroaryl.
  • -Y is a bond.
  • Y is a bond or -O-.
  • each R 4 is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one, two, or three R 4a .
  • each R 4 is independently C 1 -C 6 alkyl or cycloalkyl; wherein the alkyl and cycloalkyl are independently optionally substituted with one, two, or three R 4a . In some embodiments of a compound of Formula (III), each R 4 is independently C 1 -C 6 alkyl optionally substituted with one, two, or three R 4a . In some embodiments of a compound of Formula (III), each R 4 is independently C 1 -C 6 alkyl. In some embodiments of a compound of Formula (III), each R 4 is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl.
  • each R 4a is independently oxo, deuterium, halogen, -CN, -OR b , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl, or heterocycloalkyl.
  • each R 4a is independently deuterium or halogen.
  • each R 4a is independently halogen.
  • each R 5 is independently hydrogen, C 1 - C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one, two, or three R 5a .
  • each R 5 is independently hydrogen, C 1 -C 6 alkyl, or cycloalkyl; wherein the alkyl and cycloalkyl are independently optionally substituted with one, two, or three R 5a .
  • each R 5 is independently hydrogen or C 1 -C 6 alkyl optionally substituted with one, two, or three R 5a . In some embodiments of a compound of Formula (III), each R 5 is independently C 1 -C 6 alkyl optionally substituted with one, two, or three R 5a . In some embodiments of a compound of Formula (III), each R 5 is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (III), each R 5 is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl.
  • each R 5a is independently oxo, deuterium, halogen, -CN, -OR b , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl, or heterocycloalkyl.
  • each R 5a is independently deuterium or halogen.
  • each R 5a is independently halogen.
  • each R 6 and R 7 is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one, two, or three R 6a .
  • each R 6 and R 7 is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one, two, or three R 6a .
  • each R 6 and R 7 is independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; wherein the alkyl are independently optionally substituted with one, two, or three R 6a .
  • each R 6 and R 7 is independently hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (III), each R 6 and R 7 is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. [00122] In some embodiments of a compound of Formula (III), each R 6a is independently oxo, deuterium, halogen, -CN, -OR b , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl, or heterocycloalkyl.
  • R 6 and R 7 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R 6b .
  • each R 6b is independently oxo, deuterium, halogen, -CN, -OR b , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, cycloalkyl, or heterocycloalkyl.
  • each R 6b is independently C 1 -C 6 alkyl or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (III), each R 6b is independently C 1 -C 6 alkyl. [00125] In some embodiments of a compound of Formula (III), R x is hydrogen, -NO 2 , or -CN. In some embodiments of a compound of Formula (III), R x is -NO 2 or -CN. In some embodiments of a compound of Formula (III), R x is -CN. In some embodiments of a compound of Formula (III), R 3 is [00126] In some embodiments of a compound of Formula (III), R 3 is or .
  • R 1 is -CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (IV), R 1 is -CN or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (IV), R 1 is C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (IV), R 1 is -CN. [00129] In some embodiments of a compound of Formula (IV), R 8 is hydrogen or deuterium. In some embodiments of a compound of Formula (IV), R 8 is hydrogen.
  • R 9 is C 1 -C 6 alkyl or C 2 -C 6 alkynyl. In some embodiments of a compound of Formula (IV), R 9 is C 2 -C 6 alkynyl. In some embodiments of a compound of Formula (IV), R 9 is C 1 -C 6 alkyl. [00131] In some embodiments of a compound of Formula (IV), R 10 is C 1 -C 6 alkyl or C 2 -C 6 alkynyl. In some embodiments of a compound of Formula (IV), R 10 is C 2 -C 6 alkynyl. In some embodiments of a compound of Formula (IV), R 10 is C 1 -C 6 alkyl.
  • R 9 is C 1 -C 6 alkyl and R 10 is C 2 -C 6 alkynyl. In some embodiments of a compound of Formula (IV), R 10 is C 1 -C 6 alkyl and R 9 is C 2 -C 6 alkynyl.
  • R 11 is hydrogen, halogen, or -OH. In some embodiments of a compound of Formula (IV), R 11 is hydrogen or -OH. In some embodiments of a compound of Formula (IV), R 11 is hydrogen.
  • R 12 and R 13 are independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (IV), R 12 and R 13 are independently hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (IV), R 12 and R 13 are independently hydrogen or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (IV), R 12 and R 13 are independently C 1 -C 6 alkyl. [00136] In some embodiments of a compound of Formula (IV), R 12 and R 13 are taken together to form a cycloalkyl.
  • R 12 and R 13 are taken together to form a cycloalkyl substituted with 1-4 deuterium. In some embodiments of a compound of Formula (IV), R 12 and R 13 are taken together to form a cycloalkyl substituted with 1 or 2 deuterium. In some embodiments of a compound of Formula (IV), R 12 and R 13 are taken together to form a cycloalkyl substituted with 2-4 deuteriums. [00137] In some embodiments of a compound of Formula (IV), R 12 and R 13 are taken together to form a heterocycloalkyl.
  • R 12 and R 13 are taken together to form a heterocycloalkyl substituted with 1-4 deuterium. In some embodiments of a compound of Formula (IV), R 12 and R 13 are taken together to form a heterocycloalkyl substituted with 1 or 2 deuterium. In some embodiments of a compound of Formula (IV), R 12 and R 13 are taken together to form a heterocycloalkyl substituted with 2-4 deuteriums. [00138] In some embodiments of a compound of Formula (IV), R 15 and R 16 are independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 deuteroalkyl.
  • R 15 and R 16 are independently hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (IV), R 15 and R 16 are independently hydrogen or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (IV), R 15 and R 16 are independently C 1 -C 6 alkyl. [00139] In some embodiments of a compound of Formula (IV), R 15 and R 16 are taken together to form a cycloalkyl. In some embodiments of a compound of Formula (IV), R 15 and R 16 are taken together to form a cycloalkyl substituted with 1-4 deuterium.
  • R 15 and R 16 are taken together to form a cycloalkyl substituted with 1 or 2 deuterium. In some embodiments of a compound of Formula (IV), R 15 and R 16 are taken together to form a cycloalkyl substituted with 2-4 deuteriums. [00140] In some embodiments of a compound of Formula (IV), R 15 and R 16 are taken together to form a heterocycloalkyl. In some embodiments of a compound of Formula (IV), R 15 and R 16 are taken together to form a heterocycloalkyl substituted with 1-4 deuterium.
  • R 15 and R 16 are taken together to form a heterocycloalkyl substituted with 1 or 2 deuterium. In some embodiments of a compound of Formula (IV), R 15 and R 16 are taken together to form a heterocycloalkyl substituted with 2-4 deuteriums.
  • R 3 is C 1 -C 6 alkyl optionally substituted with one, two, or three R 3a .
  • each R 3b is independently deuterium, halogen, -CN, -OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl.
  • each R 3b is independently deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl.
  • each R 4 is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one, two, or three R 4a .
  • each R 4 is independently C 1 -C 6 alkyl or cycloalkyl; wherein the alkyl and cycloalkyl are independently optionally substituted with one, two, or three R 4a . In some embodiments of a compound of Formula (IV), each R 4 is independently C 1 -C 6 alkyl optionally substituted with one, two, or three R 4a . In some embodiments of a compound of Formula (IV), each R 4 is independently C 1 -C 6 alkyl. In some embodiments of a compound of Formula (IV), each R 4 is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl.
  • each R 4a is independently oxo, deuterium, halogen, -CN, -OR b , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl, or heterocycloalkyl.
  • each R 4a is independently deuterium or halogen.
  • each R 4a is independently halogen.
  • each R 5 is independently hydrogen, C 1 - C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one, two, or three R 5a .
  • each R 5 is independently hydrogen, C 1 -C 6 alkyl, or cycloalkyl; wherein the alkyl and cycloalkyl are independently optionally substituted with one, two, or three R 5a .
  • each R 5 is independently hydrogen or C 1 -C 6 alkyl optionally substituted with one, two, or three R 5a . In some embodiments of a compound of Formula (IV), each R 5 is independently C 1 -C 6 alkyl optionally substituted with one, two, or three R 5a . In some embodiments of a compound of Formula (IV), each R 5 is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (IV), each R 5 is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl.
  • each R 5 is independently oxo, deuterium, halogen, -CN, -OR b , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl, or heterocycloalkyl.
  • each R 5a is independently deuterium or halogen.
  • each R 5a is independently halogen.
  • each R 6 and R 7 is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one, two, or three R 6a .
  • each R 6 and R 7 is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one, two, or three R 6a .
  • each R 6 and R 7 is independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; wherein the alkyl are independently optionally substituted with one, two, or three R 6a .
  • each R 6 and R 7 is independently hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (IV), each R 6 and R 7 is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. [00153] In some embodiments of a compound of Formula (IV), each R 6a is independently oxo, deuterium, halogen, -CN, -OR b , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl, or heterocycloalkyl.
  • R 6 and R 7 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R 6b .
  • each R 6b is independently oxo, deuterium, halogen, -CN, -OR b , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, cycloalkyl, or heterocycloalkyl.
  • each R 6b is independently C 1 -C 6 alkyl or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (IV), each R 6b is independently C 1 -C 6 alkyl. [00156] In some embodiments of a compound of Formula (IV), R x is hydrogen, -NO 2 , or -CN. In some embodiments of a compound of Formula (IV), R x is -NO 2 or -CN. In some embodiments of a compound of Formula (IV), R x is -CN.
  • R 1 is -CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (V), R 1 is -CN or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (V), R 1 is C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (V), R 1 is -CN. [00159] In some embodiments of a compound of Formula (V), R 8 is hydrogen or deuterium. In some embodiments of a compound of Formula (V), R 8 is hydrogen.
  • R 9 is C 1 -C 6 alkyl or C 2 -C 6 alkynyl. In some embodiments of a compound of Formula (V), R 9 is C 2 -C 6 alkynyl. In some embodiments of a compound of Formula (V), R 9 is C 1 -C 6 alkyl. [00161] In some embodiments of a compound of Formula (V), R 10 is C 1 -C 6 alkyl or C 2 -C 6 alkynyl. In some embodiments of a compound of Formula (V), R 10 is C 2 -C 6 alkynyl. In some embodiments of a compound of Formula (V), R 10 is C 1 -C 6 alkyl.
  • R 9 is C 1 -C 6 alkyl and R 10 is C 2 -C 6 alkynyl. In some embodiments of a compound of Formula (V), R 10 is C 1 -C 6 alkyl and R 9 is C 2 -C 6 alkynyl.
  • R 11 is hydrogen, halogen, or -OH. In some embodiments of a compound of Formula (V), R 11 is hydrogen or -OH. In some embodiments of a compound of Formula (V), R 11 is hydrogen.
  • R 12 and R 13 are independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (V), R 12 and R 13 are independently hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (V), R 12 and R 13 are independently hydrogen or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (V), R 12 and R 13 are independently C 1 -C 6 alkyl. [00166] In some embodiments of a compound of Formula (V), R 12 and R 13 are taken together to form a cycloalkyl.
  • R 12 and R 13 are taken together to form a cycloalkyl substituted with 1-4 deuterium. In some embodiments of a compound of Formula (V), R 12 and R 13 are taken together to form a cycloalkyl substituted with 1 or 2 deuterium. In some embodiments of a compound of Formula (V), R 12 and R 13 are taken together to form a cycloalkyl substituted with 2-4 deuteriums. [00167] In some embodiments of a compound of Formula (V), R 12 and R 13 are taken together to form a heterocycloalkyl.
  • R 12 and R 13 are taken together to form a heterocycloalkyl substituted with 1-4 deuterium. In some embodiments of a compound of Formula (V), R 12 and R 13 are taken together to form a heterocycloalkyl substituted with 1 or 2 deuterium. In some embodiments of a compound of Formula (V), R 12 and R 13 are taken together to form a heterocycloalkyl substituted with 2-4 deuteriums. [00168] In some embodiments of a compound of Formula (V), R 17 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl.
  • R 17 is C 1 -C 6 alkyl.
  • R 3 is C 1 -C 6 alkyl optionally substituted with one, two, or three R 3a .
  • each R 3b is independently deuterium, halogen, -CN, -OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl.
  • each R 3b is independently deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl.
  • each R 4 is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one, two, or three R 4a .
  • each R 4 is independently C 1 -C 6 alkyl or cycloalkyl; wherein the alkyl and cycloalkyl are independently optionally substituted with one, two, or three R 4a . In some embodiments of a compound of Formula (V), each R 4 is independently C 1 -C 6 alkyl optionally substituted with one, two, or three R 4a . In some embodiments of a compound of Formula (V), each R 4 is independently C 1 -C 6 alkyl. In some embodiments of a compound of Formula (V), each R 4 is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl.
  • each R 4a is independently oxo, deuterium, halogen, -CN, -OR b , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl, or heterocycloalkyl.
  • each R 4a is independently deuterium or halogen.
  • each R 4a is independently halogen.
  • each R 5 is independently hydrogen, C 1 - C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one, two, or three R 5a .
  • each R 5 is independently hydrogen, C 1 -C 6 alkyl, or cycloalkyl; wherein the alkyl and cycloalkyl are independently optionally substituted with one, two, or three R 5a .
  • each R 5 is independently hydrogen or C 1 -C 6 alkyl optionally substituted with one, two, or three R 5a . In some embodiments of a compound of Formula (V), each R 5 is independently C 1 -C 6 alkyl optionally substituted with one, two, or three R 5a . In some embodiments of a compound of Formula (V), each R 5 is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (V), each R 5 is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl.
  • each R 5 is independently oxo, deuterium, halogen, -CN, -OR b , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl, or heterocycloalkyl.
  • each R 5a is independently deuterium or halogen.
  • each R 5a is independently halogen.
  • each R 6 and R 7 is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one, two, or three R 6a .
  • each R 6 and R 7 is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one, two, or three R 6a .
  • each R 6 and R 7 is independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; wherein the alkyl are independently optionally substituted with one, two, or three R 6a .
  • each R 6 and R 7 is independently hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (V), each R 6 and R 7 is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. [00181] In some embodiments of a compound of Formula (V), each R 6a is independently oxo, deuterium, halogen, -CN, -OR b , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl, or heterocycloalkyl.
  • R 6 and R 7 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R 6b .
  • each R 6b is independently oxo, deuterium, halogen, -CN, -OR b , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, cycloalkyl, or heterocycloalkyl.
  • each R 6b is independently C 1 -C 6 alkyl or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (V), each R 6b is independently C 1 -C 6 alkyl. [00184] In some embodiments of a compound of Formula (V), R x is hydrogen, -NO 2 , or -CN. In some embodiments of a compound of Formula (V), R x is -NO 2 or -CN. In some embodiments of a compound of Formula (V), R x is -CN.
  • Y 1 and Y 2 are independently hydrogen, deuterium, halogen, -OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (VI), Y 1 and Y 2 are independently hydrogen, deuterium, halogen, or -OR b . In some embodiments of a compound of Formula (VI), Y 1 and Y 2 are independently hydrogen, deuterium, - OR b , or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (VI), Y 1 and Y 2 are independently hydrogen.
  • R 12 is hydrogen, deuterium, -OR b , - NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, or cycloalkyl; provided that R 12 is not -CH 3 .
  • R 12 is hydrogen, deuterium, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl; provided that R 12 is not -CH 3 .
  • R 12 is hydrogen or deuterium. In some embodiments of a compound of Formula (VI), R 12 is hydrogen. In some embodiments of a compound of Formula (VI), R 12 is hydrogen or C 1 -C 6 alkyl; provided that R 12 is not -CH 3 . In some embodiments of a compound of Formula (VI), R 12 is C 1 -C 6 alkyl; provided that R 12 is not -CH 3 .
  • each R 13a is independently deuterium, halogen, -CN, -OR 19 , -NR 20 R 21 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 1 -C 6 heteroalkyl.
  • each R 13a is independently deuterium, halogen, -CN, -OR 19 , -NR 20 R 21 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl.
  • Y 1 and Y 2 are independently hydrogen, deuterium, halogen, -OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl; provided that one of Y 1 or Y 2 is not hydrogen.
  • Y 1 and Y 2 are independently hydrogen, deuterium, halogen, or -OR b ; provided that one of Y 1 or Y 2 is not hydrogen.
  • Y 1 and Y 2 are independently hydrogen, deuterium, -OR b , or C 1 -C 6 alkyl; provided that one of Y 1 or Y 2 is not hydrogen.
  • R 12 is hydrogen, deuterium, -OR b , - NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, or cycloalkyl.
  • R 12 is hydrogen, deuterium, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (VII), R 12 is hydrogen or deuterium. In some embodiments of a compound of Formula (VII), R 12 is hydrogen. In some embodiments of a compound of Formula (VII), R 12 is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (VII), R 12 is C 1 -C 6 alkyl.
  • each R 13a is independently deuterium, halogen, -CN, -OR 19 , -NR 20 R 21 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 1 -C 6 heteroalkyl.
  • each R 13a is independently deuterium, halogen, -CN, -OR 19 , -NR 20 R 21 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl.
  • Y 1 and Y 2 are independently hydrogen, deuterium, halogen, -OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (VIII), Y 1 and Y 2 are independently hydrogen, deuterium, halogen, or -OR b . In some embodiments of a compound of Formula (VIII), Y 1 and Y 2 are independently hydrogen, deuterium, -OR b , or C 1 -C 6 alkyl.
  • Y 1 and Y 2 are hydrogen.
  • R 12 is hydrogen, deuterium, -OR b , - NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, or cycloalkyl.
  • R 12 is hydrogen, deuterium, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl.
  • R 12 is hydrogen or deuterium. In some embodiments of a compound of Formula (VIII), R 12 is hydrogen. In some embodiments of a compound of Formula (VIII), R 12 is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (VIII), R 12 is C 1 -C 6 alkyl. [00198] In some embodiments of a compound of Formula (VIII), R 13 is –CN. [00199] In some embodiments of a compound of Formula (VIII), R 13 is C 1 -C 6 hydroxyalkyl optionally substituted with one, two, or three R 13a .
  • R 13 is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R 13a .
  • R 13 is heteroaryl optionally substituted with one, two, or three R 13a .
  • R 13 is –CN, heterocycloalkyl, heteroaryl, or -CH 2 (heteroaryl); wherein the heterocycloalkyl and heteroaryl are independently optionally substituted with one, two, or three R 13a .
  • R 13 is heterocycloalkyl or heteroaryl; wherein the heterocycloalkyl and heteroaryl are independently optionally substituted with one, two, or three R 13a .
  • R 13 is heteroaryl optionally substituted with one, two, or three R 13a .
  • R 13 is heterocycloalkyl optionally substituted with one, two, or three R 13a .
  • each R 13a is independently deuterium, halogen, -CN, -OR 19 , -NR 20 R 21 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 1 -C 6 heteroalkyl.
  • each R 13a is independently deuterium, halogen, -CN, -OR 19 , -NR 20 R 21 , C 1 - C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl.
  • each R 13a is independently -OR 19 .
  • R 1 is -CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl.
  • R 1 is -CN or C 1 -C 6 haloalkyl.
  • R 1 is C 1 -C 6 haloalkyl.
  • R 1 is -CN.
  • R 8 is hydrogen or deuterium. In some embodiments of a compound of Formula (VI)-(VIII), R 8 is hydrogen. [00205] In some embodiments of a compound of Formula (VI)-(VIII), R 9 is C 1 -C 6 alkyl or C 2 -C 6 alkynyl. In some embodiments of a compound of Formula (VI)-(VIII), R 9 is C 1 -C 6 alkyl. [00206] In some embodiments of a compound of Formula (VI)-(VIII), R 10 is C 1 -C 6 alkyl or C 2 -C 6 alkynyl.
  • R 10 is C 1 -C 6 alkyl.
  • R 9 is C 1 -C 6 alkyl and R 10 is C 2 -C 6 alkynyl.
  • R 10 is C 1 -C 6 alkyl and R 9 is C 2 -C 6 alkynyl.
  • R 10 is C 1 -C 6 alkyl and R 9 is C 2 -C 6 alkynyl.
  • R 11 is hydrogen, halogen, or - OH. In some embodiments of a compound of Formula (VI)-(VIII), R 11 is hydrogen or -OH. In some embodiments of a compound of Formula (VI)-(VIII), R 11 is hydrogen.
  • each R 18 is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one, two, or three R 18a .
  • each R 18 is independently C 1 -C 6 alkyl or cycloalkyl; wherein the alkyl and cycloalkyl are independently optionally substituted with one, two, or three R 18a . In some embodiments of a compound of Formula (VI)-(VIII), each R 18 is independently C 1 -C 6 alkyl optionally substituted with one, two, or three R 18a . In some embodiments of a compound of Formula (VI)-(VIII), each R 18 is independently C 1 -C 6 alkyl.
  • each R 18 is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl.
  • each R 18a is independently oxo, deuterium, halogen, -CN, -OR b , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl, or heterocycloalkyl.
  • each R 18a is independently deuterium or halogen.
  • each R 18a is independently halogen.
  • each R 19 is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one, two, or three R 19a .
  • each R 19 is independently hydrogen, C 1 -C 6 alkyl, or cycloalkyl; wherein the alkyl and cycloalkyl are independently optionally substituted with one, two, or three R 19a .
  • each R 19 is independently hydrogen or C 1 -C 6 alkyl optionally substituted with one, two, or three R 19a .
  • each R 19 is independently C 1 -C 6 alkyl optionally substituted with one, two, or three R 19a .
  • each R 19 is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (VI)-(VIII), each R 19 is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl.
  • each R 19a is independently oxo, deuterium, halogen, -CN, -OR b , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl, or heterocycloalkyl.
  • each R 19a is independently deuterium or halogen.
  • each R 19a is independently halogen.
  • each R 20 and R 21 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one, two, or three R 20a .
  • each R 20 and R 21 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one, two, or three R 6a .
  • each R 20 and R 21 are independently hydrogen, C 1 - C 6 alkyl, or C 1 -C 6 haloalkyl; wherein the alkyl are independently optionally substituted with one, two, or three R 6a .
  • each R 20 and R 21 are independently hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (VI)-(VIII), each R 20 and R 21 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl.
  • each R 20a is independently oxo, deuterium, halogen, -CN, -OR b , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl, or heterocycloalkyl.
  • each R 20a is independently deuterium or halogen.
  • each R 20a is independently halogen.
  • R 20 and R 21 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R 20b .
  • each R 20b is independently oxo, deuterium, halogen, -CN, -OR b , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, cycloalkyl, or heterocycloalkyl.
  • each R 20b is independently C 1 -C 6 alkyl or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (VI)- (VIII), each R 20b is independently C 1 -C 6 alkyl.
  • each R 3b is independently deuterium, halogen, -CN, -OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl.
  • each R 3b is independently deuterium, halogen, C 1 - C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl.
  • each R 4 is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one, two, or three R 4a .
  • each R 4 is independently C 1 -C 6 alkyl or cycloalkyl; wherein the alkyl and cycloalkyl are independently optionally substituted with one, two, or three R 4a . In some embodiments of a compound of Formula (VI)- (VIII), each R 4 is independently C 1 -C 6 alkyl optionally substituted with one, two, or three R 4a . In some embodiments of a compound of Formula (VI)-(VIII), each R 4 is independently C 1 -C 6 alkyl.
  • each R 4 is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl.
  • each R 4a is independently oxo, deuterium, halogen, -CN, -OR b , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl, or heterocycloalkyl.
  • each R 4a is independently deuterium or halogen. In some embodiments of a compound of Formula (VI)-(VIII), each R 4a is independently halogen. [00224] In some embodiments of a compound of Formula (VI)-(VIII), each R 5 is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one, two, or three R 5a .
  • each R 5 is independently hydrogen, C 1 -C 6 alkyl, or cycloalkyl; wherein the alkyl and cycloalkyl are independently optionally substituted with one, two, or three R 5a .
  • each R 5 is independently hydrogen or C 1 -C 6 alkyl optionally substituted with one, two, or three R 5a .
  • each R 5 is independently C 1 -C 6 alkyl optionally substituted with one, two, or three R 5a .
  • each R 5 is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (VI)-(VIII), each R 5 is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. [00225] In some embodiments of a compound of Formula (VI)-(VIII), two R 5 are taken together to form an optionally substituted heterocycloalkyl.
  • each R 5a is independently oxo, deuterium, halogen, -CN, -OR b , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl, or heterocycloalkyl.
  • each R 5a is independently deuterium or halogen.
  • each R 5a is independently halogen.
  • each R 6 and R 7 is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one, two, or three R 6a .
  • each R 6 and R 7 is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one, two, or three R 6a .
  • each R 6 and R 7 is independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; wherein the alkyl are independently optionally substituted with one, two, or three R 6a .
  • each R 6 and R 7 is independently hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (VI)-(VIII), each R 6 and R 7 is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl.
  • each R 6a is independently oxo, deuterium, halogen, -CN, -OR b , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl, or heterocycloalkyl.
  • each R 6a is independently deuterium or halogen.
  • each R 6a is independently halogen.
  • R 6 and R 7 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R 6b .
  • each R 6b is independently oxo, deuterium, halogen, -CN, -OR b , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, cycloalkyl, or heterocycloalkyl.
  • each R 6b is independently C 1 -C 6 alkyl or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (VI)- (VIII), each R 6b is independently C 1 -C 6 alkyl. [00231] In some embodiments of a compound of Formula (VI)-(VIII), R x is hydrogen, -NO 2 , or -CN. In some embodiments of a compound of Formula (VI)-(VIII), R x is -NO 2 or -CN. In some embodiments of a compound of Formula (VI)-(VIII), R x is -CN.
  • R 15 and R 16 are independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (VI)- (VIII), R 15 and R 16 are independently hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (VI)-(VIII), R 15 and R 16 are independently hydrogen or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (VI)-(VIII), R 15 and R 16 are independently C 1 -C 6 alkyl.
  • R 15 and R 16 are taken together to form a cycloalkyl. In some embodiments of a compound of Formula (VI)-(VIII), R 15 and R 16 are taken together to form a cycloalkyl substituted with 1-4 deuterium. In some embodiments of a compound of Formula (VI)-(VIII), R 15 and R 16 are taken together to form a cycloalkyl substituted with 1 or 2 deuterium. In some embodiments of a compound of Formula (VI)-(VIII), R 15 and R 16 are taken together to form a cycloalkyl substituted with 2-4 deuteriums.
  • R 15 and R 16 are taken together to form a heterocycloalkyl. In some embodiments of a compound of Formula (VI)-(VIII), R 15 and R 16 are taken together to form a heterocycloalkyl substituted with 1-4 deuterium. In some embodiments of a compound of Formula (VI)-(VIII), R 15 and R 16 are taken together to form a heterocycloalkyl substituted with 1 or 2 deuterium. In some embodiments of a compound of Formula (VI)-(VIII), R 15 and R 16 are taken together to form a heterocycloalkyl substituted with 2-4 deuteriums.
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one, two, or three deuterium, halogen, -OH, -NH 2 , or C 1 -C 6 alkyl.
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one, two, or three deuterium, halogen, - OH, -NH 2 , or C 1 -C 6 alkyl.
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl; wherein the alkyl are independently optionally substituted with one, two, or three deuterium, halogen, -OH, -NH 2 , or C 1 -C 6 alkyl.
  • each R a is independently C 1 -C 6 alkyl optionally substituted with one, two, or three deuterium, halogen, -OH, -NH 2 , or C 1 -C 6 alkyl.
  • each R a is independently C 1 -C 6 alkyl.
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one, two, or three deuterium, halogen, -OH, -NH 2 , or C 1 -C 6 alkyl.
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl; wherein the alkyl are independently optionally substituted with one, two, or three deuterium, halogen, -OH, -NH 2 , or C 1 -C 6 alkyl.
  • each R b is independently hydrogen or C 1 -C 6 alkyl optionally substituted with one, two, or three deuterium, halogen, -OH, -NH 2 , or C 1 -C 6 alkyl.
  • each R b is independently hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I)-(VIII), each R b is independently hydrogen. In some embodiments of a compound of Formula (I)-(VIII), each R b is independently C 1 -C 6 alkyl.
  • each R c and R d is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one, two, or three deuterium, halogen, -OH, -NH 2 , or C 1 -C 6 alkyl.
  • each R c and R d is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl; wherein the alkyl are independently optionally substituted with one, two, or three deuterium, halogen, - OH, -NH 2 , or C 1 -C 6 alkyl.
  • each R c and R d is independently hydrogen or C 1 -C 6 alkyl optionally substituted with one, two, or three deuterium, halogen, -OH, -NH 2 , or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I)-(VIII), each R c and R d is independently hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I)-(VIII), each R b is independently hydrogen. In some embodiments of a compound of Formula (I)-(VIII), each R c and R d is independently C 1 -C 6 alkyl.
  • R c and R d are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three deuterium, halogen, -OH, -NH 2 , or C 1 -C 6 alkyl.
  • a compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof selected from the group consisting of:
  • the compounds described herein exist as geometric isomers.
  • the compounds described herein possess one or more double bonds.
  • the compounds presented herein include cis, trans, syn, anti,
  • E
  • Z
  • the compounds described herein possess one or more chiral centers and each center exists in the R configuration or S configuration.
  • the compounds described herein include diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof.
  • mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein.
  • the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers, and recovering the optically pure enantiomers.
  • dissociable complexes are preferred.
  • the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably, by separation/resolution techniques based upon differences in solubility. In some embodiments, the optically pure enantiomer is then recovered, along with the resolving agent.
  • Labeled compounds [00242] In some embodiments, the compounds described herein exist in their isotopically-labeled forms. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds.
  • the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds as pharmaceutical compositions.
  • the compounds disclosed herein include isotopically-labeled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into compounds described herein, or a solvate, or stereoisomer thereof, include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chloride, such as 2 H, 3 H, 13 C, 14 C, l5 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl, respectively.
  • Compounds described herein, and the pharmaceutically acceptable salts, solvates, or stereoisomers thereof which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this disclosure.
  • isotopically-labeled compounds for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3 H and carbon-14, i.e., 14 C, isotopes are notable for their ease of preparation and detectability. Further, substitution with heavy isotopes such as deuterium, i.e., 2 H, produces certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements.
  • the isotopically labeled compound or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is prepared by any suitable method.
  • the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.
  • Pharmaceutically acceptable salts [00244] In some embodiments, the compounds described herein exist as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.
  • the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
  • these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.
  • Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with a mineral acid, organic acid, or inorganic base, such salts including acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-1,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1,6-dioate
  • the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid,
  • those compounds described herein which comprise a free acid group react with a suitable base, such as the hydroxide, carbonate, bicarbonate, or sulfate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine.
  • a suitable base such as the hydroxide, carbonate, bicarbonate, or sulfate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine.
  • Representative salts include the alkali or alkaline earth salts, like lithium, sodium, potassium, calcium, and magnesium, and aluminum salts, and the like.
  • bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (C 1-4 alkyl) 4 , and the like.
  • Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. It should be understood that the compounds described herein also include the quaternization of any basic nitrogen-containing groups they contain. In some embodiments, water or oil-soluble or dispersible products are obtained by such quaternization. Solvates [00250] In some embodiments, the compounds described herein exist as solvates. This disclosure provides for methods of treating diseases by administering such solvates. This disclosure further provides for methods of treating diseases by administering such solvates as pharmaceutical compositions.
  • Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and, in some embodiments, are formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein. Tautomers [00252] In some situations, compounds exist as tautomers.
  • the compounds described herein include all possible tautomers within the formulas described herein.
  • Tautomers are compounds that are interconvertible by migration of a hydrogen atom, accompanied by a switch of a single bond and adjacent double bond. In bonding arrangements where tautomerization is possible, a chemical equilibrium of the tautomers will exist. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH.
  • Preparation of the Compounds [00253] The compounds used in the reactions described herein are made according to organic synthesis techniques known to those skilled in this art, starting from commercially available chemicals and/or from compounds described in the chemical literature.
  • “Commercially available chemicals” are obtained from standard commercial sources including Acros Organics (Pittsburgh, PA), Aldrich Chemical (Milwaukee, WI, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Avocado Research (Lancashire, U.K.), BDH, Inc. (Toronto, Canada), Bionet (Cornwall, U.K.), Chem Service Inc. (West Chester, PA), Crescent Chemical Co. (Hauppauge, NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester, NY), Fisher Scientific Co. (Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc.
  • Suitable reference books and treatises that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation include for example, “Synthetic Organic Chemistry”, John Wiley & Sons, Inc., New York; S. R. Sandler et al., “Organic Functional Group Preparations,” 2nd Ed., Academic Press, New York, 1983; H. O. House, “Modern Synthetic Reactions”, 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif.1972; T. L. Gilchrist, “Heterocyclic Chemistry”, 2nd Ed., John Wiley & Sons, New York, 1992; J.
  • the compound described herein is combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21 st Ed. Mack Pub. Co., Easton, PA (2005)).
  • a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient.
  • the compound provided herein is substantially pure, in that it contains less than about 5%, or less than about 1%, or less than about 0.1%, of other organic small molecules, such as unreacted intermediates or synthesis by-products that are created, for example, in one or more of the steps of a synthesis method.
  • Pharmaceutical compositions are administered in a manner appropriate to the disease to be treated (or prevented). An appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration.
  • an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and/or prophylactic benefit (e.g., an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and/or overall survival, or a lessening of symptom severity.
  • Optimal doses are generally determined using experimental models and/or clinical trials. The optimal dose depends upon the body mass, weight, or blood volume of the patient.
  • the pharmaceutical composition is formulated for oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, intrapulmonary, intradermal, intrathecal, epidural, or intranasal administration.
  • Parenteral administration includes intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.
  • the pharmaceutical composition is formulated for intravenous injection, oral administration, inhalation, nasal administration, topical administration, or ophthalmic administration.
  • the pharmaceutical composition is formulated for oral administration.
  • the pharmaceutical composition is formulated for intravenous injection.
  • the pharmaceutical composition is formulated as a tablet, a pill, a capsule, a liquid, an inhalant, a nasal spray solution, a suppository, a suspension, a gel, a colloid, a dispersion, a suspension, a solution, an emulsion, an ointment, a lotion, an eye drop, or an ear drop.
  • the pharmaceutical composition is formulated as a tablet.
  • the present method involves the administration of about 0.1 ⁇ g to about 50 mg of at least one compound described herein per kg body weight of the subject. For a 70 kg patient, dosages of about 10 ⁇ g to about 200 mg of the compound disclosed herein would be more commonly used, depending on a subject’s physiological response.
  • the dose of the compound described herein for methods of treating a disease as described herein is about 0.001 to about 1 mg/kg body weight of the subject per day, for example, about 0.001 mg, about 0.002 mg, about 0.005 mg, about 0.010 mg, 0.015 mg, about 0.020 mg, about 0.025 mg, about 0.050 mg, about 0.075 mg, about 0.1 mg, about 0.15 mg, about 0.2 mg, about 0.25 mg, about 0.5 mg, about 0.75 mg, or about 1 mg/kg body weight per day.
  • the dose of compound described herein for the described methods is about 1 to about 1000 mg/kg body weight of the subject being treated per day, for example, about 1 mg, about 2 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 500 mg, about 750 mg, or about 1000 mg per day.
  • Methods of Treatment [00263] Disclosed herein is a method of treating a kidney disease, the method comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, to a subject in need thereof.
  • Also disclosed herein is a method of treating a disease that is systemic lupus nephritis, diabetic chronic kidney disease (CDK), Alport syndrome, focal segmental glomerulosclerosis (FSGS), pulmonary hypertension, Friedreich's ataxia, autosomal dominant polycystic kidney disease (ADPKD), or IgA nephropathy, the method comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, to a subject in need thereof.
  • CDK diabetic chronic kidney disease
  • FSGS focal segmental glomerulosclerosis
  • ADPKD autosomal dominant polycystic kidney disease
  • IgA nephropathy the method comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, to a subject in need thereof.
  • Also disclosed herein is a method of treating a kidney disease that is systemic lupus nephritis, diabetic chronic kidney disease (CDK), Alport syndrome, focal segmental glomerulosclerosis (FSGS), autosomal dominant polycystic kidney disease (ADPKD), or IgA nephropathy, the method comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, to a subject in need thereof.
  • CDK diabetic chronic kidney disease
  • FSGS focal segmental glomerulosclerosis
  • ADPKD autosomal dominant polycystic kidney disease
  • IgA nephropathy the method comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, to a subject in need thereof.
  • Disclosed herein is a method of treating systemic lupus nephritis, the method comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, to a subject in need thereof.
  • Lupus nephritis is inflammation of the kidney that is caused by systemic lupus erythematous (SLE). Also called lupus, SLE is an autoimmune disease. With lupus, the body's immune system targets its own body tissues. Lupus nephritis happens when lupus involves the kidneys.
  • Disclosed herein is a method of treating diabetic chronic kidney disease (CDK), the method comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, to a subject in need thereof.
  • CDK diabetic chronic kidney disease
  • Disclosed herein is a method of treating Alport syndrome, the method comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, to a subject in need thereof.
  • Alport syndrome is a genetic condition characterized by kidney disease, hearing loss, and eye abnormalities. People with Alport syndrome experience progressive loss of kidney function. Almost all affected individuals have blood in their urine (hematuria), which indicates abnormal functioning of the kidneys.
  • FSGS focal segmental glomerulosclerosis
  • FSGS focal segmental glomerulosclerosis
  • FSGS is a cause of nephrotic syndrome in children and adolescents, as well as a leading cause of kidney failure in adults.
  • the focal segmental glomerulosclerosis is primary focal segmental glomerulosclerosis, when no underlying cause is found; usually presents as nephrotic syndrome.
  • the focal segmental glomerulosclerosis is secondary focal segmental glomerulosclerosis, when an underlying cause is identified; usually presents with kidney failure and proteinuria.
  • Secondary focal segmental glomerulosclerosis is a heterogeneous group including numerous causes such as: toxins and drugs such as heroin and pamidronate, familial forms, and secondary to nephron loss and hyperfiltration, such as with chronic pyelonephritis and reflux, morbid obesity, diabetes mellitus.
  • toxins and drugs such as heroin and pamidronate, familial forms, and secondary to nephron loss and hyperfiltration, such as with chronic pyelonephritis and reflux, morbid obesity, diabetes mellitus.
  • Pulmonary hypertension PH or PHTN
  • Pulmonary hypertension is a condition of increased blood pressure within the arteries of the lungs.
  • Symptoms include shortness of breath, syncope, tiredness, chest pain, swelling of the legs, and a fast heartbeat. The condition may make it difficult to exercise. The cause is often unknown. Risk factors include a family history, prior blood clots in the lungs, HIV/AIDS, sickle cell disease, cocaine use, chronic obstructive pulmonary disease, sleep apnea, living at high altitudes, and problems with the mitral valve. The underlying mechanism typically involves inflammation of the arteries in the lungs. Diagnosis involves first ruling out other potential causes.
  • Friedreich's ataxia is an autosomal recessive genetic disease that causes difficulty walking, a loss of sensation in the arms and legs and impaired speech that worsens over time. Symptoms can start between 5 and 15 years of age. Many develop hypertrophic cardiomyopathy and will require a mobility aid such as a cane, walker or wheelchair in their teens. As the disease progresses, people lose their sight and hearing. Other complications include scoliosis and diabetes mellitus.
  • the condition is caused by mutations in the FXN gene on the chromosome 9.
  • the FXN gene makes a protein called frataxin.
  • Degeneration of nerve tissue in the spinal cord causes the ataxia; particularly affected are the sensory neurons essential for directing muscle movement of the arms and legs through connections with the cerebellum.
  • the spinal cord becomes thinner and nerve cells lose some myelin sheath.
  • ADPKD autosomal dominant polycystic kidney disease
  • ADPKD Autosomal dominant polycystic kidney disease
  • Symptoms vary in severity and age of onset, but usually develop between the ages of 30 and 40.
  • ADPKD is a progressive disease and symptoms tend to get worse over time. The most common symptoms are kidney cysts, pain in the back and the sides and headaches. Other symptoms include liver and pancreatic cysts, urinary tract infections, abnormal heart valves, high blood pressure, kidney stones, and brain aneurysms.
  • ADPKD is most often caused by changes in the PKD1 and PKD2 genes, and less often by changes in the GANAB and DNAJB11 genes. It is inherited in a dominant pattern.
  • IgA nephropathy also known as Berger’s disease, is a disease that causes damage to the tiny filters inside the kidneys.
  • IgA is a protein that helps fight infections. In people with IgA nephropathy, these proteins build up and form clumps inside the kidneys’ tiny filters (glomeruli).
  • the compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is administered in combination with a second therapeutic agent.
  • the benefit experienced by a patient is increased by administering one of the compounds described herein with a second therapeutic agent (which also includes a therapeutic regimen) that also has therapeutic benefit.
  • a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is co-administered with a second therapeutic agent, wherein the compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and the second therapeutic agent modulate different aspects of the disease, disorder, or condition being treated, thereby providing a greater overall benefit than administration of either therapeutic agent alone.
  • the overall benefit experienced by the patient is simply additive of the two therapeutic agents or the patient experiences a synergistic benefit.
  • different therapeutically effective dosages of the compounds disclosed herein will be utilized in formulating a pharmaceutical composition and/or treatment regimen when the compounds disclosed herein are administered in combination with a second therapeutic agent.
  • Therapeutically effective dosages of drugs and other agents for use in combination treatment regimens are optionally determined by means similar to those set forth herein for the compounds described herein.
  • the methods of prevention/treatment described herein encompass the use of metronomic dosing, i.e., providing more frequent, lower doses in order to minimize toxic side effects.
  • a combination treatment regimen encompasses treatment regimens in which administration of a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is initiated prior to, during, or after treatment with a second agent described herein, and continues until any time during treatment with the second agent or after termination of treatment with the second agent. It also includes treatments in which a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and the second agent being used in combination are administered simultaneously or at different times and/or at decreasing or increasing intervals during the treatment period. Combination treatment further includes periodic treatments that start and stop at various times to assist with the clinical management of the patient.
  • the dosage regimen to treat, prevent, or ameliorate the condition(s) for which relief is sought is modified in accordance with a variety of factors (e.g. the disease, disorder, or condition from which the subject suffers; the age, weight, sex, diet, and medical condition of the subject).
  • the dosage regimen actually employed varies and, in some embodiments, deviates from the dosage regimens set forth herein.
  • dosages of the co-administered compounds vary depending on the type of co-drug employed, on the specific drug employed, on the disease or condition being treated, and so forth.
  • the compound provided herein when co-administered with a second therapeutic agent, is administered either simultaneously with the second therapeutic agent, or sequentially.
  • the multiple therapeutic agents are administered in any order or even simultaneously. If administration is simultaneous, the multiple therapeutic agents are, by way of example only, provided in a single, unified form, or in multiple forms (e.g., as a single pill or as two separate pills).
  • the compounds described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, as well as combination therapies are administered before, during, or after the occurrence of a disease or condition, and the timing of administering the composition containing a compound varies.
  • the compounds described herein are used as a prophylactic and are administered continuously to subjects with a propensity to develop conditions or diseases in order to prevent the occurrence of the disease or condition.
  • the compounds and compositions are administered to a subject during or as soon as possible after the onset of the symptoms.
  • a compound described herein is administered as soon as is practicable after the onset of a disease or condition is detected or suspected, and for a length of time necessary for the treatment of the disease. In some embodiments, the length required for treatment varies, and the treatment length is adjusted to suit the specific needs of each subject.
  • a compound described herein or a formulation containing the compound is administered for at least 2 weeks, about 1 month, or about 5 years.
  • the compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is administered in combination with an adjuvant.
  • the therapeutic effectiveness of one of the compounds described herein is enhanced by administration of an adjuvant (i.e., by itself the adjuvant has minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced).
  • Example 1 Imiquimod-induced systemic lupus nephritis
  • Compound 26 formulated in sesame oil was administrated orally to female BALB/c mice (7-9 weeks) at 3 mg/kg daily.
  • Half hour after administration of compound 26 the skin on the right ears of the mice were treated topically, 3 times weekly, with 25mg 5% imiquimod (IMQ).
  • IMQ 25mg 5% imiquimod
  • mice were sacrificed, spleen and kidney were weighted and divided in to two parts, one part was fixed with neutral buffered formalin and embedded in paraffin. Three ⁇ micrometer sections of liver and kidney were stained with hematoxylin and eosin.
  • Topical imiquimod treatment leads to marked splenomegaly and increased expression of INF ⁇ . Treatment with compound 26 reduced the enlargement of spleen and reduce the expression of INF ⁇ (FIG.1A and FIG.1B). Topical imiquimod treatment also increased blood urea nitrogen (BUN) and proteinuria, signs of renal dysfunction. These levels were reduced by compound 26 treatment (FIG.2A and FIG.2B).
  • Topical imiquimod treatment enlarges the size of kidneys. The kidney enlargement was partially reversed by compound 26 treatment (FIG.3A).
  • CD11b Another inflammatory biomarker CD11b is expressed on the surface of many leukocytes including monocytes, neutrophils, natural killer cells, granulocytes and macrophages, it regulates leukocyte adhesion and migration to mediate the inflammatory response.
  • the expression of NGAL and CD11b were examined in kidneys by qPCR. Topical imiquimod treatment dramatically increased their expression in kidney, and compound 26 treatment decreased the expression significantly, suggesting its anti-inflammatory function (FIG.3C and FIG.3D respectively).
  • Compound 26 mitigates imiquimod-induced systemic lupus nephritis, as indicated by the improvement in spleen and kidney.
  • the examples and embodiments described herein are for illustrative purposes only and in some embodiments, various modifications or changes are to be included within the purview of disclosure and scope of the appended claims.

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Abstract

Described herein are terpinoid derivatives as NRF2 inhibitors for use in treating systemic lupus nephritis, diabetic chronic kidney disease (CDK), Alport syndrome, focal segmental glomerulosclerosis (FSGS), pulmonary hypertension, Friedreich's ataxia, autosomal dominant polycystic kidney disease (ADPKD), or IgA nephropathy.

Description

USE OF TRITERPENOID NRF2 INHIBITORS CROSS-REFERENCE [0001] This application claims the benefit of U. S. Provisional Application Serial No.63/003,719 filed April 1, 2020 which is hereby incorporated by reference in its entirety. BACKGROUND OF THE INVENTION [0002] Kidney diseases are highly prevalent worldwide, and significantly reduce the quality of life of patients, creating an urgent need for effective therapeutic modalities. Despite this significant unmet medical need, none of the drugs launched to date have demonstrated promising potential to cure kidney diseases. This is likely due to the structural complexity of the kidney as well as difficulties in setting appropriate endpoints for clinical trials and identifying appropriate therapeutic targets. Recently, an alternative endpoint for clinical trials (i.e., a 30% or 40% reduction in estimated glomerular filtration rate [eGFR] from baseline following 2–3 years of observation) has been considered in the United States, European Union, and Japan, and is expected to contribute to the progress of drug development for kidney diseases. Further, oxidative stress and inflammation are currently thought to be key factors in the progression of kidney diseases, prompting more research on drugs targeting the mechanisms related to these factors for treatment. The Kelch-like ECH-associated protein 1-nuclear factor erythroid 2-related factor 2 (Keap1-Nrf2) system has drawn much attention in recent years for its anti-oxidative and anti- inflammatory properties, and its pharmacological potential for treatment of kidney diseases is being widely investigated in both clinical and non-clinical studies. [0003] A number of reports have described the association between Nrf2 and kidney diseases. Additionally, a review by Nezu et al. discusses the role of Nrf2 in genetically modified animals (Nrf2 knockout [KO], Keap1 knockdown [KD], and Keap1 conditional KO [cKO]) (Nezu, M., Suzuki, N., Yamamoto, M., 2017. Targeting the KEAP1-NRF2 system to prevent kidney disease progression. Am. J. Nephrol.45, 473–483). The Nrf2-KO mutation results in the worsening of lupus-like nephritis, streptozotocin-induced renal disease (including renal function), ferric nitrilotriacetate-induced nephrotoxicity, and ischemia-reperfusion (IRI)-induced kidney injury. In contrast, the Keap1-KD mutation is associated with reduced IRI-induced tubular injury and reduced unilateral ureteral obstruction-induced renal fibrosis. [0004] A number of studies have evaluated the effects of Nrf2 activators, such as sulforaphane, curcumin, and synthetic triterpenoids (CDDO) such as bardoxolone methyl [CDDO-Me], on kidney injury. Similar to the results in genetically modified animals, several other studies have also shown that Nrf2 activation leads to reduced kidney injury, indicating the therapeutic potential of targeting this pathway for treatment of kidney diseases. There is a need to treat kidney diseases. BRIEF SUMMARY OF THE INVENTION [0005] Disclosed herein is a method of treating a disease that is systemic lupus nephritis, diabetic chronic kidney disease (CDK), Alport syndrome, focal segmental glomerulosclerosis (FSGS), pulmonary hypertension, Friedreich's ataxia, autosomal dominant polycystic kidney disease (ADPKD), or IgA nephropathy, the method comprising administering a compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, to a subject in need thereof:
Figure imgf000004_0001
wherein: R1 is hydrogen, deuterium, halogen, -CN, -ORb, -NRcRd, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1- C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; R3 is N-linked heterocycloalkyl, N-linked heteroaryl, -P(=O)(R4)2, -P(=O)(OR5)2, -B(OR5)2, - S(=O)R4, -S(=O)2R4, -NR5C(=NRx)R5, -NR5C(=NRx)NR6R7, -S(=O)(=NRx)R5, - S(=O)(=NRx)NR6R7, -NR5S(=O)2NR5C(=O)R5, -NR5S(=O)(=NRx)R5, -Z-O-cycloalkyl, -Z-O- heterocycloalkyl, -Z-O-aryl, -Z-O-heteroaryl, -Z-NR5-cycloalkyl, -Z-NR5-heterocycloalkyl, -Z- NR5-aryl, -Z-NR5-heteroaryl, -Y(C1-C6alkylene)S(=O)R4, -Y(C1-C6alkylene)S(=O)2R4, -Y(C1- C6alkylene)P(=O)(R4)2, -Y(C1-C6alkylene)P(=O)(OR5)2, -Y(C1-C6alkylene)B(OR5)2, -Y(C1- C6alkylene)NR5C(=NRx)R5, -Y(C1-C6alkylene)NR5C(=NRx)NR6R7, -Y(C1- C6alkylene)S(=O)(=NRx)R5, -Y(C1-C6alkylene)S(=O)(=NRx)NR6R7, -Y(C1- C6alkylene)NR5S(=O)2NR5C(=O)R5, -NR5C(=O)(C1-C6alkylene)S(=NRx)NR6R7, -NR5C(=O)(C1- C6alkylene)S(=NRx)R5, -Y(C1-C6alkylene)NR5S(=O)(=NRx)R5, -Y(C2-C6alkenylene)S(=O)2R4, - Y(C2-C6alkenylene)P(=O)(R4)2, -Y(C2-C6alkenylene)P(=O)(OR5)2, -Y(C2-C6alkenylene)B(OR5)2, -Y(C2-C6alkenylene)NR5C(=NRx)R5, -Y(C2-C6alkenylene)NR5C(=NRx)NR6R7, -Y(C2- C6alkenylene)S(=O)(=NRx)R5, -Y(C2-C6alkenylene)S(=O)(=NRx)NR6R7, -Y(C2- C6alkenylene)NR5S(=O)2NR5C(=O)R5, -Y(C2-C6alkenylene)NR5S(=O)(=NRx)R5, -Y(C2- C6alkenylene)cycloalkyl, -Y(C2-C6alkenylene)heterocycloalkyl, -Y(C2-C6alkenylene)aryl, -Y(C2- C6alkenylene)heteroaryl, -(C1-C6alkylene)OP(=O)(OR5)2, -(C1-C6alkylene)O(C1- C6alkylene)OP(=O)(OR5)2, or -(C1-C6alkylene)OP(=O)(OR5)[N(R5)2]; wherein the alkylene, alkenylene, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one, two, or three R3a; each R3a is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1- C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Y is a bond, -O-, -S-, or -NRb-; Z is a bond or C1-C6alkylene; Rx is hydrogen, -NO2, -CN, or -S(=O)2Ra; each R4 is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R4a; each R4a is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1- C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R5 is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R5a; or two R5 are taken together to form an optionally substituted heterocycloalkyl; each R5a is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1- C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R6 and R7 is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R6a; each R6a is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1- C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or R6 and R7 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R6b; each R6b is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1- C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
Figure imgf000005_0001
; R8 is hydrogen, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl; R9 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl; R10 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl; R11 is hydrogen, deuterium, halogen, or -ORb; or R3 and R11 are taken together to form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl; R12 and R13 are independently hydrogen, -ORb, -NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; or R12 and R13 are taken together to form a cycloalkyl or a heterocycloalkyl; each substituted with 0-6 R14; each R14 is independently deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1- C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; R15 and R16 are independently hydrogen, -ORb, -NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; or R15 and R16 are taken together to form a cycloalkyl or a heterocycloalkyl; each substituted with 0-6 R2; each R2 is independently deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1- C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; each Ra is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three deuterium, halogen, -OH, -NH2, or C1-C6 alkyl; each Rb is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three halogen, -OH, -NH2, or C1-C6 alkyl; and each Rc and Rd is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three deuterium, halogen, -OH, -NH2, or C1-C6 alkyl; or Rc and Rd are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three deuterium, halogen, -OH, -NH2, or C1-C6 alkyl. [0006] Also disclosed herein is a method of treating a disease that is systemic lupus nephritis, diabetic chronic kidney disease (CDK), Alport syndrome, focal segmental glomerulosclerosis (FSGS), pulmonary hypertension, Friedreich's ataxia, autosomal dominant polycystic kidney disease (ADPKD), or IgA nephropathy, the method comprising administering a compound of Formula (VIII), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, to a subject in need thereof:
Figure imgf000007_0001
wherein: R1 is hydrogen, deuterium, halogen, -CN, -ORb, -NRcRd, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; R3 is halogen, -CN, -OR5, -SR5, -S(=O)R4, -S(=O)2R4, -NO2, -NR6R7, -S(=O)2NR6R7, -C(=O)R4, - OC(=O)R4, -C(=O)OR5, -OC(=O)OR5, -C(=O)NR6R7, -OC(=O)NR6R7, -NR5C(=O)NR6R7, - NR5C(=O)OR5, -NR5S(=O)2NR6R7, -NR5S(=O)2R4, -NR5C(=O)R4, -P(=O)(R4)2, -P(=O)(OR5)2, - B(OR5)2, -NR5C(=NRx)R5, -NR5C(=NRx)NR6R7, -S(=O)(=NRx)R5, -S(=O)(=NRx)NR6R7, - NR5S(=O)2NR5C(=O)R5, -NR5S(=O)(=NRx)R5, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R3a; each R3a is independently oxo, deuterium, halogen, -CN, -OR5, -SR5, -S(=O)R4, -S(=O)2R4, -NO2, - NR6R7, -S(=O)2NR6R7, -C(=O)R4, -OC(=O)R4, -C(=O)OR5, -OC(=O)OR5, -C(=O)NR6R7, - OC(=O)NR6R7, -NR5C(=O)NR6R7, -NR5C(=O)OR5, -NR5S(=O)2NR6R7, -NR5S(=O)2R4, - NR5C(=O)R4, -P(=O)(R4)2, -P(=O)(OR5)2, -B(OR5)2, -NR5C(=NRx)R5, -NR5C(=NRx)NR6R7, - S(=O)(=NRx)R5, -S(=O)(=NRx)NR6R7, -NR5S(=O)2NR5C(=O)R5, -NR5S(=O)(=NRx)R5, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R3b; each R3b is independently deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Rx is hydrogen, -NO2, -CN, or -S(=O)2Ra; each R4 is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R4a; each R4a is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, -NRbC(=NRx)Rb, -NRbC(=NRx)NRcRd, -S(=O)(=NRx)Rb, -S(=O)(=NRx)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R5 is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R5a; or two R5 are taken together to form an optionally substituted heterocycloalkyl; each R5a is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, -NRbC(=NRx)Rb, -NRbC(=NRx)NRcRd, -S(=O)(=NRx)Rb, -S(=O)(=NRx)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R6 and R7 is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R6a; each R6a is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, -NRbC(=NRx)Rb, -NRbC(=NRx)NRcRd, -S(=O)(=NRx)Rb, -S(=O)(=NRx)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or R6 and R7 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R6b; each R6b is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
Figure imgf000008_0001
; Y1 and Y2 are independently hydrogen, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; R8 is hydrogen, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl; R9 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl; R10 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl; R11 is hydrogen, deuterium, halogen, or -ORb; or R3 and R11 are taken together to form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl; R12 is hydrogen, deuterium, -ORb, -NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R13 is -CN, -OR19, -S(=O)2NR20R21, -OC(=O)R18, -OC(=O)OR19, -OC(=O)NR20R21, -NR19C(=O)OR19, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -CH2(cycloalkyl), -CH2(heterocycloalkyl), -CH2(aryl), or - CH2(heteroaryl); wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R13a; each R13a is independently oxo, deuterium, halogen, -CN, -OR19, -SR19, -S(=O)R18, -S(=O)2R18, -NO2, - NR20R21, -S(=O)2NR20R21, -C(=O)R18, -OC(=O)R18, -C(=O)OR19, -OC(=O)OR19, -C(=O)NR20R21, - OC(=O)NR20R21, -NR19C(=O)OR19, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1- C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R18 is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R18a; each R18a is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R19 is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R19a; each R19a is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R20 and R21 are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R20a; each R20a is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or R20 and R21 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R20b; each R20b is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R15 and R16 are independently hydrogen, -ORb, -NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; or R15 and R16 are taken together to form a cycloalkyl or a heterocycloalkyl; each substituted with 0-6 R2; each R2 is independently deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; each Ra is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three deuterium, halogen, -OH, -NH2, or C1-C6 alkyl; each Rb is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three halogen, -OH, -NH2, or C1-C6 alkyl; and each Rc and Rd is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three deuterium, halogen, -OH, -NH2, or C1-C6 alkyl; or Rc and Rd are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three deuterium, halogen, -OH, -NH2, or C1- C6 alkyl. INCORPORATION BY REFERENCE [0007] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference for the specific purposes identified herein. BRIEF DESCRIPTION OF FIGURES [0008] FIG.1A displays the spleen weight to body weight following treatment with compound 26 in an imiquimod-induced systemic lupus nephritis mouse model. [0009] FIG.1B displays the fold of spleen mRNA expression following treatment with compound 26 in an imiquimod-induced systemic lupus nephritis mouse model. [0010] FIG.2A displays the serum BUN (blood urea nitrogen) levels following treatment with compound 26 in an imiquimod-induced systemic lupus nephritis mouse model. [0011] FIG.2B displays urine protein levels following treatment with compound 26 in an imiquimod- induced systemic lupus nephritis mouse model. [0012] FIG.3A displays the kidney weight to body weight following treatment with compound 26 in an imiquimod-induced systemic lupus nephritis mouse model. [0013] FIG.3B displays the renal histopathologic score following treatment with compound 26 in an imiquimod-induced systemic lupus nephritis mouse model. [0014] FIG.3C displays the expression of NGAL in the kidney following treatment with compound 26 in an imiquimod-induced systemic lupus nephritis mouse model. [0015] FIG.3D displays the expression of CD11b in the kidney following treatment with compound 26 in an imiquimod-induced systemic lupus nephritis mouse model. DETAILED DESCRIPTION OF THE INVENTION Definitions [0016] As used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “an agent” includes a plurality of such agents, and reference to “the cell” includes reference to one or more cells (or to a plurality of cells) and equivalents thereof known to those skilled in the art, and so forth. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. The term “about” when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range, in some instances, will vary between 1% and 15% of the stated number or numerical range. The term “comprising” (and related terms such as “comprise” or “comprises” or “having” or “including”) is not intended to exclude that in other certain embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, described herein, “consist of” or “consist essentially of” the described features. [0017] As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below. [0018] “Aliphatic chain” refers to a linear chemical moiety that is composed of only carbons and hydrogens. In some embodiments, the aliphatic chain is saturated. In some embodiments, the aliphatic chain is unsaturated. In some embodiments, the unsaturated aliphatic chain contains one unsaturation. In some embodiments, the unsaturated aliphatic chain contains more than one unsaturation. In some embodiments, the unsaturated aliphatic chain contains two unsaturations. In some embodiments, the unsaturated aliphatic chain contains one double bond. In some embodiments, the unsaturated aliphatic chain contains two double bonds. [0019] “Alkyl” refers to an optionally substituted straight-chain, or optionally substituted branched- chain saturated hydrocarbon monoradical having from one to about ten carbon atoms, or from one to six carbon atoms, wherein an sp3-hybridized carbon of the alkyl residue is attached to the rest of the molecule by a single bond. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2- dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3- methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl, and hexyl, and longer alkyl groups, such as heptyl, octyl, and the like. Whenever it appears herein, a numerical range such as “C1-C6 alkyl” means that the alkyl group consists of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated. In some embodiments, the alkyl is a C1-C10 alkyl, a C1- C9 alkyl, a C1-C8 alkyl, a C1-C7 alkyl, a C1-C6 alkyl, a C1-C5 alkyl, a C1-C4 alkyl, a C1-C3 alkyl, a C1-C2 alkyl, or a C1 alkyl. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, the alkyl is optionally substituted with halogen. [0020] “Alkenyl” refers to an optionally substituted straight-chain, or optionally substituted branched- chain hydrocarbon monoradical having one or more carbon-carbon double-bonds and having from two to about ten carbon atoms, more preferably two to about six carbon atoms, wherein an sp2-hybridized carbon of the alkenyl residue is attached to the rest of the molecule by a single bond. The group may be in either the cis or trans conformation about the double bond(s), and should be understood to include both isomers. Examples include, but are not limited to, ethenyl (-CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, 1,3-butadienyl, and the like. Whenever it appears herein, a numerical range such as “C2-C6 alkenyl” means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkenyl” where no numerical range is designated. In some embodiments, the alkenyl is a C2-C10 alkenyl, a C2-C9 alkenyl, a C2-C8 alkenyl, a C2-C7 alkenyl, a C2-C6 alkenyl, a C2-C5 alkenyl, a C2-C4 alkenyl, a C2-C3 alkenyl, or a C2 alkenyl. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkenyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkenyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, the alkenyl is optionally substituted with halogen. [0021] “Alkynyl” refers to an optionally substituted straight-chain or optionally substituted branched- chain hydrocarbon monoradical having one or more carbon-carbon triple-bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, and the like. Whenever it appears herein, a numerical range such as “C2-C6 alkynyl” means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkynyl” where no numerical range is designated. In some embodiments, the alkynyl is a C2-C10 alkynyl, a C2-C9 alkynyl, a C2-C8 alkynyl, a C2-C7 alkynyl, a C2-C6 alkynyl, a C2-C5 alkynyl, a C2-C4 alkynyl, a C2-C3 alkynyl, or a C2 alkynyl. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkynyl is optionally substituted with oxo, halogen, -CN, - CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkynyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, the alkynyl is optionally substituted with halogen. [0022] “Alkylene” refers to a straight or branched divalent hydrocarbon chain. Unless stated otherwise specifically in the specification, an alkylene group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkylene is optionally substituted with oxo, halogen, - CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkylene is optionally substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, the alkylene is optionally substituted with halogen. [0023] “Alkoxy” refers to a radical of the formula -ORa where Ra is an alkyl radical as defined. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkoxy is optionally substituted with oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkoxy is optionally substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, the alkoxy is optionally substituted with halogen. [0024] “Aminoalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more amines. In some embodiments, the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with one, two, or three amines. Hydroxyalkyl include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the hydroxyalkyl is aminomethyl. [0025] “Aryl” refers to a radical derived from a hydrocarbon ring system comprising hydrogen, 6 to 30 carbon atoms, and at least one aromatic ring. The aryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through an aromatic ring atom) or bridged ring systems. In some embodiments, the aryl is a 6- to 10-membered aryl. In some embodiments, the aryl is a 6-membered aryl. Aryl radicals include, but are not limited to, aryl radicals derived from the hydrocarbon ring systems of anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as- indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. In some embodiments, the aryl is phenyl. Unless stated otherwise specifically in the specification, an aryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an aryl is optionally substituted with halogen, methyl, ethyl, -CN, - CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, an aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the aryl is optionally substituted with halogen. [0026] “Cycloalkyl” refers to a stable, partially or fully saturated, monocyclic or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or a heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom), bridged, or spiro ring systems. Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (C3-C15 cycloalkyl), from three to ten carbon atoms (C3-C10 cycloalkyl), from three to eight carbon atoms (C3-C8 cycloalkyl), from three to six carbon atoms (C3-C6 cycloalkyl), from three to five carbon atoms (C3-C5 cycloalkyl), or three to four carbon atoms (C3-C4 cycloalkyl). In some embodiments, the cycloalkyl is a 3- to 6- membered cycloalkyl. In some embodiments, the cycloalkyl is a 5- to 6-membered cycloalkyl. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls or carbocycles include, for example, adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl. Partially saturated cycloalkyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless stated otherwise specifically in the specification, a cycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the cycloalkyl is optionally substituted with halogen. [0027] “Deuteroalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more deuteriums. In some embodiments, the alkyl is substituted with one deuterium. In some embodiments, the alkyl is substituted with one, two, or three deuteriums. In some embodiments, the alkyl is substituted with one, two, three, four, five, or six deuteriums. Deuteroalkyl include, for example, CD3, CH2D, CHD2, CH2 CD3, CD2CD3, CHDCD3, CH2CH2D, or CH2CHD2. In some embodiments, the deuteroalkyl is CD3. [0028] “Haloalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more halogens. In some embodiments, the alkyl is substituted with one, two, or three halogens. In some embodiments, the alkyl is substituted with one, two, three, four, five, or six halogens. Haloalkyl include, for example, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like. In some embodiments, the haloalkyl is trifluoromethyl. [0029] “Halo” or “halogen” refers to bromo, chloro, fluoro, or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro. [0030] “Heteroalkyl” refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, or combinations thereof. A heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a C1-C6 heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen (e.g. -NH-, -N(alkyl)- ), sulfur, or combinations thereof wherein the heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. Examples of such heteroalkyl are, for example, -CH2OCH3, - CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, or -CH(CH3)OCH3. Unless stated otherwise specifically in the specification, a heteroalkyl is optionally substituted for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, - CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroalkyl is optionally substituted with halogen. [0031] “Hydroxyalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more hydroxyls. In some embodiments, the alkyl is substituted with one hydroxyl. In some embodiments, the alkyl is substituted with one, two, or three hydroxyls. Hydroxyalkyl include, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl. [0032] “Heterocycloalkyl” refers to a stable 3- to 24-membered partially or fully saturated ring radical comprising 2 to 23 carbon atoms and from one to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, and sulfur. Unless stated otherwise specifically in the specification, the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom) or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized. [0033] Representative heterocycloalkyls include, but are not limited to, heterocycloalkyls having from two to fifteen carbon atoms (C2-C15 heterocycloalkyl), from two to ten carbon atoms (C2-C10 heterocycloalkyl), from two to eight carbon atoms (C2-C8 heterocycloalkyl), from two to six carbon atoms (C2-C6 heterocycloalkyl), from two to five carbon atoms (C2-C5 heterocycloalkyl), or two to four carbon atoms (C2-C4 heterocycloalkyl). In some embodiments, the heterocycloalkyl is a 3- to 6- membered heterocycloalkyl. In some embodiments, the cycloalkyl is a 5- to 6-membered heterocycloalkyl. Examples of such heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3- dihydroisobenzofuran-1-yl, 3-oxo-1,3-dihydroisobenzofuran-1-yl, methyl-2-oxo-1,3-dioxol-4-yl, and 2- oxo-1,3-dioxol-4-yl. The term heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to, the monosaccharides, the disaccharides, and the oligosaccharides. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e. skeletal atoms of the heterocycloalkyl ring). Unless stated otherwise specifically in the specification, a heterocycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, - CF3, -OH, or -OMe. In some embodiments, the heterocycloalkyl is optionally substituted with halogen. [0034] “Heteroaryl” refers to a 5- to 14-membered ring system radical comprising hydrogen atoms, one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, and sulfur, and at least one aromatic ring. The heteroaryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded through an aromatic ring atom) or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized. In some embodiments, the heteroaryl is a 5- to 10-membered heteroaryl. In some embodiments, the heteroaryl is a 5- to 6-membered heteroaryl. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwise specifically in the specification, a heteroaryl is optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, - CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroaryl is optionally substituted with halogen. [0035] The terms “treat,” “prevent,” “ameliorate,” and “inhibit,” as well as words stemming therefrom, as used herein, do not necessarily imply 100% or complete treatment, prevention, amelioration, or inhibition. Rather, there are varying degrees of treatment, prevention, amelioration, and inhibition of which one of ordinary skill in the art recognizes as having a potential benefit or therapeutic effect. In this respect, the disclosed methods can provide any amount of any level of treatment, prevention, amelioration, or inhibition of the disorder in a mammal. For example, a disorder, including symptoms or conditions thereof, may be reduced by, for example, about 100%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, or about 10%. Furthermore, the treatment, prevention, amelioration, or inhibition provided by the methods disclosed herein can include treatment, prevention, amelioration, or inhibition of one or more conditions or symptoms of the disorder, e.g., cancer or an inflammatory disease. Also, for purposes herein, “treatment,” “prevention,” “amelioration,” or “inhibition” encompass delaying the onset of the disorder, or a symptom or condition thereof. [0036] The terms “effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of a compound disclosed herein being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated, e.g., cancer or an inflammatory disease. In some embodiments, the result is a reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an “effective amount” for therapeutic uses is the amount of the composition comprising a compound disclosed herein required to provide a clinically significant decrease in disease symptoms. In some embodiments, an appropriate “effective” amount in any individual case is determined using techniques, such as a dose escalation study. Compounds [0037] Disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure imgf000018_0001
wherein: Ring A is a cycloalkyl or a heterocycloalkyl; R1 is hydrogen, deuterium, halogen, -CN, -ORb, -NRcRd, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; each R2 is independently deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; n is 0-6; R3 is halogen, -CN, -OR5, -SR5, -S(=O)R4, -S(=O)2R4, -NO2, -NR6R7, -S(=O)2NR6R7, -C(=O)R4, - OC(=O)R4, -C(=O)OR5, -OC(=O)OR5, -C(=O)NR6R7, -OC(=O)NR6R7, -NR5C(=O)NR6R7, - NR5C(=O)OR5, -NR5S(=O)2NR6R7, -NR5S(=O)2R4, -NR5C(=O)R4, -P(=O)(R4)2, -P(=O)(OR5)2, - B(OR5)2, -NR5C(=NRx)R5, -NR5C(=NRx)NR6R7, -S(=O)(=NRx)R5, -S(=O)(=NRx)NR6R7, - NR5S(=O)2NR5C(=O)R5, -NR5S(=O)(=NRx)R5, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R3a; each R3a is independently oxo, deuterium, halogen, -CN, -OR5, -SR5, -S(=O)R4, -S(=O)2R4, -NO2, - NR6R7, -S(=O)2NR6R7, -C(=O)R4, -OC(=O)R4, -C(=O)OR5, -OC(=O)OR5, -C(=O)NR6R7, - OC(=O)NR6R7, -NR5C(=O)NR6R7, -NR5C(=O)OR5, -NR5S(=O)2NR6R7, -NR5S(=O)2R4, - NR5C(=O)R4, -P(=O)(R4)2, -P(=O)(OR5)2, -B(OR5)2, -NR5C(=NRx)R5, -NR5C(=NRx)NR6R7, - S(=O)(=NRx)R5, -S(=O)(=NRx)NR6R7, -NR5S(=O)2NR5C(=O)R5, -NR5S(=O)(=NRx)R5, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R3b; each R3b is independently deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Rx is hydrogen, -NO2, -CN, or -S(=O)2Ra; each R4 is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R4a; each R4a is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, -NRbC(=NRx)Rb, -NRbC(=NRx)NRcRd, -S(=O)(=NRx)Rb, -S(=O)(=NRx)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R5 is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R5a; or two R5 are taken together to form an optionally substituted heterocycloalkyl; each R5a is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, -NRbC(=NRx)Rb, -NRbC(=NRx)NRcRd, -S(=O)(=NRx)Rb, -S(=O)(=NRx)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R6 and R7 is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R6a; each R6a is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, -NRbC(=NRx)Rb, -NRbC(=NRx)NRcRd, -S(=O)(=NRx)Rb, -S(=O)(=NRx)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or R6 and R7 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R6b; each R6b is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
Figure imgf000019_0001
; R8 is hydrogen, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl; R9 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl; R10 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl; R11 is hydrogen, deuterium, halogen, or -ORb; or R3 and R11 are taken together to form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl; R12 and R13 are independently hydrogen, -ORb, -NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; or R12 and R13 are taken together to form a cycloalkyl or a heterocycloalkyl; each substituted with 0-6 R14; each R14 is independently deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; each Ra is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three deuterium, halogen, -OH, -NH2, or C1-C6 alkyl; each Rb is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three halogen, -OH, -NH2, or C1-C6 alkyl; and each Rc and Rd is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three deuterium, halogen, -OH, -NH2, or C1-C6 alkyl; or Rc and Rd are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three deuterium, halogen, -OH, -NH2, or C1- C6 alkyl. [0038] In some embodiments of a compound of Formula (I), R1 is -CN, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. In some embodiments of a compound of Formula (I), R1 is -CN or C1-C6 haloalkyl. In some embodiments of a compound of Formula (I), R1 is C1-C6 haloalkyl. In some embodiments of a compound of Formula (I), R1 is -CN. [0039] In some embodiments of a compound of Formula (I), R8 is hydrogen or deuterium. In some embodiments of a compound of Formula (I), R8 is hydrogen. [0040] In some embodiments of a compound of Formula (I), R9 is C1-C6 alkyl or C2-C6 alkynyl. In some embodiments of a compound of Formula (I), R9 is C1-C6 alkyl. [0041] In some embodiments of a compound of Formula (I), R10 is C1-C6 alkyl or C2-C6 alkynyl. In some embodiments of a compound of Formula (I), R10 is C1-C6 alkyl. [0042] In some embodiments of a compound of Formula (I), R9 is C1-C6 alkyl and R10 is C2-C6 alkynyl. In some embodiments of a compound of Formula (I), R10 is C1-C6 alkyl and R9 is C2-C6 alkynyl. [0043] In some embodiments of a compound of Formula (I), is . In some embodiments of a compound of Formula
Figure imgf000021_0001
[0044] In some embodiments of a compound of Formula (I), R11 is hydrogen, halogen, or -OH. In some embodiments of a compound of Formula (I), R11 is hydrogen or -OH. In some embodiments of a compound of Formula (I), R11 is hydrogen. [0045] In some embodiments of a compound of Formula (I), R12 and R13 are independently hydrogen, C1-C6 alkyl, or C1-C6 deuteroalkyl. In some embodiments of a compound of Formula (I), R12 and R13 are independently hydrogen or C1-C6 alkyl. In some embodiments of a compound of Formula (I), R12 and R13 are independently hydrogen or C1-C6 deuteroalkyl. In some embodiments of a compound of Formula (I), R12 and R13 are independently C1-C6 alkyl. [0046] In some embodiments of a compound of Formula (I), R12 and R13 are taken together to form a cycloalkyl. In some embodiments of a compound of Formula (I), R12 and R13 are taken together to form a cycloalkyl substituted with 1-4 deuterium. In some embodiments of a compound of Formula (I), R12 and R13 are taken together to form a cycloalkyl substituted with 1 or 2 deuterium. In some embodiments of a compound of Formula (I), R12 and R13 are taken together to form a cycloalkyl substituted with 2-4 deuteriums. [0047] In some embodiments of a compound of Formula (I), R12 and R13 are taken together to form a heterocycloalkyl. In some embodiments of a compound of Formula (I), R12 and R13 are taken together to form a heterocycloalkyl substituted with 1-4 deuterium. In some embodiments of a compound of Formula (I), R12 and R13 are taken together to form a heterocycloalkyl substituted with 1 or 2 deuterium. In some embodiments of a compound of Formula (I), R12 and R13 are taken together to form a heterocycloalkyl substituted with 2-4 deuteriums. [0048] In some embodiments of a compound of Formula (I), R3 is halogen, -CN, -OR5, -NR6R7, - C(=O)R4, -OC(=O)R4, -C(=O)OR5, -C(=O)NR6R7, -OC(=O)NR6R7, -NR5C(=O)NR6R7, -NR5C(=O)OR5, -NR5S(=O)2R4, -NR5C(=O)R4, -NR5C(=NRx)R5, -NR5C(=NRx)NR6R7, -S(=O)(=NRx)R5, - S(=O)(=NRx)NR6R7, -NR5S(=O)2NR5C(=O)R5, -NR5S(=O)(=NRx)R5, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 heteroalkyl, or heteroaryl; wherein the alkyl, alkenyl, and heteroaryl are independently optionally substituted with one, two, or three R3a. In some embodiments of a compound of Formula (I), R3 is -NR5C(=NRx)R5 or -NR5C(=NRx)NR6R7. In some embodiments of a compound of Formula (I), R3 is -S(=O)(=NRx)R5, -S(=O)(=NRx)NR6R7, -NR5S(=O)2NR5C(=O)R5, or - NR5S(=O)(=NRx)R5. [0049] In some embodiments of a compound of Formula (I), R3 is C1-C6 alkyl optionally substituted with one, two, or three R3a. In some embodiments of a compound of Formula (I), R3 is C1-C6 alkyl. [0050] In some embodiments of a compound of Formula (I), R3 is -C(=O)OR5. [0051] In some embodiments of a compound of Formula (I), each R3a is independently deuterium, halogen, -CN, -OR5, -S(=O)R4, -S(=O)2R4, -OC(=O)R4, -C(=O)OR5, -OC(=O)OR5, -C(=O)NR6R7, - OC(=O)NR6R7, -P(=O)(R4)2, -P(=O)(OR5)2, -B(OR5)2, -NR5C(=NRx)R5, -NR5C(=NRx)NR6R7, - S(=O)(=NRx)R5, -S(=O)(=NRx)NR6R7, -NR5S(=O)2NR5C(=O)R5, -NR5S(=O)(=NRx)R5, cycloalkyl, or heterocycloalkyl. [0052] In some embodiments of a compound of Formula (I), each R3a is independently deuterium, halogen, -CN, -OR5, -S(=O)R4, -S(=O)2R4, -OC(=O)R4, -C(=O)OR5, -OC(=O)OR5, -C(=O)NR6R7, - OC(=O)NR6R7, -P(=O)(R4)2, -P(=O)(OR5)2, -B(OR5)2, -NR5C(=NRx)R5, -NR5C(=NRx)NR6R7, - S(=O)(=NRx)R5, -S(=O)(=NRx)NR6R7, -NR5S(=O)2NR5C(=O)R5, or -NR5S(=O)(=NRx)R5. In some embodiments of a compound of Formula (I), each R3a is independently deuterium, halogen, -CN, -OR5, - OC(=O)R4, -C(=O)OR5, -C(=O)NR6R7, -B(OR5)2, -S(=O)(=NRx)R5, C1-C6 heteroalkyl, heterocycloalkyl, or heteroaryl. In some embodiments of a compound of Formula (I), each R3a is independently - OC(=O)R4, -C(=O)OR5, -OC(=O)OR5, -C(=O)NR6R7, -P(=O)(R4)2, -P(=O)(OR5)2, -B(OR5)2, - NR5C(=NRx)R5, -NR5C(=NRx)NR6R7, -S(=O)(=NRx)R5, -S(=O)(=NRx)NR6R7, -NR5S(=O)2NR5C(=O)R5, or -NR5S(=O)(=NRx)R5.In some embodiments of a compound of Formula (I), each R3a is independently - OC(=O)R4, -C(=O)OR5, -OC(=O)OR5, or -C(=O)NR6R7. In some embodiments of a compound of Formula (I), each R3a is independently -P(=O)(R4)2, -P(=O)(OR5)2, or -B(OR5)2. In some embodiments of a compound of Formula (I), each R3a is independently -NR5C(=NRx)R5, -NR5C(=NRx)NR6R7, - S(=O)(=NRx)R5, -S(=O)(=NRx)NR6R7, -NR5S(=O)2NR5C(=O)R5, or -NR5S(=O)(=NRx)R5. [0053] In some embodiments of a compound of Formula (I), each R3b is independently deuterium, halogen, -CN, -ORb, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. In some embodiments of a compound of Formula (I), each R3b is independently deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. [0054] In some embodiments of a compound of Formula (I), each R4 is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one, two, or three R4a. In some embodiments of a compound of Formula (I), each R4 is independently C1- C6 alkyl or cycloalkyl; wherein the alkyl and cycloalkyl are independently optionally substituted with one, two, or three R4a. In some embodiments of a compound of Formula (I), each R4 is independently C1- C6 alkyl optionally substituted with one, two, or three R4a. In some embodiments of a compound of Formula (I), each R4 is independently C1-C6 alkyl. In some embodiments of a compound of Formula (I), each R4 is independently C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. [0055] In some embodiments of a compound of Formula (I), each R4a is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (I), each R4a is independently deuterium or halogen. In some embodiments of a compound of Formula (I), each R4a is independently halogen. [0056] In some embodiments of a compound of Formula (I), each R5 is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one, two, or three R5a. In some embodiments of a compound of Formula (I), each R5 is independently hydrogen, C1-C6 alkyl, or cycloalkyl; wherein the alkyl and cycloalkyl are independently optionally substituted with one, two, or three R5a. In some embodiments of a compound of Formula (I), each R5 is independently hydrogen or C1- C6 alkyl optionally substituted with one, two, or three R5a. In some embodiments of a compound of Formula (I), each R5 is independently C1-C6 alkyl optionally substituted with one, two, or three R5a. In some embodiments of a compound of Formula (I), each R5 is hydrogen or C1-C6 alkyl. In some embodiments of a compound of Formula (I), each R5 is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. [0057] In some embodiments of a compound of Formula (I), two R5 are taken together to form an optionally substituted heterocycloalkyl. [0058] In some embodiments of a compound of Formula (I), each R5a is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (I), each R5a is independently deuterium or halogen. In some embodiments of a compound of Formula (I), each R5a is independently halogen. In some embodiments of a compound of Formula (I), each R5a is independently -NRbC(=NRx)Rb or -NRbC(=NRx)NRcRd. In some embodiments of a compound of Formula (I), each R5a is independently -S(=O)(=NRx)Rb or - S(=O)(=NRx)NRcRd. [0059] In some embodiments of a compound of Formula (I), each R6 and R7 is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one, two, or three R6a. In some embodiments of a compound of Formula (I), each R6 and R7 is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one, two, or three R6a. In some embodiments of a compound of Formula (I), each R6 and R7 is independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl; wherein the alkyl is independently optionally substituted with one, two, or three R6a. In some embodiments of a compound of Formula (I), each R6 and R7 is independently hydrogen or C1-C6 alkyl. In some embodiments of a compound of Formula (I), each R6 and R7 is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. [0060] In some embodiments of a compound of Formula (I), each R6a is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (I), each R6a is independently deuterium or halogen. In some embodiments of a compound of Formula (I), each R6a is independently halogen. In some embodiments of a compound of Formula (I), each R5a is independently -NRbC(=NRx)Rb or -NRbC(=NRx)NRcRd. In some embodiments of a compound of Formula (I), each R6a is independently -S(=O)(=NRx)Rb or - S(=O)(=NRx)NRcRd. [0061] In some embodiments of a compound of Formula (I), R6 and R7 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R6b. [0062] In some embodiments of a compound of Formula (I), each R6b is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (I), each R6b is independently C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of a compound of Formula (I), each R6b is independently C1-C6 alkyl. [0063] In some embodiments of a compound of Formula (I), Rx is hydrogen, -NO2, or -CN. In some embodiments of a compound of Formula (I), Rx is -NO2 or -CN. In some embodiments of a compound of Formula (I), Rx is -CN. [0064] In some embodiments of a compound of Formula (I), Ring A is a cycloalkyl. In some embodiments of a compound of Formula (I), Ring A is a heterocycloalkyl. [0065] In some embodiments of a compound of Formula (I), each R2 is independently deuterium, halogen, -CN, -ORb, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of a compound of Formula (I), each R2 is deuterium. [0066] In some embodiments of a compound of Formula (I), n is 0. In some embodiments of a compound of Formula (I), n is 1. In some embodiments of a compound of Formula (I), n is 2. In some embodiments of a compound of Formula (I), n is 3. In some embodiments of a compound of Formula (I), n is 4. In some embodiments of a compound of Formula (I), n is 5. In some embodiments of a compound of Formula (I), n is 6. In some embodiments of a compound of Formula (I), n is 1-4. In some embodiments of a compound of Formula (I), n is 1 or 2. In some embodiments of a compound of Formula (I), n is 2-4. [0067] Disclosed herein is a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure imgf000024_0001
wherein: Ring B is a cycloalkyl or a heterocycloalkyl; each R14 is independently deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; m is 0-6; R1 is hydrogen, deuterium, halogen, -CN, -ORb, -NRcRd, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; R3 is halogen, -CN, -OR5, -SR5, -S(=O)R4, -S(=O)2R4, -NO2, -NR6R7, -S(=O)2NR6R7, -C(=O)R4, - OC(=O)R4, -C(=O)OR5, -OC(=O)OR5, -C(=O)NR6R7, -OC(=O)NR6R7, -NR5C(=O)NR6R7, - NR5C(=O)OR5, -NR5S(=O)2NR6R7, -NR5S(=O)2R4, -NR5C(=O)R4, -P(=O)(R4)2, -P(=O)(OR5)2, - B(OR5)2, -NR5C(=NRx)R5, -NR5C(=NRx)NR6R7, -S(=O)(=NRx)R5, -S(=O)(=NRx)NR6R7, - NR5S(=O)2NR5C(=O)R5, -NR5S(=O)(=NRx)R5, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R3a; each R3a is independently oxo, deuterium, halogen, -CN, -OR5, -SR5, -S(=O)R4, -S(=O)2R4, -NO2, - NR6R7, -S(=O)2NR6R7, -C(=O)R4, -OC(=O)R4, -C(=O)OR5, -OC(=O)OR5, -C(=O)NR6R7, - OC(=O)NR6R7, -NR5C(=O)NR6R7, -NR5C(=O)OR5, -NR5S(=O)2NR6R7, -NR5S(=O)2R4, - NR5C(=O)R4, -P(=O)(R4)2, -P(=O)(OR5)2, -B(OR5)2, -NR5C(=NRx)R5, -NR5C(=NRx)NR6R7, - S(=O)(=NRx)R5, -S(=O)(=NRx)NR6R7, -NR5S(=O)2NR5C(=O)R5, -NR5S(=O)(=NRx)R5, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R3b; each R3b is independently deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Rx is hydrogen, -NO2, -CN, or -S(=O)2Ra; each R4 is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R4a; each R4a is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, -NRbC(=NRx)Rb, -NRbC(=NRx)NRcRd, -S(=O)(=NRx)Rb, -S(=O)(=NRx)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R5 is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R5a; or two R5 are taken together to form an optionally substituted heterocycloalkyl; each R5a is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, -NRbC(=NRx)Rb, -NRbC(=NRx)NRcRd, -S(=O)(=NRx)Rb, -S(=O)(=NRx)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R6 and R7 is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R6a; each R6a is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, -NRbC(=NRx)Rb, -NRbC(=NRx)NRcRd, -S(=O)(=NRx)Rb, -S(=O)(=NRx)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or R6 and R7 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R6b; each R6b is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
Figure imgf000026_0001
s o ; R8 is hydrogen, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl; R9 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl; R10 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl; R11 is hydrogen, deuterium, halogen, or -ORb; or R3 and R11 are taken together to form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl; R15 and R16 are independently hydrogen, -ORb, -NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; or R15 and R16 are taken together to form a cycloalkyl or a heterocycloalkyl; each substituted with 0-6 R2; each R2 is independently deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; each Ra is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three deuterium, halogen, -OH, -NH2, or C1-C6 alkyl; each Rb is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three halogen, -OH, -NH2, or C1-C6 alkyl; and each Rc and Rd is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three deuterium, halogen, -OH, -NH2, or C1-C6 alkyl; or Rc and Rd are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three deuterium, halogen, -OH, -NH2, or C1- C6 alkyl. [0068] In some embodiments of a compound of Formula (II), R1 is -CN, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. In some embodiments of a compound of Formula (II), R1 is -CN or C1-C6 haloalkyl. In some embodiments of a compound of Formula (II), R1 is C1-C6 haloalkyl. In some embodiments of a compound of Formula (II), R1 is -CN. [0069] In some embodiments of a compound of Formula (II), R8 is hydrogen or deuterium. In some embodiments of a compound of Formula (II), R8 is hydrogen. [0070] In some embodiments of a compound of Formula (II), R9 is C1-C6 alkyl or C2-C6 alkynyl. In some embodiments of a compound of Formula (II), R9 is C1-C6 alkyl. [0071] In some embodiments of a compound of Formula (II), R10 is C1-C6 alkyl or C2-C6 alkynyl. In some embodiments of a compound of Formula (II), R10 is C1-C6 alkyl. [0072] In some embodiments of a compound of Formula (II), R9 is C1-C6 alkyl and R10 is C2-C6 alkynyl. In some embodiments of a compound of Formula (II), R10 is C1-C6 alkyl and R9 is C2-C6 alkynyl. [0073] In some embodiments of a compound of Formula (II),
Figure imgf000027_0001
. In some embodiments of a compound of Formula (II),
Figure imgf000027_0002
. [0074] In some embodiments of a compound of Formula (II), R11 is hydrogen, halogen, or -OH. In some embodiments of a compound of Formula (II), R11 is hydrogen or -OH. In some embodiments of a compound of Formula (II), R11 is hydrogen. [0075] In some embodiments of a compound of Formula (II), R15 and R16 are independently hydrogen, C1-C6 alkyl, or C1-C6 deuteroalkyl. In some embodiments of a compound of Formula (II), R15 and R16 are independently hydrogen or C1-C6 alkyl. In some embodiments of a compound of Formula (II), R15 and R16 are independently hydrogen or C1-C6 deuteroalkyl. In some embodiments of a compound of Formula (II), R15 and R16 are independently C1-C6 alkyl. [0076] In some embodiments of a compound of Formula (II), R15 and R16 are taken together to form a cycloalkyl. In some embodiments of a compound of Formula (II), R15 and R16 are taken together to form a cycloalkyl substituted with 1-4 deuterium. In some embodiments of a compound of Formula (II), R15 and R16 are taken together to form a cycloalkyl substituted with 1 or 2 deuterium. In some embodiments of a compound of Formula (II), R15 and R16 are taken together to form a cycloalkyl substituted with 2-4 deuteriums. [0077] In some embodiments of a compound of Formula (II), R15 and R16 are taken together to form a heterocycloalkyl. In some embodiments of a compound of Formula (II), R15 and R16 are taken together to form a heterocycloalkyl substituted with 1-4 deuterium. In some embodiments of a compound of Formula (II), R15 and R16 are taken together to form a heterocycloalkyl substituted with 1 or 2 deuterium. In some embodiments of a compound of Formula (II), R15 and R16 are taken together to form a heterocycloalkyl substituted with 2-4 deuteriums. [0078] In some embodiments of a compound of Formula (II), R3 is halogen, -CN, -OR5, -NR6R7, - C(=O)R4, -OC(=O)R4, -C(=O)OR5, -C(=O)NR6R7, -OC(=O)NR6R7, -NR5C(=O)NR6R7, -NR5C(=O)OR5, -NR5S(=O)2R4, -NR5C(=O)R4, -NR5C(=NRx)R5, -NR5C(=NRx)NR6R7, -S(=O)(=NRx)R5, - S(=O)(=NRx)NR6R7, -NR5S(=O)2NR5C(=O)R5, -NR5S(=O)(=NRx)R5, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 heteroalkyl, or heteroaryl; wherein the alkyl, alkenyl, and heteroaryl are independently optionally substituted with one, two, or three R3a. In some embodiments of a compound of Formula (II), R3 is -NR5C(=NRx)R5 or -NR5C(=NRx)NR6R7. In some embodiments of a compound of Formula (II), R3 is -S(=O)(=NRx)R5, -S(=O)(=NRx)NR6R7, -NR5S(=O)2NR5C(=O)R5, or - NR5S(=O)(=NRx)R5. [0079] In some embodiments of a compound of Formula (II), R3 is C1-C6 alkyl optionally substituted with one, two, or three R3a. In some embodiments of a compound of Formula (II), R3 is C1-C6 alkyl. [0080] In some embodiments of a compound of Formula (II), R3 is -C(=O)OR5. [0081] In some embodiments of a compound of Formula (II), each R3a is independently deuterium, halogen, -CN, -OR5, -S(=O)R4, -S(=O)2R4, -OC(=O)R4, -C(=O)OR5, -OC(=O)OR5, -C(=O)NR6R7, - OC(=O)NR6R7, -P(=O)(R4)2, -P(=O)(OR5)2, -B(OR5)2, -NR5C(=NRx)R5, -NR5C(=NRx)NR6R7, - S(=O)(=NRx)R5, -S(=O)(=NRx)NR6R7, -NR5S(=O)2NR5C(=O)R5, -NR5S(=O)(=NRx)R5, cycloalkyl, or heterocycloalkyl. [0082] In some embodiments of a compound of Formula (II), each R3a is independently deuterium, halogen, -CN, -OR5, -S(=O)R4, -S(=O)2R4, -OC(=O)R4, -C(=O)OR5, -OC(=O)OR5, -C(=O)NR6R7, - OC(=O)NR6R7, -P(=O)(R4)2, -P(=O)(OR5)2, -B(OR5)2, -NR5C(=NRx)R5, -NR5C(=NRx)NR6R7, - S(=O)(=NRx)R5, -S(=O)(=NRx)NR6R7, -NR5S(=O)2NR5C(=O)R5, or -NR5S(=O)(=NRx)R5. In some embodiments of a compound of Formula (II), each R3a is independently deuterium, halogen, -CN, -OR5, - OC(=O)R4, -C(=O)OR5, -C(=O)NR6R7, -B(OR5)2, -S(=O)(=NRx)R5, C1-C6 heteroalkyl, heterocycloalkyl, or heteroaryl. In some embodiments of a compound of Formula (II), each R3a is independently - OC(=O)R4, -C(=O)OR5, -OC(=O)OR5, -C(=O)NR6R7, -P(=O)(R4)2, -P(=O)(OR5)2, -B(OR5)2, - NR5C(=NRx)R5, -NR5C(=NRx)NR6R7, -S(=O)(=NRx)R5, -S(=O)(=NRx)NR6R7, -NR5S(=O)2NR5C(=O)R5, or -NR5S(=O)(=NRx)R5.In some embodiments of a compound of Formula (II), each R3a is independently -OC(=O)R4, -C(=O)OR5, -OC(=O)OR5, or -C(=O)NR6R7. In some embodiments of a compound of Formula (II), each R3a is independently -P(=O)(R4)2, -P(=O)(OR5)2, or -B(OR5)2. In some embodiments of a compound of Formula (II), each R3a is independently -NR5C(=NRx)R5, -NR5C(=NRx)NR6R7, - S(=O)(=NRx)R5, -S(=O)(=NRx)NR6R7, -NR5S(=O)2NR5C(=O)R5, or -NR5S(=O)(=NRx)R5. [0083] In some embodiments of a compound of Formula (II), each R3b is independently deuterium, halogen, -CN, -ORb, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. In some embodiments of a compound of Formula (II), each R3b is independently deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. [0084] In some embodiments of a compound of Formula (II), each R4 is independently C1-C6 alkyl, C2- C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one, two, or three R4a. In some embodiments of a compound of Formula (II), each R4 is independently C1-C6 alkyl or cycloalkyl; wherein the alkyl and cycloalkyl are independently optionally substituted with one, two, or three R4a. In some embodiments of a compound of Formula (II), each R4 is independently C1-C6 alkyl optionally substituted with one, two, or three R4a. In some embodiments of a compound of Formula (II), each R4 is independently C1-C6 alkyl. In some embodiments of a compound of Formula (II), each R4 is independently C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. [0085] In some embodiments of a compound of Formula (II), each R4a is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (II), each R4a is independently deuterium or halogen. In some embodiments of a compound of Formula (II), each R4a is independently halogen. [0086] In some embodiments of a compound of Formula (II), each R5 is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one, two, or three R5a. In some embodiments of a compound of Formula (II), each R5 is independently hydrogen, C1-C6 alkyl, or cycloalkyl; wherein the alkyl and cycloalkyl are independently optionally substituted with one, two, or three R5a. In some embodiments of a compound of Formula (II), each R5 is independently hydrogen or C1-C6 alkyl optionally substituted with one, two, or three R5a. In some embodiments of a compound of Formula (II), each R5 is independently C1-C6 alkyl optionally substituted with one, two, or three R5a. In some embodiments of a compound of Formula (II), each R5 is hydrogen or C1-C6 alkyl. In some embodiments of a compound of Formula (II), each R5 is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. [0087] In some embodiments of a compound of Formula (II), two R5 are taken together to form an optionally substituted heterocycloalkyl. [0088] In some embodiments of a compound of Formula (II), each R5a is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (II), each R5a is independently deuterium or halogen. In some embodiments of a compound of Formula (II), each R5a is independently halogen. In some embodiments of a compound of Formula (II), each R5a is independently -NRbC(=NRx)Rb or -NRbC(=NRx)NRcRd. In some embodiments of a compound of Formula (II), each R5a is independently -S(=O)(=NRx)Rb or - S(=O)(=NRx)NRcRd. [0089] In some embodiments of a compound of Formula (II), each R6 and R7 is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one, two, or three R6a. In some embodiments of a compound of Formula (II), each R6 and R7 is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one, two, or three R6a. In some embodiments of a compound of Formula (II), each R6 and R7 is independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl; wherein the alkyl are independently optionally substituted with one, two, or three R6a. In some embodiments of a compound of Formula (II), each R6 and R7 is independently hydrogen or C1-C6 alkyl. In some embodiments of a compound of Formula (II), each R6 and R7 is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. [0090] In some embodiments of a compound of Formula (II), each R6a is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (II), each R6a is independently deuterium or halogen. In some embodiments of a compound of Formula (II), each R6a is independently halogen. In some embodiments of a compound of Formula (II), each R5a is independently -NRbC(=NRx)Rb or -NRbC(=NRx)NRcRd. In some embodiments of a compound of Formula (II), each R6a is independently -S(=O)(=NRx)Rb or - S(=O)(=NRx)NRcRd. [0091] In some embodiments of a compound of Formula (II), R6 and R7 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R6b. [0092] In some embodiments of a compound of Formula (II), each R6b is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (II), each R6b is independently C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of a compound of Formula (II), each R6b is independently C1-C6 alkyl. [0093] In some embodiments of a compound of Formula (II), Rx is hydrogen, -NO2, or -CN. In some embodiments of a compound of Formula (II), Rx is -NO2 or -CN. In some embodiments of a compound of Formula (II), Rx is -CN. [0094] In some embodiments of a compound of Formula (II), Ring B is a cycloalkyl. In some embodiments of a compound of Formula (II), Ring B is a heterocycloalkyl. [0095] In some embodiments of a compound of Formula (II), each R14 is independently deuterium, halogen, -CN, -ORb, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of a compound of Formula (II), each R14 is deuterium. [0096] In some embodiments of a compound of Formula (II), m is 0. In some embodiments of a compound of Formula (II), m is 1. In some embodiments of a compound of Formula (II), m is 2. In some embodiments of a compound of Formula (II), m is 3. In some embodiments of a compound of Formula (II), m is 4. In some embodiments of a compound of Formula (II), m is 5. In some embodiments of a compound of Formula (II), m is 6. In some embodiments of a compound of Formula (II), m is 1-4. In some embodiments of a compound of Formula (II), m is 1 or 2. In some embodiments of a compound of Formula (II), m is 2-4. [0097] Disclosed herein is a compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure imgf000031_0001
wherein: R1 is hydrogen, deuterium, halogen, -CN, -ORb, -NRcRd, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; R3 is N-linked heterocycloalkyl, a N-linked heteroaryl, -P(=O)(R4)2, -P(=O)(OR5)2, -B(OR5)2, -S(=O)R4, -S(=O)2R4, -NR5C(=NRx)R5, -NR5C(=NRx)NR6R7, -S(=O)(=NRx)R5, -S(=O)(=NRx)NR6R7, - NR5S(=O)2NR5C(=O)R5, -NR5S(=O)(=NRx)R5, -Z-O-cycloalkyl, -Z-O-heterocycloalkyl, -Z-O-aryl, - Z-O-heteroaryl, -Z-NR5-cycloalkyl, -Z-NR5-heterocycloalkyl, -Z-NR5-aryl, -Z-NR5-heteroaryl, - Y(C1-C6alkylene)S(=O)R4, -Y(C1-C6alkylene)S(=O)2R4, -Y(C1-C6alkylene)P(=O)(R4)2, -Y(C1- C6alkylene)P(=O)(OR5)2, -Y(C1-C6alkylene)B(OR5)2, -Y(C1-C6alkylene)NR5C(=NRx)R5, -Y(C1- C6alkylene)NR5C(=NRx)NR6R7, -Y(C1-C6alkylene)S(=O)(=NRx)R5, -Y(C1- C6alkylene)S(=O)(=NRx)NR6R7, -Y(C1-C6alkylene)NR5S(=O)2NR5C(=O)R5, -NR5C(=O)(C1- C6alkylene)S(=NRx)NR6R7, -NR5C(=O)(C1-C6alkylene)S(=NRx)R5, -Y(C1- C6alkylene)NR5S(=O)(=NRx)R5, -Y(C2-C6alkenylene)S(=O)2R4, -Y(C2-C6alkenylene)P(=O)(R4)2, - Y(C2-C6alkenylene)P(=O)(OR5)2, -Y(C2-C6alkenylene)B(OR5)2, -Y(C2- C6alkenylene)NR5C(=NRx)R5, -Y(C2-C6alkenylene)NR5C(=NRx)NR6R7, -Y(C2- C6alkenylene)S(=O)(=NRx)R5, -Y(C2-C6alkenylene)S(=O)(=NRx)NR6R7, -Y(C2- C6alkenylene)NR5S(=O)2NR5C(=O)R5, -Y(C2-C6alkenylene)NR5S(=O)(=NRx)R5, -Y(C2- C6alkenylene)cycloalkyl, -Y(C2-C6alkenylene)heterocycloalkyl, -Y(C2-C6alkenylene)aryl, -Y(C2- C6alkenylene)heteroaryl, -(C1-C6alkylene)OP(=O)(OR5)2, -(C1-C6alkylene)O(C1- C6alkylene)OP(=O)(OR5)2, or -(C1-C6alkylene)OP(=O)(OR5)[N(R5)2]; wherein the alkylene, alkenylene, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one, two, or three R3a; each R3a is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Y is a bond, -O-, -S-, or -NRb-; Z is a bond or C1-C6alkylene; Rx is hydrogen, -NO2, -CN, or -S(=O)2Ra; each R4 is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R4a; each R4a is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R5 is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R5a; or two R5 are taken together to form an optionally substituted heterocycloalkyl; each R5a is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R6 and R7 is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R6a; each R6a is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or R6 and R7 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R6b; each R6b is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
Figure imgf000033_0001
s o ; R8 is hydrogen, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl; R9 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl; R10 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl; R11 is hydrogen, deuterium, halogen, or -ORb; or R3 and R11 are taken together to form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl; R12 and R13 are independently hydrogen, -ORb, -NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; or R12 and R13 are taken together to form a cycloalkyl or a heterocycloalkyl; each substituted with 0-6 R14; each R14 is independently deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; R15 and R16 are independently hydrogen, -ORb, -NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; or R15 and R16 are taken together to form a cycloalkyl or a heterocycloalkyl; each substituted with 0-6 R2; each R2 is independently deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; each Ra is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three deuterium, halogen, -OH, -NH2, or C1-C6 alkyl; each Rb is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three halogen, -OH, -NH2, or C1-C6 alkyl; and each Rc and Rd is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three deuterium, halogen, -OH, -NH2, or C1-C6 alkyl; or Rc and Rd are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three deuterium, halogen, -OH, -NH2, or C1- C6 alkyl. [0098] In some embodiments of a compound of Formula (III), R1 is -CN, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. In some embodiments of a compound of Formula (III), R1 is -CN or C1-C6 haloalkyl. In some embodiments of a compound of Formula (III), R1 is C1-C6 haloalkyl. In some embodiments of a compound of Formula (III), R1 is -CN. [0099] In some embodiments of a compound of Formula (III), R8 is hydrogen or deuterium. In some embodiments of a compound of Formula (III), R8 is hydrogen. [00100] In some embodiments of a compound of Formula (III), R9 is C1-C6 alkyl or C2-C6 alkynyl. In some embodiments of a compound of Formula (III), R9 is C1-C6 alkyl. [00101] In some embodiments of a compound of Formula (III), R10 is C1-C6 alkyl or C2-C6 alkynyl. In some embodiments of a compound of Formula (III), R10 is C1-C6 alkyl. [00102] In some embodiments of a compound of Formula (III), R9 is C1-C6 alkyl and R10 is C2-C6 alkynyl. In some embodiments of a compound of Formula (III), R10 is C1-C6 alkyl and R9 is C2-C6 alkynyl. [00103] In some embodiments of a compound of Formula (III),
Figure imgf000034_0002
is . In some embodiments of a compound of Formula (III),
Figure imgf000034_0001
. [00104] In some embodiments of a compound of Formula (III), R11 is hydrogen, halogen, or -OH. In some embodiments of a compound of Formula (III), R11 is hydrogen or -OH. In some embodiments of a compound of Formula (III), R11 is hydrogen. [00105] In some embodiments of a compound of Formula (III), R12 and R13 are independently hydrogen, C1-C6 alkyl, or C1-C6 deuteroalkyl. In some embodiments of a compound of Formula (III), R12 and R13 are independently hydrogen or C1-C6 alkyl. In some embodiments of a compound of Formula (III), R12 and R13 are independently hydrogen or C1-C6 deuteroalkyl. In some embodiments of a compound of Formula (III), R12 and R13 are independently C1-C6 alkyl. [00106] In some embodiments of a compound of Formula (III), R12 and R13 are taken together to form a cycloalkyl. In some embodiments of a compound of Formula (III), R12 and R13 are taken together to form a cycloalkyl substituted with 1-4 deuterium. In some embodiments of a compound of Formula (III), R12 and R13 are taken together to form a cycloalkyl substituted with 1 or 2 deuterium. In some embodiments of a compound of Formula (III), R12 and R13 are taken together to form a cycloalkyl substituted with 2-4 deuteriums. [00107] In some embodiments of a compound of Formula (III), R12 and R13 are taken together to form a heterocycloalkyl. In some embodiments of a compound of Formula (III), R12 and R13 are taken together to form a heterocycloalkyl substituted with 1-4 deuterium. In some embodiments of a compound of Formula (III), R12 and R13 are taken together to form a heterocycloalkyl substituted with 1 or 2 deuterium. In some embodiments of a compound of Formula (III), R12 and R13 are taken together to form a heterocycloalkyl substituted with 2-4 deuteriums. [00108] In some embodiments of a compound of Formula (III), R15 and R16 are independently hydrogen, C1-C6 alkyl, or C1-C6 deuteroalkyl. In some embodiments of a compound of Formula (III), R15 and R16 are independently hydrogen or C1-C6 alkyl. In some embodiments of a compound of Formula (III), R15 and R16 are independently hydrogen or C1-C6 deuteroalkyl. In some embodiments of a compound of Formula (III), R15 and R16 are independently C1-C6 alkyl. [00109] In some embodiments of a compound of Formula (III), R15 and R16 are taken together to form a cycloalkyl. In some embodiments of a compound of Formula (III), R15 and R16 are taken together to form a cycloalkyl substituted with 1-4 deuterium. In some embodiments of a compound of Formula (III), R15 and R16 are taken together to form a cycloalkyl substituted with 1 or 2 deuterium. In some embodiments of a compound of Formula (III), R15 and R16 are taken together to form a cycloalkyl substituted with 2-4 deuteriums. [00110] In some embodiments of a compound of Formula (III), R15 and R16 are taken together to form a heterocycloalkyl. In some embodiments of a compound of Formula (III), R15 and R16 are taken together to form a heterocycloalkyl substituted with 1-4 deuterium. In some embodiments of a compound of Formula (III), R15 and R16 are taken together to form a heterocycloalkyl substituted with 1 or 2 deuterium. In some embodiments of a compound of Formula (III), R15 and R16 are taken together to form a heterocycloalkyl substituted with 2-4 deuteriums. [00111] In some embodiments of a compound of Formula (III), R3 is -P(=O)(R4)2, -P(=O)(OR5)2, - Y(C1-C6alkylene)P(=O)(R4)2, -Y(C1-C6alkylene)P(=O)(OR5)2, -B(OR5)2, -Y(C1-C6alkylene)B(OR5)2, - S(=O)R4, -S(=O)2R4, -Y(C1-C6alkylene)S(=O)R4, -Y(C1-C6alkylene)S(=O)2R4, -NR5C(=NRx)R5, - NR5C(=NRx)NR6R7, -Y(C1-C6alkylene)NR5C(=NRx)R5, -Y(C1-C6alkylene)NR5C(=NRx)NR6R7, - S(=O)(=NRx)R5, -S(=O)(=NRx)NR6R7, -NR5S(=O)2NR5C(=O)R5, -NR5S(=O)(=NRx)R5, -Y(C1- C6alkylene)S(=O)(=NRx)R5, -Y(C1-C6alkylene)S(=O)(=NRx)NR6R7, -Y(C1- C6alkylene)NR5S(=O)2NR5C(=O)R5, -Y(C1-C6alkylene)NR5S(=O)(=NRx)R5, N-linked heterocycloalkyl, or N-linked heteroaryl. In some embodiments of a compound of Formula (III), R3 is -P(=O)(R4)2, - P(=O)(OR5)2, -Y(C1-C6alkylene)P(=O)(R4)2, or -Y(C1-C6alkylene)P(=O)(OR5)2. In some embodiments of a compound of Formula (III), R3 is -B(OR5)2 or -Y(C1-C6alkylene)B(OR5)2. In some embodiments of a compound of Formula (III), R3 is -S(=O)R4, -S(=O)2R4, -Y(C1-C6alkylene)S(=O)R4, or -Y(C1- C6alkylene)S(=O)2R4. In some embodiments of a compound of Formula (III), R3 is -NR5C(=NRx)R5, - NR5C(=NRx)NR6R7, -Y(C1-C6alkylene)NR5C(=NRx)R5, or -Y(C1-C6alkylene)NR5C(=NRx)NR6R7. In some embodiments of a compound of Formula (III), R3 is -S(=O)(=NRx)R5, -S(=O)(=NRx)NR6R7, - NR5S(=O)2NR5C(=O)R5, -NR5S(=O)(=NRx)R5, -Y(C1-C6alkylene)S(=O)(=NRx)R5, -Y(C1- C6alkylene)S(=O)(=NRx)NR6R7, -Y(C1-C6alkylene)NR5S(=O)2NR5C(=O)R5, or -Y(C1- C6alkylene)NR5S(=O)(=NRx)R5. In some embodiments of a compound of Formula (III), R3 is N-linked heterocycloalkyl or N-linked heteroaryl. [00112] In some embodiments of a compound of Formula (III), R3 is -P(=O)(R4)2, -P(=O)(OR5)2, - Y(C1-C6alkylene)P(=O)(R4)2, -Y(C1-C6alkylene)P(=O)(OR5)2, -B(OR5)2, -Y(C1-C6alkylene)B(OR5)2, - S(=O)R4, -S(=O)2R4, -Y(C1-C6alkylene)S(=O)R4, -Y(C1-C6alkylene)S(=O)2R4, -NR5C(=NRx)R5, - NR5C(=NRx)NR6R7, -Y(C1-C6alkylene)NR5C(=NRx)R5, -Y(C1-C6alkylene)NR5C(=NRx)NR6R7, - NR5C(=O)(C1-C6alkylene)S(=NRx)NR6R7, -NR5C(=O)(C1-C6alkylene)S(=NRx)R5, -S(=O)(=NRx)R5, - S(=O)(=NRx)NR6R7, -NR5S(=O)2NR5C(=O)R5, -NR5S(=O)(=NRx)R5, -Y(C1- C6alkylene)S(=O)(=NRx)R5, -Y(C1-C6alkylene)S(=O)(=NRx)NR6R7, -Y(C1- C6alkylene)NR5S(=O)2NR5C(=O)R5, -Y(C1-C6alkylene)NR5S(=O)(=NRx)R5, a N-linked heterocycloalkyl, or a N-linked heteroaryl. [00113] In some embodiments of a compound of Formula (III), R3 is -Y(C1-C6alkylene)NR5C(=NRx)R5 or -Y(C1-C6alkylene)NR5C(=NRx)NR6R7. [00114] In some embodiments of a compound of Formula (III), -Y is a bond. In some embodiments of a compound of Formula (III), Y is a bond or -O-. [00115] In some embodiments of a compound of Formula (III), each R4 is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one, two, or three R4a. In some embodiments of a compound of Formula (III), each R4 is independently C1-C6 alkyl or cycloalkyl; wherein the alkyl and cycloalkyl are independently optionally substituted with one, two, or three R4a. In some embodiments of a compound of Formula (III), each R4 is independently C1-C6 alkyl optionally substituted with one, two, or three R4a. In some embodiments of a compound of Formula (III), each R4 is independently C1-C6 alkyl. In some embodiments of a compound of Formula (III), each R4 is independently C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. [00116] In some embodiments of a compound of Formula (III), each R4a is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (III), each R4a is independently deuterium or halogen. In some embodiments of a compound of Formula (III), each R4a is independently halogen. [00117] In some embodiments of a compound of Formula (III), each R5 is independently hydrogen, C1- C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one, two, or three R5a. In some embodiments of a compound of Formula (III), each R5 is independently hydrogen, C1-C6 alkyl, or cycloalkyl; wherein the alkyl and cycloalkyl are independently optionally substituted with one, two, or three R5a. In some embodiments of a compound of Formula (III), each R5 is independently hydrogen or C1-C6 alkyl optionally substituted with one, two, or three R5a. In some embodiments of a compound of Formula (III), each R5 is independently C1-C6 alkyl optionally substituted with one, two, or three R5a. In some embodiments of a compound of Formula (III), each R5 is hydrogen or C1-C6 alkyl. In some embodiments of a compound of Formula (III), each R5 is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. [00118] In some embodiments of a compound of Formula (III), two R5 are taken together to form an optionally substituted heterocycloalkyl. [00119] In some embodiments of a compound of Formula (III), each R5a is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, or C1-C6 alkyl. In some embodiments of a compound of Formula (III), each R5a is independently halogen, -CN, -ORb, -NRcRd, - C(=O)ORb, or C1-C6 alkyl. [00120] In some embodiments of a compound of Formula (III), each R5a is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (III), each R5a is independently deuterium or halogen. In some embodiments of a compound of Formula (III), each R5a is independently halogen. [00121] In some embodiments of a compound of Formula (III), each R6 and R7 is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one, two, or three R6a. In some embodiments of a compound of Formula (III), each R6 and R7 is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one, two, or three R6a. In some embodiments of a compound of Formula (III), each R6 and R7 is independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl; wherein the alkyl are independently optionally substituted with one, two, or three R6a. In some embodiments of a compound of Formula (III), each R6 and R7 is independently hydrogen or C1-C6 alkyl. In some embodiments of a compound of Formula (III), each R6 and R7 is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. [00122] In some embodiments of a compound of Formula (III), each R6a is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (III), each R6a is independently deuterium or halogen. In some embodiments of a compound of Formula (III), each R6a is independently halogen. In some embodiments of a compound of Formula (III), each R5a is independently -NRbC(=NRx)Rb or - NRbC(=NRx)NRcRd. In some embodiments of a compound of Formula (III), each R6a is independently - S(=O)(=NRx)Rb or -S(=O)(=NRx)NRcRd. [00123] In some embodiments of a compound of Formula (III), R6 and R7 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R6b. [00124] In some embodiments of a compound of Formula (III), each R6b is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (III), each R6b is independently C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of a compound of Formula (III), each R6b is independently C1-C6 alkyl. [00125] In some embodiments of a compound of Formula (III), Rx is hydrogen, -NO2, or -CN. In some embodiments of a compound of Formula (III), Rx is -NO2 or -CN. In some embodiments of a compound of Formula (III), Rx is -CN. In some embodiments of a compound of Formula (III), R3 is
Figure imgf000038_0001
Figure imgf000038_0002
[00126] In some embodiments of a compound of Formula (III), R3 is
Figure imgf000039_0002
or
Figure imgf000039_0001
. [00127] Disclosed herein is a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure imgf000039_0003
wherein: R1 is hydrogen, deuterium, halogen, -CN, -ORb, -NRcRd, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; R3 is halogen, -CN, -OR5, -SR5, -S(=O)R4, -S(=O)2R4, -NO2, -NR6R7, -S(=O)2NR6R7, -C(=O)R4, - OC(=O)R4, -C(=O)OR5, -OC(=O)OR5, -C(=O)NR6R7, -OC(=O)NR6R7, -NR5C(=O)NR6R7, - NR5C(=O)OR5, -NR5S(=O)2NR6R7, -NR5S(=O)2R4, -NR5C(=O)R4, -P(=O)(R4)2, -P(=O)(OR5)2, - B(OR5)2, -NR5C(=NRx)R5, -NR5C(=NRx)NR6R7, -S(=O)(=NRx)R5, -S(=O)(=NRx)NR6R7, - NR5S(=O)2NR5C(=O)R5, -NR5S(=O)(=NRx)R5, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R3a; each R3a is independently oxo, deuterium, halogen, -CN, -OR5, -SR5, -S(=O)R4, -S(=O)2R4, -NO2, - NR6R7, -S(=O)2NR6R7, -C(=O)R4, -OC(=O)R4, -C(=O)OR5, -OC(=O)OR5, -C(=O)NR6R7, - OC(=O)NR6R7, -NR5C(=O)NR6R7, -NR5C(=O)OR5, -NR5S(=O)2NR6R7, -NR5S(=O)2R4, - NR5C(=O)R4, -P(=O)(R4)2, -P(=O)(OR5)2, -B(OR5)2, -NR5C(=NRx)R5, -NR5C(=NRx)NR6R7, - S(=O)(=NRx)R5, -S(=O)(=NRx)NR6R7, -NR5S(=O)2NR5C(=O)R5, -NR5S(=O)(=NRx)R5, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R3b; each R3b is independently deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Rx is hydrogen, -NO2, -CN, or -S(=O)2Ra; each R4 is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R4a; each R4a is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, -NRbC(=NRx)Rb, -NRbC(=NRx)NRcRd, -S(=O)(=NRx)Rb, -S(=O)(=NRx)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R5 is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R5a; or two R5 are taken together to form an optionally substituted heterocycloalkyl; each R5a is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, -NRbC(=NRx)Rb, -NRbC(=NRx)NRcRd, -S(=O)(=NRx)Rb, -S(=O)(=NRx)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R6 and R7 is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R6a; each R6a is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, -NRbC(=NRx)Rb, -NRbC(=NRx)NRcRd, -S(=O)(=NRx)Rb, -S(=O)(=NRx)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or R6 and R7 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R6b; each R6b is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
Figure imgf000040_0001
R8 is hydrogen, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl; R9 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl; R10 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl; provided that one of R9 or R10 is C2-C6 alkynyl; R11 is hydrogen, deuterium, halogen, or -ORb; or R3 and R11 are taken together to form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl; R12 and R13 are independently hydrogen, -ORb, -NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; or R12 and R13 are taken together to form a cycloalkyl or a heterocycloalkyl; each substituted with 0-6 R14; each R14 is independently deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; R15 and R16 are independently hydrogen, -ORb, -NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, or C1-C6 hydroxyalkyl; or R15 and R16 are taken together to form a cycloalkyl or a heterocycloalkyl; each substituted with 0-6 R2; each R2 is independently deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; each Ra is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three deuterium, halogen, -OH, -NH2, or C1-C6 alkyl; each Rb is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three halogen, -OH, -NH2, or C1-C6 alkyl; and each Rc and Rd is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three deuterium, halogen, -OH, -NH2, or C1-C6 alkyl; or Rc and Rd are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three deuterium, halogen, -OH, -NH2, or C1- C6 alkyl. [00128] In some embodiments of a compound of Formula (IV), R1 is -CN, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. In some embodiments of a compound of Formula (IV), R1 is -CN or C1-C6 haloalkyl. In some embodiments of a compound of Formula (IV), R1 is C1-C6 haloalkyl. In some embodiments of a compound of Formula (IV), R1 is -CN. [00129] In some embodiments of a compound of Formula (IV), R8 is hydrogen or deuterium. In some embodiments of a compound of Formula (IV), R8 is hydrogen. [00130] In some embodiments of a compound of Formula (IV), R9 is C1-C6 alkyl or C2-C6 alkynyl. In some embodiments of a compound of Formula (IV), R9 is C2-C6 alkynyl. In some embodiments of a compound of Formula (IV), R9 is C1-C6 alkyl. [00131] In some embodiments of a compound of Formula (IV), R10 is C1-C6 alkyl or C2-C6 alkynyl. In some embodiments of a compound of Formula (IV), R10 is C2-C6 alkynyl. In some embodiments of a compound of Formula (IV), R10 is C1-C6 alkyl. [00132] In some embodiments of a compound of Formula (IV), R9 is C1-C6 alkyl and R10 is C2-C6 alkynyl. In some embodiments of a compound of Formula (IV), R10 is C1-C6 alkyl and R9 is C2-C6 alkynyl. [00133] In some embodiments of a compound of Formula (IV),
Figure imgf000042_0001
. In some embodiments of a compound of Formula (IV),
Figure imgf000042_0002
. [00134] In some embodiments of a compound of Formula (IV), R11 is hydrogen, halogen, or -OH. In some embodiments of a compound of Formula (IV), R11 is hydrogen or -OH. In some embodiments of a compound of Formula (IV), R11 is hydrogen. [00135] In some embodiments of a compound of Formula (IV), R12 and R13 are independently hydrogen, C1-C6 alkyl, or C1-C6 deuteroalkyl. In some embodiments of a compound of Formula (IV), R12 and R13 are independently hydrogen or C1-C6 alkyl. In some embodiments of a compound of Formula (IV), R12 and R13 are independently hydrogen or C1-C6 deuteroalkyl. In some embodiments of a compound of Formula (IV), R12 and R13 are independently C1-C6 alkyl. [00136] In some embodiments of a compound of Formula (IV), R12 and R13 are taken together to form a cycloalkyl. In some embodiments of a compound of Formula (IV), R12 and R13 are taken together to form a cycloalkyl substituted with 1-4 deuterium. In some embodiments of a compound of Formula (IV), R12 and R13 are taken together to form a cycloalkyl substituted with 1 or 2 deuterium. In some embodiments of a compound of Formula (IV), R12 and R13 are taken together to form a cycloalkyl substituted with 2-4 deuteriums. [00137] In some embodiments of a compound of Formula (IV), R12 and R13 are taken together to form a heterocycloalkyl. In some embodiments of a compound of Formula (IV), R12 and R13 are taken together to form a heterocycloalkyl substituted with 1-4 deuterium. In some embodiments of a compound of Formula (IV), R12 and R13 are taken together to form a heterocycloalkyl substituted with 1 or 2 deuterium. In some embodiments of a compound of Formula (IV), R12 and R13 are taken together to form a heterocycloalkyl substituted with 2-4 deuteriums. [00138] In some embodiments of a compound of Formula (IV), R15 and R16 are independently hydrogen, C1-C6 alkyl, or C1-C6 deuteroalkyl. In some embodiments of a compound of Formula (IV), R15 and R16 are independently hydrogen or C1-C6 alkyl. In some embodiments of a compound of Formula (IV), R15 and R16 are independently hydrogen or C1-C6 deuteroalkyl. In some embodiments of a compound of Formula (IV), R15 and R16 are independently C1-C6 alkyl. [00139] In some embodiments of a compound of Formula (IV), R15 and R16 are taken together to form a cycloalkyl. In some embodiments of a compound of Formula (IV), R15 and R16 are taken together to form a cycloalkyl substituted with 1-4 deuterium. In some embodiments of a compound of Formula (IV), R15 and R16 are taken together to form a cycloalkyl substituted with 1 or 2 deuterium. In some embodiments of a compound of Formula (IV), R15 and R16 are taken together to form a cycloalkyl substituted with 2-4 deuteriums. [00140] In some embodiments of a compound of Formula (IV), R15 and R16 are taken together to form a heterocycloalkyl. In some embodiments of a compound of Formula (IV), R15 and R16 are taken together to form a heterocycloalkyl substituted with 1-4 deuterium. In some embodiments of a compound of Formula (IV), R15 and R16 are taken together to form a heterocycloalkyl substituted with 1 or 2 deuterium. In some embodiments of a compound of Formula (IV), R15 and R16 are taken together to form a heterocycloalkyl substituted with 2-4 deuteriums. [00141] In some embodiments of a compound of Formula (IV), R3 is halogen, -CN, -OR5, -NR6R7, - C(=O)R4, -OC(=O)R4, -C(=O)OR5, -C(=O)NR6R7, -OC(=O)NR6R7, -NR5C(=O)NR6R7, -NR5C(=O)OR5, -NR5S(=O)2R4, -NR5C(=O)R4, -NR5C(=NRx)R5, -NR5C(=NRx)NR6R7, -S(=O)(=NRx)R5, - S(=O)(=NRx)NR6R7, -NR5S(=O)2NR5C(=O)R5, -NR5S(=O)(=NRx)R5, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 heteroalkyl, or heteroaryl; wherein the alkyl, alkenyl, and heteroaryl are independently optionally substituted with one, two, or three R3a. In some embodiments of a compound of Formula (IV), R3 is -NR5C(=NRx)R5 or -NR5C(=NRx)NR6R7. In some embodiments of a compound of Formula (IV), R3 is -S(=O)(=NRx)R5, -S(=O)(=NRx)NR6R7, -NR5S(=O)2NR5C(=O)R5, or - NR5S(=O)(=NRx)R5. [00142] In some embodiments of a compound of Formula (IV), R3 is C1-C6 alkyl optionally substituted with one, two, or three R3a. In some embodiments of a compound of Formula (IV), R3 is C1-C6 alkyl. [00143] In some embodiments of a compound of Formula (IV), R3 is -C(=O)OR5. [00144] In some embodiments of a compound of Formula (IV), each R3a is independently deuterium, halogen, -CN, -OR5, -S(=O)R4, -S(=O)2R4, -OC(=O)R4, -C(=O)OR5, -OC(=O)OR5, -C(=O)NR6R7, - OC(=O)NR6R7, -P(=O)(R4)2, -P(=O)(OR5)2, -B(OR5)2, -NR5C(=NRx)R5, -NR5C(=NRx)NR6R7, - S(=O)(=NRx)R5, -S(=O)(=NRx)NR6R7, -NR5S(=O)2NR5C(=O)R5, -NR5S(=O)(=NRx)R5, cycloalkyl, or heterocycloalkyl. [00145] In some embodiments of a compound of Formula (IV), each R3a is independently deuterium, halogen, -CN, -OR5, -S(=O)R4, -S(=O)2R4, -OC(=O)R4, -C(=O)OR5, -OC(=O)OR5, -C(=O)NR6R7, - OC(=O)NR6R7, -P(=O)(R4)2, -P(=O)(OR5)2, -B(OR5)2, -NR5C(=NRx)R5, -NR5C(=NRx)NR6R7, - S(=O)(=NRx)R5, -S(=O)(=NRx)NR6R7, -NR5S(=O)2NR5C(=O)R5, or -NR5S(=O)(=NRx)R5. In some embodiments of a compound of Formula (IV), each R3a is independently deuterium, halogen, -CN, -OR5, -OC(=O)R4, -C(=O)OR5, -C(=O)NR6R7, -B(OR5)2, -S(=O)(=NRx)R5, C1-C6 heteroalkyl, heterocycloalkyl, or heteroaryl. In some embodiments of a compound of Formula (IV), each R3a is independently -OC(=O)R4, -C(=O)OR5, -OC(=O)OR5, -C(=O)NR6R7, -P(=O)(R4)2, -P(=O)(OR5)2, - B(OR5)2, -NR5C(=NRx)R5, -NR5C(=NRx)NR6R7, -S(=O)(=NRx)R5, -S(=O)(=NRx)NR6R7, - NR5S(=O)2NR5C(=O)R5, or -NR5S(=O)(=NRx)R5.In some embodiments of a compound of Formula (IV), each R3a is independently -OC(=O)R4, -C(=O)OR5, -OC(=O)OR5, or -C(=O)NR6R7. In some embodiments of a compound of Formula (IV), each R3a is independently -P(=O)(R4)2, -P(=O)(OR5)2, or - B(OR5)2. In some embodiments of a compound of Formula (IV), each R3a is independently - NR5C(=NRx)R5, -NR5C(=NRx)NR6R7, -S(=O)(=NRx)R5, -S(=O)(=NRx)NR6R7, -NR5S(=O)2NR5C(=O)R5, or -NR5S(=O)(=NRx)R5. [00146] In some embodiments of a compound of Formula (IV), each R3b is independently deuterium, halogen, -CN, -ORb, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. In some embodiments of a compound of Formula (IV), each R3b is independently deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. [00147] In some embodiments of a compound of Formula (IV), each R4 is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one, two, or three R4a. In some embodiments of a compound of Formula (IV), each R4 is independently C1-C6 alkyl or cycloalkyl; wherein the alkyl and cycloalkyl are independently optionally substituted with one, two, or three R4a. In some embodiments of a compound of Formula (IV), each R4 is independently C1-C6 alkyl optionally substituted with one, two, or three R4a. In some embodiments of a compound of Formula (IV), each R4 is independently C1-C6 alkyl. In some embodiments of a compound of Formula (IV), each R4 is independently C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. [00148] In some embodiments of a compound of Formula (IV), each R4a is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (IV), each R4a is independently deuterium or halogen. In some embodiments of a compound of Formula (IV), each R4a is independently halogen. [00149] In some embodiments of a compound of Formula (IV), each R5 is independently hydrogen, C1- C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one, two, or three R5a. In some embodiments of a compound of Formula (IV), each R5 is independently hydrogen, C1-C6 alkyl, or cycloalkyl; wherein the alkyl and cycloalkyl are independently optionally substituted with one, two, or three R5a. In some embodiments of a compound of Formula (IV), each R5 is independently hydrogen or C1-C6 alkyl optionally substituted with one, two, or three R5a. In some embodiments of a compound of Formula (IV), each R5 is independently C1-C6 alkyl optionally substituted with one, two, or three R5a. In some embodiments of a compound of Formula (IV), each R5 is hydrogen or C1-C6 alkyl. In some embodiments of a compound of Formula (IV), each R5 is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. [00150] In some embodiments of a compound of Formula (IV), two R5 are taken together to form an optionally substituted heterocycloalkyl. [00151] In some embodiments of a compound of Formula (IV), each R5a is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (IV), each R5a is independently deuterium or halogen. In some embodiments of a compound of Formula (IV), each R5a is independently halogen. In some embodiments of a compound of Formula (IV), each R5a is independently -NRbC(=NRx)Rb or - NRbC(=NRx)NRcRd. In some embodiments of a compound of Formula (IV), each R5a is independently - S(=O)(=NRx)Rb or -S(=O)(=NRx)NRcRd. [00152] In some embodiments of a compound of Formula (IV), each R6 and R7 is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one, two, or three R6a. In some embodiments of a compound of Formula (IV), each R6 and R7 is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one, two, or three R6a. In some embodiments of a compound of Formula (IV), each R6 and R7 is independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl; wherein the alkyl are independently optionally substituted with one, two, or three R6a. In some embodiments of a compound of Formula (IV), each R6 and R7 is independently hydrogen or C1-C6 alkyl. In some embodiments of a compound of Formula (IV), each R6 and R7 is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. [00153] In some embodiments of a compound of Formula (IV), each R6a is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (IV), each R6a is independently deuterium or halogen. In some embodiments of a compound of Formula (IV), each R6a is independently halogen. In some embodiments of a compound of Formula (IV), each R5a is independently -NRbC(=NRx)Rb or - NRbC(=NRx)NRcRd. In some embodiments of a compound of Formula (IV), each R6a is independently - S(=O)(=NRx)Rb or -S(=O)(=NRx)NRcRd. [00154] In some embodiments of a compound of Formula (IV), R6 and R7 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R6b. [00155] In some embodiments of a compound of Formula (IV), each R6b is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (IV), each R6b is independently C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of a compound of Formula (IV), each R6b is independently C1-C6 alkyl. [00156] In some embodiments of a compound of Formula (IV), Rx is hydrogen, -NO2, or -CN. In some embodiments of a compound of Formula (IV), Rx is -NO2 or -CN. In some embodiments of a compound of Formula (IV), Rx is -CN. [00157] Disclosed herein is a compound of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure imgf000046_0001
wherein: R1 is hydrogen, deuterium, halogen, -CN, -ORb, -NRcRd, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; R3 is halogen, -CN, -OR5, -SR5, -S(=O)R4, -S(=O)2R4, -NO2, -NR6R7, -S(=O)2NR6R7, -C(=O)R4, - OC(=O)R4, -C(=O)OR5, -OC(=O)OR5, -C(=O)NR6R7, -OC(=O)NR6R7, -NR5C(=O)NR6R7, - NR5C(=O)OR5, -NR5S(=O)2NR6R7, -NR5S(=O)2R4, -NR5C(=O)R4, -P(=O)(R4)2, -P(=O)(OR5)2, - B(OR5)2, -NR5C(=NRx)R5, -NR5C(=NRx)NR6R7, -S(=O)(=NRx)R5, -S(=O)(=NRx)NR6R7, - NR5S(=O)2NR5C(=O)R5, -NR5S(=O)(=NRx)R5, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R3a; each R3a is independently oxo, deuterium, halogen, -CN, -OR5, -SR5, -S(=O)R4, -S(=O)2R4, -NO2, - NR6R7, -S(=O)2NR6R7, -C(=O)R4, -OC(=O)R4, -C(=O)OR5, -OC(=O)OR5, -C(=O)NR6R7, - OC(=O)NR6R7, -NR5C(=O)NR6R7, -NR5C(=O)OR5, -NR5S(=O)2NR6R7, -NR5S(=O)2R4, - NR5C(=O)R4, -P(=O)(R4)2, -P(=O)(OR5)2, -B(OR5)2, -NR5C(=NRx)R5, -NR5C(=NRx)NR6R7, - S(=O)(=NRx)R5, -S(=O)(=NRx)NR6R7, -NR5S(=O)2NR5C(=O)R5, -NR5S(=O)(=NRx)R5, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R3b; each R3b is independently deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Rx is hydrogen, -NO2, -CN, or -S(=O)2Ra; each R4 is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R4a; each R4a is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, -NRbC(=NRx)Rb, -NRbC(=NRx)NRcRd, -S(=O)(=NRx)Rb, -S(=O)(=NRx)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R5 is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R5a; or two R5 are taken together to form an optionally substituted heterocycloalkyl; each R5a is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, -NRbC(=NRx)Rb, -NRbC(=NRx)NRcRd, -S(=O)(=NRx)Rb, -S(=O)(=NRx)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R6 and R7 is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R6a; each R6a is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, -NRbC(=NRx)Rb, -NRbC(=NRx)NRcRd, -S(=O)(=NRx)Rb, -S(=O)(=NRx)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or R6 and R7 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R6b; each R6b is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
Figure imgf000047_0001
R8 is hydrogen, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl; R9 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl; R10 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl; R11 is hydrogen, deuterium, halogen, or -ORb; or R3 and R11 are taken together to form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl; R12 and R13 are independently hydrogen, -ORb, -NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; or R12 and R13 are taken together to form a cycloalkyl or a heterocycloalkyl; each substituted with 0-6 R14; each R14 is independently deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; R17 is hydrogen, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; each Ra is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three deuterium, halogen, -OH, -NH2, or C1-C6 alkyl; each Rb is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three halogen, -OH, -NH2, or C1-C6 alkyl; and each Rc and Rd is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three deuterium, halogen, -OH, -NH2, or C1-C6 alkyl; or Rc and Rd are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three deuterium, halogen, -OH, -NH2, or C1- C6 alkyl. [00158] In some embodiments of a compound of Formula (V), R1 is -CN, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. In some embodiments of a compound of Formula (V), R1 is -CN or C1-C6 haloalkyl. In some embodiments of a compound of Formula (V), R1 is C1-C6 haloalkyl. In some embodiments of a compound of Formula (V), R1 is -CN. [00159] In some embodiments of a compound of Formula (V), R8 is hydrogen or deuterium. In some embodiments of a compound of Formula (V), R8 is hydrogen. [00160] In some embodiments of a compound of Formula (V), R9 is C1-C6 alkyl or C2-C6 alkynyl. In some embodiments of a compound of Formula (V), R9 is C2-C6 alkynyl. In some embodiments of a compound of Formula (V), R9 is C1-C6 alkyl. [00161] In some embodiments of a compound of Formula (V), R10 is C1-C6 alkyl or C2-C6 alkynyl. In some embodiments of a compound of Formula (V), R10 is C2-C6 alkynyl. In some embodiments of a compound of Formula (V), R10 is C1-C6 alkyl. [00162] In some embodiments of a compound of Formula (V), R9 is C1-C6 alkyl and R10 is C2-C6 alkynyl. In some embodiments of a compound of Formula (V), R10 is C1-C6 alkyl and R9 is C2-C6 alkynyl. [00163] In some embodiments of a compound of Formula (V),
Figure imgf000049_0001
. In some embodiments of a compound of Formula (V),
Figure imgf000049_0002
. [00164] In some embodiments of a compound of Formula (V), R11 is hydrogen, halogen, or -OH. In some embodiments of a compound of Formula (V), R11 is hydrogen or -OH. In some embodiments of a compound of Formula (V), R11 is hydrogen. [00165] In some embodiments of a compound of Formula (V), R12 and R13 are independently hydrogen, C1-C6 alkyl, or C1-C6 deuteroalkyl. In some embodiments of a compound of Formula (V), R12 and R13 are independently hydrogen or C1-C6 alkyl. In some embodiments of a compound of Formula (V), R12 and R13 are independently hydrogen or C1-C6 deuteroalkyl. In some embodiments of a compound of Formula (V), R12 and R13 are independently C1-C6 alkyl. [00166] In some embodiments of a compound of Formula (V), R12 and R13 are taken together to form a cycloalkyl. In some embodiments of a compound of Formula (V), R12 and R13 are taken together to form a cycloalkyl substituted with 1-4 deuterium. In some embodiments of a compound of Formula (V), R12 and R13 are taken together to form a cycloalkyl substituted with 1 or 2 deuterium. In some embodiments of a compound of Formula (V), R12 and R13 are taken together to form a cycloalkyl substituted with 2-4 deuteriums. [00167] In some embodiments of a compound of Formula (V), R12 and R13 are taken together to form a heterocycloalkyl. In some embodiments of a compound of Formula (V), R12 and R13 are taken together to form a heterocycloalkyl substituted with 1-4 deuterium. In some embodiments of a compound of Formula (V), R12 and R13 are taken together to form a heterocycloalkyl substituted with 1 or 2 deuterium. In some embodiments of a compound of Formula (V), R12 and R13 are taken together to form a heterocycloalkyl substituted with 2-4 deuteriums. [00168] In some embodiments of a compound of Formula (V), R17 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. In some embodiments of a compound of Formula (V), R17 is C1-C6 alkyl. [00169] In some embodiments of a compound of Formula (V), R3 is halogen, -CN, -OR5, -NR6R7, - C(=O)R4, -OC(=O)R4, -C(=O)OR5, -C(=O)NR6R7, -OC(=O)NR6R7, -NR5C(=O)NR6R7, -NR5C(=O)OR5, -NR5S(=O)2R4, -NR5C(=O)R4, -NR5C(=NRx)R5, -NR5C(=NRx)NR6R7, -S(=O)(=NRx)R5, - S(=O)(=NRx)NR6R7, -NR5S(=O)2NR5C(=O)R5, -NR5S(=O)(=NRx)R5, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 heteroalkyl, or heteroaryl; wherein the alkyl, alkenyl, and heteroaryl are independently optionally substituted with one, two, or three R3a. In some embodiments of a compound of Formula (V), R3 is -NR5C(=NRx)R5 or -NR5C(=NRx)NR6R7. In some embodiments of a compound of Formula (V), R3 is -S(=O)(=NRx)R5, -S(=O)(=NRx)NR6R7, -NR5S(=O)2NR5C(=O)R5, or - NR5S(=O)(=NRx)R5. [00170] In some embodiments of a compound of Formula (V), R3 is C1-C6 alkyl optionally substituted with one, two, or three R3a. In some embodiments of a compound of Formula (V), R3 is C1-C6 alkyl. [00171] In some embodiments of a compound of Formula (V), R3 is -C(=O)OR5. [00172] In some embodiments of a compound of Formula (V), each R3a is independently deuterium, halogen, -CN, -OR5, -S(=O)R4, -S(=O)2R4, -OC(=O)R4, -C(=O)OR5, -OC(=O)OR5, -C(=O)NR6R7, - OC(=O)NR6R7, -P(=O)(R4)2, -P(=O)(OR5)2, -B(OR5)2, -NR5C(=NRx)R5, -NR5C(=NRx)NR6R7, - S(=O)(=NRx)R5, -S(=O)(=NRx)NR6R7, -NR5S(=O)2NR5C(=O)R5, -NR5S(=O)(=NRx)R5, cycloalkyl, or heterocycloalkyl. [00173] In some embodiments of a compound of Formula (V), each R3a is independently deuterium, halogen, -CN, -OR5, -S(=O)R4, -S(=O)2R4, -OC(=O)R4, -C(=O)OR5, -OC(=O)OR5, -C(=O)NR6R7, - OC(=O)NR6R7, -P(=O)(R4)2, -P(=O)(OR5)2, -B(OR5)2, -NR5C(=NRx)R5, -NR5C(=NRx)NR6R7, - S(=O)(=NRx)R5, -S(=O)(=NRx)NR6R7, -NR5S(=O)2NR5C(=O)R5, or -NR5S(=O)(=NRx)R5. In some embodiments of a compound of Formula (V), each R3a is independently deuterium, halogen, -CN, -OR5, - OC(=O)R4, -C(=O)OR5, -C(=O)NR6R7, -B(OR5)2, -S(=O)(=NRx)R5, C1-C6 heteroalkyl, heterocycloalkyl, or heteroaryl. In some embodiments of a compound of Formula (V), each R3a is independently - OC(=O)R4, -C(=O)OR5, -OC(=O)OR5, -C(=O)NR6R7, -P(=O)(R4)2, -P(=O)(OR5)2, -B(OR5)2, - NR5C(=NRx)R5, -NR5C(=NRx)NR6R7, -S(=O)(=NRx)R5, -S(=O)(=NRx)NR6R7, -NR5S(=O)2NR5C(=O)R5, or -NR5S(=O)(=NRx)R5.In some embodiments of a compound of Formula (V), each R3a is independently -OC(=O)R4, -C(=O)OR5, -OC(=O)OR5, or -C(=O)NR6R7. In some embodiments of a compound of Formula (V), each R3a is independently -P(=O)(R4)2, -P(=O)(OR5)2, or -B(OR5)2. In some embodiments of a compound of Formula (V), each R3a is independently -NR5C(=NRx)R5, -NR5C(=NRx)NR6R7, - S(=O)(=NRx)R5, -S(=O)(=NRx)NR6R7, -NR5S(=O)2NR5C(=O)R5, or -NR5S(=O)(=NRx)R5. [00174] In some embodiments of a compound of Formula (V), each R3b is independently deuterium, halogen, -CN, -ORb, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. In some embodiments of a compound of Formula (V), each R3b is independently deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. [00175] In some embodiments of a compound of Formula (V), each R4 is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one, two, or three R4a. In some embodiments of a compound of Formula (V), each R4 is independently C1-C6 alkyl or cycloalkyl; wherein the alkyl and cycloalkyl are independently optionally substituted with one, two, or three R4a. In some embodiments of a compound of Formula (V), each R4 is independently C1-C6 alkyl optionally substituted with one, two, or three R4a. In some embodiments of a compound of Formula (V), each R4 is independently C1-C6 alkyl. In some embodiments of a compound of Formula (V), each R4 is independently C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. [00176] In some embodiments of a compound of Formula (V), each R4a is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (V), each R4a is independently deuterium or halogen. In some embodiments of a compound of Formula (V), each R4a is independently halogen. [00177] In some embodiments of a compound of Formula (V), each R5 is independently hydrogen, C1- C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one, two, or three R5a. In some embodiments of a compound of Formula (V), each R5 is independently hydrogen, C1-C6 alkyl, or cycloalkyl; wherein the alkyl and cycloalkyl are independently optionally substituted with one, two, or three R5a. In some embodiments of a compound of Formula (V), each R5 is independently hydrogen or C1-C6 alkyl optionally substituted with one, two, or three R5a. In some embodiments of a compound of Formula (V), each R5 is independently C1-C6 alkyl optionally substituted with one, two, or three R5a. In some embodiments of a compound of Formula (V), each R5 is hydrogen or C1-C6 alkyl. In some embodiments of a compound of Formula (V), each R5 is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. [00178] In some embodiments of a compound of Formula (V), two R5 are taken together to form an optionally substituted heterocycloalkyl. [00179] In some embodiments of a compound of Formula (V), each R5a is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (V), each R5a is independently deuterium or halogen. In some embodiments of a compound of Formula (V), each R5a is independently halogen. In some embodiments of a compound of Formula (V), each R5a is independently -NRbC(=NRx)Rb or - NRbC(=NRx)NRcRd. In some embodiments of a compound of Formula (V), each R5a is independently - S(=O)(=NRx)Rb or -S(=O)(=NRx)NRcRd. [00180] In some embodiments of a compound of Formula (V), each R6 and R7 is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one, two, or three R6a. In some embodiments of a compound of Formula (V), each R6 and R7 is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one, two, or three R6a. In some embodiments of a compound of Formula (V), each R6 and R7 is independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl; wherein the alkyl are independently optionally substituted with one, two, or three R6a. In some embodiments of a compound of Formula (V), each R6 and R7 is independently hydrogen or C1-C6 alkyl. In some embodiments of a compound of Formula (V), each R6 and R7 is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. [00181] In some embodiments of a compound of Formula (V), each R6a is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (V), each R6a is independently deuterium or halogen. In some embodiments of a compound of Formula (V), each R6a is independently halogen. In some embodiments of a compound of Formula (V), each R6a is independently -NRbC(=NRx)Rb or - NRbC(=NRx)NRcRd. In some embodiments of a compound of Formula (V), each R6a is independently - S(=O)(=NRx)Rb or -S(=O)(=NRx)NRcRd. [00182] In some embodiments of a compound of Formula (V), R6 and R7 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R6b. [00183] In some embodiments of a compound of Formula (V), each R6b is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (V), each R6b is independently C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of a compound of Formula (V), each R6b is independently C1-C6 alkyl. [00184] In some embodiments of a compound of Formula (V), Rx is hydrogen, -NO2, or -CN. In some embodiments of a compound of Formula (V), Rx is -NO2 or -CN. In some embodiments of a compound of Formula (V), Rx is -CN. [00185] Disclosed herein is a compound of Formula (VI), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: wherein:
Figure imgf000052_0001
R1 is hydrogen, deuterium, halogen, -CN, -ORb, -NRcRd, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; R3 is halogen, -CN, -OR5, -SR5, -S(=O)R4, -S(=O)2R4, -NO2, -NR6R7, -S(=O)2NR6R7, -C(=O)R4, - OC(=O)R4, -C(=O)OR5, -OC(=O)OR5, -C(=O)NR6R7, -OC(=O)NR6R7, -NR5C(=O)NR6R7, - NR5C(=O)OR5, -NR5S(=O)2NR6R7, -NR5S(=O)2R4, -NR5C(=O)R4, -P(=O)(R4)2, -P(=O)(OR5)2, - B(OR5)2, -NR5C(=NRx)R5, -NR5C(=NRx)NR6R7, -S(=O)(=NRx)R5, -S(=O)(=NRx)NR6R7, - NR5S(=O)2NR5C(=O)R5, -NR5S(=O)(=NRx)R5, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R3a; each R3a is independently oxo, deuterium, halogen, -CN, -OR5, -SR5, -S(=O)R4, -S(=O)2R4, -NO2, - NR6R7, -S(=O)2NR6R7, -C(=O)R4, -OC(=O)R4, -C(=O)OR5, -OC(=O)OR5, -C(=O)NR6R7, - OC(=O)NR6R7, -NR5C(=O)NR6R7, -NR5C(=O)OR5, -NR5S(=O)2NR6R7, -NR5S(=O)2R4, - NR5C(=O)R4, -P(=O)(R4)2, -P(=O)(OR5)2, -B(OR5)2, -NR5C(=NRx)R5, -NR5C(=NRx)NR6R7, - S(=O)(=NRx)R5, -S(=O)(=NRx)NR6R7, -NR5S(=O)2NR5C(=O)R5, -NR5S(=O)(=NRx)R5, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R3b; each R3b is independently deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Rx is hydrogen, -NO2, -CN, or -S(=O)2Ra; each R4 is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R4a; each R4a is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, -NRbC(=NRx)Rb, -NRbC(=NRx)NRcRd, -S(=O)(=NRx)Rb, -S(=O)(=NRx)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R5 is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R5a; or two R5 are taken together to form an optionally substituted heterocycloalkyl; each R5a is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, -NRbC(=NRx)Rb, -NRbC(=NRx)NRcRd, -S(=O)(=NRx)Rb, -S(=O)(=NRx)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R6 and R7 is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R6a; each R6a is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, -NRbC(=NRx)Rb, -NRbC(=NRx)NRcRd, -S(=O)(=NRx)Rb, -S(=O)(=NRx)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or R6 and R7 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R6b; each R6b is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
Figure imgf000054_0001
Y1 and Y2 are independently hydrogen, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; R8 is hydrogen, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl; R9 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl; R10 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl; R11 is hydrogen, deuterium, halogen, or -ORb; or R3 and R11 are taken together to form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl; R12 is hydrogen, deuterium, -ORb, -NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; provided that R12 is not -CH3; R13 is -OR19, -NR20R21, -S(=O)2NR20R21, -C(=O)R18, -OC(=O)R18, -C(=O)OR19, -OC(=O)OR19, - C(=O)NR20R21, -OC(=O)NR20R21, -NR19C(=O)NR20R21, -NR19C(=O)OR19, -NR19S(=O)2NR20R21, - NR19S(=O)2R18, -NR19C(=O)R18, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R13a; each R13a is independently oxo, deuterium, halogen, -CN, -OR19, -SR19, -S(=O)R18, -S(=O)2R18, -NO2, - NR20R21, -S(=O)2NR20R21, -C(=O)R18, -OC(=O)R18, -C(=O)OR19, -OC(=O)OR19, -C(=O)NR20R21, - OC(=O)NR20R21, -NR19C(=O)NR20R21, -NR19C(=O)OR19, -NR19S(=O)2NR20R21, -NR19S(=O)2R18, - NR19C(=O)R18, -NR19C(=O)OR19, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; each R18 is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R18a; each R18a is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R19 is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R19a; each R19a is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R20 and R21 are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R20a; each R20a is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or R20 and R21 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R20b; each R20b is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R15 and R16 are independently hydrogen, -ORb, -NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; or R15 and R16 are taken together to form a cycloalkyl or a heterocycloalkyl; each substituted with 0-6 R2; each R2 is independently deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; each Ra is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three deuterium, halogen, -OH, -NH2, or C1-C6 alkyl; each Rb is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three halogen, -OH, -NH2, or C1-C6 alkyl; and each Rc and Rd is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three deuterium, halogen, -OH, -NH2, or C1-C6 alkyl; or Rc and Rd are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three deuterium, halogen, -OH, -NH2, or C1- C6 alkyl. [00186] In some embodiments of a compound of Formula (VI), Y1 and Y2 are independently hydrogen, deuterium, halogen, -ORb, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. In some embodiments of a compound of Formula (VI), Y1 and Y2 are independently hydrogen, deuterium, halogen, or -ORb. In some embodiments of a compound of Formula (VI), Y1 and Y2 are independently hydrogen, deuterium, - ORb, or C1-C6 alkyl. In some embodiments of a compound of Formula (VI), Y1 and Y2 are independently hydrogen. [00187] In some embodiments of a compound of Formula (VI), R12 is hydrogen, deuterium, -ORb, - NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, or cycloalkyl; provided that R12 is not -CH3. In some embodiments of a compound of Formula (VI), R12 is hydrogen, deuterium, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl; provided that R12 is not -CH3. In some embodiments of a compound of Formula (VI), R12 is hydrogen or deuterium. In some embodiments of a compound of Formula (VI), R12 is hydrogen. In some embodiments of a compound of Formula (VI), R12 is hydrogen or C1-C6 alkyl; provided that R12 is not -CH3. In some embodiments of a compound of Formula (VI), R12 is C1-C6 alkyl; provided that R12 is not -CH3. [00188] In some embodiments of a compound of Formula (VI), R13 is -NR20R21, -S(=O)2NR20R21, - C(=O)R18, -C(=O)OR19, -C(=O)NR20R21, -NR19C(=O)NR20R21, -NR19C(=O)OR19, -NR19S(=O)2NR20R21, - NR19S(=O)2R18, -NR19C(=O)R18, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R13a. In some embodiments of a compound of Formula (VI), R13 is -C(=O)R18, -C(=O)OR19, -C(=O)NR20R21, -NR19S(=O)2NR20R21, - NR19S(=O)2R18, -NR19C(=O)R18, C1-C6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R13a. In some embodiments of a compound of Formula (VI), R13 is -C(=O)R18, - C(=O)OR19, -C(=O)NR20R21, -NR19S(=O)2NR20R21, -NR19S(=O)2R18, or -NR19C(=O)R18. In some embodiments of a compound of Formula (VI), R13 is -C(=O)NR20R21, -NR19S(=O)2NR20R21, - NR19S(=O)2R18, or -NR19C(=O)R18. In some embodiments of a compound of Formula (VI), R13 is - C(=O)NR20R21. In some embodiments of a compound of Formula (VI), R13 is -NR19C(=O)R18. In some embodiments of a compound of Formula (VI), R13 is C1-C6 alkyl optionally substituted with one, two, or three R13a. In some embodiments of a compound of Formula (VI), R13 is heteroaryl optionally substituted with one, two, or three R13a. [00189] In some embodiments of a compound of Formula (VI), each R13a is independently deuterium, halogen, -CN, -OR19, -NR20R21, -S(=O)2NR20R21, -C(=O)R18, -C(=O)OR19, -C(=O)NR20R21, - NR19C(=O)NR20R21, -NR19C(=O)OR19, -NR19S(=O)2NR20R21, -NR19S(=O)2R18, -NR19C(=O)R18, - NR19C(=O)OR19, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. In some embodiments of a compound of Formula (VI), each R13a is independently deuterium, halogen, -CN, -OR19, -NR20R21, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. In some embodiments of a compound of Formula (VI), each R13a is independently deuterium, halogen, -CN, -OR19, -NR20R21, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. In some embodiments of a compound of Formula (VI), each R13a is independently -NR19S(=O)2R18 or -NR19C(=O)R18. [00190] Disclosed herein is a compound of Formula (VII), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure imgf000057_0001
wherein: R1 is hydrogen, deuterium, halogen, -CN, -ORb, -NRcRd, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; R3 is halogen, -CN, -OR5, -SR5, -S(=O)R4, -S(=O)2R4, -NO2, -NR6R7, -S(=O)2NR6R7, -C(=O)R4, - OC(=O)R4, -C(=O)OR5, -OC(=O)OR5, -C(=O)NR6R7, -OC(=O)NR6R7, -NR5C(=O)NR6R7, - NR5C(=O)OR5, -NR5S(=O)2NR6R7, -NR5S(=O)2R4, -NR5C(=O)R4, -P(=O)(R4)2, -P(=O)(OR5)2, - B(OR5)2, -NR5C(=NRx)R5, -NR5C(=NRx)NR6R7, -S(=O)(=NRx)R5, -S(=O)(=NRx)NR6R7, - NR5S(=O)2NR5C(=O)R5, -NR5S(=O)(=NRx)R5, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R3a; each R3a is independently oxo, deuterium, halogen, -CN, -OR5, -SR5, -S(=O)R4, -S(=O)2R4, -NO2, - NR6R7, -S(=O)2NR6R7, -C(=O)R4, -OC(=O)R4, -C(=O)OR5, -OC(=O)OR5, -C(=O)NR6R7, - OC(=O)NR6R7, -NR5C(=O)NR6R7, -NR5C(=O)OR5, -NR5S(=O)2NR6R7, -NR5S(=O)2R4, - NR5C(=O)R4, -P(=O)(R4)2, -P(=O)(OR5)2, -B(OR5)2, -NR5C(=NRx)R5, -NR5C(=NRx)NR6R7, - S(=O)(=NRx)R5, -S(=O)(=NRx)NR6R7, -NR5S(=O)2NR5C(=O)R5, -NR5S(=O)(=NRx)R5, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R3b; each R3b is independently deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Rx is hydrogen, -NO2, -CN, or -S(=O)2Ra; each R4 is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R4a; each R4a is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, -NRbC(=NRx)Rb, -NRbC(=NRx)NRcRd, -S(=O)(=NRx)Rb, -S(=O)(=NRx)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R5 is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R5a; or two R5 are taken together to form an optionally substituted heterocycloalkyl; each R5a is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, -NRbC(=NRx)Rb, -NRbC(=NRx)NRcRd, -S(=O)(=NRx)Rb, -S(=O)(=NRx)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R6 and R7 is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R6a; each R6a is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, -NRbC(=NRx)Rb, -NRbC(=NRx)NRcRd, -S(=O)(=NRx)Rb, -S(=O)(=NRx)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or R6 and R7 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R6b; each R6b is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
Figure imgf000059_0001
; Y1 and Y2 are independently hydrogen, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; provided that one of Y1 or Y2 is not hydrogen; R8 is hydrogen, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl; R9 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl; R10 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl; R11 is hydrogen, deuterium, halogen, or -ORb; or R3 and R11 are taken together to form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl; R12 is hydrogen, deuterium, -ORb, -NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R13 is -OR19, -NR20R21, -S(=O)2NR20R21, -C(=O)R18, -OC(=O)R18, -C(=O)OR19, -OC(=O)OR19, - C(=O)NR20R21, -OC(=O)NR20R21, -NR19C(=O)NR20R21, -NR19C(=O)OR19, -NR19S(=O)2NR20R21, - NR19S(=O)2R18, -NR19C(=O)R18, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R13a; each R13a is independently oxo, deuterium, halogen, -CN, -OR19, -SR19, -S(=O)R18, -S(=O)2R18, -NO2, - NR20R21, -S(=O)2NR20R21, -C(=O)R18, -OC(=O)R18, -C(=O)OR19, -OC(=O)OR19, -C(=O)NR20R21, - OC(=O)NR20R21, -NR19C(=O)NR20R21, -NR19C(=O)OR19, -NR19S(=O)2NR20R21, -NR19S(=O)2R18, - NR19C(=O)R18, -NR19C(=O)OR19, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl; each R18 is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R18a; each R18a is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R19 is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R19a; each R19a is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R20 and R21 are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R20a; each R20a is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or R20 and R21 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R20b; each R20b is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R15 and R16 are independently hydrogen, -ORb, -NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; or R15 and R16 are taken together to form a cycloalkyl or a heterocycloalkyl; each substituted with 0-6 R2; each R2 is independently deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; each Ra is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three deuterium, halogen, -OH, -NH2, or C1-C6 alkyl; each Rb is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three halogen, -OH, -NH2, or C1-C6 alkyl; and each Rc and Rd is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three deuterium, halogen, -OH, -NH2, or C1-C6 alkyl; or Rc and Rd are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three deuterium, halogen, -OH, -NH2, or C1- C6 alkyl. [00191] In some embodiments of a compound of Formula (VII), Y1 and Y2 are independently hydrogen, deuterium, halogen, -ORb, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl; provided that one of Y1 or Y2 is not hydrogen. In some embodiments of a compound of Formula (VII), Y1 and Y2 are independently hydrogen, deuterium, halogen, or -ORb; provided that one of Y1 or Y2 is not hydrogen. In some embodiments of a compound of Formula (VII), Y1 and Y2 are independently hydrogen, deuterium, -ORb, or C1-C6 alkyl; provided that one of Y1 or Y2 is not hydrogen. [00192] In some embodiments of a compound of Formula (VII), R12 is hydrogen, deuterium, -ORb, - NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, or cycloalkyl. In some embodiments of a compound of Formula (VII), R12 is hydrogen, deuterium, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. In some embodiments of a compound of Formula (VII), R12 is hydrogen or deuterium. In some embodiments of a compound of Formula (VII), R12 is hydrogen. In some embodiments of a compound of Formula (VII), R12 is hydrogen or C1-C6 alkyl. In some embodiments of a compound of Formula (VII), R12 is C1-C6 alkyl. [00193] In some embodiments of a compound of Formula (VII), R13 is -NR20R21, -S(=O)2NR20R21, - C(=O)R18, -C(=O)OR19, -C(=O)NR20R21, -NR19C(=O)NR20R21, -NR19C(=O)OR19, -NR19S(=O)2NR20R21, - NR19S(=O)2R18, -NR19C(=O)R18, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R13a. In some embodiments of a compound of Formula (VII), R13 is -C(=O)R18, -C(=O)OR19, -C(=O)NR20R21, -NR19S(=O)2NR20R21, - NR19S(=O)2R18, -NR19C(=O)R18, C1-C6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R13a. In some embodiments of a compound of Formula (VII), R13 is -C(=O)R18, - C(=O)OR19, -C(=O)NR20R21, -NR19S(=O)2NR20R21, -NR19S(=O)2R18, or -NR19C(=O)R18. In some embodiments of a compound of Formula (VII), R13 is -C(=O)NR20R21, -NR19S(=O)2NR20R21, - NR19S(=O)2R18, or -NR19C(=O)R18. In some embodiments of a compound of Formula (VII), R13 is - C(=O)NR20R21. In some embodiments of a compound of Formula (VII), R13 is -NR19C(=O)R18. In some embodiments of a compound of Formula (VII), R13 is C1-C6 alkyl optionally substituted with one, two, or three R13a. In some embodiments of a compound of Formula (VII), R13 is heteroaryl optionally substituted with one, two, or three R13a. [00194] In some embodiments of a compound of Formula (VII), each R13a is independently deuterium, halogen, -CN, -OR19, -NR20R21, -S(=O)2NR20R21, -C(=O)R18, -C(=O)OR19, -C(=O)NR20R21, - NR19C(=O)NR20R21, -NR19C(=O)OR19, -NR19S(=O)2NR20R21, -NR19S(=O)2R18, -NR19C(=O)R18, - NR19C(=O)OR19, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. In some embodiments of a compound of Formula (VII), each R13a is independently deuterium, halogen, -CN, -OR19, -NR20R21, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. In some embodiments of a compound of Formula (VII), each R13a is independently deuterium, halogen, -CN, -OR19, -NR20R21, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. In some embodiments of a compound of Formula (VII), each R13a is independently -NR19S(=O)2R18 or -NR19C(=O)R18. [00195] Disclosed herein is a compound of Formula (VIII), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure imgf000062_0001
wherein: R1 is hydrogen, deuterium, halogen, -CN, -ORb, -NRcRd, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; R3 is halogen, -CN, -OR5, -SR5, -S(=O)R4, -S(=O)2R4, -NO2, -NR6R7, -S(=O)2NR6R7, -C(=O)R4, - OC(=O)R4, -C(=O)OR5, -OC(=O)OR5, -C(=O)NR6R7, -OC(=O)NR6R7, -NR5C(=O)NR6R7, - NR5C(=O)OR5, -NR5S(=O)2NR6R7, -NR5S(=O)2R4, -NR5C(=O)R4, -P(=O)(R4)2, -P(=O)(OR5)2, - B(OR5)2, -NR5C(=NRx)R5, -NR5C(=NRx)NR6R7, -S(=O)(=NRx)R5, -S(=O)(=NRx)NR6R7, - NR5S(=O)2NR5C(=O)R5, -NR5S(=O)(=NRx)R5, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R3a; each R3a is independently oxo, deuterium, halogen, -CN, -OR5, -SR5, -S(=O)R4, -S(=O)2R4, -NO2, - NR6R7, -S(=O)2NR6R7, -C(=O)R4, -OC(=O)R4, -C(=O)OR5, -OC(=O)OR5, -C(=O)NR6R7, - OC(=O)NR6R7, -NR5C(=O)NR6R7, -NR5C(=O)OR5, -NR5S(=O)2NR6R7, -NR5S(=O)2R4, - NR5C(=O)R4, -P(=O)(R4)2, -P(=O)(OR5)2, -B(OR5)2, -NR5C(=NRx)R5, -NR5C(=NRx)NR6R7, - S(=O)(=NRx)R5, -S(=O)(=NRx)NR6R7, -NR5S(=O)2NR5C(=O)R5, -NR5S(=O)(=NRx)R5, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R3b; each R3b is independently deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Rx is hydrogen, -NO2, -CN, or -S(=O)2Ra; each R4 is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R4a; each R4a is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, -NRbC(=NRx)Rb, -NRbC(=NRx)NRcRd, -S(=O)(=NRx)Rb, -S(=O)(=NRx)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R5 is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R5a; or two R5 are taken together to form an optionally substituted heterocycloalkyl; each R5a is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, -NRbC(=NRx)Rb, -NRbC(=NRx)NRcRd, -S(=O)(=NRx)Rb, -S(=O)(=NRx)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R6 and R7 is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R6a; each R6a is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, -NRbC(=NRx)Rb, -NRbC(=NRx)NRcRd, -S(=O)(=NRx)Rb, -S(=O)(=NRx)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or R6 and R7 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R6b; each R6b is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
Figure imgf000063_0001
Y1 and Y2 are independently hydrogen, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; R8 is hydrogen, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl; R9 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl; R10 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl; R11 is hydrogen, deuterium, halogen, or -ORb; or R3 and R11 are taken together to form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl; R12 is hydrogen, deuterium, -ORb, -NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R13 is –CN, -OR19, -S(=O)2NR20R21, -OC(=O)R18, -OC(=O)OR19, -OC(=O)NR20R21, -NR19C(=O)OR19, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -CH2(cycloalkyl), -CH2(heterocycloalkyl), -CH2(aryl), or - CH2(heteroaryl); wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R13a; each R13a is independently oxo, deuterium, halogen, -CN, -OR19, -SR19, -S(=O)R18, -S(=O)2R18, -NO2, - NR20R21, -S(=O)2NR20R21, -C(=O)R18, -OC(=O)R18, -C(=O)OR19, -OC(=O)OR19, -C(=O)NR20R21, - OC(=O)NR20R21, -NR19C(=O)OR19, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1- C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R18 is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R18a; each R18a is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R19 is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R19a; each R19a is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R20 and R21 are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R20a; each R20a is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or R20 and R21 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R20b; each R20b is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R15 and R16 are independently hydrogen, -ORb, -NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; or R15 and R16 are taken together to form a cycloalkyl or a heterocycloalkyl; each substituted with 0-6 R2; each R2 is independently deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; each Ra is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three deuterium, halogen, -OH, -NH2, or C1-C6 alkyl; each Rb is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three halogen, -OH, -NH2, or C1-C6 alkyl; and each Rc and Rd is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three deuterium, halogen, -OH, -NH2, or C1-C6 alkyl; or Rc and Rd are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three deuterium, halogen, -OH, -NH2, or C1- C6 alkyl. [00196] In some embodiments of a compound of Formula (VIII), Y1 and Y2 are independently hydrogen, deuterium, halogen, -ORb, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. In some embodiments of a compound of Formula (VIII), Y1 and Y2 are independently hydrogen, deuterium, halogen, or -ORb. In some embodiments of a compound of Formula (VIII), Y1 and Y2 are independently hydrogen, deuterium, -ORb, or C1-C6 alkyl. In some embodiments of a compound of Formula (VIII), Y1 and Y2 are hydrogen. [00197] In some embodiments of a compound of Formula (VIII), R12 is hydrogen, deuterium, -ORb, - NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, or cycloalkyl. In some embodiments of a compound of Formula (VIII), R12 is hydrogen, deuterium, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. In some embodiments of a compound of Formula (VIII), R12 is hydrogen or deuterium. In some embodiments of a compound of Formula (VIII), R12 is hydrogen. In some embodiments of a compound of Formula (VIII), R12 is hydrogen or C1-C6 alkyl. In some embodiments of a compound of Formula (VIII), R12 is C1-C6 alkyl. [00198] In some embodiments of a compound of Formula (VIII), R13 is –CN. [00199] In some embodiments of a compound of Formula (VIII), R13 is C1-C6 hydroxyalkyl optionally substituted with one, two, or three R13a. In some embodiments of a compound of Formula (VIII), R13 is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R13a. In some embodiments of a compound of Formula (VIII), R13 is heteroaryl optionally substituted with one, two, or three R13a. [00200] In some embodiments of a compound of Formula (VIII), R13 is –CN, heterocycloalkyl, heteroaryl, or -CH2(heteroaryl); wherein the heterocycloalkyl and heteroaryl are independently optionally substituted with one, two, or three R13a. In some embodiments of a compound of Formula (VIII), R13 is heterocycloalkyl or heteroaryl; wherein the heterocycloalkyl and heteroaryl are independently optionally substituted with one, two, or three R13a. In some embodiments of a compound of Formula (VIII), R13 is heteroaryl optionally substituted with one, two, or three R13a. In some embodiments of a compound of Formula (VIII), R13 is heterocycloalkyl optionally substituted with one, two, or three R13a. [00201] In some embodiments of a compound of Formula (VIII), each R13a is independently deuterium, halogen, -CN, -OR19, -NR20R21, -S(=O)2NR20R21, -C(=O)R18, -C(=O)OR19, -C(=O)NR20R21, - NR19C(=O)OR19, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. In some embodiments of a compound of Formula (VIII), each R13a is independently deuterium, halogen, -CN, -OR19, -NR20R21, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. In some embodiments of a compound of Formula (VIII), each R13a is independently deuterium, halogen, -CN, -OR19, -NR20R21, C1- C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. [00202] In some embodiments of a compound of Formula (VIII), each R13a is independently oxo, -OR19, - NR20R21, -C(=O)R18, -C(=O)OR19, -C(=O)NR20R21, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1- C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, or aryl. In some embodiments of a compound of Formula (VIII), each R13a is independently oxo, -OR19, -NR20R21, -C(=O)NR20R21, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or aryl. In some embodiments of a compound of Formula (VIII), each R13a is independently -OR19, -NR20R21, or -C(=O)NR20R21. In some embodiments of a compound of Formula (VIII), each R13a is independently -OR19 or -C(=O)NR20R21. In some embodiments of a compound of Formula (VIII), each R13a is independently -OR19. [00203] In some embodiments of a compound of Formula (VI)-(VIII), R1 is -CN, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. In some embodiments of a compound of Formula (VI)-(VIII), R1 is -CN or C1-C6 haloalkyl. In some embodiments of a compound of Formula (VI)-(VIII), R1 is C1-C6 haloalkyl. In some embodiments of a compound of Formula (VI)-(VIII), R1 is -CN. [00204] In some embodiments of a compound of Formula (VI)-(VIII), R8 is hydrogen or deuterium. In some embodiments of a compound of Formula (VI)-(VIII), R8 is hydrogen. [00205] In some embodiments of a compound of Formula (VI)-(VIII), R9 is C1-C6 alkyl or C2-C6 alkynyl. In some embodiments of a compound of Formula (VI)-(VIII), R9 is C1-C6 alkyl. [00206] In some embodiments of a compound of Formula (VI)-(VIII), R10 is C1-C6 alkyl or C2-C6 alkynyl. In some embodiments of a compound of Formula (VI)-(VIII), R10 is C1-C6 alkyl. [00207] In some embodiments of a compound of Formula (VI)-(VIII), R9 is C1-C6 alkyl and R10 is C2-C6 alkynyl. In some embodiments of a compound of Formula (VI)-(VIII), R10 is C1-C6 alkyl and R9 is C2-C6 alkynyl. [00208] In some embodiments of a compound of Formula (VI)-(VIII),
Figure imgf000067_0001
is . In some embodiments of a compound of Formula (VI)-(VIII),
Figure imgf000067_0002
. [00209] In some embodiments of a compound of Formula (VI)-(VIII), R11 is hydrogen, halogen, or - OH. In some embodiments of a compound of Formula (VI)-(VIII), R11 is hydrogen or -OH. In some embodiments of a compound of Formula (VI)-(VIII), R11 is hydrogen. [00210] In some embodiments of a compound of Formula (VI)-(VIII), each R18 is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one, two, or three R18a. In some embodiments of a compound of Formula (VI)-(VIII), each R18 is independently C1-C6 alkyl or cycloalkyl; wherein the alkyl and cycloalkyl are independently optionally substituted with one, two, or three R18a. In some embodiments of a compound of Formula (VI)-(VIII), each R18 is independently C1-C6 alkyl optionally substituted with one, two, or three R18a. In some embodiments of a compound of Formula (VI)-(VIII), each R18 is independently C1-C6 alkyl. In some embodiments of a compound of Formula (VI)-(VIII), each R18 is independently C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. [00211] In some embodiments of a compound of Formula (VI)-(VIII), each R18a is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (VI)-(VIII), each R18a is independently deuterium or halogen. In some embodiments of a compound of Formula (VI)-(VIII), each R18a is independently halogen. [00212] In some embodiments of a compound of Formula (VI)-(VIII), each R19 is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one, two, or three R19a. In some embodiments of a compound of Formula (VI)-(VIII), each R19 is independently hydrogen, C1-C6 alkyl, or cycloalkyl; wherein the alkyl and cycloalkyl are independently optionally substituted with one, two, or three R19a. In some embodiments of a compound of Formula (VI)-(VIII), each R19 is independently hydrogen or C1-C6 alkyl optionally substituted with one, two, or three R19a. In some embodiments of a compound of Formula (VI)-(VIII), each R19 is independently C1-C6 alkyl optionally substituted with one, two, or three R19a. In some embodiments of a compound of Formula (VI)-(VIII), each R19 is hydrogen or C1-C6 alkyl. In some embodiments of a compound of Formula (VI)-(VIII), each R19 is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. [00213] In some embodiments of a compound of Formula (VI)-(VIII), each R19a is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (VI)-(VIII), each R19a is independently deuterium or halogen. In some embodiments of a compound of Formula (VI)-(VIII), each R19a is independently halogen. [00214] In some embodiments of a compound of Formula (VI)-(VIII), each R20 and R21 are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one, two, or three R20a. In some embodiments of a compound of Formula (VI)-(VIII), each R20 and R21 are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one, two, or three R6a. In some embodiments of a compound of Formula (VI)-(VIII), each R20 and R21 are independently hydrogen, C1- C6 alkyl, or C1-C6 haloalkyl; wherein the alkyl are independently optionally substituted with one, two, or three R6a. In some embodiments of a compound of Formula (VI)-(VIII), each R20 and R21 are independently hydrogen or C1-C6 alkyl. In some embodiments of a compound of Formula (VI)-(VIII), each R20 and R21 are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. [00215] In some embodiments of a compound of Formula (VI)-(VIII), each R20a is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (VI)-(VIII), each R20a is independently deuterium or halogen. In some embodiments of a compound of Formula (VI)-(VIII), each R20a is independently halogen. In some embodiments of a compound of Formula (VI)-(VIII), each R20a is independently - NRbC(=NRx)Rb or -NRbC(=NRx)NRcRd. In some embodiments of a compound of Formula (VI)-(VIII), each R20a is independently -S(=O)(=NRx)Rb or -S(=O)(=NRx)NRcRd. [00216] In some embodiments of a compound of Formula (VI)-(VIII), R20 and R21 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R20b. [00217] In some embodiments of a compound of Formula (VI)-(VIII), each R20b is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (VI)-(VIII), each R20b is independently C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of a compound of Formula (VI)- (VIII), each R20b is independently C1-C6 alkyl. [00218] In some embodiments of a compound of Formula (VI)-(VIII), R3 is halogen, -CN, -OR5, -NR6R7, -C(=O)R4, -OC(=O)R4, -C(=O)OR5, -C(=O)NR6R7, -OC(=O)NR6R7, -NR5C(=O)NR6R7, -NR5C(=O)OR5, -NR5S(=O)2R4, -NR5C(=O)R4, -NR5C(=NRx)R5, -NR5C(=NRx)NR6R7, -S(=O)(=NRx)R5, - S(=O)(=NRx)NR6R7, -NR5S(=O)2NR5C(=O)R5, -NR5S(=O)(=NRx)R5, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 hydroxyalkyl, C1-C6 heteroalkyl, or heteroaryl; wherein the alkyl, alkenyl, and heteroaryl are independently optionally substituted with one, two, or three R3a. In some embodiments of a compound of Formula (VI)-(VIII), R3 is -NR5C(=NRx)R5 or -NR5C(=NRx)NR6R7. In some embodiments of a compound of Formula (VI)-(VIII), R3 is -S(=O)(=NRx)R5, -S(=O)(=NRx)NR6R7, - NR5S(=O)2NR5C(=O)R5, or -NR5S(=O)(=NRx)R5. [00219] In some embodiments of a compound of Formula (VI)-(VIII), R3 is C1-C6 alkyl or -C(=O)OR5. In some embodiments of a compound of Formula (VI)-(VIII), R3 is C1-C6 alkyl optionally substituted with one, two, or three R3a. In some embodiments of a compound of Formula (VI)-(VIII), R3 is C1-C6 alkyl. In some embodiments of a compound of Formula (VI)-(VIII), R3 is -C(=O)OR5. [00220] In some embodiments of a compound of Formula (VI)-(VIII), each R3a is independently deuterium, halogen, -CN, -OR5, -S(=O)R4, -S(=O)2R4, -OC(=O)R4, -C(=O)OR5, -OC(=O)OR5, - C(=O)NR6R7, -OC(=O)NR6R7, -P(=O)(R4)2, -P(=O)(OR5)2, -B(OR5)2, -NR5C(=NRx)R5, - NR5C(=NRx)NR6R7, -S(=O)(=NRx)R5, -S(=O)(=NRx)NR6R7, -NR5S(=O)2NR5C(=O)R5, - NR5S(=O)(=NRx)R5, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (VI)-(VIII), each R3a is independently deuterium, halogen, -CN, -OR5, -S(=O)R4, -S(=O)2R4, -OC(=O)R4, -C(=O)OR5, -OC(=O)OR5, -C(=O)NR6R7, -OC(=O)NR6R7, -P(=O)(R4)2, -P(=O)(OR5)2, -B(OR5)2, - NR5C(=NRx)R5, -NR5C(=NRx)NR6R7, -S(=O)(=NRx)R5, -S(=O)(=NRx)NR6R7, -NR5S(=O)2NR5C(=O)R5, or -NR5S(=O)(=NRx)R5. In some embodiments of a compound of Formula (VI)-(VIII), each R3a is independently deuterium, halogen, -CN, -OR5, -OC(=O)R4, -C(=O)OR5, -C(=O)NR6R7, -B(OR5)2, - S(=O)(=NRx)R5, C1-C6 heteroalkyl, heterocycloalkyl, or heteroaryl. In some embodiments of a compound of Formula (VI)-(VIII), each R3a is independently -OC(=O)R4, -C(=O)OR5, -OC(=O)OR5, - C(=O)NR6R7, -P(=O)(R4)2, -P(=O)(OR5)2, -B(OR5)2, -NR5C(=NRx)R5, -NR5C(=NRx)NR6R7, - S(=O)(=NRx)R5, -S(=O)(=NRx)NR6R7, -NR5S(=O)2NR5C(=O)R5, or -NR5S(=O)(=NRx)R5.In some embodiments of a compound of Formula (VI)-(VIII), each R3a is independently -OC(=O)R4, -C(=O)OR5, -OC(=O)OR5, or -C(=O)NR6R7. In some embodiments of a compound of Formula (VI)-(VIII), each R3a is independently -P(=O)(R4)2, -P(=O)(OR5)2, or -B(OR5)2. In some embodiments of a compound of Formula (VI)-(VIII), each R3a is independently -NR5C(=NRx)R5, -NR5C(=NRx)NR6R7, -S(=O)(=NRx)R5, -S(=O)(=NRx)NR6R7, -NR5S(=O)2NR5C(=O)R5, or -NR5S(=O)(=NRx)R5. [00221] In some embodiments of a compound of Formula (VI)-(VIII), each R3b is independently deuterium, halogen, -CN, -ORb, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. In some embodiments of a compound of Formula (VI)-(VIII), each R3b is independently deuterium, halogen, C1- C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. [00222] In some embodiments of a compound of Formula (VI)-(VIII), each R4 is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one, two, or three R4a. In some embodiments of a compound of Formula (VI)-(VIII), each R4 is independently C1-C6 alkyl or cycloalkyl; wherein the alkyl and cycloalkyl are independently optionally substituted with one, two, or three R4a. In some embodiments of a compound of Formula (VI)- (VIII), each R4 is independently C1-C6 alkyl optionally substituted with one, two, or three R4a. In some embodiments of a compound of Formula (VI)-(VIII), each R4 is independently C1-C6 alkyl. In some embodiments of a compound of Formula (VI)-(VIII), each R4 is independently C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. [00223] In some embodiments of a compound of Formula (VI)-(VIII), each R4a is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (VI)-(VIII), each R4a is independently deuterium or halogen. In some embodiments of a compound of Formula (VI)-(VIII), each R4a is independently halogen. [00224] In some embodiments of a compound of Formula (VI)-(VIII), each R5 is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one, two, or three R5a. In some embodiments of a compound of Formula (VI)-(VIII), each R5 is independently hydrogen, C1-C6 alkyl, or cycloalkyl; wherein the alkyl and cycloalkyl are independently optionally substituted with one, two, or three R5a. In some embodiments of a compound of Formula (VI)-(VIII), each R5 is independently hydrogen or C1-C6 alkyl optionally substituted with one, two, or three R5a. In some embodiments of a compound of Formula (VI)-(VIII), each R5 is independently C1-C6 alkyl optionally substituted with one, two, or three R5a. In some embodiments of a compound of Formula (VI)-(VIII), each R5 is hydrogen or C1-C6 alkyl. In some embodiments of a compound of Formula (VI)-(VIII), each R5 is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. [00225] In some embodiments of a compound of Formula (VI)-(VIII), two R5 are taken together to form an optionally substituted heterocycloalkyl. [00226] In some embodiments of a compound of Formula (VI)-(VIII), each R5a is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (VI)-(VIII), each R5a is independently deuterium or halogen. In some embodiments of a compound of Formula (VI)-(VIII), each R5a is independently halogen. In some embodiments of a compound of Formula (VI)-(VIII), each R5a is independently - NRbC(=NRx)Rb or -NRbC(=NRx)NRcRd. In some embodiments of a compound of Formula (VI)-(VIII), each R5a is independently -S(=O)(=NRx)Rb or -S(=O)(=NRx)NRcRd. [00227] In some embodiments of a compound of Formula (VI)-(VIII), each R6 and R7 is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one, two, or three R6a. In some embodiments of a compound of Formula (VI)-(VIII), each R6 and R7 is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one, two, or three R6a. In some embodiments of a compound of Formula (VI)-(VIII), each R6 and R7 is independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl; wherein the alkyl are independently optionally substituted with one, two, or three R6a. In some embodiments of a compound of Formula (VI)-(VIII), each R6 and R7 is independently hydrogen or C1-C6 alkyl. In some embodiments of a compound of Formula (VI)-(VIII), each R6 and R7 is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. [00228] In some embodiments of a compound of Formula (VI)-(VIII), each R6a is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (VI)-(VIII), each R6a is independently deuterium or halogen. In some embodiments of a compound of Formula (VI)-(VIII), each R6a is independently halogen. In some embodiments of a compound of Formula (VI)-(VIII), each R5a is independently - NRbC(=NRx)Rb or -NRbC(=NRx)NRcRd. In some embodiments of a compound of Formula (VI)-(VIII), each R6a is independently -S(=O)(=NRx)Rb or -S(=O)(=NRx)NRcRd. [00229] In some embodiments of a compound of Formula (VI)-(VIII), R6 and R7 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R6b. [00230] In some embodiments of a compound of Formula (VI)-(VIII), each R6b is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (VI)-(VIII), each R6b is independently C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of a compound of Formula (VI)- (VIII), each R6b is independently C1-C6 alkyl. [00231] In some embodiments of a compound of Formula (VI)-(VIII), Rx is hydrogen, -NO2, or -CN. In some embodiments of a compound of Formula (VI)-(VIII), Rx is -NO2 or -CN. In some embodiments of a compound of Formula (VI)-(VIII), Rx is -CN. [00232] In some embodiments of a compound of Formula (VI)-(VIII), R15 and R16 are independently hydrogen, C1-C6 alkyl, or C1-C6 deuteroalkyl. In some embodiments of a compound of Formula (VI)- (VIII), R15 and R16 are independently hydrogen or C1-C6 alkyl. In some embodiments of a compound of Formula (VI)-(VIII), R15 and R16 are independently hydrogen or C1-C6 deuteroalkyl. In some embodiments of a compound of Formula (VI)-(VIII), R15 and R16 are independently C1-C6 alkyl. [00233] In some embodiments of a compound of Formula (VI)-(VIII), R15 and R16 are taken together to form a cycloalkyl. In some embodiments of a compound of Formula (VI)-(VIII), R15 and R16 are taken together to form a cycloalkyl substituted with 1-4 deuterium. In some embodiments of a compound of Formula (VI)-(VIII), R15 and R16 are taken together to form a cycloalkyl substituted with 1 or 2 deuterium. In some embodiments of a compound of Formula (VI)-(VIII), R15 and R16 are taken together to form a cycloalkyl substituted with 2-4 deuteriums. [00234] In some embodiments of a compound of Formula (VI)-(VIII), R15 and R16 are taken together to form a heterocycloalkyl. In some embodiments of a compound of Formula (VI)-(VIII), R15 and R16 are taken together to form a heterocycloalkyl substituted with 1-4 deuterium. In some embodiments of a compound of Formula (VI)-(VIII), R15 and R16 are taken together to form a heterocycloalkyl substituted with 1 or 2 deuterium. In some embodiments of a compound of Formula (VI)-(VIII), R15 and R16 are taken together to form a heterocycloalkyl substituted with 2-4 deuteriums. [00235] In some embodiments of a compound of Formula (I)-(VIII), each Ra is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one, two, or three deuterium, halogen, -OH, -NH2, or C1-C6 alkyl. In some embodiments of a compound of Formula (I)-(VIII), each Ra is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one, two, or three deuterium, halogen, - OH, -NH2, or C1-C6 alkyl. In some embodiments of a compound of Formula (I)-(VIII), each Ra is independently C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl; wherein the alkyl are independently optionally substituted with one, two, or three deuterium, halogen, -OH, -NH2, or C1-C6 alkyl. In some embodiments of a compound of Formula (I)-(VIII), each Ra is independently C1-C6 alkyl optionally substituted with one, two, or three deuterium, halogen, -OH, -NH2, or C1-C6 alkyl. In some embodiments of a compound of Formula (I)-(VIII), each Ra is independently C1-C6 alkyl. [00236] In some embodiments of a compound of Formula (I)-(VIII), each Rb is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one, two, or three deuterium, halogen, -OH, -NH2, or C1-C6 alkyl. In some embodiments of a compound of Formula (I)- (VIII), each Rb is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl; wherein the alkyl are independently optionally substituted with one, two, or three deuterium, halogen, -OH, -NH2, or C1-C6 alkyl. In some embodiments of a compound of Formula (I)-(VIII), each Rb is independently hydrogen or C1-C6 alkyl optionally substituted with one, two, or three deuterium, halogen, -OH, -NH2, or C1-C6 alkyl. In some embodiments of a compound of Formula (I)-(VIII), each Rb is independently hydrogen or C1-C6 alkyl. In some embodiments of a compound of Formula (I)-(VIII), each Rb is independently hydrogen. In some embodiments of a compound of Formula (I)-(VIII), each Rb is independently C1-C6 alkyl. [00237] In some embodiments of a compound of Formula (I)-(VIII), each Rc and Rd is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one, two, or three deuterium, halogen, -OH, -NH2, or C1-C6 alkyl. In some embodiments of a compound of Formula (I)- (VIII), each Rc and Rd is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl; wherein the alkyl are independently optionally substituted with one, two, or three deuterium, halogen, - OH, -NH2, or C1-C6 alkyl. In some embodiments of a compound of Formula (I)-(VIII), each Rc and Rd is independently hydrogen or C1-C6 alkyl optionally substituted with one, two, or three deuterium, halogen, -OH, -NH2, or C1-C6 alkyl. In some embodiments of a compound of Formula (I)-(VIII), each Rc and Rd is independently hydrogen or C1-C6 alkyl. In some embodiments of a compound of Formula (I)-(VIII), each Rb is independently hydrogen. In some embodiments of a compound of Formula (I)-(VIII), each Rc and Rd is independently C1-C6 alkyl. [00238] In some embodiments of a compound of Formula (I)-(VIII), Rc and Rd are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three deuterium, halogen, -OH, -NH2, or C1-C6 alkyl. [00239] Disclosed herein is a compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, selected from the group consisting of:
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
Figure imgf000077_0001
[00240] Disclosed herein is a compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, selected from the group consisting of:
Figure imgf000078_0001
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0001
Figure imgf000087_0001
. Further Forms of Compounds Disclosed Herein Isomers/Stereoisomers [00241] In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess one or more double bonds. The compounds presented herein include cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the corresponding mixtures thereof. In some situations, the compounds described herein possess one or more chiral centers and each center exists in the R configuration or S configuration. The compounds described herein include diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof. In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers, and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred. In some embodiments, the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably, by separation/resolution techniques based upon differences in solubility. In some embodiments, the optically pure enantiomer is then recovered, along with the resolving agent. Labeled compounds [00242] In some embodiments, the compounds described herein exist in their isotopically-labeled forms. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds as pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include isotopically-labeled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds described herein, or a solvate, or stereoisomer thereof, include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chloride, such as 2H, 3H, 13C, 14C, l5N, 18O, 17O, 31P, 32P, 35S, 18F, and 36Cl, respectively. Compounds described herein, and the pharmaceutically acceptable salts, solvates, or stereoisomers thereof which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this disclosure. Certain isotopically-labeled compounds, for example those into which radioactive isotopes such as 3H and 14C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3H and carbon-14, i.e., 14C, isotopes are notable for their ease of preparation and detectability. Further, substitution with heavy isotopes such as deuterium, i.e., 2H, produces certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. In some embodiments, the isotopically labeled compound or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is prepared by any suitable method. [00243] In some embodiments, the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels. Pharmaceutically acceptable salts [00244] In some embodiments, the compounds described herein exist as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions. [00245] In some embodiments, the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed. [00246] Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with a mineral acid, organic acid, or inorganic base, such salts including acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-1,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1,6-dioate, hydroxybenzoate, γ-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate, metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1-napthalenesulfonate, 2-napthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylate, undeconate, and xylenesulfonate. [00247] Further, the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2- hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo- [2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4’-methylenebis-(3-hydroxy-2-ene-1- carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid. [00248] In some embodiments, those compounds described herein which comprise a free acid group react with a suitable base, such as the hydroxide, carbonate, bicarbonate, or sulfate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine. Representative salts include the alkali or alkaline earth salts, like lithium, sodium, potassium, calcium, and magnesium, and aluminum salts, and the like. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N+(C1-4 alkyl)4, and the like. [00249] Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. It should be understood that the compounds described herein also include the quaternization of any basic nitrogen-containing groups they contain. In some embodiments, water or oil-soluble or dispersible products are obtained by such quaternization. Solvates [00250] In some embodiments, the compounds described herein exist as solvates. This disclosure provides for methods of treating diseases by administering such solvates. This disclosure further provides for methods of treating diseases by administering such solvates as pharmaceutical compositions. [00251] Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and, in some embodiments, are formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein. Tautomers [00252] In some situations, compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. Tautomers are compounds that are interconvertible by migration of a hydrogen atom, accompanied by a switch of a single bond and adjacent double bond. In bonding arrangements where tautomerization is possible, a chemical equilibrium of the tautomers will exist. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. Preparation of the Compounds [00253] The compounds used in the reactions described herein are made according to organic synthesis techniques known to those skilled in this art, starting from commercially available chemicals and/or from compounds described in the chemical literature. “Commercially available chemicals” are obtained from standard commercial sources including Acros Organics (Pittsburgh, PA), Aldrich Chemical (Milwaukee, WI, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Avocado Research (Lancashire, U.K.), BDH, Inc. (Toronto, Canada), Bionet (Cornwall, U.K.), Chem Service Inc. (West Chester, PA), Crescent Chemical Co. (Hauppauge, NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester, NY), Fisher Scientific Co. (Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc. (Costa Mesa, CA), Key Organics (Cornwall, U.K.), Lancaster Synthesis (Windham, NH), Maybridge Chemical Co. Ltd. (Cornwall, U.K.), Parish Chemical Co. (Orem, UT), Pfaltz & Bauer, Inc. (Waterbury, CN), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hanover, Germany), Spectrum Quality Product, Inc. (New Brunswick, NJ), TCI America (Portland, OR), Trans World Chemicals, Inc. (Rockville, MD), and Wako Chemicals USA, Inc. (Richmond, VA). [00254] Suitable reference books and treatises that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, “Synthetic Organic Chemistry”, John Wiley & Sons, Inc., New York; S. R. Sandler et al., “Organic Functional Group Preparations,” 2nd Ed., Academic Press, New York, 1983; H. O. House, “Modern Synthetic Reactions”, 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif.1972; T. L. Gilchrist, “Heterocyclic Chemistry”, 2nd Ed., John Wiley & Sons, New York, 1992; J. March, “Advanced Organic Chemistry: Reactions, Mechanisms and Structure”, 4th Ed., Wiley-Interscience, New York, 1992. Additional suitable reference books and treatises that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, Fuhrhop, J. and Penzlin G. “Organic Synthesis: Concepts, Methods, Starting Materials”, Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, R.V. “Organic Chemistry, An Intermediate Text” (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, R. C. “Comprehensive Organic Transformations: A Guide to Functional Group Preparations” 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. “Advanced Organic Chemistry: Reactions, Mechanisms, and Structure” 4th Edition (1992) John Wiley & Sons, ISBN: 0-471-60180-2; Otera, J. (editor) “Modern Carbonyl Chemistry” (2000) Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. “Patai's 1992 Guide to the Chemistry of Functional Groups” (1992) Interscience ISBN: 0-471-93022-9; Solomons, T. W. G. “Organic Chemistry” 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J.C., “Intermediate Organic Chemistry” 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471- 57456-2; “Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia” (1999) John Wiley & Sons, ISBN: 3-527-29645-X, in 8 volumes; “Organic Reactions” (1942-2000) John Wiley & Sons, in over 55 volumes; and “Chemistry of Functional Groups” John Wiley & Sons, in 73 volumes. [00255] Specific and analogous reactants are optionally identified through the indices of known chemicals prepared by the Chemical Abstract Service of the American Chemical Society, which are available in most public and university libraries, as well as on-line. Chemicals that are known but not commercially available in catalogs are optionally prepared by custom chemical synthesis houses, where many of the standard chemical supply houses (e.g., those listed above) provide custom synthesis services. A reference for the preparation and selection of pharmaceutical salts of the compounds described herein is P. H. Stahl & C. G. Wermuth “Handbook of Pharmaceutical Salts”, Verlag Helvetica Chimica Acta, Zurich, 2002. Pharmaceutical Compositions [00256] In certain embodiments, the compound described herein is administered as a pure chemical. In some embodiments, the compound described herein is combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005)). [00257] Accordingly, provided herein is a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient. [00258] In certain embodiments, the compound provided herein is substantially pure, in that it contains less than about 5%, or less than about 1%, or less than about 0.1%, of other organic small molecules, such as unreacted intermediates or synthesis by-products that are created, for example, in one or more of the steps of a synthesis method. [00259] Pharmaceutical compositions are administered in a manner appropriate to the disease to be treated (or prevented). An appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration. In general, an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and/or prophylactic benefit (e.g., an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and/or overall survival, or a lessening of symptom severity. Optimal doses are generally determined using experimental models and/or clinical trials. The optimal dose depends upon the body mass, weight, or blood volume of the patient. [00260] In some embodiments, the pharmaceutical composition is formulated for oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, intrapulmonary, intradermal, intrathecal, epidural, or intranasal administration. Parenteral administration includes intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. In some embodiments, the pharmaceutical composition is formulated for intravenous injection, oral administration, inhalation, nasal administration, topical administration, or ophthalmic administration. In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated for intravenous injection. In some embodiments, the pharmaceutical composition is formulated as a tablet, a pill, a capsule, a liquid, an inhalant, a nasal spray solution, a suppository, a suspension, a gel, a colloid, a dispersion, a suspension, a solution, an emulsion, an ointment, a lotion, an eye drop, or an ear drop. In some embodiments, the pharmaceutical composition is formulated as a tablet. [00261] Suitable doses and dosage regimens are determined by conventional range-finding techniques known to those of ordinary skill in the art. Generally, treatment is initiated with smaller dosages that are less than the optimum dose of the compound disclosed herein. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. In some embodiments, the present method involves the administration of about 0.1 µg to about 50 mg of at least one compound described herein per kg body weight of the subject. For a 70 kg patient, dosages of about 10 µg to about 200 mg of the compound disclosed herein would be more commonly used, depending on a subject’s physiological response. [00262] By way of example only, the dose of the compound described herein for methods of treating a disease as described herein is about 0.001 to about 1 mg/kg body weight of the subject per day, for example, about 0.001 mg, about 0.002 mg, about 0.005 mg, about 0.010 mg, 0.015 mg, about 0.020 mg, about 0.025 mg, about 0.050 mg, about 0.075 mg, about 0.1 mg, about 0.15 mg, about 0.2 mg, about 0.25 mg, about 0.5 mg, about 0.75 mg, or about 1 mg/kg body weight per day. In some embodiments, the dose of compound described herein for the described methods is about 1 to about 1000 mg/kg body weight of the subject being treated per day, for example, about 1 mg, about 2 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 500 mg, about 750 mg, or about 1000 mg per day. Methods of Treatment [00263] Disclosed herein is a method of treating a kidney disease, the method comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, to a subject in need thereof. [00264] Also disclosed herein is a method of treating a disease that is systemic lupus nephritis, diabetic chronic kidney disease (CDK), Alport syndrome, focal segmental glomerulosclerosis (FSGS), pulmonary hypertension, Friedreich's ataxia, autosomal dominant polycystic kidney disease (ADPKD), or IgA nephropathy, the method comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, to a subject in need thereof. [00265] Also disclosed herein is a method of treating a kidney disease that is systemic lupus nephritis, diabetic chronic kidney disease (CDK), Alport syndrome, focal segmental glomerulosclerosis (FSGS), autosomal dominant polycystic kidney disease (ADPKD), or IgA nephropathy, the method comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, to a subject in need thereof. [00266] Disclosed herein is a method of treating systemic lupus nephritis, the method comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, to a subject in need thereof. Lupus nephritis is inflammation of the kidney that is caused by systemic lupus erythematous (SLE). Also called lupus, SLE is an autoimmune disease. With lupus, the body's immune system targets its own body tissues. Lupus nephritis happens when lupus involves the kidneys. [00267] Disclosed herein is a method of treating diabetic chronic kidney disease (CDK), the method comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, to a subject in need thereof. [00268] Disclosed herein is a method of treating Alport syndrome, the method comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, to a subject in need thereof. Alport syndrome is a genetic condition characterized by kidney disease, hearing loss, and eye abnormalities. People with Alport syndrome experience progressive loss of kidney function. Almost all affected individuals have blood in their urine (hematuria), which indicates abnormal functioning of the kidneys. Many people with Alport syndrome also develop high levels of protein in their urine (proteinuria). The kidneys become less able to function as this condition progresses, resulting in end-stage renal disease (ESRD). [00269] Disclosed herein is a method of treating focal segmental glomerulosclerosis (FSGS), the method comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, to a subject in need thereof. Focal segmental glomerulosclerosis (FSGS) is a cause of nephrotic syndrome in children and adolescents, as well as a leading cause of kidney failure in adults. It is also known as "focal glomerular sclerosis" or "focal nodular glomerulosclerosis." It accounts for about a sixth of the cases of nephrotic syndrome. In some embodiments, the focal segmental glomerulosclerosis is primary focal segmental glomerulosclerosis, when no underlying cause is found; usually presents as nephrotic syndrome. In some embodiments, the focal segmental glomerulosclerosis is secondary focal segmental glomerulosclerosis, when an underlying cause is identified; usually presents with kidney failure and proteinuria. Secondary focal segmental glomerulosclerosis is a heterogeneous group including numerous causes such as: toxins and drugs such as heroin and pamidronate, familial forms, and secondary to nephron loss and hyperfiltration, such as with chronic pyelonephritis and reflux, morbid obesity, diabetes mellitus. [00270] Disclosed herein is a method of treating pulmonary hypertension, the method comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, to a subject in need thereof. Pulmonary hypertension (PH or PHTN) is a condition of increased blood pressure within the arteries of the lungs. Symptoms include shortness of breath, syncope, tiredness, chest pain, swelling of the legs, and a fast heartbeat. The condition may make it difficult to exercise. The cause is often unknown. Risk factors include a family history, prior blood clots in the lungs, HIV/AIDS, sickle cell disease, cocaine use, chronic obstructive pulmonary disease, sleep apnea, living at high altitudes, and problems with the mitral valve. The underlying mechanism typically involves inflammation of the arteries in the lungs. Diagnosis involves first ruling out other potential causes. [00271] Disclosed herein is a method of treating Friedreich's ataxia, the method comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, to a subject in need thereof. Friedreich's ataxia (FRDA or FA) is an autosomal recessive genetic disease that causes difficulty walking, a loss of sensation in the arms and legs and impaired speech that worsens over time. Symptoms can start between 5 and 15 years of age. Many develop hypertrophic cardiomyopathy and will require a mobility aid such as a cane, walker or wheelchair in their teens. As the disease progresses, people lose their sight and hearing. Other complications include scoliosis and diabetes mellitus. The condition is caused by mutations in the FXN gene on the chromosome 9. The FXN gene makes a protein called frataxin. Degeneration of nerve tissue in the spinal cord causes the ataxia; particularly affected are the sensory neurons essential for directing muscle movement of the arms and legs through connections with the cerebellum. The spinal cord becomes thinner and nerve cells lose some myelin sheath. [00272] Disclosed herein is a method of treating autosomal dominant polycystic kidney disease (ADPKD), the method comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, to a subject in need thereof. Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disorder characterized by the growth of numerous cysts in the kidneys. Symptoms vary in severity and age of onset, but usually develop between the ages of 30 and 40. ADPKD is a progressive disease and symptoms tend to get worse over time. The most common symptoms are kidney cysts, pain in the back and the sides and headaches. Other symptoms include liver and pancreatic cysts, urinary tract infections, abnormal heart valves, high blood pressure, kidney stones, and brain aneurysms. ADPKD is most often caused by changes in the PKD1 and PKD2 genes, and less often by changes in the GANAB and DNAJB11 genes. It is inherited in a dominant pattern. Treatment for ADPKD involves managing the symptoms and slowing disease progression. The most serious complication of ADPKD is kidney disease and kidney failure. ADPKD is the most common inherited disorder of the kidneys. [00273] Disclosed herein is a method of treating IgA nephropathy, the method comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, to a subject in need thereof. IgA nephropathy, also known as Berger’s disease, is a disease that causes damage to the tiny filters inside the kidneys. IgA is a protein that helps fight infections. In people with IgA nephropathy, these proteins build up and form clumps inside the kidneys’ tiny filters (glomeruli). These clumps of proteins damage the glomeruli. This damage can cause chronic kidney disease and can lead to kidney failure/ESRD. Combination Therapy [00274] In certain instances, the compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is administered in combination with a second therapeutic agent. [00275] In some embodiments, the benefit experienced by a patient is increased by administering one of the compounds described herein with a second therapeutic agent (which also includes a therapeutic regimen) that also has therapeutic benefit. [00276] In one specific embodiment, a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is co-administered with a second therapeutic agent, wherein the compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and the second therapeutic agent modulate different aspects of the disease, disorder, or condition being treated, thereby providing a greater overall benefit than administration of either therapeutic agent alone. [00277] In any case, regardless of the disease, disorder, or condition being treated, the overall benefit experienced by the patient is simply additive of the two therapeutic agents or the patient experiences a synergistic benefit. [00278] In certain embodiments, different therapeutically effective dosages of the compounds disclosed herein will be utilized in formulating a pharmaceutical composition and/or treatment regimen when the compounds disclosed herein are administered in combination with a second therapeutic agent. Therapeutically effective dosages of drugs and other agents for use in combination treatment regimens are optionally determined by means similar to those set forth herein for the compounds described herein. Furthermore, the methods of prevention/treatment described herein encompass the use of metronomic dosing, i.e., providing more frequent, lower doses in order to minimize toxic side effects. In some embodiments, a combination treatment regimen encompasses treatment regimens in which administration of a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is initiated prior to, during, or after treatment with a second agent described herein, and continues until any time during treatment with the second agent or after termination of treatment with the second agent. It also includes treatments in which a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and the second agent being used in combination are administered simultaneously or at different times and/or at decreasing or increasing intervals during the treatment period. Combination treatment further includes periodic treatments that start and stop at various times to assist with the clinical management of the patient. [00279] It is understood that the dosage regimen to treat, prevent, or ameliorate the condition(s) for which relief is sought is modified in accordance with a variety of factors (e.g. the disease, disorder, or condition from which the subject suffers; the age, weight, sex, diet, and medical condition of the subject). Thus, in some instances, the dosage regimen actually employed varies and, in some embodiments, deviates from the dosage regimens set forth herein. [00280] For combination therapies described herein, dosages of the co-administered compounds vary depending on the type of co-drug employed, on the specific drug employed, on the disease or condition being treated, and so forth. In additional embodiments, when co-administered with a second therapeutic agent, the compound provided herein is administered either simultaneously with the second therapeutic agent, or sequentially. [00281] In combination therapies, the multiple therapeutic agents (one of which is one of the compounds described herein) are administered in any order or even simultaneously. If administration is simultaneous, the multiple therapeutic agents are, by way of example only, provided in a single, unified form, or in multiple forms (e.g., as a single pill or as two separate pills). [00282] The compounds described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, as well as combination therapies, are administered before, during, or after the occurrence of a disease or condition, and the timing of administering the composition containing a compound varies. Thus, in one embodiment, the compounds described herein are used as a prophylactic and are administered continuously to subjects with a propensity to develop conditions or diseases in order to prevent the occurrence of the disease or condition. In another embodiment, the compounds and compositions are administered to a subject during or as soon as possible after the onset of the symptoms. In specific embodiments, a compound described herein is administered as soon as is practicable after the onset of a disease or condition is detected or suspected, and for a length of time necessary for the treatment of the disease. In some embodiments, the length required for treatment varies, and the treatment length is adjusted to suit the specific needs of each subject. For example, in specific embodiments, a compound described herein or a formulation containing the compound is administered for at least 2 weeks, about 1 month, or about 5 years. [00283] In some embodiments, the compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is administered in combination with an adjuvant. In one embodiment, the therapeutic effectiveness of one of the compounds described herein is enhanced by administration of an adjuvant (i.e., by itself the adjuvant has minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced). EXAMPLES Example 1: Imiquimod-induced systemic lupus nephritis [00284] Compound 26 formulated in sesame oil, was administrated orally to female BALB/c mice (7-9 weeks) at 3 mg/kg daily. Half hour after administration of compound 26, the skin on the right ears of the mice were treated topically, 3 times weekly, with 25mg 5% imiquimod (IMQ). The study was repeated for 8 weeks, At the end of study, mice were sacrificed, spleen and kidney were weighted and divided in to two parts, one part was fixed with neutral buffered formalin and embedded in paraffin. Three‐ micrometer sections of liver and kidney were stained with hematoxylin and eosin. Another part was snap- frozen and subjected to gene expression analysis by qPCR. [00285] Topical imiquimod treatment (Model group) leads to marked splenomegaly and increased expression of INFγ. Treatment with compound 26 reduced the enlargement of spleen and reduce the expression of INFγ (FIG.1A and FIG.1B). Topical imiquimod treatment also increased blood urea nitrogen (BUN) and proteinuria, signs of renal dysfunction. These levels were reduced by compound 26 treatment (FIG.2A and FIG.2B). [00286] Topical imiquimod treatment enlarges the size of kidneys. The kidney enlargement was partially reversed by compound 26 treatment (FIG.3A). Histologic examination of the kidneys showed enlarged hypercellular glomeruli, an increase in the mesangial matrix, and mild peritubular mononuclear cell infiltrates, with increased IgG deposits within the glomeruli. The significant increase in the renal histopathologic score suggested glomerulonephritis with immune complex deposits, and compound 26 treatment significantly reduced the renal histopathologic score (FIG.3B). Lipocalin-2 (LCN2), also known as neutrophil gelatinase-associated lipocalin (NGAL), is released by various cell types and is an attractive biomarker of kidney damage and inflammation. Another inflammatory biomarker CD11b is expressed on the surface of many leukocytes including monocytes, neutrophils, natural killer cells, granulocytes and macrophages, it regulates leukocyte adhesion and migration to mediate the inflammatory response. The expression of NGAL and CD11b were examined in kidneys by qPCR. Topical imiquimod treatment dramatically increased their expression in kidney, and compound 26 treatment decreased the expression significantly, suggesting its anti-inflammatory function (FIG.3C and FIG.3D respectively). [00287] Compound 26 mitigates imiquimod-induced systemic lupus nephritis, as indicated by the improvement in spleen and kidney. [00288] The examples and embodiments described herein are for illustrative purposes only and in some embodiments, various modifications or changes are to be included within the purview of disclosure and scope of the appended claims.

Claims

CLAIMS WHAT IS CLAIMED IS: 1. A method of treating a disease that is systemic lupus nephritis, diabetic chronic kidney disease (CDK), Alport syndrome, focal segmental glomerulosclerosis (FSGS), pulmonary hypertension, Friedreich's ataxia, autosomal dominant polycystic kidney disease (ADPKD), or IgA nephropathy, the method comprising administering a compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, to a subject in need thereof:
Figure imgf000099_0001
wherein: R1 is hydrogen, deuterium, halogen, -CN, -ORb, -NRcRd, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1- C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; R3 is N-linked heterocycloalkyl, N-linked heteroaryl, -P(=O)(R4)2, -P(=O)(OR5)2, -B(OR5)2, - S(=O)R4, -S(=O)2R4, -NR5C(=NRx)R5, -NR5C(=NRx)NR6R7, -S(=O)(=NRx)R5, - S(=O)(=NRx)NR6R7, -NR5S(=O)2NR5C(=O)R5, -NR5S(=O)(=NRx)R5, -Z-O-cycloalkyl, -Z-O- heterocycloalkyl, -Z-O-aryl, -Z-O-heteroaryl, -Z-NR5-cycloalkyl, -Z-NR5-heterocycloalkyl, -Z- NR5-aryl, -Z-NR5-heteroaryl, -Y(C1-C6alkylene)S(=O)R4, -Y(C1-C6alkylene)S(=O)2R4, -Y(C1- C6alkylene)P(=O)(R4)2, -Y(C1-C6alkylene)P(=O)(OR5)2, -Y(C1-C6alkylene)B(OR5)2, -Y(C1- C6alkylene)NR5C(=NRx)R5, -Y(C1-C6alkylene)NR5C(=NRx)NR6R7, -Y(C1- C6alkylene)S(=O)(=NRx)R5, -Y(C1-C6alkylene)S(=O)(=NRx)NR6R7, -Y(C1- C6alkylene)NR5S(=O)2NR5C(=O)R5, -NR5C(=O)(C1-C6alkylene)S(=NRx)NR6R7, -NR5C(=O)(C1- C6alkylene)S(=NRx)R5, -Y(C1-C6alkylene)NR5S(=O)(=NRx)R5, -Y(C2-C6alkenylene)S(=O)2R4, - Y(C2-C6alkenylene)P(=O)(R4)2, -Y(C2-C6alkenylene)P(=O)(OR5)2, -Y(C2-C6alkenylene)B(OR5)2, -Y(C2-C6alkenylene)NR5C(=NRx)R5, -Y(C2-C6alkenylene)NR5C(=NRx)NR6R7, -Y(C2- C6alkenylene)S(=O)(=NRx)R5, -Y(C2-C6alkenylene)S(=O)(=NRx)NR6R7, -Y(C2- C6alkenylene)NR5S(=O)2NR5C(=O)R5, -Y(C2-C6alkenylene)NR5S(=O)(=NRx)R5, -Y(C2- C6alkenylene)cycloalkyl, -Y(C2-C6alkenylene)heterocycloalkyl, -Y(C2-C6alkenylene)aryl, -Y(C2- C6alkenylene)heteroaryl, -(C1-C6alkylene)OP(=O)(OR5)2, -(C1-C6alkylene)O(C1- C6alkylene)OP(=O)(OR5)2, or -(C1-C6alkylene)OP(=O)(OR5)[N(R5)2]; wherein the alkylene, alkenylene, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one, two, or three R3a; each R3a is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1- C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Y is a bond, -O-, -S-, or -NRb-; Z is a bond or C1-C6alkylene; Rx is hydrogen, -NO2, -CN, or -S(=O)2Ra; each R4 is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R4a; each R4a is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1- C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R5 is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R5a; or two R5 are taken together to form an optionally substituted heterocycloalkyl; each R5a is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1- C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R6 and R7 is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R6a; each R6a is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1- C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or R6 and R7 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R6b; each R6b is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1- C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
Figure imgf000101_0001
s o ; R8 is hydrogen, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl; R9 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl; R10 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl; R11 is hydrogen, deuterium, halogen, or -ORb; or R3 and R11 are taken together to form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl; R12 and R13 are independently hydrogen, -ORb, -NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; or R12 and R13 are taken together to form a cycloalkyl or a heterocycloalkyl; each substituted with 0-6 R14; each R14 is independently deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1- C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; R15 and R16 are independently hydrogen, -ORb, -NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; or R15 and R16 are taken together to form a cycloalkyl or a heterocycloalkyl; each substituted with 0-6 R2; each R2 is independently deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1- C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; each Ra is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three deuterium, halogen, -OH, -NH2, or C1-C6 alkyl; each Rb is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three halogen, -OH, -NH2, or C1-C6 alkyl; and each Rc and Rd is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three deuterium, halogen, -OH, -NH2, or C1-C6 alkyl; or Rc and Rd are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three deuterium, halogen, -OH, -NH2, or C1-C6 alkyl.
2. The method of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: R1 is -CN, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl.
3. The method of claim 1 or 2, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: R1 is -CN.
4. The method of any one of claims 1-3, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: R8 is hydrogen or deuterium.
5. The method of any one of claims 1-4, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: R8 is hydrogen.
6. The method of any one of claims 1-5, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: R9 is C1-C6 alkyl.
7. The method of any one of claims 1-6, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: R10 is C1-C6 alkyl.
8. The method of any one of claims 1-7, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
Figure imgf000102_0001
.
9. The method of any one of claims 1-8, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: R11 is hydrogen.
10. The method of any one of claims 1-9, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: R12 and R13 are independently hydrogen, C1-C6 alkyl, or C1-C6 deuteroalkyl.
11. The method of any one of claims 1-10, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: R12 and R13 are independently C1-C6 alkyl.
12. The method of any one of claims 1-11, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: R15 and R16 are independently hydrogen, C1-C6 alkyl, or C1-C6 deuteroalkyl.
13. The method of any one of claims 1-12, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: R15 and R16 are independently C1-C6 alkyl.
14. The method of any one of claims 1-13, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: R3 is -P(=O)(R4)2, -P(=O)(OR5)2, -Y(C1-C6alkylene)P(=O)(R4)2, -Y(C1-C6alkylene)P(=O)(OR5)2, -B(OR5)2, -Y(C1-C6alkylene)B(OR5)2, -S(=O)R4, -S(=O)2R4, -Y(C1-C6alkylene)S(=O)R4, -Y(C1- C6alkylene)S(=O)2R4, -NR5C(=NRx)R5, -NR5C(=NRx)NR6R7, -Y(C1-C6alkylene)NR5C(=NRx)R5, -Y(C1-C6alkylene)NR5C(=NRx)NR6R7, -NR5C(=O)(C1-C6alkylene)S(=NRx)NR6R7, - NR5C(=O)(C1-C6alkylene)S(=NRx)R5, -S(=O)(=NRx)R5, -S(=O)(=NRx)NR6R7, - NR5S(=O)2NR5C(=O)R5, -NR5S(=O)(=NRx)R5, -Y(C1-C6alkylene)S(=O)(=NRx)R5, -Y(C1- C6alkylene)S(=O)(=NRx)NR6R7, -Y(C1-C6alkylene)NR5S(=O)2NR5C(=O)R5, -Y(C1- C6alkylene)NR5S(=O)(=NRx)R5, a N-linked heterocycloalkyl, or a N-linked heteroaryl.
15. The method of any one of claims 1-13, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: R3 is -P(=O)(R4)2, -P(=O)(OR5)2, -Y(C1-C6alkylene)P(=O)(R4)2, -Y(C1-C6alkylene)P(=O)(OR5)2, -B(OR5)2, -Y(C1-C6alkylene)B(OR5)2, -S(=O)R4, -S(=O)2R4, -Y(C1-C6alkylene)S(=O)R4, -Y(C1- C6alkylene)S(=O)2R4, -NR5C(=NRx)R5, -NR5C(=NRx)NR6R7, -Y(C1-C6alkylene)NR5C(=NRx)R5, -Y(C1-C6alkylene)NR5C(=NRx)NR6R7, -S(=O)(=NRx)R5, -S(=O)(=NRx)NR6R7, - NR5S(=O)2NR5C(=O)R5, -NR5S(=O)(=NRx)R5, -Y(C1-C6alkylene)S(=O)(=NRx)R5, -Y(C1- C6alkylene)S(=O)(=NRx)NR6R7, -Y(C1-C6alkylene)NR5S(=O)2NR5C(=O)R5, -Y(C1- C6alkylene)NR5S(=O)(=NRx)R5, a N-linked heterocycloalkyl, or a N-linked heteroaryl.
16. The method of any one of claims 1-13, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: R3 is -P(=O)(R4)2, -P(=O)(OR5)2, -Y(C1-C6alkylene)P(=O)(R4)2, or -Y(C1- C6alkylene)P(=O)(OR5)2.
17. The method of any one of claims 1-13, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: R3 is -B(OR5)2 or -Y(C1-C6alkylene)B(OR5)2.
18. The method of any one of claims 1-13, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: R3 is -S(=O)R4, -S(=O)2R4, -Y(C1-C6alkylene)S(=O)R4, or -Y(C1-C6alkylene)S(=O)2R4.
19. The method of any one of claims 1-13, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: R3 is -NR5C(=NRx)R5, -NR5C(=NRx)NR6R7, -Y(C1-C6alkylene)NR5C(=NRx)R5, or -Y(C1- C6alkylene)NR5C(=NRx)NR6R7.
20. The method of any one of claims 1-13, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: R3 is -Y(C1-C6alkylene)NR5C(=NRx)R5 or -Y(C1-C6alkylene)NR5C(=NRx)NR6R7.
21. The method of any one of claims 1-13, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: R3 is -S(=O)(=NRx)R5, -S(=O)(=NRx)NR6R7, -NR5S(=O)2NR5C(=O)R5, -NR5S(=O)(=NRx)R5, - Y(C1-C6alkylene)S(=O)(=NRx)R5, -Y(C1-C6alkylene)S(=O)(=NRx)NR6R7, -Y(C1- C6alkylene)NR5S(=O)2NR5C(=O)R5, or -Y(C1-C6alkylene)NR5S(=O)(=NRx)R5.
22. The method of any one of claims 1-13, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: R3 is -NR5C(=O)(C1-C6alkylene)S(=NRx)NR6R7 or -NR5C(=O)(C1-C6alkylene)S(=NRx)R5.
23. The method of any one of claims 1-13, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: R3 is an N-linked heterocycloalkyl or an N-linked heteroaryl.
24. The method of any one of claims 1-21, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: Y is a bond.
25. The method of any one of claims 1-24, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: RX is -CN.
26. The method of any one of claims 1-25, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: each R4 is independently C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl.
27. The method of any one of claims 1-26, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: each R5 is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl.
28. The method of any one of claims 1-27, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: two R5 are taken together to form an optionally substituted heterocycloalkyl.
29. The method of any one of claims 1-28, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: each R6 and R7 is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl.
30. The method of any one of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound is:
Figure imgf000105_0001
Figure imgf000106_0001
,
Figure imgf000107_0001
31. The method of any one of claims 1-30, wherein the disease is systemic lupus nephritis.
32. The method of any one of claims 1-30, wherein the disease is diabetic chronic kidney disease (CDK).
33. The method of any one of claims 1-30, wherein the disease is Alport syndrome.
34. The method of any one of claims 1-30, wherein the disease is focal segmental glomerulosclerosis (FSGS).
35. The method of any one of claims 1-30, wherein the disease is pulmonary hypertension.
36. The method of any one of claims 1-30, wherein the disease is Friedreich's ataxia.
37. The method of any one of claims 1-30, wherein the disease is autosomal dominant polycystic kidney disease (ADPKD)
38. The method of any one of claims 1-30, wherein the disease is IgA nephropathy.
39. A method of treating a disease that is systemic lupus nephritis, diabetic chronic kidney disease (CDK), Alport syndrome, focal segmental glomerulosclerosis (FSGS), pulmonary hypertension, Friedreich's ataxia, autosomal dominant polycystic kidney disease (ADPKD), or IgA nephropathy, the method comprising administering a compound of Formula (VIII), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, to a subject in need thereof:
Figure imgf000108_0001
wherein: R1 is hydrogen, deuterium, halogen, -CN, -ORb, -NRcRd, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; R3 is halogen, -CN, -OR5, -SR5, -S(=O)R4, -S(=O)2R4, -NO2, -NR6R7, -S(=O)2NR6R7, -C(=O)R4, - OC(=O)R4, -C(=O)OR5, -OC(=O)OR5, -C(=O)NR6R7, -OC(=O)NR6R7, -NR5C(=O)NR6R7, - NR5C(=O)OR5, -NR5S(=O)2NR6R7, -NR5S(=O)2R4, -NR5C(=O)R4, -P(=O)(R4)2, -P(=O)(OR5)2, - B(OR5)2, -NR5C(=NRx)R5, -NR5C(=NRx)NR6R7, -S(=O)(=NRx)R5, -S(=O)(=NRx)NR6R7, - NR5S(=O)2NR5C(=O)R5, -NR5S(=O)(=NRx)R5, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R3a; each R3a is independently oxo, deuterium, halogen, -CN, -OR5, -SR5, -S(=O)R4, -S(=O)2R4, -NO2, - NR6R7, -S(=O)2NR6R7, -C(=O)R4, -OC(=O)R4, -C(=O)OR5, -OC(=O)OR5, -C(=O)NR6R7, - OC(=O)NR6R7, -NR5C(=O)NR6R7, -NR5C(=O)OR5, -NR5S(=O)2NR6R7, -NR5S(=O)2R4, - NR5C(=O)R4, -P(=O)(R4)2, -P(=O)(OR5)2, -B(OR5)2, -NR5C(=NRx)R5, -NR5C(=NRx)NR6R7, - S(=O)(=NRx)R5, -S(=O)(=NRx)NR6R7, -NR5S(=O)2NR5C(=O)R5, -NR5S(=O)(=NRx)R5, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R3b; each R3b is independently deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Rx is hydrogen, -NO2, -CN, or -S(=O)2Ra; each R4 is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R4a; each R4a is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, -NRbC(=NRx)Rb, -NRbC(=NRx)NRcRd, -S(=O)(=NRx)Rb, -S(=O)(=NRx)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R5 is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R5a; or two R5 are taken together to form an optionally substituted heterocycloalkyl; each R5a is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, -NRbC(=NRx)Rb, -NRbC(=NRx)NRcRd, -S(=O)(=NRx)Rb, -S(=O)(=NRx)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R6 and R7 is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R6a; each R6a is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, -NRbC(=NRx)Rb, -NRbC(=NRx)NRcRd, -S(=O)(=NRx)Rb, -S(=O)(=NRx)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or R6 and R7 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R6b; each R6b is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
Figure imgf000109_0001
; Y1 and Y2 are independently hydrogen, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; R8 is hydrogen, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl; R9 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl; R10 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl; R11 is hydrogen, deuterium, halogen, or -ORb; or R3 and R11 are taken together to form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl; R12 is hydrogen, deuterium, -ORb, -NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R13 is -CN, -OR19, -S(=O)2NR20R21, -OC(=O)R18, -OC(=O)OR19, -OC(=O)NR20R21, -NR19C(=O)OR19, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -CH2(cycloalkyl), -CH2(heterocycloalkyl), -CH2(aryl), or - CH2(heteroaryl); wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R13a; each R13a is independently oxo, deuterium, halogen, -CN, -OR19, -SR19, -S(=O)R18, -S(=O)2R18, -NO2, - NR20R21, -S(=O)2NR20R21, -C(=O)R18, -OC(=O)R18, -C(=O)OR19, -OC(=O)OR19, -C(=O)NR20R21, - OC(=O)NR20R21, -NR19C(=O)OR19, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1- C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R18 is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R18a; each R18a is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R19 is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R19a; each R19a is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R20 and R21 are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R20a; each R20a is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or R20 and R21 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R20b; each R20b is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R15 and R16 are independently hydrogen, -ORb, -NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; or R15 and R16 are taken together to form a cycloalkyl or a heterocycloalkyl; each substituted with 0-6 R2; each R2 is independently deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; each Ra is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three deuterium, halogen, -OH, -NH2, or C1-C6 alkyl; each Rb is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three halogen, -OH, -NH2, or C1-C6 alkyl; and each Rc and Rd is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three deuterium, halogen, -OH, -NH2, or C1-C6 alkyl; or Rc and Rd are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three deuterium, halogen, -OH, -NH2, or C1- C6 alkyl.
40. The method of claim 39, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: R1 is -CN, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl.
41. The method of claim 39 or 40, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: R1 is -CN.
42. The method of any one of claims 39-41, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: R8 is hydrogen.
43. The method of any one of claims 39-42, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: R9 is C1-C6 alkyl.
44. The method of any one of claims 39-43, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: R10 is C1-C6 alkyl.
45. The method of any one of claims 39-44, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
Figure imgf000112_0001
.
46. The method of any one of claims 39-45, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: Y1 and Y2 are hydrogen.
47. The method of any one of claims 39-46, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: R11 is hydrogen, halogen, or -OH.
48. The method of any one of claims 39-47, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: R11 is hydrogen.
49. The method of any one of claims 39-48, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: R12 is hydrogen, C1-C6 alkyl, or C1-C6 deuteroalkyl.
50. The method of any one of claims 39-49, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: R12 is C1-C6 alkyl.
51. The method of any one of claims 39-50, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: R13 is –CN, heterocycloalkyl, heteroaryl, or -CH2(heteroaryl); wherein the heterocycloalkyl and heteroaryl are independently optionally substituted with one, two, or three R13a.
52. The method of any one of claims 39-51, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: R13 is heterocycloalkyl or heteroaryl; wherein the heterocycloalkyl and heteroaryl are independently optionally substituted with one, two, or three R13a.
53. The method of any one of claims 39-52, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: R13 is heteroaryl optionally substituted with one, two, or three R13a.
54. The method of any one of claims 39-53, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: R13 is heterocycloalkyl optionally substituted with one, two, or three R13a.
55. The method of any one of claims 39-54, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: each R13a is independently oxo, -OR19, -NR20R21, -C(=O)R18, -C(=O)OR19, -C(=O)NR20R21, C1- C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, or aryl.
56. The method of any one of claims 39-55, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: each R13a is independently oxo, -OR19, -NR20R21, -C(=O)NR20R21, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or aryl.
57. The method of any one of claims 39-56, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: each R13a is independently -OR19, -NR20R21, or -C(=O)NR20R21.
58. The method of any one of claims 39-57, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: R15 and R16 are independently hydrogen, C1-C6 alkyl, or C1-C6 deuteroalkyl.
59. The method of any one of claims 39-58, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: R15 and R16 are independently C1-C6 alkyl.
60. The method of any one of claims 39-59, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: R3 is C1-C6 alkyl or -C(=O)OR5.
61. The method of any one of claims 39-60, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: R3 is C1-C6 alkyl.
62. The compound of claim 38, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound is:
Figure imgf000114_0001
Figure imgf000115_0001
,
63. The method of any one of claims 39-62, wherein the disease is systemic lupus nephritis.
64. The method of any one of claims 39-62, wherein the disease is diabetic chronic kidney disease (CDK).
65. The method of any one of claims 39-62, wherein the disease is Alport syndrome.
66. The method of any one of claims 39-62, wherein the disease is focal segmental glomerulosclerosis (FSGS).
67. The method of any one of claims 39-62, wherein the disease is pulmonary hypertension.
68. The method of any one of claims 39-62, wherein the disease is Friedreich's ataxia.
69. The method of any one of claims 39-62, wherein the disease is autosomal dominant polycystic kidney disease (ADPKD) 70. The method of any one of claims 39-62, wherein the disease is IgA nephropathy.
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