WO2020068689A1 - Terpinoid derivatives and uses thereof - Google Patents

Terpinoid derivatives and uses thereof Download PDF

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Publication number
WO2020068689A1
WO2020068689A1 PCT/US2019/052472 US2019052472W WO2020068689A1 WO 2020068689 A1 WO2020068689 A1 WO 2020068689A1 US 2019052472 W US2019052472 W US 2019052472W WO 2020068689 A1 WO2020068689 A1 WO 2020068689A1
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Prior art keywords
alkyl
heterocycloalkyl
compound
cycloalkyl
independently
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PCT/US2019/052472
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French (fr)
Inventor
Bohan Jin
Qing Dong
Gene Hung
Stephen W. Kaldor
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Fronthera U.S. Pharmaceuticals Llc
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Application filed by Fronthera U.S. Pharmaceuticals Llc filed Critical Fronthera U.S. Pharmaceuticals Llc
Priority to JP2021543112A priority Critical patent/JP2022501445A/en
Priority to MX2021003643A priority patent/MX2021003643A/en
Priority to US17/280,824 priority patent/US20220017566A1/en
Priority to EP19864744.8A priority patent/EP3856755A4/en
Priority to AU2019346395A priority patent/AU2019346395A1/en
Priority to CN201980063930.2A priority patent/CN113366010A/en
Priority to BR112021005919-9A priority patent/BR112021005919A2/en
Priority to CA3114354A priority patent/CA3114354A1/en
Publication of WO2020068689A1 publication Critical patent/WO2020068689A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
    • C07J63/008—Expansion of ring D by one atom, e.g. D homo steroids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/008—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J73/00—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms
    • C07J73/001—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom
    • C07J73/005—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom by nitrogen as hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
    • C07J71/0005—Oxygen-containing hetero ring
    • C07J71/001—Oxiranes

Definitions

  • Described herein are compounds, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds to treat, prevent or diagnose diseases, disorders, or conditions associated with oxidative stress and inflammation.
  • CDDO 2-cyano-3, 12-diooxooleana- 1,9(1 l)-dien-28-oic acid
  • CDDO-Me Bardoxolone methyl
  • Synthetic triterpenoid analogs of oleanolic acid have also been shown to be inhibitors of cellular inflammatory processes, such as the induction by IFN-g of inducible nitric oxide synthase (iNOS), and of COX-2 in mouse macrophages.
  • IFN-g inducible nitric oxide synthase
  • COX-2 in mouse macrophages.
  • Compounds derived from oleanolic acid have been shown to affect the function of multiple protein targets and thereby modulate the activity of several important cellular signaling pathways related to oxidative stress, cell cycle control, and inflammation.
  • Y is a bond, -0-, -S-, or -NR b -;
  • Z is a bond or G-Galkylcnc:
  • each R 4 is independently -Cs alkyl, G-G, alkenyl, C -C alkynyl, C -C haloalkyl, C -G,
  • deuteroalkyl -Ce hydroxyalkyl, C -G, aminoalkyl, C -C ( , heteroalkyl, cycloalkyl,
  • heterocycloalkyl aryl, or heteroaryl
  • alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R 4a ;
  • each R 5 is independently hydrogen, C 1 -C,, alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -G, deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, G-G 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 R 5a ;
  • R 5 are taken together to form an optionally substituted heterocycloalkyl
  • each R 6 and R 7 is independently hydrogen, G-G alkyl, G-G alkenyl, G-G alkynyl, C 1 -G, haloalkyl, G-G deuteroalkyl, C 1 -G, hydroxyalkyl, C 1 -G, aminoalkyl, C 1 -G, 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 R 6a ;
  • 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( _ 0)R a , -CGO)OR b .
  • R 9 is G-G alkyl, G-G alkenyl, G-G alkynyl, C 1 -G, haloalkyl, or 1 -G, deuteroalkyl;
  • R 10 is G-G alkyl, G-G, alkenyl, G-G alkynyl, G-G haloalkyl, or C 1 -G, deuteroalkyl;
  • R 11 is hydrogen, deuterium, halogen, or -OR b ; or R 3 and R 11 are taken together to form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl;
  • R 12 and R 13 are independently hydrogen, -OR b , -NR c R d , Ci-C ⁇ 5 alkyl, G-G alkenyl, C 2 -C 6 alkynyl, G- G, haloalkyl, C 1 -G, deuteroalkyl, C 1 -C 6 hydroxyalkyl, G-G, aminoalkyl, or C 1 -G, heteroalkyl; or R 12 and R 13 are taken together to form a cycloalkyl or a heterocycloalkyl; each substituted with 0-6
  • R 15 and R 16 are independently hydrogen, -OR b , -NR c R d , G-G, alkyl, C 2 -C 6 alkenyl, G-G alkynyl, G- G, haloalkyl, C 1 -G, deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -G, aminoalkyl, or G-G heteroalkyl; or R 15 and R 16 are taken together to form a cycloalkyl or a heterocycloalkyl; each substituted with 0-6 R 2 ;
  • each R a is independently C 1 -G, alkyl, G-G alkenyl, G-G, alkynyl, C 1 -G, haloalkyl, C 1 -G,
  • deuteroalkyl G-G hydroxyalkyl, C 1 -G, aminoalkyl, G-G 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, -N3 ⁇ 4, or C 1 -G, alkyl;
  • each R b is independently hydrogen, G-G, alkyl, G-G alkenyl, G-G alkynyl, C 1 -G, haloalkyl, G-G deuteroalkyl, C 1 -G, hydroxyalkyl, C 1 -G, aminoalkyl, G-G 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, -NH 2 , or C 1 -G, alkyl;
  • each R c and R d is independently hydrogen, G-G alkyl, G-G alkenyl, G-G alkynyl, G-G haloalkyl, C 1 -G, deuteroalkyl, C 1 -G, hydroxyalkyl, C 1 -G, aminoalkyl, C 1 -G, 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 statutoryum, halogen, -OH, -NH 2 , or C 1 -G, 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 G-G alkyl.
  • each R 4 is independently Ci-Ce alkyl, G-G alkenyl, G-G, alkynyl, C i -G, haloalkyl, C i-G, deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, G-G 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 R 4a ;
  • each R 5 is independently hydrogen, C -G alkyl, G-G, alkenyl, G-G alkynyl, C -G, haloalkyl, C -G, deuteroalkyl, C -G, hydroxyalkyl, C -G, aminoalkyl, C -G, 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 R 5a ;
  • R 5 are taken together to form an optionally substituted heterocycloalkyl
  • each R 6 and R 7 is independently hydrogen, G-G alkyl, G-G alkenyl, G-G alkynyl, C -G, haloalkyl, G- G deuteroalkyl, G-G hydroxyalkyl, C -G, aminoalkyl, G-G heteroalkyl, cycloalkyl,
  • heterocycloalkyl aryl, or heteroaryl
  • alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R 6a ;
  • 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 ;
  • R 9 is G-G alkyl, G-G alkenyl, G-G alkynyl, G-G haloalkyl, or G-G deuteroalkyl;
  • R 10 is G-G alkyl, G-G alkenyl, G-G alkynyl, G-G haloalkyl, or G-G deuteroalkyl;
  • R 11 is hydrogen, deuterium, halogen, or -OR b ;
  • R 3 and R 11 are taken together to form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl ;
  • R 12 is hydrogen, deuterium, -OR b , -NR c R d , G-G alkyl, G-G, alkenyl, G-G alkynyl, G-G haloalkyl, G- G deuteroalkyl, G-G hydroxyalkyl, G-G aminoalkyl, G-G heteroalkyl, cycloalkyl,
  • each R 18 is independently Ci-Ce alkyl, C 2 -C 6 alkenyl, G-G, alkynyl, C i -CV, haloalkyl, C i -G, deuteroalkyl, C1-C6 hydroxyalkyl, Ci-Ce aminoalkyl, Ci-Ce 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 R 18a ;
  • each R 19 is independently hydrogen, Ci-Ce alkyl, C 2 -CY, alkenyl, C 2 -C6 alkynyl, C 1 -G, haloalkyl, Ci-Ce deuteroalkyl, Ci-Ce hydroxyalkyl, Ci-Ce aminoalkyl, C 1 -G, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl, Ci-Ce hydroxyalkyl, C 1 -G, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cyclo
  • each R 20 and R 21 are independently hydrogen, Ci-Ce alkyl, C 2 -G, alkenyl, C 2 -G, alkynyl, C 1 -G, haloalkyl, C1-C6 deuteroalkyl, C 1 -G, hydroxyalkyl, Ci-C ⁇ 5 aminoalkyl, C 1 -G, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl,
  • heterocycloalkyl optionally substituted with one, two, or three R 20b ;
  • R 15 and R 16 are independently hydrogen, -OR b , -NR c R d , C 1 -CY, alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, Ci-Ce haloalkyl, Ci-Ce deuteroalkyl, C1-C6 hydroxyalkyl, C 1 -CY, aminoalkyl, C 1 -CY, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • R 15 and R 16 are independently hydrogen, -OR b , -NR c R d , C 1 -CY, alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, Ci-Ce haloalkyl, Ci-Ce deuteroalkyl, C 1 -CY, hydroxyalkyl, Ci-Ce aminoalkyl, or Ci-Ce heteroalkyl;
  • Ci-C 6 alkyl C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, Ci-Ce haloalkyl, Ci-Ce deuteroalkyl, G-G > hydroxyalkyl, Ci-Ce aminoalkyl, Ci-Ce heteroalkyl, cycloalkyl, or heterocycloalkyl;
  • each R a is independently C 1 -G, alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, Ci-Ce haloalkyl, C 1 -G, deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, Ci-Ce 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, -NH 2 , or C 1 -G, alkyl;
  • each R b is independently hydrogen, C 1 -G, alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, Ci-Ce haloalkyl, C 1 -G, deuteroalkyl, C 1 -G, hydroxyalkyl, Ci-Ce aminoalkyl, C 1 -G, 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, -NH 2 , or Ci- Ce alkyl; and
  • each R c and R d is independently hydrogen, Ci-Ce alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -G, haloalkyl, Ci- Ce deuteroalkyl, 1 -G, hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -G, heteroalkyl, cycloalkyl,
  • heterocycloalkyl aryl, or heteroaryl
  • alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three deuterium, halogen, -OH, -NH 2 , or Ci-Ce 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 Ci- C 6 alkyl.
  • composition comprising a therapeutically effective amount of a compound disclosed herein, and a pharmaceutically acceptable excipient.
  • a method for treating a disease in a mammal comprising administering to the mammal a therapeutically effective amount of a compound or a pharmaceutical composition disclosed herein.
  • the disease is an inflammatory disease.
  • the disease is diabetic nephropathy or chronic kidney disease.
  • the disease is chronic obstructive pulmonary disease (COPD) or inflammatory bowel disease (IBD).
  • COPD chronic obstructive pulmonary disease
  • IBD inflammatory bowel disease
  • the disease is nonalcoholic steatohepatitis (NASH).
  • “Aliphatic chain” refers to a linear chemical moiety that is composed of only carbons and hydrogens
  • the aliphatic chain is saturated.
  • the aliphatic chain is unsaturated.
  • the unsaturated aliphatic chain contains one unsaturation.
  • the unsaturated aliphatic chain contains more than one unsaturation.
  • the unsaturated aliphatic chain contains two unsaturations.
  • the unsaturated aliphatic chain contains one double bond.
  • 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-l- 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-l -pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4- methyl -2 -pentyl, 2,2-dimethyl- 1 -butyl, 3,3-dimethyl-l-butyl, 2 -ethyl-1 -butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl, and
  • a numerical range such as“Ci-Ce 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 Ci-Cio alkyl, a C1-C9 alkyl, a Ci-Cs alkyl, a C1-C7 alkyl, a CVG, alkyl, a C1-C5 alkyl, a C1-C4 alkyl, a C1-C3 alkyl, a C1-C2 alkyl, or a Ci 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 -NO2.
  • 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 as 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 -Cio alkenyl, a C 2 -Cg alkenyl, a C 2 -Cg alkenyl, a C 2 -C 7 alkenyl, a C 2 -C 6 alkenyl, a C 2 -Cs 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 -N0 2.
  • an alkenyl is optionally substituted with oxo, halogen, -CN, -CF 3 , -OH, or -OMe.
  • the 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.
  • a numerical range such as“C 2 -C ⁇ 5 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 -Cio alkynyl, a C 2 -Cg alkynyl, a C 2 -Cs alkynyl, a C 2 -C 7 alkynyl, a CVG, alkynyl, a CS-CN 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, nitnle, 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 -N0 2 .
  • an alkynyl is optionally substituted with oxo, halogen, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the 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 -N0 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 -N0 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.
  • 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.
  • 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.
  • 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 -N0 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 -CA cycloalkyl), from three to ten carbon atoms (C 3 -Cio cycloalkyl), from three to eight carbon atoms (C 3 -Cs cycloalkyl), from three to six carbon atoms (C -G, cycloalkyl), from three to five carbon atoms (C 3 -C 3 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, norbomyl, 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
  • 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, mtnle, 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 -NO2.
  • 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. 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, 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 .
  • 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.
  • 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 i-C , hcteroalkyl 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.
  • heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
  • heteroalkyl examples include, 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 -N0 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 quatemized.
  • 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 (C2-C8 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[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl,
  • heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to, the monosaccharides, the disaccharides, and the oligosaccharides.
  • 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.
  • 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 quatemized.
  • 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, acridmyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][l,4]dioxepinyl,
  • 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, -CF3, -OH, -OMe, -NH2, or -NO2.
  • a heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroaryl is optionally substituted with halogen.
  • 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.
  • triterpenoid derivatives that exhibit, for example, anti-inflammatory and/or antioxidant properties.
  • Ring A is a cycloalkyl or a heterocycloalkyl
  • Ci-Ce alkyl C 2 -C ⁇ 5 alkenyl, C2-G5 alkynyl, C 1 -G, haloalkyl, C 1 -G, deuteroalkyl, Ci-Ce hydroxyalkyl, C1-C6 aminoalkyl, or Ci-Ce heteroalkyl;
  • n 0-6;
  • haloalkyl Ci-Ce deuteroalkyl, C 1 -C,, hydroxyalkyl, Ci-Ce aminoalkyl, C 1 -G, 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 R 3a ;
  • each R 4 is independently Ci-Ce alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C ( haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -G, aminoalkyl, C 1 -G, 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 R 4a ;
  • each R 5 is independently hydrogen, Ci-Gs alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1 -G, haloalkyl, C 1 -G, deuteroalkyl, Ci-Gs hydroxyalkyl, Ci-Ce aminoalkyl, C 1 -G, 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 R 5a ;
  • R 5 are taken together to form an optionally substituted heterocycloalkyl
  • each R 6 and R 7 is independently hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-G5 alkynyl, C 1 -CV, haloalkyl, Ci- C (5 deuteroalkyl, C 1 -G, hydroxyalkyl, C 1 -CV, aminoalkyl, Ci-Ce heteroalkyl, cycloalkyl,
  • heterocycloalkyl aryl, or heteroaryl
  • alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R 6a ;
  • 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 ;
  • R 9 is Ci-Ce alkyl, C 2 -C6 alkenyl, C 2 -C6 alkynyl, C 1 -G, haloalkyl, or C 1 -G, deuteroalkyl;
  • R 10 is Ci-C ⁇ 5 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, or C 1 -G > deuteroalkyl;
  • R 11 is hydrogen, deuterium, halogen, or -OR b ;
  • R 3 and R 11 are taken together to form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl;
  • R 12 and R 13 are independently hydrogen, -OR b , -NR c R d , C 1 -G, alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -G, deuteroalkyl, C 1 -C, hydroxyalkyl, Ci-Ce aminoalkyl, or C 1 -G, heteroalkyl;
  • each R a is independently C 1 -G, alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -G, deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -G, aminoalkyl, C 1 -CV, 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, -NH 2 , or C 1 -G, alkyl;
  • each R b is independently hydrogen, C 1 -G, alkyl, C 2 -C 6 alkenyl, G-G, alkynyl, C 1 -G, haloalkyl, C 1 -G, deuteroalkyl, C 1 -G, hydroxyalkyl, C 1 -G, aminoalkyl, C 1 -G, 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, -NH 2 , or Ci- C 5 alkyl; and
  • each R c and R d is independently hydrogen, C 1 -G, alkyl, C2-G5 alkenyl, C2-G5 alkynyl, C 1 -G, haloalkyl, Ci- C ( 5 deuteroalkyl, C 1 -G, hydroxyalkyl, C1-C6 aminoalkyl, C1-G5 heteroalkyl, cycloalkyl,
  • heterocycloalkyl aryl, or heteroaryl
  • alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three deuterium, halogen, -OH, -NH 2 , or C 1 -G, 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 Ci- C 6 alkyl.
  • R 1 is -CN, Ci-Ce alkyl, Ci-G, haloalkyl, or Ci-Ce deuteroalkyl. In some embodiments of a compound of Formula (I), R 1 is -CN or C 1 -G, haloalkyl. In some embodiments of a compound of Formula (I), R 1 is G-Ce haloalkyl. In some embodiments of a compound of Formula (I), R 1 is -CN.
  • R 8 is hydrogen or deuterium. In some embodiments of a compound of Formula (I), R 8 is hydrogen.
  • R 9 is Ci-Ce alkyl or C2-C6 alkynyl. In some embodiments of a compound of Formula (I), R 9 is Ci-Ce alkyl.
  • R 10 is G-G; alkyl or C 2 -C 6 alkynyl. In some embodiments of a compound of Formula (I), R 10 is C 1 -C 6 alkyl. [0037] In some embodiments of a compound of Formula (I), R 9 is C i -G > alkyl and R 10 is G-G > alkynyl.
  • R 10 is Ci-Ce alkyl and R 9 is G-Ce alkynyl.
  • R 11 is hydrogen, halogen, or -OH. In some embodiments of a compound of Formula (I), R 11 is hydrogen or -OH. In some embodiments of a compound of Formula (I), R 11 is hydrogen.
  • R 12 and R 13 are independently hydrogen, Ci- C ( , alkyl, or C -C, deuteroalkyl. In some embodiments of a compound of Formula (I), R 12 and R 13 are independently hydrogen or Ci-Ce alkyl. In some embodiments of a compound of Formula (I), R 12 and R 13 are independently hydrogen or Ci-Ce deuteroalkyl. In some embodiments of a compound of Formula (I), R 12 and R 13 are independently Ci-Ce alkyl.
  • 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. In some embodiments of a compound of Formula (I), 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.
  • 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. In some embodiments of a compound of Formula (I), 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 Ci-Ce alkyl optionally substituted with one, two, or three R 3a . In some embodiments of a compound of Formula (I), R 3 is C -G, alkyl.
  • each R 3b is independently deuterium, halogen, -CN, -OR b , C i -G, alkyl, -C 6 haloalkyl, or C i -G, deuteroalkyl.
  • each R 3b is independently deuterium, halogen, C rG, alkyl, Ci-Ce haloalkyl, or C i -C o deuteroalkyl.
  • each R 4 is independently Ci-C 5 alkyl, C 2 -G, alkenyl, G-G, alkynyl, C i -G, haloalkyl, C i -G, 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 G- G, alkyl or cycloalkyl; wherein the alkyl and cycloalkyl are independently optionally substituted with one, two, or three R 4a .
  • each R 4 is independently C i -G, alkyl optionally substituted with one, two, or three R 4a .
  • each R 4 is independently C i -G, alkyl.
  • each R 4 is independently C i -G, alkyl, C i -G, haloalkyl, or C i -G, deuteroalkyl.
  • each R 4a is independently oxo, deuterium, halogen, -CN, -OR b , -NR c R d , C i -G, alkyl, C i -G, haloalkyl, cycloalkyl, or heterocycloalkyl.
  • each R 4a is independently deuterium or halogen.
  • each R 4a is independently halogen.
  • each R 5 is independently hydrogen, G-C 6 alkyl, C i -G, haloalkyl, G-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 i -G, 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 Ci- C (1 alkyl optionally substituted with one, two, or three R 5a . In some embodiments of a compound of Formula (I), each R 5 is independently Ci-Ce 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 Ci-Ce alkyl. In some embodiments of a compound of Formula (I), each R 5 is independently hydrogen, Ci-Ce alkyl, C1-C6 haloalkyl, or C 1 -G, 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 -G, alkyl, C 1 -G, 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, Ci-Ce alkyl, Ci-Ce haloalkyl, C 1 -G, 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, Ci-Ce alkyl, C 1 -C o 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 -G, alkyl, or C 1 -G, 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 Ci-Ce alkyl. In some embodiments of a compound of Formula (I), each R 6 and R 7 is independently hydrogen, Ci-C ⁇ 5 alkyl, C 1 -G, haloalkyl, or G- C , deuteroalkyl.
  • each R 6a is independently oxo, deuterium, halogen, -CN, -OR b , -NR c R d , C 1 -G, alkyl, G-G, 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 , 1 -G, alkyl, C 1 -G, haloalkyl, C 1 -G, hydroxyalkyl, cycloalkyl, or heterocycloalkyl.
  • each R 6b is independently C 1 -G, alkyl or G-G haloalkyl. In some embodiments of a compound of Formula (I), each R 6b is independently G-G alkyl.
  • R x is hydrogen, -NO2, or -CN. In some embodiments of a compound of Formula (I), R x is -NO2 or -CN. In some embodiments of a compound of Formula (I), R x is -CN.
  • Ring A is a cycloalkyl. In some embodiments of a compound of Formula (I), Ring A is a heterocycloalkyl.
  • each R 2 is independently deuterium, halogen, -CN, -OR b , C 1 -G, alkyl, or C i-G, 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. 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.
  • Ring B is a cycloalkyl or a heterocycloalkyl
  • n 0-6;
  • each R 4 is independently C 1 -G, alkyl, G-G alkenyl, C 2 -C ( , alkynyl, C 1 -G, haloalkyl, G-G, deuteroalkyl, G-G hydroxyalkyl, G-G aminoalkyl, C 1 -CV, 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 R 4a ;
  • each R 5 is independently hydrogen, C 1 -G, alkyl, G-G, alkenyl, G-G, alkynyl, C 1 -G, haloalkyl, C 1 -G, deuteroalkyl, G-G, hydroxyalkyl, C 1 -G, aminoalkyl, C 1 -G, 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 R 5a ;
  • R 5 are taken together to form an optionally substituted heterocycloalkyl
  • each R 6 and R 7 is independently hydrogen, Ci-Ce alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C1-C6 haloalkyl, G- C 6 deuteroalkyl, C1-C6 hydroxyalkyl, G-G, aminoalkyl, C 1 -G, 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 R 6a ;
  • 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 ;
  • R 9 is G-G alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, G-G haloalkyl, or C 1 -G deuteroalkyl;
  • R 10 is G-G alkyl, C 2 -C 6 alkenyl, G-G alkynyl, G-G haloalkyl, or C 1 -G, deuteroalkyl;
  • R 11 is hydrogen, deuterium, halogen, or -OR b ;
  • R 3 and R 1 1 are taken together to form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl;
  • R 15 and R 16 are independently hydrogen, -OR b , -NR c R d , C 1 -G, alkyl, G-G alkenyl, G-G alkynyl, C 1 -G, haloalkyl, Ci-Ce deuteroalkyl, G-G hydroxyalkyl, C 1 -G, aminoalkyl, or C 1 -G, heteroalkyl;
  • each R a is independently C 1 -G, alkyl, G-G alkenyl, G-G alkynyl, C 1 -G, haloalkyl, C 1 -G, deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -G, aminoalkyl, G-G 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, -NH 2 , or C 1 -G, alkyl;
  • each R b is independently hydrogen, C 1 -G, alkyl, G-G alkenyl, G-G alkynyl, G-G haloalkyl, C 1 -G, deuteroalkyl, G-G hydroxyalkyl, G-G aminoalkyl, Ci-Ce 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, -NH 2 , or G- C6 alkyl; and
  • each R c and R d is independently hydrogen, G-G alkyl, G-G alkenyl, G-G alkynyl, G-G haloalkyl, G- G deuteroalkyl, G-G hydroxyalkyl, G-G aminoalkyl, G-G heteroalkyl, cycloalkyl,
  • heterocycloalkyl aryl, or heteroaryl
  • alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three deuterium, halogen, -OH, -NH 2 , or C i -G, 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 3 ⁇ 4 or Ci- C 6 alkyl.
  • R 1 is -CN, C i -G, alkyl, C i -G, haloalkyl, or Ci-Ce deuteroalkyl. In some embodiments of a compound of Formula (II), R 1 is -CN or C i -G, haloalkyl.
  • R 1 is Ci-Gs haloalkyl. In some embodiments of a compound of Formula (II), R 1 is -CN.
  • R 8 is hydrogen or deuterium. In some embodiments of a compound of Formula (II), R 8 is hydrogen.
  • R 9 is Ci-Ce alkyl or C 2 -C 6 alkynyl. In some embodiments of a compound of Formula (II), R 9 is C i -G, alkyl.
  • R 10 is C1-C6 alkyl or C 2 -C 6 alkynyl. In some embodiments of a compound of Formula (II), R 10 is C1-C6 alkyl.
  • R 9 is Ci-Ce alkyl and R 10 is Ci-Ce alkynyl.
  • R 10 is Ci-Cs alkyl and R 9 is C 2 -C6 alkynyl.
  • R 11 is hydrogen, halogen, or -OH. In some embodiments of a compound of Formula (II), R 11 is hydrogen or -OH. In some embodiments of a compound of Formula (II), R 11 is hydrogen.
  • R 15 and R 16 are independently hydrogen, Ci-Ce alkyl, or C i -G, deuteroalkyl. In some embodiments of a compound of Formula (II), R 15 and R 16 are independently hydrogen or Ci-Gs alkyl. In some embodiments of a compound of Formula (II), R 15 and R 16 are independently hydrogen or Ci-Ce deuteroalkyl. In some embodiments of a compound of Formula (II), R 15 and R 16 are independently Ci-Ce 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.
  • R 3 is Ci-Ce alkyl optionally substituted with one, two, or three R 3a . In some embodiments of a compound of Formula (II), R 3 is C i -C,, alkyl
  • each R 3b is independently deuterium, halogen, -CN, -OR b , Ci-Ce alkyl, C i -G, haloalkyl, or C1-G5 deuteroalkyl.
  • each R 3b is independently deuterium, halogen, Ci-Gs alkyl, Ci-Gs haloalkyl, or Ci-Ce deuteroalkyl.
  • each R 4 is independently C1-C6 alkyl, C 2 -C 6 alkenyl, C 2 -C 3 ⁇ 4 alkynyl, Ci-Ce haloalkyl, C i -G, 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 Ci- C , alkyl or cycloalkyl; wherein the alkyl and cycloalkyl are independently optionally substituted with one, two, or three R 4a .
  • each R 4 is independently C i -G, alkyl optionally substituted with one, two, or three R 4a .
  • each R 4 is independently Ci-Ce alkyl.
  • each R 4 is independently C1-C6 alkyl, Ci-Ce haloalkyl, or Ci-Ce deuteroalkyl.
  • each R 4a is independently oxo, deuterium, halogen, -CN, -OR b , -NR c R d , C 1 -G, alkyl, C 1 -G, haloalkyl, cycloalkyl, or heterocycloalkyl.
  • each R 4a is independently deuterium or halogen.
  • each R 4a is independently halogen.
  • each R 5 is independently hydrogen, Ci-Gs alkyl, Ci-Ce haloalkyl, C 1 -G, 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, Ci-Ce 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 Ci- C6 alkyl optionally substituted with one, two, or three R 5a . In some embodiments of a compound of Formula (II), each R 5 is independently C 1 -C,, alkyl optionally substituted with one, two, or three R 5a . In some embodiments of a compound of Formula (II), each R 5 is hydrogen or Ci-Ce alkyl. In some embodiments of a compound of Formula (II), each R 5 is independently hydrogen, Ci-Ce alkyl, C 1 -G, haloalkyl, or C1-C6 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 -G, alkyl, Ci-Cs 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, Ci-Ce alkyl, C -G > haloalkyl, C -G, 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, Ci-Ce alkyl, C -G, 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, Ci-Ce alkyl, or Ci-Ce haloalkyl; wherein the alkyl are independently optionally substituted with one, two, or three R 6a .
  • each R 5 and R 7 is independently hydrogen or C i -G, alkyl.
  • each R 6 and R 7 is independently hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, or C i -G, deuteroalkyl.
  • each R 6a is independently oxo, deuterium, halogen, -CN, -OR b , -NR c R d , C1-C6 alkyl, Ci-Ce 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 , Ci-Gs alkyl, C i -G, haloalkyl, Ci-Gs hydroxyalkyl, cycloalkyl, or heterocycloalkyl.
  • each R 6b is independently C i -G, alkyl or Ci-Ce haloalkyl.
  • each R 6b is independently Ci-Ce alkyl.
  • R x is hydrogen, -NO2, or -CN. In some embodiments of a compound of Formula (II), R x is -NO2 or -CN. In some embodiments of a compound of Formula (II), R x is -CN.
  • Ring B is a cycloalkyl. In some embodiments of a compound of Formula (II), Ring B is a heterocycloalkyl.
  • each R 14 is independently deuterium, halogen, -CN, -OR b , C 1 -G, alkyl, or CVG, 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. 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.
  • Ci-Ce alkyl Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1 -G, haloalkyl, Ci-Ce deuteroalkyl, C 1 -G, hydroxyalkyl, C1-C6 aminoalkyl, or Ci-Ce heteroalkyl;
  • Y is a bond, -0-, -S-, or -NR b -;
  • Z is a bond or Ci -G, alkylene:
  • each R 5 is independently hydrogen, C 1 -G, alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -G, haloalkyl, C 1 -G, deuteroalkyl, Ci-Ce hydroxyalkyl, C1-C aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, C 1 -G, haloalkyl, Ci-Ce deuteroalkyl, C1-C aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl
  • R 5 are taken together to form an optionally substituted heterocycloalkyl
  • each R 6 and R 7 is independently hydrogen, Ci-Ce alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -G, haloalkyl, Ci- Ce deuteroalkyl, C 1 -G, hydroxyalkyl, C 1 -G, aminoalkyl, C 1 -G, heteroalkyl, cycloalkyl,
  • heterocycloalkyl aryl, or heteroaryl
  • alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R 6a ;
  • Ci-Ce alkyl C 2 -C6 alkenyl, C 2 -C6 alkynyl, C 1 -G, haloalkyl, C 1 -G, deuteroalkyl, C 1 -G, hydroxyalkyl, C 1 -G, aminoalkyl, C 1 -G, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or 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 ;
  • Ci-Ce alkyl C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -G, haloalkyl, C 1 -G, deuteroalkyl, C 1 -G, hydroxyalkyl, C 1 -G, aminoalkyl, C 1 -G, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • R 9 is Ci-Ce alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, or Ci-Ce deuteroalkyl;
  • R 10 is Ci-Ce alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, Ci-Cs haloalkyl, or Ci-Gs deuteroalkyl;
  • R 11 is hydrogen, deuterium, halogen, or -OR b ;
  • R 3 and R 11 are taken together to form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl;
  • R 12 and R 13 are independently hydrogen, -OR b , -NR c R d , Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1 -G, haloalkyl, Ci-Ce deuteroalkyl, C 1 -G, hydroxyalkyl, C 1 -G, aminoalkyl, or C 1 -G, heteroalkyl;
  • each R a is independently C 1 -C 6 alkyl, C 2 -C alkenyl, C 2 -C 6 alkynyl, C 1 -C haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, Ci-Ce aminoalkyl, Ci-Ce 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, -NH 2 , or C 1 -G > alkyl;
  • each R b is independently hydrogen, C 1 -G, alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C 1 -G, deuteroalkyl, Ci-Ce hydroxyalkyl, C 1 -G, aminoalkyl, C 1 -G, 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 Ci- Ce alkyl; and
  • each R c and R d is independently hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1 -G, haloalkyl, Ci- Ce deuteroalkyl, C 1 -G, hydroxyalkyl, C 1 -G, aminoalkyl, C 1 -G, heteroalkyl, cycloalkyl,
  • heterocycloalkyl aryl, or heteroaryl
  • alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three deuterium, halogen, -OH, -NH2, or C 1 -G, 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 Ci- C 6 alkyl.
  • R 1 is -CN, Ci-Ce alkyl, C 1 -G, haloalkyl, or Ci-Ce deuteroalkyl. In some embodiments of a compound of Formula (III), R 1 is -CN or C 1 -G, haloalkyl. In some embodiments of a compound of Formula (III), R 1 is Ci-Cs haloalkyl. In some embodiments of a compound of Formula (III), R 1 is -CN.
  • R 8 is hydrogen or deuterium. In some embodiments of a compound of Formula (III), R 8 is hydrogen.
  • R 9 is Ci-C ⁇ 5 alkyl or C2-C6 alkynyl. In some embodiments of a compound of Formula (III), R 9 is Ci-C ⁇ 5 alkyl.
  • R 10 is Ci-Ce alkyl or C2-C6 alkynyl. In some embodiments of a compound of Formula (III), R 10 is Ci-Ce alkyl.
  • R 9 is C1-C6 alkyl and R 10 is C2-C6 alkynyl.
  • R 10 is C 1 -C,, alkyl and R 9 is C2-C6 alkynyl.
  • R 11 is hydrogen, halogen, or -OH. In some embodiments of a compound of Formula (III), R 11 is hydrogen or -OH. In some embodiments of a compound of Formula (III), R 11 is hydrogen.
  • R 12 and R 13 are independently hydrogen, Ci-Ce alkyl, or C i -G, deuteroalkyl. In some embodiments of a compound of Formula (III), R 12 and R 13 are independently hydrogen or Ci-Ce alkyl. In some embodiments of a compound of Formula (III), R 12 and R 13 are independently hydrogen or Ci-Ce deuteroalkyl. In some embodiments of a compound of Formula (III), R 12 and R 13 are independently Ci-Ce alkyl.
  • R 12 and R 13 are taken together to form a cycloalkyl. In some embodiments of a compound of Formula (III), 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.
  • R 12 and R 13 are taken together to form a heterocycloalkyl. In some embodiments of a compound of Formula (III), 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.
  • R 15 and R 16 are independently hydrogen, Ci-Ce alkyl, or C i -C-, deuteroalkyl. In some embodiments of a compound of Formula (III), R 15 and R 16 are independently hydrogen or Ci-Ce alkyl. In some embodiments of a compound of Formula (III), R 15 and R 16 are independently hydrogen or Ci-Ce deuteroalkyl. In some embodiments of a compound of Formula (III), R 15 and R 16 are independently Ci-Ce alkyl.
  • 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. In some embodiments of a compound of Formula (III), 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.
  • 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. In some embodiments of a compound of Formula (III), 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 N-linked heterocycloalkyl or N-linked heteroaryl.
  • -Y is a bond. In some embodiments of a compound of Formula (III), Y is a bond or -0-.
  • each R 4 is independently Ci-Ce alkyl, C 2 -Ce alkenyl, CVG, alkynyl, Ci-Ce haloalkyl, C i -G, 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 Ci-Ce alkyl or cycloalkyl; wherein the alkyl and cycloalkyl are independently optionally substituted with one, two, or three R 4a .
  • each R 4 is independently Ci-Ce alkyl optionally substituted with one, two, or three R 4a .
  • each R 4 is independently C i -G, alkyl.
  • each R 4 is independently G-G alkyl, G-G haloalkyl, or G-G deuteroalkyl.
  • each R 4a is independently oxo, deuterium, halogen, -CN, -OR b , -NR c R d , C i -G, alkyl, G-G haloalkyl, cycloalkyl, or heterocycloalkyl.
  • each R 4a is independently deuterium or halogen.
  • each R 4a is independently halogen.
  • each R 5 is independently hydrogen, G- G alkyl, G-G haloalkyl, C i -G, 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, G-G 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 G-G 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 i -G, 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 G-G alkyl. In some embodiments of a compound of Formula (III), each R 5 is independently hydrogen, G-G alkyl, C i -G, haloalkyl, or G-G 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 i -G, alkyl, C i -G, 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, G-G alkyl, G-G, haloalkyl, G-G, 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, G- G, alkyl, Ci-Ce 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, Ci-Ce alkyl, or Ci-Ce 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 G-G alkyl.
  • each R 6 and R 7 is independently hydrogen, G-G alkyl, G-G haloalkyl, or G-G deuteroalkyl.
  • each R 6a is independently oxo, deuterium, halogen, -CN, -OR b , -NR c R d , Ci-Ce alkyl, Ci-Ce haloalkyl, cycloalkyl, or heterocycloalkyl.
  • each R 6a is independently deuterium or halogen.
  • each R 6a is independently halogen.
  • R 5 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 , Ci-Ce alkyl, C i -G, haloalkyl, C i -G, hydroxyalkyl, cycloalkyl, or heterocycloalkyl.
  • each R 6b is independently C i -G, alkyl or Ci-Ce haloalkyl.
  • each R 6b is independently Ci-Ce alkyl.
  • R x is hydrogen, -NO2, or -CN. In some embodiments of a compound of Formula (III), R x is -NO2 or -CN. In some embodiments of a compound of Formula (III), R x is -CN.
  • R 3 is H , H H H
  • R 3 is
  • Ci-Ce alkyl Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C 1 -G, deuteroalkyl, C 1 -G, hydroxyalkyl, Ci-Ce aminoalkyl, or Ci-Ce heteroalkyl;
  • each R 4 is independently C 1 -G, alkyl, G-G alkenyl, G-G alkynyl, C 1 -G, haloalkyl, C i-G, deuteroalkyl, C1-C6 hydroxyalkyl, G-G aminoalkyl, C 1 -G, 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 R 4a ;
  • each R 5 is independently hydrogen, C 1 -G, alkyl, G-G, alkenyl, G-G, alkynyl, C 1 -G, haloalkyl, C 1 -G, deuteroalkyl, C 1 -G, hydroxyalkyl, C 1 -G, aminoalkyl, C 1 -G, 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 R 5a ;
  • R 5 are taken together to form an optionally substituted heterocycloalkyl
  • each R 6 and R 7 is independently hydrogen, G-G alkyl, G-G alkenyl, G-G, alkynyl, C 1 -G, haloalkyl, G- G deuteroalkyl, C 1 -G, hydroxyalkyl, G-G aminoalkyl, C 1 -G, heteroalkyl, cycloalkyl,
  • heterocycloalkyl aryl, or heteroaryl
  • alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R 6a ;
  • 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 ;
  • JL is JL or J TM .
  • R 9 is G-G alkyl, C 2 -C6 alkenyl, C 2 -C6 alkynyl, C 1 -G, haloalkyl, or C 1 -G, deuteroalkyl;
  • R 10 is Ci-Ce alkyl, G-G alkenyl, G-G alkynyl, G-G haloalkyl, or C 1 -G, deuteroalkyl;
  • R 9 or R 10 is G-G alkynyl
  • R 11 is hydrogen, deuterium, halogen, or -OR b ;
  • R 3 and R 11 are taken together to form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl;
  • R 12 and R 13 are independently hydrogen, -OR b , -NR c R d , C 1 -G, alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -G, haloalkyl, G-G deuteroalkyl, C 1 -G, hydroxyalkyl, C 1 -G, aminoalkyl, or C 1 -G, heteroalkyl;
  • R 15 and R 1S are independently hydrogen, -OR b , -NR c R d , C 1 -G, alkyl, G-G alkenyl, G-G alkynyl, C 1 -G, haloalkyl, C 1 -G, deuteroalkyl, or C 1 -G, hydroxyalkyl;
  • each R a is independently C 1 -C 6 alkyl, G-G alkenyl, G-G alkynyl, G-G haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -G, aminoalkyl, C 1 -G, 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, -NH 2 , or C 1 -G, alkyl;
  • each R b is independently hydrogen, C 1 -G, alkyl, C 2 -C 6 alkenyl, G-G alkynyl, C 1 -G, haloalkyl, C 1 -G, deuteroalkyl, C 1 -G, hydroxyalkyl, G-G aminoalkyl, C 1 -G, 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, -NH 2 , or G- G alkyl; and each R c and R d is independently hydrogen, C i -C , alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, Ci-Ce haloalkyl, Ci-
  • heterocycloalkyl aryl, or heteroaryl
  • alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three deuterium, halogen, -OH, -NH 2 , or Ci-Ce 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 Ci- C 6 alkyl.
  • R 1 is -CN, Ci-Ce alkyl, C 1 -G, haloalkyl, or Ci-Ce deuteroalkyl. In some embodiments of a compound of Formula (IV), R 1 is -CN or C 1 -G, haloalkyl. In some embodiments of a compound of Formula (IV), R 1 is Ci-Ce haloalkyl. In some embodiments of a compound of Formula (IV), R 1 is -CN.
  • R 8 is hydrogen or deuterium. In some embodiments of a compound of Formula (IV), R 8 is hydrogen.
  • R 9 is Ci-Ce alkyl or C2-C6 alkynyl. In some embodiments of a compound of Formula (IV), R 9 is C2-C alkynyl. In some embodiments of a compound of Formula (IV), R 9 is Ci-Gs alkyl.
  • R 10 is Ci-Ce alkyl or C2-C6 alkynyl. In some embodiments of a compound of Formula (IV), R 10 is C2-C6 alkynyl. In some embodiments of a compound of Formula (IV), R 10 is Ci-Ce alkyl.
  • R 9 is Ci-Ce alkyl and R 10 is C2-C6 alkynyl.
  • R 10 is Ci-Ce alkyl and R 9 is C2-C6 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, Ci-Ce alkyl, or C 1 -G, deuteroalkyl. In some embodiments of a compound of Formula (IV), R 12 and R 13 are independently hydrogen or Ci-Ce alkyl. In some embodiments of a compound of Formula (IV), R 12 and R 13 are independently hydrogen or Ci-Ce deuteroalkyl. In some embodiments of a compound of Formula (IV), R 12 and R 13 are independently Ci-Gs alkyl.
  • R 12 and R 13 are taken together to form a cycloalkyl. In some embodiments of a compound of Formula (IV), 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.
  • R 12 and R 13 are taken together to form a heterocycloalkyl. In some embodiments of a compound of Formula (IV), 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.
  • R 15 and R 16 are independently hydrogen, Ci-Ce alkyl, or C i -O, deuteroalkyl. In some embodiments of a compound of Formula (IV), R 15 and R 16 are independently hydrogen or Ci-Gs alkyl. In some embodiments of a compound of Formula (IV), R 15 and R 16 are independently hydrogen or Ci-Ce deuteroalkyl. In some embodiments of a compound of Formula (IV), R 15 and R 16 are independently Ci-Gs alkyl.
  • 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. In some embodiments of a compound of Formula (IV), 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 1S 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 (IV), 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 (IV), 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 halogen, -CN, -OR 5 , -NR 6 R 7 , -
  • R 3 is Ci-Ce alkyl optionally substituted with one, two, or three R 3a . In some embodiments of a compound of Formula (IV), R 3 is Ci-Ce alkyl.
  • each R 3b is independently deuterium, halogen, -CN, -OR b , G-G alkyl, G-G haloalkyl, or C i -G, deuteroalkyl.
  • each R 3b is independently deuterium, halogen, C i -G, alkyl, G-G haloalkyl, or G-G, deuteroalkyl.
  • each R 4 is independently C i -G, alkyl, G-G alkenyl, G-G alkynyl, G-G haloalkyl, C i -G, 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 i -G alkyl or cycloalkyl; wherein the alkyl and cycloalkyl are independently optionally substituted with one, two, or three R 4a .
  • each R 4 is independently C i -G, alkyl optionally substituted with one, two, or three R 4a .
  • each R 4 is independently G-G alkyl.
  • each R 4 is independently G-G alkyl, G-G haloalkyl, or G-G deuteroalkyl.
  • each R 4a is independently oxo, deuterium, halogen, -CN, -OR b , -NR c R d , G-G alkyl, G-G haloalkyl, cycloalkyl, or heterocycloalkyl.
  • each R 4a is independently deuterium or halogen.
  • each R 4a is independently halogen.
  • each R 5 is independently hydrogen, G- G alkyl, G-G haloalkyl, G-G 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, G-G 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 i -G, 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 i -C , 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 Ci-G, alkyl. In some embodiments of a compound of Formula (IV), each R 5 is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C 1 -G, 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 , C1-C6 alkyl, C 1 -G, 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, Ci-Gs alkyl, C 1 -G, haloalkyl, C 1 -G, 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, Ci-Cs alkyl, C 1 -G, haloalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one, two, or three R" a .
  • each R 6 and R 7 is independently hydrogen, G-G, alkyl, or C 1 -G, 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 C1-C6 alkyl. In some embodiments of a compound of Formula (IV), each R 6 and R 7 is independently hydrogen, C 1 -C o alkyl, C 1 -G, haloalkyl, or C 1 -G, deuteroalkyl.
  • each R 6a is independently oxo, deuterium, halogen, -CN, -OR b , -NR c R d , C 1 -G, alkyl, C 1 -G, 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 ® is independently oxo, deuterium, halogen, -CN, -OR b , -NR c R d , C1-C alkyl, C 1 -G, haloalkyl, C1-C6 hydroxyalkyl, cycloalkyl, or heterocycloalkyl.
  • each R 6b is independently C 1 -G, alkyl or Ci-C ⁇ 5 haloalkyl.
  • each R 6b is independently Ci-Ce alkyl.
  • R x is hydrogen, -NO2, or -CN. In some embodiments of a compound of Formula (IV), R x is -NO2 or -CN. In some embodiments of a compound of Formula (IV), R x is -CN.
  • Ci-Ce alkyl C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -G, haloalkyl, Ci-Ce deuteroalkyl, Ci-Ce hydroxyalkyl, C1-C6 aminoalkyl, or Ci-Ce heteroalkyl;
  • haloalkyl Ci-Ce deuteroalkyl, C 1 -C, hydroxyalkyl, Ci-Ce aminoalkyl, C 1 -G, 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 R 3a ;
  • each R 5 is independently hydrogen, G-G alkyl, G-G alkenyl, C 2 -C 6 alkynyl, G-G haloalkyl, G-G deuteroalkyl, G-G hydroxyalkyl, G-G aminoalkyl, C 1 -G, 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 R 5a ;
  • R 5 are taken together to form an optionally substituted heterocycloalkyl
  • each R 6 and R 7 is independently hydrogen, G-G alkyl, G-G, alkenyl, G-G alkynyl, G-G haloalkyl, G- G deuteroalkyl, G-G hydroxyalkyl, G-G aminoalkyl, G-G heteroalkyl, cycloalkyl,
  • heterocycloalkyl aryl, or heteroaryl
  • alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R 6a ;
  • 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 ;
  • R 9 is G-G alkyl, G-G alkenyl, G-G alkynyl, G-G haloalkyl, or G-G deuteroalkyl;
  • R 10 is G-G alkyl, G-G alkenyl, G-G alkynyl, G-G haloalkyl, or G-G deuteroalkyl;
  • R 11 is hydrogen, deuterium, halogen, or -OR b ;
  • R 12 and R 13 are independently hydrogen, -OR b , -NR c R d , C i -G, alkyl, C 2 -G 5 alkenyl, C 2 -C 6 alkynyl, Ci-Ce haloalkyl, C 1 -G, deuteroalkyl, C 1 -C,, hydroxyalkyl, Ci-Ce aminoalkyl, or C 1 -G, heteroalkyl;
  • each R a is independently C 1 -G, alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -G, deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -G, aminoalkyl, C 1 -G, 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, -NH 2 , or C 1 -G, alkyl;
  • each R b is independently hydrogen, C 1 -G, alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -G, deuteroalkyl, C 1 -G, hydroxyalkyl, C 1 -G, aminoalkyl, C 1 -G, 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, -NH 2 , or Ci- C6 alkyl; and
  • each R c and R d is independently hydrogen, C 1 -G, alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -G, haloalkyl, Ci- C 5 deuteroalkyl, C 1 -G, hydroxyalkyl, Ci-C ⁇ 5 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl,
  • heterocycloalkyl aryl, or heteroaryl
  • alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three deuterium, halogen, -OH, -NH 2 , or C 1 -G, 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 Ci- C 6 alkyl.
  • R 1 is -CN, Ci-Ce alkyl, C 1 -G, haloalkyl, or Ci-Ce deuteroalkyl. In some embodiments of a compound of Formula (V), R 1 is -CN or Ci-C ⁇ 5 haloalkyl. In some embodiments of a compound of Formula (V), R 1 is Ci-Ce haloalkyl. In some embodiments of a compound of Formula (V), R 1 is -CN.
  • R 8 is hydrogen or deuterium. In some embodiments of a compound of Formula (V), R 8 is hydrogen.
  • R 9 is C 1 -G, 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 -G 5 alkyl.
  • R 10 is Ci-Ce 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 Ci-Ce alkyl.
  • R 9 is C i -G, alkyl and R 10 is C2-C6 alkynyl. In some embodiments of a compound of Formula (V), R 10 is C 1 -G > alkyl and R 9 is C2-G5 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 (Y), R 11 is hydrogen.
  • R 12 and R 13 are independently hydrogen, C 1 -Co alkyl, or C 1 -C:, deuteroalkyl. In some embodiments of a compound of Formula (V), R 12 and R 13 are independently hydrogen or C 1 -G, alkyl. In some embodiments of a compound of Formula (V), R 12 and R 13 are independently hydrogen or C 1 -G, deuteroalkyl. In some embodiments of a compound of Formula (V), R 12 and R 13 are independently C 1 -G, alkyl.
  • R 12 and R 13 are taken together to form a cycloalkyl. In some embodiments of a compound of Formula (V), 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 (Y), R 12 and R 13 are taken together to form a cycloalkyl substituted with 2-4 deuteriums.
  • R 12 and R 13 are taken together to form a heterocycloalkyl. In some embodiments of a compound of Formula (V), 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.
  • R 17 is hydrogen, C 1 -G, alkyl, C 1 -G, haloalkyl, or C 1 -G, deuteroalkyl. In some embodiments of a compound of Formula (V), R 17 is C 1 -G, alkyl.
  • R 3 is halogen, -CN, -OR 5 , -NR 6 R 7 , -
  • each R 3a is independently -
  • each R 3b is independently deuterium, halogen, -CN, -OR b , C i -G, alkyl, G-G haloalkyl, or C i -G, deuteroalkyl.
  • each R 3b is independently deuterium, halogen, C i -G, alkyl, C i -G, haloalkyl, or C i -C o deuteroalkyl.
  • each R 4 is independently C i -G, alkyl, C 2 - C ( , alkenyl, G-G, alkynyl, Ci-C (5 haloalkyl, C i -G, 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 G- C , alkyl or cycloalkyl; wherein the alkyl and cycloalkyl are independently optionally substituted with one, two, or three R 4a .
  • each R 4 is independently G-G alkyl optionally substituted with one, two, or three R 4a .
  • each R 4 is independently Ci-C ⁇ 5 alkyl.
  • each R 4 is independently G-G alkyl, C i -G, haloalkyl, or G-G, deuteroalkyl.
  • each R 4a is independently oxo, deuterium, halogen, -CN, -OR b , -NR c R d , G-G alkyl, G-G haloalkyl, cycloalkyl, or heterocycloalkyl.
  • each R 4a is independently deuterium or halogen.
  • each R 4a is independently halogen.
  • each R 5 is independently hydrogen, G- G, alkyl, G-G haloalkyl, G-G 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 i -G, 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 Ci- Ce 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 i -G, 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 C1-C6 alkyl. In some embodiments of a compound of Formula (V), each R 5 is independently hydrogen, C1-C alkyl, Ci-Ce haloalkyl, or C 1 -G, 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 -G, alkyl, C 1 -G, 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, Ci-Ce alkyl, C 1 -G, haloalkyl, Ci-Ce 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, Ci- C , alkyl, C 1 -G, haloalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and
  • heterocycloalkyl are independently optionally substituted with one, two, or three R" a .
  • each R 6 and R 7 is independently hydrogen, Ci-C ⁇ 5 alkyl, or C 1 -Co 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 Ci-Ce alkyl.
  • each R 6 and R 7 is independently hydrogen, Ci-Ce alkyl, C 1 -G > haloalkyl, or C rG, deuteroalkyl.
  • each R 6a is independently oxo, deuterium, halogen, -CN, -OR b , -NR c R d , C 1 -C, alkyl, C 1 -G, 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, alkyl, C 1 -G haloalkyl, C 1 -G, hydroxyalkyl, cycloalkyl, or heterocycloalkyl.
  • each R" b is independently C 1 -G, alkyl or G-G, haloalkyl. In some embodiments of a compound of Formula (V), each R 6b is independently G-G alkyl.
  • R x is hydrogen, -N0 2 , or -CN. In some embodiments of a compound of Formula (V), R x is -N0 2 or -CN. In some embodiments of a compound of Formula (V), R x is -CN.
  • Ci-Ce alkyl C 2 -C ⁇ 5 alkenyl, C 2 -Ce alkynyl, C 1 -G, haloalkyl, C 1 -G, deuteroalkyl, Ci-Ce hydroxyalkyl, C 1 -G, aminoalkyl, or C 1 -G, heteroalkyl;
  • haloalkyl Ci-Ce deuteroalkyl, C 1 -C, hydroxyalkyl, Ci-Ce aminoalkyl, C 1 -G, 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 R 3a ;
  • each R 4 is independently Ci-Ce alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -G, aminoalkyl, C 1 -G, 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 R 4a ;
  • each R 5 is independently hydrogen, Ci-Ce alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -G, haloalkyl, C 1 -G, deuteroalkyl, Ci-Ce hydroxyalkyl, Ci-Ce aminoalkyl, C 1 -G, 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 R 5a ;
  • R 5 are taken together to form an optionally substituted heterocycloalkyl
  • each R 6 and R 7 is independently hydrogen, Ci-Ce alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -G, haloalkyl, Ci- C 5 deuteroalkyl, C 1 -G, hydroxyalkyl, C 1 -CY, aminoalkyl, Ci-Ce heteroalkyl, cycloalkyl,
  • heterocycloalkyl aryl, or heteroaryl
  • alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R 6a ;
  • 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 ;
  • R 9 is G-G alkyl, G-G alkenyl, G-G alkynyl, C 1 -G, haloalkyl, or C 1 -G deuteroalkyl;
  • R 10 is G-G alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1 -G, haloalkyl, or C 1 -G, deuteroalkyl;
  • R 11 is hydrogen, deuterium, halogen, or -OR b ;
  • R 3 and R 11 are taken together to form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl;
  • R 12 is hydrogen, deuterium, -OR b , -NR c R d , G-G alkyl, G-G alkenyl, C 2 -C 6 alkynyl, G-G haloalkyl, G- G deuteroalkyl, C 1 -G, hydroxyalkyl, C 1 -G aminoalkyl, G-G heteroalkyl, cycloalkyl,
  • heterocycloalkyl aryl, or heteroaryl; provided that R 12 is not -CH 3 ;
  • each R 18 is independently G-G alkyl, alkenyl, G-G alkynyl, C 1 -G, haloalkyl, C 1 -G, deuteroalkyl, C1-C6 hydroxyalkyl, G-G aminoalkyl, C 1 -G, 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 R 18a ;
  • each R 19 is independently hydrogen, G-G alkyl, G-G alkenyl, G-G alkynyl, G-G, haloalkyl, G-G deuteroalkyl, G-G hydroxyalkyl, G-G aminoalkyl, G-G heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, hetero
  • each R 20 and R 21 are independently hydrogen, G-G alkyl, G-G alkenyl, G-G alkynyl, G-G haloalkyl, G-G deuteroalkyl, G-G hydroxyalkyl, G-G aminoalkyl, G-G heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R 20 and R 21 are independently hydrogen, G-G alkyl, G-G alkenyl, G-G alkynyl, G-G haloalkyl, G-G deuteroalkyl, G-G hydroxyalkyl, G-G aminoalkyl, G-G heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally
  • heterocycloalkyl optionally substituted with one, two, or three R 20b ;
  • R 15 and R 16 are independently hydrogen, -OR b , -NR c R d , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -G, haloalkyl, G-G deuteroalkyl, C 1 -C, hydroxyalkyl, C 1 -G, aminoalkyl, or C 1 -G, heteroalkyl;
  • each R a is independently C 1 -G, alkyl, G-G alkenyl, G-G alkynyl, G-G haloalkyl, G-G deuteroalkyl, C 1 -C 6 hydroxyalkyl, G-G aminoalkyl, G-G 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, -NH 2 , or C 1 -G, alkyl;
  • each R b is independently hydrogen, C 1 -G, alkyl, G-G, alkenyl, G-G alkynyl, C 1 -G, haloalkyl, C 1 -G, deuteroalkyl, C 1 -G, hydroxyalkyl, C 1 -G, aminoalkyl, C 1 -G, 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, -NH 2 , or G- C 5 alkyl; and
  • each R c and R d is independently hydrogen, C 1 -G, alkyl, G-G alkenyl, G-G alkynyl, C 1 -G, haloalkyl, G- G deuteroalkyl, C 1 -G, hydroxyalkyl, G-G aminoalkyl, C 1 -C, heteroalkyl, cycloalkyl,
  • heterocycloalkyl aryl, or heteroaryl
  • alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three deuterium, halogen, -OH, -NH 2 , or C 1 -G, 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 doctrineum, halogen, -OH, -NH 2 , or G- G alkyl.
  • Y 1 and Y 2 are independently hydrogen, deuterium, halogen, -OR b , C 1 -G, alkyl, C 1 -G, haloalkyl, or G-G 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 G-G 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 , Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce deuteroalkyl, C i -C , hydroxyalkyl, or cycloalkyl; provided that R 12 is not -CH 3 .
  • R 12 is hydrogen, deuterium, C i -G, alkyl, Ci-Ce haloalkyl, or Ci-Ce 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 Ci-Ce alkyl; provided that R 12 is not -CH 3 . In some embodiments of a compound of Formula (VI), R 12 is Ci-Ce alkyl; provided that R 12 is not -CH 3 .
  • each R 13a is independently deuterium, halogen, -CN, -OR 19 , -NR 20 R 21 , C i -G, alkyl, C i -CV, haloalkyl, Ci-Ce deuteroalkyl, Ci-C ⁇ 3 ⁇ 4 hydroxyalkyl, C i -G, aminoalkyl, or C i -C , heteroalkyl.
  • each R 13a is independently deuterium, halogen, -CN, -OR 19 , -NR 20 R 21 , Ci-Ce alkyl, Ci-C ⁇ 3 ⁇ 4 haloalkyl, or C i -C , deuteroalkyl.
  • Ci-Ce alkyl C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, Ci-C 6 haloalkyl, Ci-C 6 deuteroalkyl, G-G, hydroxyalkyl, Ci-Ce aminoalkyl, or Ci-Ce heteroalkyl;
  • each R 4 is independently Ci-Ce alkyl, C 2 -Ce alkenyl, C 2 -C alkynyl, Ci-Ce haloalkyl, G-G, deuteroalkyl, C1-C6 hydroxyalkyl, C i -G, aminoalkyl, Ci-Ce 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 R 4a ;
  • each R 5 is independently hydrogen, C -G alkyl, G-G, alkenyl, G-G alkynyl, C -G, haloalkyl, C -G, deuteroalkyl, C -G, hydroxyalkyl, C -G, aminoalkyl, C -G, 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 R 5a ;
  • R 5 are taken together to form an optionally substituted heterocycloalkyl
  • each R 6 and R 7 is independently hydrogen, G-G alkyl, G-G alkenyl, G-G alkynyl, C -G, haloalkyl, G- G deuteroalkyl, G-G hydroxyalkyl, C -G, aminoalkyl, G-G heteroalkyl, cycloalkyl,
  • heterocycloalkyl aryl, or heteroaryl
  • alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R 6a ;
  • 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 ;
  • R 9 is G-G alkyl, G-G alkenyl, G-G alkynyl, G-G haloalkyl, or G-G deuteroalkyl;
  • R 10 is G-G alkyl, G-G alkenyl, G-G alkynyl, G-G haloalkyl, or G-G deuteroalkyl;
  • R 11 is hydrogen, deuterium, halogen, or -OR b ;
  • R 3 and R 11 are taken together to form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl ;
  • R 12 is hydrogen, deuterium, -OR b , -NR c R d , G-G alkyl, G-G, alkenyl, G-G alkynyl, G-G haloalkyl, G- G deuteroalkyl, G-G hydroxyalkyl, G-G aminoalkyl, G-G heteroalkyl, cycloalkyl,
  • each R 18 is independently G-G alkyl, C 2 -C 6 alkenyl, G-G, alkynyl, C i -G, haloalkyl, C i -G, deuteroalkyl, -C 6 hydroxyalkyl, C i -G, aminoalkyl, G-G 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 R 18a ;
  • each R 19 is independently hydrogen, G-G alkyl, G-G alkenyl, G-G alkynyl, G-G haloalkyl, G-G deuteroalkyl, G-G hydroxyalkyl, G-G aminoalkyl, G-G heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R 19 is independently hydrogen, G-G alkyl, G-G alkenyl, G-G alkynyl, G-G haloalkyl, G-G deuteroalkyl, G-G hydroxyalkyl, G-G aminoalkyl, G-G heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with
  • each R 20 and R 21 are independently hydrogen, G-G alkyl, G-G, alkenyl, G-G, alkynyl, G-G haloalkyl, G-G deuteroalkyl, G-G hydroxyalkyl, G-G aminoalkyl, G-G heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R 20 and R 21 are independently hydrogen, G-G alkyl, G-G, alkenyl, G-G, alkynyl, G-G haloalkyl, G-G deuteroalkyl, G-G hydroxyalkyl, G-G aminoalkyl, G-G heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are
  • heterocycloalkyl optionally substituted with one, two, or three R 20b ;
  • R 15 and R 16 are independently hydrogen, -OR b , -NR c R d , G-G alkyl, G-G alkenyl, G-G alkynyl, G-G haloalkyl, G-G deuteroalkyl, G-G hydroxyalkyl, G-G aminoalkyl, G-G heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R 15 and R 16 are independently hydrogen, -OR b , -NR c R d , G-G alkyl, G-G alkenyl, G-G alkynyl, G-G haloalkyl, G-G deuteroalkyl, G-G hydroxyalkyl, G-G aminoalkyl, or G-G heteroalkyl; or R 15 and R 16 are taken together to form a cycloalkyl or a heterocycloalkyl; each substituted with 0-6 R 2 ;
  • Ci-C 6 alkyl C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, Ci-Ce haloalkyl, C 1 -G, deuteroalkyl, Ci-Ce hydroxyalkyl, C 1 -C 6 aminoalkyl, Ci-Ce heteroalkyl, cycloalkyl, or heterocycloalkyl;
  • each R a is independently C 1 -C 6 alkyl, C 2 -C alkenyl, C 2 -C 6 alkynyl, C 1 -C haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -G, aminoalkyl, Ci-Ce 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, -NH 2 , or C 1 -G, alkyl;
  • each R b is independently hydrogen, C 1 -G, alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, Ci-Ce haloalkyl, C 1 -G, deuteroalkyl, C 1 -G, hydroxyalkyl, Ci-Ce aminoalkyl, C 1 -G, 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, -NH 2 , or G- Ce alkyl; and
  • each R c and R d is independently hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1 -G, haloalkyl, G- Ce deuteroalkyl, C 1 -G, hydroxyalkyl, C 1 -CY, aminoalkyl, C 1 -G, heteroalkyl, cycloalkyl,
  • heterocycloalkyl aryl, or heteroaryl
  • alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three deuterium, halogen, -OH, -NH2, or G-G 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 G- C 6 alkyl.
  • Y 1 and Y 2 are independently hydrogen, deuterium, halogen, -OR b , C 1 -G, alkyl, C 1 -G, haloalkyl, or C 1 -G, 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 Ci-Ce alkyl; provided that one of Y 1 or Y 2 is not hydrogen.
  • R 12 is hydrogen, deuterium, -OR b , - NR c R d , Ci-Ce alkyl, C 1 -G, haloalkyl, Ci-Ce deuteroalkyl, G -G, hydroxyalkyl, or cycloalkyl.
  • R 12 is hydrogen, deuterium, G-G alkyl, C 1 -C, haloalkyl, or G-G deuteroalkyl.
  • R 12 is hydrogen or deuterium.
  • R 12 is hydrogen.
  • R 12 is hydrogen or C1-C6 alkyl. In some embodiments of a compound of Formula (VII), R 12 is G-G alkyl.
  • each R 13a is independently deuterium, halogen, -CN, -OR 19 , -NR 20 R 21 , Ci-Ce alkyl, C 1 -G, haloalkyl, C 1 -G, deuteroalkyl, C1-C6 hydroxyalkyl, Ci-Ce aminoalkyl, or Ci-Ce heteroalkyl.
  • each R 13a is independently deuterium, halogen, -CN, -OR 19 , -NR 20 R 21 , C 1 -G, alkyl, Ci-Ce haloalkyl, or C 1 -G, deuteroalkyl.
  • each R 4 is independently C 1 -G, alkyl, G-G alkenyl, G-G alkynyl, C 1 -G, haloalkyl, G-G, deuteroalkyl, C1-C6 hydroxyalkyl, C 1 -G, aminoalkyl, C 1 -CV, 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 R 4a ;
  • each R 5 is independently hydrogen, C 1 -G, alkyl, G-G, alkenyl, G-G, alkynyl, C 1 -G, haloalkyl, C 1 -G, deuteroalkyl, C 1 -G, hydroxyalkyl, C 1 -G, aminoalkyl, C 1 -G, 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 R 5a ;
  • R 5 are taken together to form an optionally substituted heterocycloalkyl
  • each R 6 and R 7 is independently hydrogen, C 1 -G, alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C1-C6 haloalkyl, G- G deuteroalkyl, C1-C6 hydroxyalkyl, G-G, aminoalkyl, C 1 -G, heteroalkyl, cycloalkyl,
  • heterocycloalkyl aryl, or heteroaryl
  • 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 ;
  • R 9 is G-G alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -G, haloalkyl, or C 1 -G, deuteroalkyl;
  • R 10 is G-G alkyl, G-G alkenyl, G-G alkynyl, C 1 -G, haloalkyl, or C 1 -G, deuteroalkyl;
  • R 11 is hydrogen, deuterium, halogen, or -OR b ;
  • R 3 and R 11 are taken together to form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl;
  • R 12 is hydrogen, deuterium, -OR b , -NR c R d , C 1 -G alkyl, G-G, alkenyl, G-G alkynyl, C 1 -G, haloalkyl, G- G deuteroalkyl, G-G hydroxyalkyl, G-G aminoalkyl, G-G heteroalkyl, cycloalkyl,
  • heterocycloalkyl aryl, or heteroaryl
  • each R 19 is independently hydrogen, C 1 -G, alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -G, haloalkyl, C 1 -G, deuteroalkyl, C 1 -C 6 hydroxyalkyl, G-G aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R 19 is independently hydrogen, C 1 -G, alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -G, haloalkyl, C 1 -G, deuteroalkyl, C 1 -C 6 hydroxyalkyl, G-G aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alky
  • each R 20 and R 21 are independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -G, haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -G > aminoalkyl, C 1 -G, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R 20 and R 21 are independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -G, haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -G, hydroxyalkyl, C 1 -G, aminoalkyl, C 1 -G, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein
  • heterocycloalkyl optionally substituted with one, two, or three R 20b ;
  • R 15 and R 16 are independently hydrogen, -OR b , -NR c R d , C 1 -G, alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -G, haloalkyl, C 1 -G, deuteroalkyl, C 1 -C,, hydroxyalkyl, C 1 -G, aminoalkyl, or C 1 -G, heteroalkyl;
  • each R a is independently C 1 -G, alkyl, G-G alkenyl, G-G, alkynyl, C 1 -G, haloalkyl, C 1 -G, deuteroalkyl, G-G hydroxyalkyl, C 1 -G, aminoalkyl, C 1 -G, 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, -NH 2 , or C 1 -G, alkyl;
  • each R b is independently hydrogen, C 1 -G, alkyl, G-G alkenyl, G-G alkynyl, C 1 -G, haloalkyl, C 1 -G, deuteroalkyl, G-G hydroxyalkyl, G-G aminoalkyl, G-G 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, -NH 2 , or G- G alkyl; and each R c and R d is independently hydrogen, C i -C ( , alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, Ci- C5 deuteroalkyl, Ci-C
  • heterocycloalkyl aryl, or heteroaryl
  • alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three deuterium, halogen, -OH, -NH 2 , or Ci-Ce 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 Ci- C 6 alkyl.
  • Y 1 and Y 2 are independently hydrogen, deuterium, halogen, -OR b , Ci-Ce alkyl, C 1 -G, haloalkyl, or C 1 -G, deuteroalkyl.
  • Y 1 and Y 2 are independently hydrogen, deuterium, halogen, or -OR b .
  • Y 1 and Y 2 are independently hydrogen, deuterium, -OR b , or C 1 -G, alkyl.
  • Y 1 and Y 2 are hydrogen.
  • R 12 is hydrogen, deuterium, -OR b , - NR c R d , C 1 -G, alkyl, Ci-Ce haloalkyl, C 1 -G, deuteroalkyl, C 1 -G, hydroxyalkyl, or cycloalkyl.
  • R 12 is hydrogen, deuterium, Ci-Ce alkyl, C1-C6 haloalkyl, or Ci-Ce deuteroalkyl.
  • R 12 is hydrogen or deuterium.
  • R 12 is hydrogen. In some embodiments of a compound of Formula (VIII), R 12 is hydrogen or Ci-Ce alkyl. In some embodiments of a compound of Formula (VIII), R 12 is C1-C6 alkyl.
  • R 13 is -CN.
  • R 13 is Ci-Ce 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 , Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce deuteroalkyl, Ci-Ce hydroxyalkyl, Ci-Ce aminoalkyl, or Ci-Ce heteroalkyl.
  • each R 13a is independently deuterium, halogen, -CN, -OR 19 , -NR 20 R 21 , C i -C, alkyl, Ci-C ⁇ 5 haloalkyl, or C 1 -G, deuteroalkyl.
  • each R 13a is independently -OR 19 .
  • R 1 is -CN, C 1 -G, alkyl, Ci-Ce haloalkyl, or Ci-Ce deuteroalkyl. In some embodiments of a compound of Formula (VI)-(VIII), R 1 is -CN or Ci-Ce haloalkyl. In some embodiments of a compound of Formula (VI) -(VIII), R 1 is C 1 -G, haloalkyl. In some embodiments of a compound of Formula (VI)-(VIII), R 1 is -CN.
  • R 8 is hydrogen or deuterium. In some embodiments of a compound of Formula (VI)-(VIII), R 8 is hydrogen.
  • R 9 is C 1 -G, alkyl or C2-C6 alkynyl. In some embodiments of a compound of Formula (VI)-(VIII), R 9 is Ci-G, alkyl.
  • R 10 is Ci-Ce alkyl or C2-C6 alkynyl. In some embodiments of a compound of Formula (VI)-(VIII), R 10 is C 1 -G, alkyl.
  • R 9 is C1-C6 alkyl and R 10 is G-G, alkynyl. In some embodiments of a compound of Formula (VI)-(VIII), R 10 is C 1 -G, alkyl and R 9 is C2-C6 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 -G, alkyl, G-G, alkenyl, C2-C6 alkynyl, C 1 -G, haloalkyl, C 1 -G, 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 -G, alkyl or cycloalkyl; wherein the alkyl and cycloalkyl are independently optionally substituted with one, two, or three R 18a .
  • each R 18 is independently C 1 -G, alkyl optionally substituted with one, two, or three R 18a .
  • each R 18 is independently C 1 -G, alkyl.
  • each R 18 is independently C i -G, alkyl, Ci-Ce haloalkyl, or Ci-Ce deuteroalkyl.
  • each R 18a is independently oxo, deuterium, halogen, -CN, -OR b , -NR c R d , C i -G, alkyl, Ci-Ce haloalkyl, cycloalkyl, or heterocycloalkyl.
  • each R 18a is independently deuterium or halogen.
  • each R 18a is independently halogen.
  • each R 19 is independently hydrogen, Ci-Gs alkyl, C i -G, haloalkyl, C i -G, 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, Ci-Ce 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 Ci-Ce alkyl optionally substituted with one, two, or three R 19a . In some embodiments of a compound of Formula (VI)-(VIII), each R 19 is independently Ci-Ce alkyl optionally substituted with one, two, or three R 19a . In some embodiments of a compound of Formula (VI)-(VIII), each R 19 is hydrogen or Ci-Gs alkyl. In some embodiments of a compound of Formula (YI)-(VIII), each R 19 is independently hydrogen, Ci-Cs alkyl, Ci-Ce haloalkyl, or C i -C,, deuteroalkyl.
  • each R 19a is independently oxo, deuterium, halogen, -CN, -OR b , -NR c R d , C i -G, alkyl, Ci-Ce 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, Ci-Ce alkyl, C i -G, haloalkyl, Ci-Ce 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, Ci-Ce alkyl, C i -G, haloalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one, two, or three R" a .
  • each R 20 and R 21 are independently hydrogen, Ci-Ce alkyl, or C i -G, 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 Ci-Ce alkyl. In some embodiments of a compound of Formula (VI)-(YIII), each R 20 and R 21 are independently hydrogen, C i -G, alkyl, C i -G, haloalkyl, or Ci-Ce deuteroalkyl.
  • each R 20a is independently oxo, deuterium, halogen, -CN, -OR b , -NR c R d , Ci-G; alkyl, Ci-Ce 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 , C1-C alkyl, C i -C ( haloalkyl, Ci-Ce hydroxyalkyl, cycloalkyl, or heterocycloalkyl.
  • each R 20b is independently oxo, deuterium, halogen, -CN, -OR b , -NR c R d , C1-C alkyl, C i -C ( haloalkyl, Ci-Ce hydroxyalkyl, cycloalkyl, or heterocycloalkyl.
  • each R 20b is independently oxo, deuterium, halogen, -CN, -OR b , -NR c R d , C1-C alkyl, C i -C ( haloalkyl, Ci-Ce hydroxyalkyl, cycloal
  • each R 20b is independently C i -G, alkyl.
  • each R 3b is independently deuterium, halogen, -CN, -OR b , G-G, alkyl, C i -CV, haloalkyl, or C1-C deuteroalkyl.
  • each R 3b is independently deuterium, halogen, C i -G, alkyl, C1-C6 haloalkyl, or C i -G, deuteroalkyl.
  • each R 4 is independently Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1 -G, haloalkyl, C 1 -G, 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 -Gs alkyl or cycloalkyl; wherein the alkyl and cycloalkyl are independently optionally substituted with one, two, or three R 4a .
  • each R 4 is independently C 1 -C,, alkyl optionally substituted with one, two, or three R 4a .
  • each R 4 is independently C 1 -G, alkyl.
  • each R 4 is independently C 1 -G, alkyl, C 1 -G, haloalkyl, or G-G deuteroalkyl.
  • each R 4a is independently oxo, deuterium, halogen, -CN, -OR b , -NR c R d , G-G alkyl, C 1 -G, 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 o alkyl, C 1 -G, haloalkyl, C 1 -G, 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 -G, 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 C1-C6 alkyl optionally substituted with one, two, or three R 5a .
  • each R 5 is independently G -G alkyl optionally substituted with one, two, or three R 5a .
  • each R 5 is hydrogen or G-G alkyl. In some embodiments of a compound of Formula (VI)-(VIII), each R 5 is independently hydrogen, G-G alkyl, C 1 -G, haloalkyl, or G-C ⁇ 5 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 , G-G alkyl, C 1 -G, 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, G-G alkyl, G-G haloalkyl, C i -G, 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 i -G, alkyl, C1-C6 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, G-G alkyl, or C i -G, 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 C1-C6 alkyl. In some embodiments of a compound of Formula (VI)-(VIII), each R 6 and R 7 is independently hydrogen, G-G alkyl, C i -G, haloalkyl, or C i -G, deuteroalkyl.
  • each R 6a is independently oxo, deuterium, halogen, -CN, -OR b , -NR c R d , G-G alkyl, G-G 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 i -G, alkyl, C i -G, haloalkyl, Ci-Ce hydroxyalkyl, cycloalkyl, or heterocycloalkyl.
  • each R 6b is independently G-G alkyl or G-G haloalkyl.
  • each R 6b is independently G-G alkyl.
  • R x is hydrogen, -NO2, or -CN. In some embodiments of a compound of Formula (VI)-(VIII), R x is -NO2 or -CN. In some embodiments of a compound of Formula (VI)-(VIII), R x is -CN.
  • R 15 and R 16 are independently hydrogen, - alkyl, or G-G deuteroalkyl. In some embodiments of a compound of Formula (VI)- (VIII), R 15 and R 16 are independently hydrogen or G-G alkyl. In some embodiments of a compound of Formula (VI)-(VIII), R 15 and R 16 are independently hydrogen or G-G deuteroalkyl. In some embodiments of a compound of Formula (VI)-(VIII), R 15 and R 16 are independently hydrogen or G-G deuteroalkyl. In some
  • R 15 and R 16 are independently G-G 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"' are taken together to form a cycloalkyl substituted with 1 or 2 deuterium. In some embodiments of a compound of Formula (YI)-(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 Ci-Ce alkyl, Ci-Ce haloalkyl, C i -G, deuteroalkyl, Ci-Ce hydroxyalkyl, C i -G, aminoalkyl, C i -G, 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 i -G, alkyl
  • each R a is independently G-G alkyl, G-G haloalkyl, C i -G deuteroalkyl, cycloalkyl, or heterocycloalkyl; wherein
  • each R a is independently C i -G, alkyl, C i -G, haloalkyl, or C i -G, deuteroalkyl; wherein the alkyl are independently optionally substituted with one, two, or three deuterium, halogen, -OH, -NFF, or Oi-Ob alkyl.
  • each R a is independently G-G alkyl optionally substituted with one, two, or three deuterium, halogen, -OH, -NFF. or G-G alkyl.
  • each R a is independently G-G alkyl.
  • each R b is independently hydrogen, C i -G alkyl, C i -CV > haloalkyl, G-G 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 G-G, alkyl.
  • each R b is independently hydrogen, C i -G, alkyl, C i -G, haloalkyl, or C1-C6 deuteroalkyl; wherein the alkyl are independently optionally substituted with one, two, or three deuterium, halogen, -OH, -NH 2 , or G-G alkyl.
  • each R b is independently hydrogen or G-C ⁇ 5 alkyl optionally substituted with one, two, or three deuterium, halogen, -OH, -NH 2 , or G-G alkyl.
  • each R b is independently hydrogen or G-G 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 G-G alkyl.
  • each R c and R d is independently hydrogen, C i -G, alkyl, -C 6 haloalkyl, G-G 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 6 alkyl.
  • each R c and R d is independently hydrogen, C i -G, alkyl, C i -G, haloalkyl, or C i -G, deuteroalkyl; wherein the alkyl are independently optionally substituted with one, two, or three deuterium, halogen, - OH, -NH 2 , or C i -Co alkyl.
  • each R c and R d is independently hydrogen or Ci-Ce alkyl optionally substituted with one, two, or three deuterium, halogen, - OH, -NH 2 , or C i -C , alkyl.
  • each R c and R d is independently hydrogen or Ci-Ce alkyl.
  • each R b is independently hydrogen.
  • each R c and R d is independently C1-C6 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 Ci-Ce alkyl.
  • 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,
  • 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.
  • 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.
  • the diastereomers are separated by chiral chromatography, or preferably, by separation/resolution techniques based upon differences in solubility.
  • the optically pure enantiomer is then recovered, along with the resolving agent. Labeled compounds
  • the compounds described herein exist in their isotopically-labeled forms.
  • 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 descnbed 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, 13 N, 18 0, 17 0, 31 P, 32 P, 35 S, 18 F, and 3S C1, 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, biolumine scent labels, or chemiluminescent labels.
  • the compounds described herein exist as their pharmaceutically acceptable salts.
  • the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts.
  • 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-l,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-l,6-di
  • 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, methane sulfonic 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 I-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 quatemization of any basic nitrogen-containing groups they contain. In some embodiments, water or oil-soluble or dispersible products are obtained by such quatemization.
  • 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.
  • 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,“Modem
  • the compound described herein is administered as a pure chemical.
  • 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)).
  • 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.
  • 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 pg 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 pg 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.
  • Inflammation is a biological process that provides resistance to infectious or parasitic organisms and the repair of damaged tissue. Inflammation is commonly characterized by localized vasodilation, redness, swelling, and pain, the recruitment of leukocytes to the site of infection or injury, production of inflammatory cytokines such as TNF-a and IL-1, and production of reactive oxygen or nitrogen species such as hydrogen peroxide, superoxide, and peroxynitrite. In later stages of inflammation, tissue remodeling, angiogenesis, and scar formation (fibrosis) may occur as part of the wound healing process. Under normal circumstances, the inflammatory response is regulated and temporary and is resolved in an orchestrated fashion once the infection or injury has been dealt with adequately. However, acute inflammation can become excessive and life-threatening if regulatory mechanisms fail. Alternatively, inflammation can become chronic and cause cumulative tissue damage or systemic complications.
  • Atherosclerosis long viewed as a disorder of lipid metabolism, is now understood to be primarily an inflammatory condition, with activated macrophages playing an important role in the formation and eventual rapture of atherosclerotic plaques. Activation of inflammatory signaling pathways has also been shown to play a role in the development of insulin resistance, as well as in the peripheral tissue damage associated with diabetic hyperglycemia.
  • Autoimmune diseases such as rheumatoid arthritis, lupus, psoriasis, and multiple sclerosis involve inappropriate and chronic activation of inflammatory processes in affected tissues, arising from dysfunction of self vs. non-self recognition and response mechanisms in the immune system.
  • neurodegenerative diseases such as Alzheimer's and Parkinson's diseases
  • neural damage is correlated with activation of microglia and elevated levels of pro -inflammatory proteins such as inducible nitric oxide synthase (iNOS).
  • iNOS inducible nitric oxide synthase
  • Chronic organ failure such as renal failure, heart failure, liver failure, and chronic obstructive pulmonary disease is closely associated with the presence of chronic oxidative stress and inflammation, leading to the development of fibrosis and eventual loss of organ function.
  • Oxidative stress in vascular endothelial cells which line major and minor blood vessels, can lead to endothelial dysfunction and is believed to be an important contributing factor in the development of systemic cardiovascular disease, complications of diabetes, chronic kidney disease, and other forms of organ failure, and a number of other aging -related diseases including degenerative diseases of the central nervous system and the retina.
  • oxidative stress and inflammation in affected tissues including inflammatory bowel disease; inflammatory skin diseases; mucositis related to radiation therapy and chemotherapy; eye diseases such as uveitis, glaucoma, macular degeneration, and various forms of retinopathy; transplant failure and rejection; ischemia-reperfusion injury; chronic pain; degenerative conditions of the bones and joints including osteoarthritis and osteoporosis; asthma and cystic fibrosis; seizure disorders; and neuropsychiatric conditions including schizophrenia, depression, bipolar disorder, post-traumatic stress disorder, attention deficit disorders, autism-spectrum disorders, and eating disorders such as anorexia nervosa. Dysregulation of inflammatory signaling pathways is believed to be a major factor in the pathology of muscle wasting diseases including muscular dystrophy and various forms of cachexia.
  • a variety of life -threatening acute disorders also involve dysregulated inflammatory signaling, including acute organ failure involving the pancreas, kidneys, liver, or lungs, myocardial infarction or acute coronary syndrome, stroke, septic shock, trauma, severe bums, and anaphylaxis.
  • an excessive inflammatory response can also lead to systemic complications due to overproduction of inflammatory cytokines such as TNF-a and IL-1. This is believed to be a factor in mortality arising from severe influenza, severe acute respiratory syndrome, and sepsis.
  • compounds disclosed herein are characterized by their ability to inhibit the production of nitric oxide in macrophage-derived RAW 264.7 cells induced by exposure to g-interferon. They are further characterized by their ability to induce the expression of antioxidant proteins such as NQOl and reduce the expression of pro-inflammatory proteins such as COX-2 and inducible nitric oxide synthase (iNOS).
  • antioxidant proteins such as NQOl
  • pro-inflammatory proteins such as COX-2 and inducible nitric oxide synthase (iNOS).
  • autoimmune diseases cardiovascular diseases including atherosclerosis, ischemia- reperfusion injury, acute and chronic organ failure including renal failure and heart failure, respiratory diseases, diabetes and complications of diabetes, severe allergies, transplant rejection, graft-versus-host disease, neurodegenerative diseases, diseases of the eye and retina, acute and chronic pain, degenerative bone diseases including osteoarthritis and osteoporosis, inflammatory bowel diseases, dermatitis and other skin diseases, sepsis, bums, seizure disorders, and neuropsychiatric disorders.
  • cardiovascular diseases including atherosclerosis, ischemia- reperfusion injury, acute and chronic organ failure including renal failure and heart failure, respiratory diseases, diabetes and complications of diabetes, severe allergies, transplant rejection, graft-versus-host disease, neurodegenerative diseases, diseases of the eye and retina, acute and chronic pain, degenerative bone diseases including osteoarthritis and osteoporosis, inflammatory bowel diseases, dermatitis and other skin diseases, sepsis, bums, seizure disorders, and neuropsychiatric disorders.
  • compounds disclosed herein are used in preventing or treating tissue damage or organ failure, acute and chronic, resulting from oxidative stress exacerbated by inflammation.
  • diseases that fall in this category include: heart failure, liver failure, transplant failure and rejection, renal failure, pancreatitis, fibrotic lung diseases (cystic fibrosis, COPD, and idiopathic pulmonary fibrosis, among others), diabetes (including complications), atherosclerosis, ischemia- reperfusion injury, glaucoma, stroke, autoimmune disease, autism, macular degeneration, and muscular dystrophy.
  • the compounds disclosed herein are generally applied to the treatment of inflammatory conditions, such as sepsis, dermatitis, autoimmune disease, and osteoarthritis.
  • the compounds disclosed herein are used to treat inflammatory pain and/or neuropathic pain, for example, by inducing Nrf2 and/or inhibiting NF-KB.
  • the compounds disclosed herein are used in the treatment and prevention of diseases such as cancer, inflammation, Alzheimer's disease, Parkinson's disease, multiple sclerosis, autism, amyotrophic lateral sclerosis, Huntington's disease, autoimmune diseases such as rheumatoid arthritis, lupus, Crohn's disease, and psoriasis, inflammatory bowel disease, other diseases whose pathogenesis is believed to involve excessive production of either nitric oxide or prostaglandins, and pathologies involving oxidative stress alone or oxidative stress exacerbated by inflammation.
  • diseases such as cancer, inflammation, Alzheimer's disease, Parkinson's disease, multiple sclerosis, autism, amyotrophic lateral sclerosis, Huntington's disease, autoimmune diseases such as rheumatoid arthritis, lupus, Crohn's disease, and psoriasis, inflammatory bowel disease, other diseases whose pathogenesis is believed to involve excessive production of either nitric oxide or prostaglandins
  • the compounds disclosed herein are used in the treatment and prevention of diseases such as NASH. In some embodiments, the compounds disclosed herein are used in the treatment and prevention of diseases such as irritable bowel disease. In some embodiments, the compounds disclosed herein are used in the treatment and prevention of diabetic nephropathy. In some embodiments, the compounds disclosed herein are used in the treatment and prevention of chronic kidney disease.
  • the compounds disclosed herein are used to control the production of pro- inflammatory cytokines within the cell by selectively activating regulatory cysteine residues (RCRs) on proteins that regulate the activity of redox- sensitive transcription factors.
  • RCRs regulatory cysteine residues
  • Activation of RCRs by cyPGs has been shown to initiate a pro-resolution program in which the activity of the antioxidant and cytoprotective transcription factor Nrf2 is potently induced and the activities of the pro -oxidant and pro- inflammatory transcription factors NF-kB and the STATs are suppressed.
  • this increases the production of antioxidant and reductive molecules (NQO l, HO-1, SOD1, g-GCS) and decreases oxidative stress and the production of pro- oxidant and pro-inflammatory molecules (iNOS, COX-2, TNF-a).
  • the compounds disclosed herein cause the cells that host the inflammatory event to revert to a non-inflammatory state by promoting the resolution of inflammation and limiting excessive tissue damage to the host.
  • 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.
  • 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.
  • 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.
  • 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).
  • 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.
  • 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).
  • Step 1 benzyl (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-hydroxy-2,4a,6a,6b,9,9,12a- heptamethyl-13-oxo-l,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,ll,12,12a,12b,13,14b-icosahydropicene-2- carboxylate (IB)
  • Step 2 benzyl (2S,4aS,6aS,6bR,8aR,10S,12aR,12bR,14bR)-10-hydroxy-2,4a,6a,6b,9,9,12a- heptamethyl-l,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,ll,12,12a,12b,13,14b-icosahydropicene-2-carboxylate
  • Step 3 benzyl (2S,4aS,6aS,6bR,8aR,12aR,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-10- oxo- l,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,12b,13,14b-octadecahydropicene-2-carboxylate (ID)
  • Step 4 benzyl (2S,4aS,6aR,6bR,8aR,12aR,12bR,14aR,14bS)-2,4a,6a,6b,9,9,12a-heptamethyl- 10,14- dioxo-l -icosahydropicene-2-carboxylate (IE)
  • Step 5 benzyl (2S,4aS,6aR,6bS,8aR,12aR,14aR,14bS)-ll-bromo-2,4a,6a,6b,9,9,12a-heptamethyl - 10,14-dioxo-l,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b-octadecahydropicene-2-carboxylate (IF)
  • Step 6 benzyl (2S,4aS,6aR,6bS,8aR,12aS,14aR,14bS)-ll-cyano-2,4a,6a,6b,9,9,12a-heptamethyl- 10,14-dioxo-l,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b-octadecahydropicene-2-carboxylate (1G)
  • Step 7 (2S,4aS,6aR,6bS,8aR,12aS,14aR,14bS)-ll-cyano-10-hydroxy-2,4a,6a,6b,9,9,12a- heptamethyl-14-oxo-l,2,3,4,4a,5,6,6a,6b,7,8,8a,9,12,12a,14,14a,14b-octadecahydropicene-2- carboxylic acid (1H)
  • Step 7 (2S,4aS,6aR,6bS,8aR,12aS,14aR,14bS)-ll-cyano-2,4a,6a,6b,9,9,12a-heptamethyl- 10,14- dioxo-l,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b-octadecahydropicene-2-carboxylic acid (intermediate 1)
  • Step 2 (3S,4aR,6aR,6bS,8aS,12aS,14aR,14bR)-8a-(aminomethyl)-4,4,6a,6b,ll,ll,14b- heptamethyl- l,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,ll,12,12a,14,14a,14b-icosahydropicen-3-ol (2C)
  • Step 3 tert-butyl (((4aS,6aS,6bR,8aR,12aR,12bR,14bS)-10-hydroxy-2,2,6a,6b,9,9,12a- heptamethyl- l,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,ll,12,12a,12b,13,14b-icosahydropicen-4a-yl)methyl)carbamate (2D)
  • Step 4 tert-butyl (((4aS,6aS,6bR,8aR,12aR,12bR,14bS)-2,2,6a,6b,9,9,12a-heptamethyl-10-oxo- l,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,12b,13,14b-octadecahydropicen-4a-yl)methyl)carbamate (2E)
  • Step 5 tert-butyl (((4aS,6aR,6bR,8aR,12aR,14aR,14bS)-2,2,6a,6b,9,9,12a-heptamethyl-10,14- dioxo- l,3,4,5,6,6a,6b,7,8,8a,9,10,12a,12b,13,14,14a,14b-octadecahydropicen-4a(2iT)-yl)methyl)carbamate
  • Step 6 tert-butyl (((4aS,6aR,6bS,8aR,12aR,14aR,14bS)-ll-bromo-2,2,6a,6b,9,9,12a-heptamethyl - 10,14-dioxo-l,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b-hexadecahydropicen-4a(2i/)- yl)methyl)carbamate (2H)
  • Step 7 tert-butyl (((4aS,6aR,6bS,8aR,12aS,14aR,14bS)-ll-cyano-2,2,6a,6b,9,9,12a-heptamethyl - 10,14-dioxo-l,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b-hexadecahydropicen-4a(2/7)- yl)methyl)ca
  • Step 1 (2S,4aS,6aR,6bS,8aR,12aS,14aR,14bS)-ll-cyano-2,4a,6a,6b,9,9,12a-heptamethyl -10,14- dioxo-l,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b-octadecahydropicene-2-carbonyl azide (3A)
  • Step 2 (4aR,6aS,6bR,8aS,llS,12aS,12bR,14bS)-ll-amino-4,4,6a,6b,8a,ll,14b-heptamethyl -3,13- dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,ll,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile
  • Example 1 (4aR,6aS,6bR,8aS,llS,12aS,12bR,14bS)-4,4,6a,6b,8a,ll,14b-heptamethyl-ll-(5- methyl-l,3,4-oxadiazol-2-yl)-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11 2,12a,12b,13,14b- octadecahydropicene-2-carbonitrile (compound 1)
  • Step 1 (2S,4aS,6aR,6bS,8aR,12aS,14aR,14bS)-N'-acetyl-ll-cyano-2,4a,6a,6b,9,9,12a- heptamethyl-
  • Step 2 (4aR,6aS,6bR,8aS,llS,12aS,12bR,14bS)-4,4,6a,6b,8a,ll,14b-heptamethyl-ll-(5-methyl - l,3,4-oxadiazol-2-yl)-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,ll,12,12a,12b,13,14b- octadecahydropicene-2-carbonitrile (compound 1)
  • Step 1 (2S,4aS,6aR,6bS,8aR,12aS,14aR,14bS)-ll-cyano-2,4a,6a,6b,9,9,12a-heptamethyl-10,14 - dioxo-l,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b-octadecahydropicene-2-carboxamide (2a)
  • Step 2 (2S,4aS,6aR,6bS,8aR,12aS,14aR,14bS)-2,4a,6a,6b,9,9,12a-heptamethyl- 10,14-dioxo- l,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b-octadecahydropicene-2,ll-dicarbonitrile (compound 2)
  • Example 3 2-cyano-l-(((4aS,6aR,6bS,8aR,12aS,14aR,14bS)-ll-cyano-2,2,6a,6b,9,9,12a- heptamethyl-10,14-dioxo-l,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b-hexadecahydropicen-4a(2f/)- yl)methyl)-3-methylguanidine (compound 3)
  • Step 1 (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-(aminomethyl)-4,4,6a,6b,ll,ll,14b-heptamethyl - 3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,ll,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile (3a)
  • Step 2 2-cyano-l-(((4aS,6aR,6bS,8aR,12aS,14aR,14bS)-ll-cyano-2,2,6a,6b,9,9,12a- heptamethyl- 10,14-dioxo-l,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b-hexadecahydropicen-4a(2i/)-yl)methyl)-3- methylguanidine (compound 3)
  • Example 4 A , -cyano-N-(((4aS,6aR,6bS,8aR,12aS,14aR,14bS)-ll-cyano-2,2,6a,6b,9,9,12a- heptamethyl-10,14-dioxo-l,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b-hexadecahydropicen-4a(2f/)- yl)methyl)acetimidamide (compound 4)
  • Example 5 A r -((4aS,6aR,6bS,8aR,12aS,14aR,14bS)-ll-cyano-2,2,6a,6b,9,9,12a-heptamethyl- 10,14- dioxo-l,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b-hexadecahydropicen-4a(2i/)-yl)-2-((ls)-/V-cyano-S- methylsulfinimidoyl)acetamide (compound 5)
  • Step 1 /V-((4aS,6aR,6bS,8aR,12aS,14aR,14bS)-ll-cyano-2,2,6a,6b,9,9,12a-heptamethyl -10,14 - dioxo-l,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b-hexadecahydropicen-4a(2i/)-yl)-2- (methylthio)acetamide (5b)
  • Step 2 /V-((4aS,6aR,6bS,8aR,12aS,14aR,14bS)-ll-cyano-2,2,6a,6b,9,9,12a-heptamethyl-10,14 - dioxo-l,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b-hexadecahydropicen-4a(2i/)-yl)-2-((E)-iV- cyano-S- methylsulfinimidoyl)acetamide (compound 5)
  • Example 6 (4aR,6aS,6bR,8aS,llS,12aS,12bR,14bS)-4,4,6a,6b,8a,ll,14b-heptamethyl-ll- (oxazol- 2-yl)-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,ll,12,12a,12b,13,14b-octadecahydropicene-2- carbonitrile (compound 6)
  • Step 1 (2S,4aS,6aR,6bS,8aR,12aS,14aR,14bS)-ll-cyano-N-(2-hydroxyethyl)-2,4a,6a,6b,9,9, 12a- heptamethyl-10,14-dioxo-l,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b-octadecahydropicene-2- carboxamide (6a)

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Abstract

Described herein are terpinoid derivatives as NRF2 inhibitors and pharmaceutical compositions comprising said compounds. The subject compounds and compositions are useful for the treatment of inflammatory diseases.

Description

TERPINOID DERIVATIVES AND USES THEREOF
CROSS-REFERENCE
[0001] This patent application claims the benefit of US Provisional Application No. 62/738,762, filed September 28, 2018; US Provisional Application No. 62/770,569, filed, November 21, 2018; US Provisional Application No. 62/808, 192, filed, February 20, 2019; and US Provisional Application No. 62/823,846, filed March 26, 2019; each of which is incorporated herein by reference in their entirety.
FIELD OF THE INVENTION
[0002] Described herein are compounds, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds to treat, prevent or diagnose diseases, disorders, or conditions associated with oxidative stress and inflammation.
BACKGROUND OF THE INVENTION
[0003] The anti-inflammatory and anti -proliferative activity of the naturally occurring triterpenoid, oleanolic acid, has been improved by chemical modifications. For example, 2-cyano-3, 12-diooxooleana- 1,9(1 l)-dien-28-oic acid (CDDO) and related compounds have been developed. Bardoxolone methyl (CDDO-Me) is currently being evaluated in phase III clinical trials for the treatment of diabetic nephropathy and chronic kidney disease.
[0004] Synthetic triterpenoid analogs of oleanolic acid have also been shown to be inhibitors of cellular inflammatory processes, such as the induction by IFN-g of inducible nitric oxide synthase (iNOS), and of COX-2 in mouse macrophages. Compounds derived from oleanolic acid have been shown to affect the function of multiple protein targets and thereby modulate the activity of several important cellular signaling pathways related to oxidative stress, cell cycle control, and inflammation. Given that the biological activity profiles of known triterpenoid derivatives vary, and in view of the wide variety of diseases that may be treated or prevented with compounds having potent antioxidant and anti inflammatory effects, and the high degree of unmet medical need represented within this variety of diseases, it is desirable to synthesize new compounds with diverse structures that may have improved biological activity profiles for the treatment of one or more indications.
BRIEF SUMMARY OF THE INVENTION
[0005] Disclosed herein is a compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure imgf000003_0001
Formula (III);
wherein:
R1 is hydrogen, deuterium, halogen, -CN, -ORb, -NRCR:I. -NRbS(=0)2Ra, -C(=0)Ra, -C(=0)0Rb, - C(=0)NRcRd, C i -Co alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1 -G, haloalkyl, G-G, deuteroalkyl, G- G, hydroxyalkyl, G-G, ammoalkyl, or G-G heteroalkyl;
R3 is N-linked heterocycloalkyl, N-linked heteroaryl, -P(=0)(R4)2, -P(=0)(0R5)2, -B(OR5)2, -
Figure imgf000003_0002
C6alkenylene)cycloalkyl, -Y(C2-C6alkenylene)heterocycloalkyl, -Y(C2-C6alkenylene)aryl, -Y(C2- C6alkenylene)heteroaryl, -(C i-G,alkylcnc)0P(-0)(0R5)2. -(Ci-C6alkylene)0(Ci- C6alkylene)0P(=0)(0R5)2, or -(Ci-C6alkylene)0P(=0)(0R5)[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(=0)Ra, -C(=0)0Rb, - C(=0)NRcRd, C 1 -C(, alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1 -G, haloalkyl, C 1 -C , deuteroalkyl, Ci- C , hydroxyalkyl, C 1 -G, aminoalkyl, or Ci-Ce heteroalkyl;
Y is a bond, -0-, -S-, or -NRb-;
Z is a bond or G-Galkylcnc:
Rx is hydrogen, -NO2, -CN, or -S(=0)2Ra;
each R4 is independently -Cs alkyl, G-G, alkenyl, C -C alkynyl, C -C haloalkyl, C -G,
deuteroalkyl, -Ce hydroxyalkyl, C -G, aminoalkyl, C -C(, 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(=0)Ra, -C(=0)0Rb, - C(=0)NRcRd, C i -C alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1 -G, haloalkyl, C 1 -G, deuteroalkyl, G- G hydroxyalkyl, C 1 -G, aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R5 is independently hydrogen, C 1 -C,, alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C 1 -G, deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, G-G 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(=0)Ra, -C(=0)0Rb, - C(=0)NRcRd, G-G alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1 -G, haloalkyl, C 1 -G deuteroalkyl, G- G hydroxyalkyl, G-G aminoalkyl, G-G heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R6 and R7 is independently hydrogen, G-G alkyl, G-G alkenyl, G-G alkynyl, C 1 -G, haloalkyl, G-G deuteroalkyl, C 1 -G, hydroxyalkyl, C 1 -G, aminoalkyl, C 1 -G, 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(=0)Ra, -C(=0)0Rb, - C(=0)NRcRd, C 1 -G, alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1 -G, haloalkyl, C 1 -G, deuteroalkyl, G- G, hydroxyalkyl, C 1 -G, aminoalkyl, C 1 -G, 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(_0)Ra, -CGO)ORb. - C(=0)NRcRd, C 1 -Co alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1 -G, haloalkyl, G-G deuteroalkyl, G- G, hydroxyalkyl, G-G, aminoalkyl, C 1 -G, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
X O OH
J 1S JL or J ;
R8 is hydrogen, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=0)Ra, -C(=0)0Rb, G-G alkyl, G-G alkenyl, G-G alkynyl, C 1 -G, haloalkyl, or C 1 -G, deuteroalkyl;
R9 is G-G alkyl, G-G alkenyl, G-G alkynyl, C 1 -G, haloalkyl, or 1 -G, deuteroalkyl;
R10 is G-G alkyl, G-G, alkenyl, G-G alkynyl, G-G haloalkyl, or C 1 -G, 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, Ci-C<5 alkyl, G-G alkenyl, C2-C6 alkynyl, G- G, haloalkyl, C 1 -G, deuteroalkyl, C1-C6 hydroxyalkyl, G-G, aminoalkyl, or C 1 -G, 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(=0)Ra, -C(=0)0Rb, -
C(=0)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, G-G deuteroalkyl, G- G, hydroxyalkyl, G-G aminoalkyl, C 1 -G, heteroalkyl, cycloalkyl, or heterocycloalkyl;
R15 and R16 are independently hydrogen, -ORb, -NRcRd, G-G, alkyl, C2-C6 alkenyl, G-G alkynyl, G- G, haloalkyl, C 1 -G, deuteroalkyl, C1-C6 hydroxyalkyl, C 1 -G, aminoalkyl, or G-G 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(=0)Ra, -C(=0)ORb, -
C(=0)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 1 -G, haloalkyl, G-G deuteroalkyl, G- G, hydroxyalkyl, C 1 -G, aminoalkyl, C 1 -G, heteroalkyl, cycloalkyl, or heterocycloalkyl;
each Ra is independently C 1 -G, alkyl, G-G alkenyl, G-G, alkynyl, C 1 -G, haloalkyl, C 1 -G,
deuteroalkyl, G-G hydroxyalkyl, C 1 -G, aminoalkyl, G-G 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, -N¾, or C 1 -G, alkyl;
each Rb is independently hydrogen, G-G, alkyl, G-G alkenyl, G-G alkynyl, C 1 -G, haloalkyl, G-G deuteroalkyl, C 1 -G, hydroxyalkyl, C 1 -G, aminoalkyl, G-G 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 C 1 -G, alkyl; and
each Rc and Rd is independently hydrogen, G-G alkyl, G-G alkenyl, G-G alkynyl, G-G haloalkyl, C 1 -G, deuteroalkyl, C 1 -G, hydroxyalkyl, C 1 -G, aminoalkyl, C 1 -G, 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 deutenum, halogen, -OH, -NH2, or C 1 -G, 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 G-G alkyl.
[0006] Also disclosed herein is a compound of Formula (VIII), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure imgf000006_0001
Formula (VIII);
wherein:
R1 is hydrogen, deuterium, halogen, -CN, -ORb, -NRcRd, -NRbS(=0)2Ra, -C(=0)Ra, -C(=0)0Rb, -
C(=0)NRcRd, G-G alkyl, G-G alkenyl, G-G alkynyl, Ci-Ce haloalkyl, Ci-Ce deuteroalkyl, G-G, hydroxyalkyl, G-G aminoalkyl, or Ci-G heteroalkyl;
R3 is halogen, -CN, -OR5, -SR5, -S(=0)R4, -S(=0)2R4, -N02, -NR6R7, -S(=0)2NR6R7, -C(=0)R4, -
0C(=0)R4, -C(-0)0R\ -0C(-0)0R\ -C(=0)NR6R7, -0C(=0)NR¾7, -NR5C(=0)NR6R7, - NR5C(=0)0R5, -NR5S(=0)2NR6R7, -NR5S(=0)2R4, -NR5C(=0)R4, -P(=0)(R4)2, -P(=0)(0R5)2, - B(OR5)2, -NR5C(=NRX)R5, -NR5C(=NRX)NR6R7, -S(-0)(-NRX)R5. -S(=0)(=NRX)NR6R7, - NR5S(=0)2NR5C(=0)R5, -NR5S(=0)(=NRX)R5, CI -G, alkyl, C2-C„ alkenyl, G-G, alkynyl, C i-G, haloalkyl, C i -G, deuteroalkyl, C i -C,, hydroxyalkyl, C i -G, 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(=0)R4, -S(=0)2R4, -NO2, -NR6R7,
Figure imgf000006_0002
C5 alkynyl, C1-C6 haloalkyl, C i -G, deuteroalkyl, C i -C(, hydroxyalkyl, G-G 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(=0)Ra, -C(=0)0Rb, -C(=0)NRcRd, G-G alkyl, G-G, alkenyl, C2-G, alkynyl, G-G haloalkyl, C i -C(, deuteroalkyl, G-G, hydroxyalkyl, C1-C6 aminoalkyl, G-G heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
Rx is hydrogen, -N02, -CN, or -S(=0)2Ra;
each R4 is independently Ci-Ce alkyl, G-G alkenyl, G-G, alkynyl, C i -G, haloalkyl, C i-G, deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, G-G 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(=0)Ra, -C(=0)0Rb, -
C(=0)NRcRd, -NRbC(=NRx)Rb, -NRbC(=NRx)NRcRd, -S(=0)(=NRx)Rb, -S(=0)(=NRx)NRcRd, Ci-C6 alkyl, G-G alkenyl, G-G alkynyl, C 1 -G haloalkyl, G-G deuteroalkyl, C 1 -G hydroxyalkyl, G-G ammoalkyl, C -G heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R5 is independently hydrogen, C -G alkyl, G-G, alkenyl, G-G alkynyl, C -G, haloalkyl, C -G, deuteroalkyl, C -G, hydroxyalkyl, C -G, aminoalkyl, C -G, 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(=0)Ra, -C(=0)0Rb, -
C(=0)NRcRd, -NRbC(=NRx)Rb, -NRbC(=NRx)NRcRd, -S(=0)(=NRx)Rb, -S(=0)(=NRx)NRcRd, Ci-C6 alkyl, C -C alkenyl, G-G alkynyl, G-G haloalkyl, G-G deuteroalkyl, C -G, hydroxyalkyl, G-G aminoalkyl, C -G, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R6 and R7 is independently hydrogen, G-G alkyl, G-G alkenyl, G-G alkynyl, C -G, haloalkyl, G- G deuteroalkyl, G-G hydroxyalkyl, C -G, aminoalkyl, G-G 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(=0)Ra, -C(=0)0Rb, -
C(=0)NRcRd, -NRbC(=NRx)R\ -NRbC(=NRx)NRcRd, -S(=0)(=NRx)Rb, -S(=0)(=NRx)NRcRd, G-G alkyl, G-G alkenyl, G-G, alkynyl, G-G haloalkyl, G-G deuteroalkyl, G-G hydroxyalkyl, G-G aminoalkyl, G-G heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaiyl;
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 Rib is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=0)Ra, -C(=0)0Rb, -
C(=0)NRcRd, G-G alkyl, G-G alkenyl, G-G alkynyl, G-G haloalkyl, G-G deuteroalkyl, G-G hydroxyalkyl, G-G aminoalkyl, G-G heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
Figure imgf000007_0001
Y1 and Y2 are independently hydrogen, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=0)Ra, -C(=0)0Rb, - C(=0)NRcRd, G-G alkyl, G-G alkenyl, G-G alkynyl, G-G haloalkyl, G-G deuteroalkyl, G-G hydroxyalkyl, G-G aminoalkyl, or G-G heteroalkyl;
R8 is hydrogen, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=0)Ra, -C(=0)0Rb, G-G alkyl, G-G, alkenyl, G-G alkynyl, G-G haloalkyl, or G-G deuteroalkyl;
R9 is G-G alkyl, G-G alkenyl, G-G alkynyl, G-G haloalkyl, or G-G deuteroalkyl;
R10 is G-G alkyl, G-G alkenyl, G-G alkynyl, G-G haloalkyl, or G-G 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, G-G alkyl, G-G, alkenyl, G-G alkynyl, G-G haloalkyl, G- G deuteroalkyl, G-G hydroxyalkyl, G-G aminoalkyl, G-G heteroalkyl, cycloalkyl,
heterocycloalkyl, aryl, or heteroaryl; R13 is -CN, -OR19, -S(=O)2NR20R21, -0C(=0)R18, -0C(=0)0R19, -OC(=O)NR20R21, -NR19C(=0)0R19, CI-C6 deuteroalkyl, Ci-Ce hydroxyalkyl, C1-G5 aminoalkyl, Ci-Cs 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(=0)R18, -S(=0)2R18, -N02, - NR20R21, -S(=O)2NR20R21, -C(=0)R18, -0C(=0)R18, -C(=0)0R19, -0C(=0)0R19, -C(=O)NR20R21, - OC(=O)NR20R21, -NR19C(=0)0R19, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, Ci-C6 deuteroalkyl, Ci-Gs hydroxyalkyl, Ci-Gs aminoalkyl, C i -CY, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R18 is independently Ci-Ce alkyl, C2-C6 alkenyl, G-G, alkynyl, C i -CV, haloalkyl, C i -G, deuteroalkyl, C1-C6 hydroxyalkyl, Ci-Ce aminoalkyl, Ci-Ce 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(=0)Ra, -C(=0)0Rb, -
C(=0)NRcRd, C 1 -G, alkyl, C2-C6 alkenyl, Ci-Ce alkynyl, Ci-Ce haloalkyl, Ci-Ce deuteroalkyl, Ci-Ce hydroxyalkyl, C 1 -G, aminoalkyl, C 1 -G, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R19 is independently hydrogen, Ci-Ce alkyl, C2-CY, alkenyl, C2-C6 alkynyl, C 1 -G, haloalkyl, Ci-Ce deuteroalkyl, Ci-Ce hydroxyalkyl, Ci-Ce aminoalkyl, C 1 -G, 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(=0)Ra, -C(=0)0Rb, -
C(=0)NRcRd, C 1 -G, alkyl, C2-C(5 alkenyl, G-G, alkynyl, C 1 -G, haloalkyl, C 1 -G, deuteroalkyl, C 1 -G, hydroxyalkyl, C 1 -G, aminoalkyl, C 1 -G, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R20 and R21 are independently hydrogen, Ci-Ce alkyl, C2-G, alkenyl, C2-G, alkynyl, C 1 -G, haloalkyl, C1-C6 deuteroalkyl, C 1 -G, hydroxyalkyl, Ci-C<5 aminoalkyl, C 1 -G, 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(=0)Ra, -C(=0)0Rb, -
C(=0)NRcRd, G-G, alkyl, C2-C(5 alkenyl, G-G, alkynyl, C 1 -CY, haloalkyl, C 1 -G, deuteroalkyl, C i-CY, hydroxyalkyl, C 1 -CY, aminoalkyl, C 1 -CY, 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(=0)Ra, -C(=0)0Rb, -
C(=0)NRcRd, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, Ci-Ce deuteroalkyl, C1-C6 hydroxyalkyl, C 1 -CY, aminoalkyl, C 1 -CY, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R15 and R16 are independently hydrogen, -ORb, -NRcRd, C 1 -CY, alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, Ci-Ce deuteroalkyl, C 1 -CY, hydroxyalkyl, Ci-Ce aminoalkyl, or Ci-Ce 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(=0)Ru. -C(=0)0Rb, -C(=0)NRcRd, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, Ci-Ce deuteroalkyl, G-G> hydroxyalkyl, Ci-Ce aminoalkyl, Ci-Ce heteroalkyl, cycloalkyl, or heterocycloalkyl;
each Ra is independently C 1 -G, alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C 1 -G, deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, Ci-Ce 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 C 1 -G, alkyl;
each Rb is independently hydrogen, C 1 -G, alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C 1 -G, deuteroalkyl, C 1 -G, hydroxyalkyl, Ci-Ce aminoalkyl, C 1 -G, 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 Ci- Ce alkyl; and
each Rc and Rd is independently hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1 -G, haloalkyl, Ci- Ce deuteroalkyl, 1 -G, hydroxyalkyl, C1-C6 aminoalkyl, C 1 -G, 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 Ci-Ce 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 Ci- C6 alkyl.
[0007] Disclosed herein is a pharmaceutical composition comprising a therapeutically effective amount of a compound disclosed herein, and a pharmaceutically acceptable excipient.
[0008] Also disclosed herein is a method for treating a disease in a mammal comprising administering to the mammal a therapeutically effective amount of a compound or a pharmaceutical composition disclosed herein. In some embodiments, the disease is an inflammatory disease. In some embodiments, the disease is diabetic nephropathy or chronic kidney disease. In some embodiments, the disease is chronic obstructive pulmonary disease (COPD) or inflammatory bowel disease (IBD). In some embodiments, the disease is nonalcoholic steatohepatitis (NASH).
INCORPORATION BY REFERENCE
[0009] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference for the specific purposes identified herein.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0010] 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.
[0011] As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below.
[0012] “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.
[0013] “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-l- 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-l -pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4- methyl -2 -pentyl, 2,2-dimethyl- 1 -butyl, 3,3-dimethyl-l-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“Ci-Ce 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 Ci-Cio alkyl, a C1-C9 alkyl, a Ci-Cs alkyl, a C1-C7 alkyl, a CVG, alkyl, a C1-C5 alkyl, a C1-C4 alkyl, a C1-C3 alkyl, a C1-C2 alkyl, or a Ci 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. [0014] “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 as 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-Cio alkenyl, a C2-Cg alkenyl, a C2-Cg alkenyl, a C2-C7 alkenyl, a C2-C6 alkenyl, a C2-Cs 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 -N02. 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.
[0015] “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-C<5 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-Cio alkynyl, a C2-Cg alkynyl, a C2-Cs alkynyl, a C2-C7 alkynyl, a CVG, alkynyl, a CS-CN 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, nitnle, 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 -N02. 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.
[0016] “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 -N02. 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. [0017] “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 -N02. 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.
[0018] 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.
[0019] “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 -N02. 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.
[0020] “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 -CA cycloalkyl), from three to ten carbon atoms (C3-Cio cycloalkyl), from three to eight carbon atoms (C3-Cs cycloalkyl), from three to six carbon atoms (C -G, cycloalkyl), from three to five carbon atoms (C3-C3 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, norbomyl, 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, mtnle, 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.
[0021] “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, CH2CD3, CD2CD3, CHDCD3, CH2CH2D, or CH2CHD2. In some embodiments, the deuteroalkyl is CD3.
[0022] “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.
[0023] ‘ Halo” or“halogen” refers to bromo, chloro, fluoro, or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.
[0024] “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 C i-C , hcteroalkyl 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 -N02. 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.
[0025] “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. [0026] “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 quatemized.
[0027] 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[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl,
2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl,
thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-l-yl, 3- oxo-l,3-dihydroisobenzofuran-l-yl, methyl-2 -oxo-l,3-dioxol-4-yl, and 2-oxo-l,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.
[0028] “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 quatemized. 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, acridmyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][l,4]dioxepinyl,
1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofiiranyl, 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-lH-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.
[0029] 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.
[0030] 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
[0031] Described herein are triterpenoid derivatives that exhibit, for example, anti-inflammatory and/or antioxidant properties.
[0032] Diclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure imgf000016_0001
Formula (I);
wherein:
Ring A is a cycloalkyl or a heterocycloalkyl;
R1 is hydrogen, deuterium, halogen, -CN, -ORb, -NRcRd, -NRbS(=0)2Ra, -C(=0)Ra, -C(=0)0Rb, -
C(=0)NRcRd, Ci-Ce alkyl, C2-C<5 alkenyl, C2-G5 alkynyl, C 1 -G, haloalkyl, C 1 -G, deuteroalkyl, Ci-Ce hydroxyalkyl, C1-C6 aminoalkyl, or Ci-Ce heteroalkyl;
each R2 is independently deuterium, halogen, -CN, -ORb, -NRcRd, -C(=0)Ra, -C(=0)0Rb, -C(=0)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C 1 -G, deuteroalkyl, C rG, hydroxyalkyl, C1-C6 aminoalkyl, Ci-Ce heteroalkyl, cycloalkyl, or heterocycloalkyl;
n is 0-6;
R3 is halogen, -CN, -OR5, -SR5, -S(=0)R4, -S(=0)2R4, -N02, -NR6R7, -S(=0)2NR6R7, -C(=0)R4, -
Figure imgf000016_0002
haloalkyl, Ci-Ce deuteroalkyl, C 1 -C,, hydroxyalkyl, Ci-Ce aminoalkyl, C 1 -G, 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(=0)R4, -S(=0)2R4, -N02, -NR6R7,
Figure imgf000016_0003
Ce alkynyl, Ci-Ce haloalkyl, C 1 -G, deuteroalkyl, Ci-Ce hydroxyalkyl, Ci-Ce 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(=0)Ra, -C(=0)0Rb, -C(=0)NRcRd, Ci-Ce alkyl, C2-G5 alkenyl, C2-G5 alkynyl, C 1 -G, haloalkyl, Ci-Ce deuteroalkyl, Ci-Ce hydroxyalkyl, Ci-Ce aminoalkyl, C 1 -G, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
Rx is hydrogen, -NO2, -CN, or -S(=0)2Ra;
each R4 is independently Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1 -C( haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C 1 -G, aminoalkyl, C 1 -G, 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(=0)Ra, -C(=0)0Rb, -
C(=0)NRcRd, -NRbC(=NRx)Rb, -NRbC(=NRx)NRcRd, -S(=0)(=NRx)Rb, -S(=0)(=NRx)NRcRd, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1 -G, haloalkyl, Ci-Ce deuteroalkyl, C 1 -G, hydroxyalkyl, Ci-Ce aminoalkyl, Ci-Ce heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R5 is independently hydrogen, Ci-Gs alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1 -G, haloalkyl, C 1 -G, deuteroalkyl, Ci-Gs hydroxyalkyl, Ci-Ce aminoalkyl, C 1 -G, 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(=0)Ra, -C(=0)0Rb, -
C(=0)NRcRd, -NRbC(=NRx)R\ -NRbC(=NRx)NRcRd, -S(=0)(=NRx)Rb, -S(=0)(=NRx)NRcRd, Ci-C6 alkyl, C2-G5 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C 1 -G, deuteroalkyl, C 1 -CV, hydroxyalkyl, C 1 -G, aminoalkyl, C 1 -G, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R6 and R7 is independently hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-G5 alkynyl, C 1 -CV, haloalkyl, Ci- C(5 deuteroalkyl, C 1 -G, hydroxyalkyl, C 1 -CV, aminoalkyl, Ci-Ce 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(=0)Ra, -C(=0)0Rb, -
C(=0)NRcRd, -NRbC(=NRx)R\ -NRbC(=NRx)NRcRd, -S(=0)(=NRx)Rb, -S(=0)(=NRx)NRcRd, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1 -G, haloalkyl, C 1 -G, deuteroalkyl, C 1 -CV, hydroxyalkyl, C 1 -C(, aminoalkyl, Ci-Ce 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(=0)Ra, -C(=0)0Rb, -
C(=0)NRcRd, C 1 -G, alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1 -G, haloalkyl, C 1 -G, deuteroalkyl, C 1 -G, hydroxyalkyl, C 1 -G, aminoalkyl, Ci-Ce heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
X O OH
is—— or
R8 is hydrogen, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=0)Ra, -C(=0)0Rb, Ci-Ce alkyl, CS-CV, alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or Ci-Ce deuteroalkyl;
R9 is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1 -G, haloalkyl, or C 1 -G, deuteroalkyl; R10 is Ci-C<5 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, or C 1 -G> 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, C 1 -G, alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C 1 -G, deuteroalkyl, C 1 -C, hydroxyalkyl, Ci-Ce aminoalkyl, or C 1 -G, 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(=0)Ra, -C(=0)0Rb, -C(=0)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1 -G> haloalkyl, C1-C6 deuteroalkyl, C 1 -G> hydroxyalkyl, C1-C6 aminoalkyl, C 1 -G> heteroalkyl, cycloalkyl, or heterocycloalkyl;
each Ra is independently C 1 -G, alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C 1 -G, deuteroalkyl, C1-C6 hydroxyalkyl, C 1 -G, aminoalkyl, C 1 -CV, 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 C 1 -G, alkyl;
each Rb is independently hydrogen, C 1 -G, alkyl, C2-C6 alkenyl, G-G, alkynyl, C 1 -G, haloalkyl, C 1 -G, deuteroalkyl, C 1 -G, hydroxyalkyl, C 1 -G, aminoalkyl, C 1 -G, 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 Ci- C5 alkyl; and
each Rc and Rd is independently hydrogen, C 1 -G, alkyl, C2-G5 alkenyl, C2-G5 alkynyl, C 1 -G, haloalkyl, Ci- C(5 deuteroalkyl, C 1 -G, hydroxyalkyl, C1-C6 aminoalkyl, C1-G5 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 C 1 -G, 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 Ci- C6 alkyl.
[0033] In some embodiments of a compound of Formula (I), R1 is -CN, Ci-Ce alkyl, Ci-G, haloalkyl, or Ci-Ce deuteroalkyl. In some embodiments of a compound of Formula (I), R1 is -CN or C 1 -G, haloalkyl. In some embodiments of a compound of Formula (I), R1 is G-Ce haloalkyl. In some embodiments of a compound of Formula (I), R1 is -CN.
[0034] 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.
[0035] In some embodiments of a compound of Formula (I), R9 is Ci-Ce alkyl or C2-C6 alkynyl. In some embodiments of a compound of Formula (I), R9 is Ci-Ce alkyl.
[0036] In some embodiments of a compound of Formula (I), R10 is G-G; alkyl or C2-C6 alkynyl. In some embodiments of a compound of Formula (I), R10 is C1-C6 alkyl. [0037] In some embodiments of a compound of Formula (I), R9 is C i -G> alkyl and R10 is G-G> alkynyl.
In some embodiments of a compound of Formula (I), R10 is Ci-Ce alkyl and R9 is G-Ce alkynyl.
X O
[0038] In some embodiments of a compound of Formula (I), is . In some embodiments of a compound of Formula
Figure imgf000019_0001
[0039] 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.
[0040] In some embodiments of a compound of Formula (I), R12 and R13 are independently hydrogen, Ci- C(, alkyl, or C -C, deuteroalkyl. In some embodiments of a compound of Formula (I), R12 and R13 are independently hydrogen or Ci-Ce alkyl. In some embodiments of a compound of Formula (I), R12 and R13 are independently hydrogen or Ci-Ce deuteroalkyl. In some embodiments of a compound of Formula (I), R12 and R13 are independently Ci-Ce alkyl.
[0041] 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.
[0042] 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.
[0043] In some embodiments of a compound of Formula (I), R3 is halogen, -CN, -OR5, -NR6R7, - -0C(=0)NR6R7, -NR5C(=0)NR6R7, -NR5C(=0)0R5, - R5C(=NRX)NR6R7, -S(=0)(=NRX)R5, -
Figure imgf000019_0002
R5S(=0)(=NRX)R5, G-C6 alkyl, C2-C6 alkenyl, G-G, hydroxyalkyl, C -G, 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(=0)(=NRx)R5, -S(=0)(=NRx)NR6R7, -NR5S(=0)2NR5C(=0)R5, or - NR5S (=0) (=NRX)R5.
[0044] In some embodiments of a compound of Formula (I), R3 is Ci-Ce alkyl optionally substituted with one, two, or three R3a. In some embodiments of a compound of Formula (I), R3 is C -G, alkyl.
[0045] In some embodiments of a compound of Formula (I), R3 is -C(=0)OR5. [0046] In some embodiments of a compound of Formula (I), each R3a is independently deuterium, halogen, -CN, -OR5, -S(=0)R4, -S(=0)2R4, -OC 0)NR6R7, - 0C(=0)NR6R7, -P(=0)(R4)2, -P(=0)(0R5)2, -B R6R7, - S(=0)(=NRx)R5, -S(=0)(=NRx)NR6R7, -NR5S(
Figure imgf000020_0001
cycloalkyl, or heterocycloalkyl.
[0047] In some embodiments of a compound of Formula (I), each R3a is independently deuterium, halogen, -CN, -OR5, -S(=0)R4, -S(=0)2R4, -OC(=0)R4, -C(=0)OR5, -OC(=0)OR5, -C(=0)NR6R7, - 0C(=0)NR6R7, -P(=0)(R4)2, -P(=0)(0R5)2, -B(OR5)2, -NR5C(=NRX)R5, -NR5C(=NRX)NR6R7, - S(=0)(=NRx)R5, -S(=0)(=NRx)NR6R7, -NR5S(=0)2NR5C(=0)R5, or -NR5S(=0)(=NRx)R5. In some embodiments of a compound of Formula (I), each R3a is independently deuterium, halogen, -CN, -OR5, - OC(=0)R4, -C(=0)OR5, -C(=0)NR6R7, -B(OR5)2, -S(=0)(=NRx)R5, G-G, heteroalkyl, heterocycloalkyl, or heteroaryl. In some embodiments of a compound of Formula (I), each R3a is independently -OC(=0)R4, -C(=0)OR5, -OC(=0)OR5, -C(=0)NR6R7, -P(=0)(R4)2, -P(=0)(0R5)2, -B(OR5)2, -NR5C(=NRX)R5, - NR5C(=NRX)NR6R7, -S(=0)(=NRx)R5, -S(=0)(=NRx)NR6R7, -NR5S(=0)2NR5C(=0)R5, or - NR5S(=0)(=NRx)R5.In some embodiments of a compound of Formula (I), each R3a is independently - OC(=0)R4, -C(=0)OR5, -OC(=0)OR5, or -C(=0)NR6R7. In some embodiments of a compound of Formula (I), each R3a is independently -P(=0)(R4)2, -P(=0)(0R5)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(=0)(=NRx)R5, -S(=0)(=NRx)NR6R7, -NR5S(=0)2NR5C(=0)R5, or -NR5S(=0)(=NRx)R5.
[0048] In some embodiments of a compound of Formula (I), each R3b is independently deuterium, halogen, -CN, -ORb, C i -G, alkyl, -C6 haloalkyl, or C i -G, deuteroalkyl. In some embodiments of a compound of Formula (I), each R3b is independently deuterium, halogen, C rG, alkyl, Ci-Ce haloalkyl, or C i -Co deuteroalkyl.
[0049] In some embodiments of a compound of Formula (I), each R4 is independently Ci-C5 alkyl, C2-G, alkenyl, G-G, alkynyl, C i -G, haloalkyl, C i -G, 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 G- G, 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 C i -G, alkyl optionally substituted with one, two, or three R4a. In some embodiments of a compound of Formula (I), each R4 is independently C i -G, alkyl. In some embodiments of a compound of Formula (I), each R4 is independently C i -G, alkyl, C i -G, haloalkyl, or C i -G, deuteroalkyl.
[0050] In some embodiments of a compound of Formula (I), each R4a is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, C i -G, alkyl, C i -G, 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.
[0051] In some embodiments of a compound of Formula (I), each R5 is independently hydrogen, G-C6 alkyl, C i -G, haloalkyl, G-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, C i -G, 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 Ci- C(1 alkyl optionally substituted with one, two, or three R5a. In some embodiments of a compound of Formula (I), each R5 is independently Ci-Ce alkyl optionally substituted with one, two, or three R5a. In some embodiments of a compound of Formula (I), each R5 is hydrogen or Ci-Ce alkyl. In some embodiments of a compound of Formula (I), each R5 is independently hydrogen, Ci-Ce alkyl, C1-C6 haloalkyl, or C 1 -G, deuteroalkyl.
[0052] In some embodiments of a compound of Formula (I), two R5 are taken together to form an optionally substituted heterocycloalkyl.
[0053] In some embodiments of a compound of Formula (I), each R5a is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, C 1 -G, alkyl, C 1 -G, 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(=0)(=NRx)Rb or - S(=0)(=NRx)NRcRd.
[0054] In some embodiments of a compound of Formula (I), each R6 and R7 is independently hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, C 1 -G, 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, Ci-Ce alkyl, C 1 -Co 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, C 1 -G, alkyl, or C 1 -G, 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 Ci-Ce alkyl. In some embodiments of a compound of Formula (I), each R6 and R7 is independently hydrogen, Ci-C<5 alkyl, C 1 -G, haloalkyl, or G- C , deuteroalkyl.
[0055] In some embodiments of a compound of Formula (I), each R6a is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, C 1 -G, alkyl, G-G, 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(=0)(=NRx)Rb or - S(=0)(=NRx)NRcRd.
[0056] 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. [0057] In some embodiments of a compound of Formula (I), each R6b is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, 1 -G, alkyl, C 1 -G, haloalkyl, C 1 -G, hydroxyalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (I), each R6b is independently C 1 -G, alkyl or G-G haloalkyl. In some embodiments of a compound of Formula (I), each R6b is independently G-G alkyl.
[0058] 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.
[0059] 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.
[0060] In some embodiments of a compound of Formula (I), each R2 is independently deuterium, halogen, -CN, -ORb, C 1 -G, alkyl, or C i-G, haloalkyl. In some embodiments of a compound of Formula (I), each R2 is deuterium.
[0061] 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.
[0062] Diclosed herein is a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure imgf000022_0001
Formula (II);
wherein:
Ring B is a cycloalkyl or a heterocycloalkyl;
each R14 is independently deuterium, halogen, -CN, -ORb, -NRcRd, -C(=0)Ra, -C(=0)0Rb, -C(=0)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1 -G, haloalkyl, C 1 -C( deuteroalkyl, Ci-Ce hydroxyalkyl, C1-C6 aminoalkyl, C 1 -G, heteroalkyl, cycloalkyl, or heterocycloalkyl;
m is 0-6;
R1 is hydrogen, deuterium, halogen, -CN, -ORb, -NRcRd, -NRbS(=0)2Ra, -C(=0)Ra, -C(=0)0Rb, -
C(=0)NRcRd, C 1 -G, alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1 -G, haloalkyl, C 1 -G, deuteroalkyl, C1-C6 hydroxyalkyl, C 1 -G, aminoalkyl, or C 1 -G, heteroalkyl;
R3 is halogen, -CN, -OR5, -SR5, -S(=0)R4, -S(=0)2R4, -NO2, -NR6R7, -S(=0)2NR6R7, -C(=0)R4, - 0C(=0)R4, -C(=0)0R5, -0C(=0)0R5, -C(=0)NR6R7, -0C(=0)NR6R7, -NR5C(=0)NR6R7, - NR5C(=0)0R5, -NR5S(=0)2NR6R7, -NR5S(=0)2R4, -NR5C(=0)R4, -P(=0)(R4)2, -P(=0)(0R5)2, - B(OR5)2, -NR5C(=NRX)R5, -NR5C(=NRx)NRbR7, -S(=0)(=NRX)R5, -S(=0)(=NRX)NR6R7, - NR5S(=0)2NR5C(=0)R5, -NR5S(=0)(=NRX)R5, Ci-Ce alkyl, C2-C6 alkenyl, G-G, alkynyl, G-G haloalkyl, C i -G, deuteroalkyl, G-G hydroxyalkyl, G-G aminoalkyl, G-G 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(=0)R4, -S(=0)2R4, -N02, -NR6R7, -S(=0)2NR6R7, -C(=0)R4, -0C(=0)R4, -C(=0)0R5, -0C(=0)0R5, -C(=0)NR6R7, -0C(=0)NR6R7, - NR5C(=0)NR6R7, -NR5C(=0)0R5, -NR5S(=0)2NR6R7, -NR5S(=0)2R4, -NR5C(=0)R4, -P(=0)(R4)2, - P(=0)(0R5)2, -B(OR5)2, -NR5C(=NRX)R5, -NR5C(=NRX)NR6R7, -S(=0)(=NRX)R5, - S(=0)(=NRx)NR6R7, -NR5S(=0)2NR5C(=0)R5, -NR5S(=0)(=NRX)R5, G-G alkyl, G-G alkenyl, G- G, alkynyl, G-G haloalkyl, C i -G, deuteroalkyl, C i -C(, hydroxyalkyl, C i -CV, aminoalkyl, G-G, 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(=0)Ra, -C(=0)0Rb, -C(=0)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1 -G, haloalkyl, C 1 -G, deuteroalkyl, G-G, hydroxyalkyl, C1-C6 aminoalkyl, C 1 -G, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
Rx is hydrogen, -NO2, -CN, or -S(=0)2Ra;
each R4 is independently C 1 -G, alkyl, G-G alkenyl, C2-C(, alkynyl, C 1 -G, haloalkyl, G-G, deuteroalkyl, G-G hydroxyalkyl, G-G aminoalkyl, C 1 -CV, 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(=0)Ra, -C(=0)0Rb, -
C(=0)NRcRd, -NRbC(=NRx)Rb, -NRbC(=NRx)NRcRd, -S(=0)(=NRx)Rb, -S(=0)(=NRx)NRcRd, Ci-C6 alkyl, G-G, alkenyl, G-G, alkynyl, C 1 -G, haloalkyl, C 1 -G, deuteroalkyl, C 1 -G, hydroxyalkyl, C 1 -G, aminoalkyl, C 1 -G, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R5 is independently hydrogen, C 1 -G, alkyl, G-G, alkenyl, G-G, alkynyl, C 1 -G, haloalkyl, C 1 -G, deuteroalkyl, G-G, hydroxyalkyl, C 1 -G, aminoalkyl, C 1 -G, 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(=0)Ra, -C(=0)0Rb, -
C(=0)NRcRd, -NRbC(=NRx)Rb, -NRbC(=NRx)NRcRd, -S(=0)(=NRx)Rb, -S(=0)(=NRx)NRcRd, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, G-G deuteroalkyl, C1-C6 hydroxyalkyl, C 1 -G, aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R6 and R7 is independently hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, G- C6 deuteroalkyl, C1-C6 hydroxyalkyl, G-G, aminoalkyl, C 1 -G, 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(=0)Ra, -C(=0)0Rb, -
C(=0)NRcRd, -NRbC(=NRx)Rb, -NRbC(=NRx)NRcRd, -S(=0)(=NRx)Rb, -S(=0)(=NRx)NRcRd, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, G-G haloalkyl, G-G deuteroalkyl, G-G hydroxyalkyl, C 1 -G, aminoalkyl, C 1 -G, 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(=0)Ra, -C(=0)0Rb, -
C(=0)NRcRd, C 1 -G, alkyl, C2-C6 alkenyl, C2-C6 alkynyl, G-G haloalkyl, C 1 -G, deuteroalkyl, G-G hydroxyalkyl, G-G aminoalkyl, G-G heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
X O OH
_ 1S JL or J™ .
R8 is hydrogen, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=0)Ra, -C(=0)0Rb, C 1 -C(, alkyl, G-G
alkenyl, G-G alkynyl, G-G haloalkyl, or G-G deuteroalkyl;
R9 is G-G alkyl, C2-C6 alkenyl, C2-C6 alkynyl, G-G haloalkyl, or C 1 -G deuteroalkyl;
R10 is G-G alkyl, C2-C6 alkenyl, G-G alkynyl, G-G haloalkyl, or C 1 -G, deuteroalkyl;
R11 is hydrogen, deuterium, halogen, or -ORb;
or R3 and R1 1 are taken together to form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl;
R15 and R16 are independently hydrogen, -ORb, -NRcRd, C 1 -G, alkyl, G-G alkenyl, G-G alkynyl, C 1 -G, haloalkyl, Ci-Ce deuteroalkyl, G-G hydroxyalkyl, C 1 -G, aminoalkyl, or C 1 -G, 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(=0)Ra, -C(=0)0Rb, -C(=0)NRcRd, G-G alkyl, G-G alkenyl, G-G alkynyl, G-G haloalkyl, C 1 -G, deuteroalkyl, G-G hydroxyalkyl, G-G aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl;
each Ra is independently C 1 -G, alkyl, G-G alkenyl, G-G alkynyl, C 1 -G, haloalkyl, C 1 -G, deuteroalkyl, C1-C6 hydroxyalkyl, C 1 -G, aminoalkyl, G-G 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 C 1 -G, alkyl;
each Rb is independently hydrogen, C 1 -G, alkyl, G-G alkenyl, G-G alkynyl, G-G haloalkyl, C 1 -G, deuteroalkyl, G-G hydroxyalkyl, G-G aminoalkyl, Ci-Ce 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 G- C6 alkyl; and
each Rc and Rd is independently hydrogen, G-G alkyl, G-G alkenyl, G-G alkynyl, G-G haloalkyl, G- G deuteroalkyl, G-G hydroxyalkyl, G-G aminoalkyl, G-G 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 C i -G, 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, -NH¾ or Ci- C6 alkyl.
[0063] In some embodiments of a compound of Formula (II), R1 is -CN, C i -G, alkyl, C i -G, haloalkyl, or Ci-Ce deuteroalkyl. In some embodiments of a compound of Formula (II), R1 is -CN or C i -G, haloalkyl.
In some embodiments of a compound of Formula (II), R1 is Ci-Gs haloalkyl. In some embodiments of a compound of Formula (II), R1 is -CN.
[0064] 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.
[0065] In some embodiments of a compound of Formula (II), R9 is Ci-Ce alkyl or C2-C6 alkynyl. In some embodiments of a compound of Formula (II), R9 is C i -G, alkyl.
[0066] 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.
[0067] In some embodiments of a compound of Formula (II), R9 is Ci-Ce alkyl and R10 is Ci-Ce alkynyl. In some embodiments of a compound of Formula (II), R10 is Ci-Cs alkyl and R9 is C2-C6 alkynyl.
X O
[0068] In some embodiments of a compound of Formula (II),
Figure imgf000025_0001
is—— . In some embodiments of a compound of Formula
Figure imgf000025_0002
[0069] 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.
[0070] In some embodiments of a compound of Formula (II), R15 and R16 are independently hydrogen, Ci-Ce alkyl, or C i -G, deuteroalkyl. In some embodiments of a compound of Formula (II), R15 and R16 are independently hydrogen or Ci-Gs alkyl. In some embodiments of a compound of Formula (II), R15 and R16 are independently hydrogen or Ci-Ce deuteroalkyl. In some embodiments of a compound of Formula (II), R15 and R16 are independently Ci-Ce alkyl.
[0071] 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.
[0072] 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.
[0073] In some embodiments of a compound of Formula (II), R3 is halogen, -CN, -OR5, -NR“R7. - -0C(=0)NR6R7, -NR5C(=0)NR6R7, -NR5C(=0)0R5, - R5C(=NRX)NR6R7, -S(=0)(=NRX)R5, -
Figure imgf000026_0001
R5S(=0)(=NRX)R5, CI-C6 alkyl, C2-C„ alkenyl, Ci-C6 hydroxyalkyl, Ci-Ce 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(=0)(=NRx)R5, -S(=0)(=NRx)NR6R7, -NR5S(=0)2NR5C(=0)R5, or - NR5S (=0) (=NRX)R5.
[0074] In some embodiments of a compound of Formula (II), R3 is Ci-Ce alkyl optionally substituted with one, two, or three R3a. In some embodiments of a compound of Formula (II), R3 is C i -C,, alkyl
[0075] In some embodiments of a compound of Formula (II), R3 is -C(=0)OR5.
[0076] In some embodiments of a compound of Formula (II), each R3a is independently deuterium, halogen, -CN, -OR5, -S(=0)R4, -S(=0)2R4, -OC 0)NR6R7, - 0C(=0)NR6R7, -P(=0)(R4)2, -P(=0)(0R5)2, -B R6R7, - S(=0)(=NRx)R5, -S(=0)(=NRx)NR6R7, -NR5S(
Figure imgf000026_0002
cycloalkyl, or heterocycloalkyl.
[0077] In some embodiments of a compound of Formula (II), each R3a is independently deuterium, halogen, -CN, -OR5, -S(=0) R6R7, - 0C(=0)NR6R7, -P(=0)(R4)2 7, - S(=0)(=NRx)R5, -S(=0)(=N
Figure imgf000026_0003
n some embodiments of a compound of Formula (II), each R3a is independently deuterium, halogen, -CN, -OR5, - OC(=0)R4, -C(=0)OR5, -C(=0)NR6R7, -B(OR5)2, -S(=0)(=NRx)R5, Ci-Ce heteroalkyl, heterocycloalkyl, or heteroaryl. In some embodiments of a compound of Formula (II), each R3a is independently -
Figure imgf000026_0004
or -NR5S(=0)(=NRx)R5.In some embodiments of a compound of Formula (II), each R3a is independently - OC(=0)R4, -C(=0)OR5, -OC(=0)OR5, or -C(=0)NR6R7. In some embodiments of a compound of Formula (II), each R3a is independently -P(=0)(R4)2, -P(=0)(0R5)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(=0)(=NRx)R5, -S(=0)(=NRx)NR6R7, -NR5S(=0)2NR5C(=0)R5, or -NR5S(=0)(=NRx)R5.
[0078] In some embodiments of a compound of Formula (II), each R3b is independently deuterium, halogen, -CN, -ORb, Ci-Ce alkyl, C i -G, haloalkyl, or C1-G5 deuteroalkyl. In some embodiments of a compound of Formula (II), each R3b is independently deuterium, halogen, Ci-Gs alkyl, Ci-Gs haloalkyl, or Ci-Ce deuteroalkyl.
[0079] In some embodiments of a compound of Formula (II), each R4 is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C¾ alkynyl, Ci-Ce haloalkyl, C i -G, 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 Ci- C , 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 C i -G, alkyl optionally substituted with one, two, or three R4a. In some embodiments of a compound of Formula (II), each R4 is independently Ci-Ce alkyl. In some embodiments of a compound of Formula (II), each R4 is independently C1-C6 alkyl, Ci-Ce haloalkyl, or Ci-Ce deuteroalkyl.
[0080] In some embodiments of a compound of Formula (II), each R4a is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, C 1 -G, alkyl, C 1 -G, 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.
[0081] In some embodiments of a compound of Formula (II), each R5 is independently hydrogen, Ci-Gs alkyl, Ci-Ce haloalkyl, C 1 -G, 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, Ci-Ce 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 Ci- C6 alkyl optionally substituted with one, two, or three R5a. In some embodiments of a compound of Formula (II), each R5 is independently C 1 -C,, alkyl optionally substituted with one, two, or three R5a. In some embodiments of a compound of Formula (II), each R5 is hydrogen or Ci-Ce alkyl. In some embodiments of a compound of Formula (II), each R5 is independently hydrogen, Ci-Ce alkyl, C 1 -G, haloalkyl, or C1-C6 deuteroalkyl.
[0082] In some embodiments of a compound of Formula (II), two R5 are taken together to form an optionally substituted heterocycloalkyl.
[0083] In some embodiments of a compound of Formula (II), each R5a is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, C 1 -G, alkyl, Ci-Cs 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(=0)(=NRx)Rb or - S(=0)(=NRx)NRcRd.
[0084] In some embodiments of a compound of Formula (II), each R6 and R7 is independently hydrogen, Ci-Ce alkyl, C -G> haloalkyl, C -G, 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, Ci-Ce alkyl, C -G, 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, Ci-Ce alkyl, or Ci-Ce haloalkyl; wherein the alkyl are independently optionally substituted with one, two, or three R6a. In some embodiments of a compound of Formula (II), each R5 and R7 is independently hydrogen or C i -G, alkyl. In some embodiments of a compound of Formula (II), each R6 and R7 is independently hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, or C i -G, deuteroalkyl.
[0085] In some embodiments of a compound of Formula (II), each R6a is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, C1-C6 alkyl, Ci-Ce 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(=0)(=NRx)Rb or - S(=0)(=NRx)NRcRd.
[0086] 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.
[0087] In some embodiments of a compound of Formula (II), each R6b is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, Ci-Gs alkyl, C i -G, haloalkyl, Ci-Gs hydroxyalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (II), each R6b is independently C i -G, alkyl or Ci-Ce haloalkyl. In some embodiments of a compound of Formula (II), each R6b is independently Ci-Ce alkyl.
[0088] 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.
[0089] 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.
[0090] In some embodiments of a compound of Formula (II), each R14 is independently deuterium, halogen, -CN, -ORb, C 1 -G, alkyl, or CVG, haloalkyl. In some embodiments of a compound of Formula (II), each R14 is deuterium.
[0091] 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.
[0092] Diclosed herein is a compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure imgf000029_0001
Formula (III);
wherein:
R1 is hydrogen, deuterium, halogen, -CN, -ORb, -NRcRd, -NRbS(_OkRa, -C(=0)Ra, -C(=0)0Rb, -
C(=0)NRcRd, G-G, alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C 1 -G, deuteroalkyl, G-G, hydroxyalkyl, C 1 -G, aminoalkyl, or Ci-Ce heteroalkyl;
R3 is N-linked heterocycloalkyl, a N-linked heteroaryl, -P(=0)(R4)2, -P(=0)(0R5)2, -B(OR5)2, -S(=0)R4, - S(=0)2R4, -NR5C(=NRX)R5, -NR5C(=NRX)NR6R7, -S(=0)(=NRX)R5, -S(=0)(=NRX)NR6R7, - NR5S(=0)2NR5C(=0)R5, -NR5S(=0)(=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(G- C6alkylene)S(=0)R4, -Y(Ci-C6alkylene)S(=0)2R4, -Y(Ci-C6alkylene)P(=0)(R4)2, -Y(G- C6alkylene)P(=0)(0R5)2, -Y(Ci-C6alkylene)B(OR5)2, -Y(Ci-C6alkylene)NR5C(=NRx)R5, -Y(G- C6alkylene)NR5C(=NRx)NR6R7, -Y(Ci-C6alkylene)S(=0)(=NRx)R5, -Y(Ci- C6alkylene)S(=0)(=NRx)NR6R7, -Y(Ci-C6alkylene)NR5S(=0)2NR5C(=0)R5, -NR5C(=0)(Ci- C6alkylene)S(=NRx)NR6R7, -NR5C(=0)(Ci-C6alkylene)S(=NRx)R5, -Y(Ci- C6alkylene)NR5S(=0)(=NRx)R5, -Y(C2-C6alkenylene)S(=0)2R4, -Y(C2-C6alkenylene)P(=0)(R4)2, - Y (C2-C6alkenylene)P(=0)(0R5)2, -Y (C2-CV,alkcnylcne)B(OR )2. -Y (C2-C6alkenylene)NR5C(=NRx)R5, -Y(C2-C6alkenylene)NR5C(=NRx)NR6R7, -Y(C2-C6alkenylene)S(=0)(=NRx)R5, -Y(C2- C6alkenylene)S(=0)(=NRx)NR6R7, -Y(C2-C6alkenylene)NR5S(=0)2NR5C(=0)R5, -Y(C2- C6alkenylene)NR5S(=0)(=NRx)R5, -Y (C2-C6alkenylene)cycloalkyl, -Y (C2- C6alkenylene)heterocycloalkyl, -Y(C2-C6alkenylene)aryl, -Y(C2-C6alkenylene)heteroaryl, -(Ci- C6alkylene)0P(=0)(0R5)2, -(Ci-C6alkylene)0(Ci-C6alkylene)0P(=0)(0R5)¾ or -(Ci- C6alkylene)0P(=0)(0R5)[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(=0)Ra, -C(=0)0Rb, -
C(=0)NRcRd, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1 -G, haloalkyl, Ci-Ce deuteroalkyl, C 1 -G, hydroxyalkyl, C1-C6 aminoalkyl, or Ci-Ce heteroalkyl;
Y is a bond, -0-, -S-, or -NRb-;
Z is a bond or Ci -G, alkylene:
Rx is hydrogen, -NO2, -CN, or -S(=0)2Ra;
each R4 is independently Ci-Ce alkyl, C2-C15 alkenyl, CN-Ck, alkynyl, C 1 -G, haloalkyl, G-G, deuteroalkyl, C1-C6 hydroxyalkyl, C 1 -G, aminoalkyl, C 1 -G, 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(=0)Ra, -C(=0)0Rb, -
C(=0)NRcRd, Ci-Ce alkyl, C2-C6 alkenyl, C2-G5 alkynyl, C 1 -G, haloalkyl, Ci-Ce deuteroalkyl, C 1 -G, hydroxyalkyl, C 1 -G, aminoalkyl, Ci-G heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R5 is independently hydrogen, C 1 -G, alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1 -G, haloalkyl, C 1 -G, deuteroalkyl, Ci-Ce hydroxyalkyl, C1-C 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(=0)Ra, -C(=0)0Rb, -
C(=0)NRcRd, C 1 -G, alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1 -G, haloalkyl, C 1 -G, deuteroalkyl, C1-G5 hydroxyalkyl, C 1 -G, aminoalkyl, Ci-Ce heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R6 and R7 is independently hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1 -G, haloalkyl, Ci- Ce deuteroalkyl, C 1 -G, hydroxyalkyl, C 1 -G, aminoalkyl, C 1 -G, 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(=0)Ra, -C(=0)0Rb, -
C(=0)NRcRd, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1 -G, haloalkyl, C 1 -G, deuteroalkyl, C 1 -G, hydroxyalkyl, C 1 -G, aminoalkyl, C 1 -G, 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 Rib is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=0)Ra, -C(=0)0Rb, -
C(=0)NRcRd, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1 -G, haloalkyl, C 1 -G, deuteroalkyl, C 1 -G, hydroxyalkyl, C 1 -G, aminoalkyl, C 1 -G, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
Figure imgf000030_0001
R8 is hydrogen, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=0)Ra, -C(=0)0Rb, C 1 -G, alkyl, G-G, alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, or C 1 -G, deuteroalkyl;
R9 is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or Ci-Ce deuteroalkyl;
R10 is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Cs haloalkyl, or Ci-Gs 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, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1 -G, haloalkyl, Ci-Ce deuteroalkyl, C 1 -G, hydroxyalkyl, C 1 -G, aminoalkyl, or C 1 -G, 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(=0)Ra, -C(=0)0Rb, -C(=0)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1 -G, haloalkyl, Ci-Ce deuteroalkyl, Ci-Ce hydroxyalkyl, C1-C6 aminoalkyl, C 1 -G, heteroalkyl, cycloalkyl, or heterocycloalkyl; R15 and R16 are independently hydrogen, -ORb, -NRcRd, C i -G, alkyl, C2-G5 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C 1 -G, deuteroalkyl, C 1 -C,, hydroxyalkyl, Ci-Ce aminoalkyl, or C 1 -G, 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(=0)Ra, -C(=0)ORb, -C(=0)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C 1 -G, deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C 1 -G, heteroalkyl, cycloalkyl, or heterocycloalkyl;
each Ra is independently C1-C6 alkyl, C2-C alkenyl, C2-C6 alkynyl, C1-C haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, Ci-Ce aminoalkyl, Ci-Ce 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 C 1 -G> alkyl;
each Rb is independently hydrogen, C 1 -G, alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C 1 -G, deuteroalkyl, Ci-Ce hydroxyalkyl, C 1 -G, aminoalkyl, C 1 -G, 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 Ci- Ce alkyl; and
each Rc and Rd is independently hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1 -G, haloalkyl, Ci- Ce deuteroalkyl, C 1 -G, hydroxyalkyl, C 1 -G, aminoalkyl, C 1 -G, 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 C 1 -G, 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 Ci- C6 alkyl.
[0093] In some embodiments of a compound of Formula (III), R1 is -CN, Ci-Ce alkyl, C 1 -G, haloalkyl, or Ci-Ce deuteroalkyl. In some embodiments of a compound of Formula (III), R1 is -CN or C 1 -G, haloalkyl. In some embodiments of a compound of Formula (III), R1 is Ci-Cs haloalkyl. In some embodiments of a compound of Formula (III), R1 is -CN.
[0094] 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.
[0095] In some embodiments of a compound of Formula (III), R9 is Ci-C<5 alkyl or C2-C6 alkynyl. In some embodiments of a compound of Formula (III), R9 is Ci-C<5 alkyl.
[0096] In some embodiments of a compound of Formula (III), R10 is Ci-Ce alkyl or C2-C6 alkynyl. In some embodiments of a compound of Formula (III), R10 is Ci-Ce alkyl.
[0097] 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 C 1 -C,, alkyl and R9 is C2-C6 alkynyl. X o
[0098] In some embodiments of a compound of Formula (III), — is ~J1~ . in some embodiments of a compound of Formula (
Figure imgf000032_0001
[0099] 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.
[00100] In some embodiments of a compound of Formula (III), R12 and R13 are independently hydrogen, Ci-Ce alkyl, or C i -G, deuteroalkyl. In some embodiments of a compound of Formula (III), R12 and R13 are independently hydrogen or Ci-Ce alkyl. In some embodiments of a compound of Formula (III), R12 and R13 are independently hydrogen or Ci-Ce deuteroalkyl. In some embodiments of a compound of Formula (III), R12 and R13 are independently Ci-Ce alkyl.
[00101] 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.
[00102] 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.
[00103] In some embodiments of a compound of Formula (III), R15 and R16 are independently hydrogen, Ci-Ce alkyl, or C i -C-, deuteroalkyl. In some embodiments of a compound of Formula (III), R15 and R16 are independently hydrogen or Ci-Ce alkyl. In some embodiments of a compound of Formula (III), R15 and R16 are independently hydrogen or Ci-Ce deuteroalkyl. In some embodiments of a compound of Formula (III), R15 and R16 are independently Ci-Ce alkyl.
[00104] 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.
[00105] 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.
[00106] In some embodiments of a compound of Formula (III), R3 is -P(=0)(R4)2, -P(=0)(0R5)2, -Y(Ci-
Figure imgf000033_0001
C6alkylene)NR5S(=0)(=NRx)R5. In some embodiments of a compound of Formula (III), R3 is N-linked heterocycloalkyl or N-linked heteroaryl.
[00107] In some embodiments of a compound of Formula (III), R3 is -P(=0)(R4)2, -P(=0)(0R5)2, -Y(Ci- C6alkylene)P(=0)(R4)2, -Y(Ci-C6alkylene)P(=0)(0R5)2, -B(OR5)2, -Y(Ci-C6alkylene)B(OR5)2, -S(=0)R4, -S(=0)2R4, -Y(C I -G,alkvlcnc)S(=0) R4. -Y(Ci-C6alkylene)S(=0)2R4, -NR5C(=NRX)R5, - NR5C(=NRX)NR6R7, -Y(Ci-C6alkylene)NR5C(=NRx)R5, -Y(Ci-C6alkylene)NR5C(=NRx)NR6R7, - NR5C(=0)(Ci-C6alkylene)S(=NRx)NR6R7, -NR5C(=0)(Ci-C6alkylene)S(=NRx)R5, -S(=0)(=NRx)R5, - S(=0)(=NRx)NRsR7, -NR5S(=0)2NR5C(=0)R5, -NR5S(=0)(=NRX)R5, -Y(Ci-C6alkylene)S(=0)(=NRx)R5, -Y(Ci-C6alkylene)S(=0)(=NRx)NR6R7, -Y(Ci-C6alkylene)NR5S(=0)2NR5C(=0)R5, -Y(Ci- C6alkylene)NR5S(=0)(=NRx)R5, a N-linked heterocycloalkyl, or a N-linked heteroaryl.
[00108] In some embodiments of a compound of Formula (III), R3 is -Y(Ci-Cf,alkylene)NR5C(=NRx)R5 or -Y(Ci-C6alkylene)NR5C(=NRx)NR6R7.
[00109] 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 -0-.
[00110] In some embodiments of a compound of Formula (III), each R4 is independently Ci-Ce alkyl, C2-Ce alkenyl, CVG, alkynyl, Ci-Ce haloalkyl, C i -G, 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 Ci-Ce 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 Ci-Ce alkyl optionally substituted with one, two, or three R4a. In some embodiments of a compound of Formula (III), each R4 is independently C i -G, alkyl. In some embodiments of a compound of Formula (III), each R4 is independently G-G alkyl, G-G haloalkyl, or G-G deuteroalkyl.
[00111] In some embodiments of a compound of Formula (III), each R4a is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, C i -G, alkyl, G-G 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.
[00112] In some embodiments of a compound of Formula (III), each R5 is independently hydrogen, G- G alkyl, G-G haloalkyl, C i -G, 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, G-G 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 G-G alkyl optionally substituted with one, two, or three R5a. In some embodiments of a compound of Formula (III), each R5 is independently C i -G, alkyl optionally substituted with one, two, or three R5a. In some embodiments of a compound of Formula (III), each R5 is hydrogen or G-G alkyl. In some embodiments of a compound of Formula (III), each R5 is independently hydrogen, G-G alkyl, C i -G, haloalkyl, or G-G deuteroalkyl.
[00113] In some embodiments of a compound of Formula (III), two R5 are taken together to form an optionally substituted heterocycloalkyl.
[00114] In some embodiments of a compound of Formula (III), each R5a is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=0)Ra, -C(=0)ORb, -C(=0)NRcRd, or G-G alkyl. In some embodiments of a compound of Formula (III), each R5a is independently halogen, -CN, -ORb, -NRcRd, - C(=0)ORb, or G-G alkyl.
[00115] In some embodiments of a compound of Formula (III), each R5a is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, C i -G, alkyl, C i -G, 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.
[00116] In some embodiments of a compound of Formula (III), each R6 and R7 is independently hydrogen, G-G alkyl, G-G, haloalkyl, G-G, 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, G- G, alkyl, Ci-Ce 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, Ci-Ce alkyl, or Ci-Ce 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 G-G alkyl. In some embodiments of a compound of Formula (III), each R6 and R7 is independently hydrogen, G-G alkyl, G-G haloalkyl, or G-G deuteroalkyl. [00117] In some embodiments of a compound of Formula (III), each R6a is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, Ci-Ce alkyl, Ci-Ce 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(=0)(=NRx)Rb or -S(=0)(=NRx)NRcRd.
[00118] In some embodiments of a compound of Formula (III), R5 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.
[00119] In some embodiments of a compound of Formula (III), each R6b is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, Ci-Ce alkyl, C i -G, haloalkyl, C i -G, hydroxyalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (III), each R6b is independently C i -G, alkyl or Ci-Ce haloalkyl. In some embodiments of a compound of Formula (III), each R6b is independently Ci-Ce alkyl.
[00120] 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.
N'CN N^N N.NO2
Figure imgf000035_0001
In some embodiments of a compound of Formula (III), R3 is H , H H H
Figure imgf000035_0002
Figure imgf000036_0001
[00121] In some embodiments of a compound of Formula (III), R3 is
Figure imgf000036_0002
[00122] Diclosed herein is a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure imgf000036_0003
Formula (IV);
wherein:
R1 is hydrogen, deuterium, halogen, -CN, -ORb, -NRcRd, -NRbS(=0)2Ra, -C(=0)Ra, -C(=0)ORb, -
C(=0)NRcRd, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C 1 -G, deuteroalkyl, C 1 -G, hydroxyalkyl, Ci-Ce aminoalkyl, or Ci-Ce heteroalkyl;
R3 is halogen, -CN, -OR5, -SR5, -S(=0)R4, -S(=0)2R4, -NO2, -NR6R7, -S(=0)2NR6R7, -C(=0)R4, - OC(=0)R4, -C(-0)OR\ -OC(-0)OR\ -C(=0)NR6R7, -0C(=0)NR¾7, -NR5C(=0)NR6R7, - NR5C(=0)0R5, -NR5S(=0)2NR¾7, -NR5S(=0)2R4, -NR5C(=0)R4, -P(=0)(R4)2, -P(=0)(0R5)2, - B(OR5)2, -NR5C(=NRX)R5, -NR5C(=NRX)NR6R7, -S(=0)(=NRX)R5, -S(=0)(=NRX)NR6R7, - NR5S(=0)2NR5C(=0)R5, -NR5S(=0)(=NRX)R5, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, Ci-Ce deuteroalkyl, C 1 -C,, hydroxyalkyl, Ci-Ce aminoalkyl, Ci-Ce 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(=0)R4, -S(=0)2R4, -NO2, -NR6R7,
Figure imgf000037_0001
G alkynyl, G-G, haloalkyl, G-G deuteroalkyl, G-G hydroxyalkyl, G-G 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(=0)Ra, -C(=0)0Rb, -C(=0)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1 -G, haloalkyl, G-G deuteroalkyl, G-G hydroxyalkyl, C1-C6 aminoalkyl, C 1 -G, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
Rx is hydrogen, -N02, -CN, or -S(=0)2Ra;
each R4 is independently C 1 -G, alkyl, G-G alkenyl, G-G alkynyl, C 1 -G, haloalkyl, C i-G, deuteroalkyl, C1-C6 hydroxyalkyl, G-G aminoalkyl, C 1 -G, 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(=0)Ra, -C(=0)0Rb, -
C(=0)NRcRd, -NRbC(=NRx)Rb, -NRbC(=NRx)NRcRd, -S(=0)(=NRx)Rb, -S(=0)(=NRx)NRcRd, G-G alkyl, G-G alkenyl, G-G, alkynyl, G-G haloalkyl, C 1 -G, deuteroalkyl, C 1 -G, hydroxyalkyl, C 1 -G, aminoalkyl, C 1 -G, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R5 is independently hydrogen, C 1 -G, alkyl, G-G, alkenyl, G-G, alkynyl, C 1 -G, haloalkyl, C 1 -G, deuteroalkyl, C 1 -G, hydroxyalkyl, C 1 -G, aminoalkyl, C 1 -G, 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, deutenum, halogen, -CN, -ORb, -NRcRd, -C(=0)Ra, -C(=0)0Rb, -
C(=0)NRcRd, -NRbC(=NRx)Rb, -NRbC(=NRx)NRcRd, -S(=0)(=NRx)Rb, -S(=0)(=NRx)NRcRd, G-G alkyl, G-G, alkenyl, G-G, alkynyl, C 1 -G, haloalkyl, G-G deuteroalkyl, C 1 -G, hydroxyalkyl, G-G aminoalkyl, C 1 -G, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R6 and R7 is independently hydrogen, G-G alkyl, G-G alkenyl, G-G, alkynyl, C 1 -G, haloalkyl, G- G deuteroalkyl, C 1 -G, hydroxyalkyl, G-G aminoalkyl, C 1 -G, 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(=0)Ra, -C(=0)0Rb, -
C(=0)NRcRd, -NRbC(=NRx)Rb, -NRbC(=NRx)NRcRd, -S(=0)(=NRx)Rb, -S(=0)(=NRx)NRcRd, G-G alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, G-G deuteroalkyl, Ci-Ce hydroxyalkyl, G-G ammoalkyl, C 1 -G, 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(=0)Ra, -C(=0)0Rb, -
C(=0)NRcRd, C 1 -G, alkyl, C2-C6 alkenyl, C2-C6 alkynyl, G-G haloalkyl, C 1 -G, deuteroalkyl, C 1 -G, hydroxyalkyl, G-G aminoalkyl, C 1 -G, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
X O OH
JL is JL or J™ .
R8 is hydrogen, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=0)Ra, -C(=0)0Rb, C 1 -G, alkyl, G-G, alkenyl, G-G alkynyl, C 1 -G, haloalkyl, or C 1 -G, deuteroalkyl;
R9 is G-G alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1 -G, haloalkyl, or C 1 -G, deuteroalkyl;
R10 is Ci-Ce alkyl, G-G alkenyl, G-G alkynyl, G-G haloalkyl, or C 1 -G, deuteroalkyl;
provided that one of R9 or R10 is G-G 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, C 1 -G, alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1 -G, haloalkyl, G-G deuteroalkyl, C 1 -G, hydroxyalkyl, C 1 -G, aminoalkyl, or C 1 -G, 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(=0)Ra, -C(-0)0R". -C(=0)NRcRd, G-G alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1 -G, haloalkyl, C 1 -C , deuteroalkyl, C 1 -G, hydroxyalkyl, G-G ammoalkyl, G-G heteroalkyl, cycloalkyl, or heterocycloalkyl;
R15 and R1S are independently hydrogen, -ORb, -NRcRd, C 1 -G, alkyl, G-G alkenyl, G-G alkynyl, C 1 -G, haloalkyl, C 1 -G, deuteroalkyl, or C 1 -G, 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(=0)Ra, -C(=0)ORb, -C(=0)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C 1 -G, deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C 1 -G, heteroalkyl, cycloalkyl, or heterocycloalkyl;
each Ra is independently C1-C6 alkyl, G-G alkenyl, G-G alkynyl, G-G haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C 1 -G, aminoalkyl, C 1 -G, 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 C 1 -G, alkyl;
each Rb is independently hydrogen, C 1 -G, alkyl, C2-C6 alkenyl, G-G alkynyl, C 1 -G, haloalkyl, C 1 -G, deuteroalkyl, C 1 -G, hydroxyalkyl, G-G aminoalkyl, C 1 -G, 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 G- G alkyl; and each Rc and Rd is independently hydrogen, C i -C , alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, Ci- C5 deuteroalkyl, Ci-Ce hydroxyalkyl, Ci-C<5 aminoalkyl, C 1 -G, 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 Ci-Ce 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 Ci- C6 alkyl.
[00123] In some embodiments of a compound of Formula (IV), R1 is -CN, Ci-Ce alkyl, C 1 -G, haloalkyl, or Ci-Ce deuteroalkyl. In some embodiments of a compound of Formula (IV), R1 is -CN or C 1 -G, haloalkyl. In some embodiments of a compound of Formula (IV), R1 is Ci-Ce haloalkyl. In some embodiments of a compound of Formula (IV), R1 is -CN.
[00124] 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.
[00125] In some embodiments of a compound of Formula (IV), R9 is Ci-Ce alkyl or C2-C6 alkynyl. In some embodiments of a compound of Formula (IV), R9 is C2-C alkynyl. In some embodiments of a compound of Formula (IV), R9 is Ci-Gs alkyl.
[00126] In some embodiments of a compound of Formula (IV), R10 is Ci-Ce 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 Ci-Ce alkyl.
[00127] In some embodiments of a compound of Formula (IV), R9 is Ci-Ce alkyl and R10 is C2-C6 alkynyl. In some embodiments of a compound of Formula (IV), R10 is Ci-Ce alkyl and R9 is C2-C6 alkynyl.
X O
[00128] In some embodiments of a compound of Formula (IV),
Figure imgf000039_0001
is— M— . In some embodiments of a compound of Formula
Figure imgf000039_0002
[00129] 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.
[00130] In some embodiments of a compound of Formula (IV), R12 and R13 are independently hydrogen, Ci-Ce alkyl, or C 1 -G, deuteroalkyl. In some embodiments of a compound of Formula (IV), R12 and R13 are independently hydrogen or Ci-Ce alkyl. In some embodiments of a compound of Formula (IV), R12 and R13 are independently hydrogen or Ci-Ce deuteroalkyl. In some embodiments of a compound of Formula (IV), R12 and R13 are independently Ci-Gs alkyl.
[00131] 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.
[00132] 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.
[00133] In some embodiments of a compound of Formula (IV), R15 and R16 are independently hydrogen, Ci-Ce alkyl, or C i -O, deuteroalkyl. In some embodiments of a compound of Formula (IV), R15 and R16 are independently hydrogen or Ci-Gs alkyl. In some embodiments of a compound of Formula (IV), R15 and R16 are independently hydrogen or Ci-Ce deuteroalkyl. In some embodiments of a compound of Formula (IV), R15 and R16 are independently Ci-Gs alkyl.
[00134] 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 R1S are taken together to form a cycloalkyl substituted with 2-4 deuteriums.
[00135] 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.
[00136] In some embodiments of a compound of Formula (IV), R3 is halogen, -CN, -OR5, -NR6R7, -
Figure imgf000040_0001
S(=0)(=NRx)NR¾7, -NR5S(=0)2NR5C(=0)R5, -NR5S(=0)(=NRX)R5, Ci-Ce alkyl, C2-C„ alkenyl, C ,-G, hydroxyalkyl, Ci-G, 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(=0)(=NRx)R5, -S(=0)(=NRx)NR6R7, -NR5S(=0)2NR5C(=0)R5, or - NR5S (=0) (=NRX)R5.
[00137] In some embodiments of a compound of Formula (IV), R3 is Ci-Ce alkyl optionally substituted with one, two, or three R3a. In some embodiments of a compound of Formula (IV), R3 is Ci-Ce alkyl.
[00138] In some embodiments of a compound of Formula (IV), R3 is -C(=0)OR5.
[00139] In some embodiments of a compound of Formula (IV), each R3a is independently deuterium, halogen, -CN, -OR5, -S(=0)R4, -S(=0)2R4, -OC(=0)R4, -C(=0)OR5, -OC(=0)OR5, -C(=0)NR6R7, - 0C(=0)NR6R7, -P(=0)(R4)2, -P(=0)(0R5)2, -B(OR5)2, -NR5C(=NRX)R5, -NR5C(=NRX)NR6R7, - S(=0)(=NRx)R5, -S(=0)(=NRx)NR6R7, -NR5S(=0)2NR5C(=0)R5, -NR5S(=0)(=NRx)R5, cycloalkyl, or heterocycloalkyl.
[00140] In some embodiments of a compound of Formula (IV), each R3a is independently deuterium, halogen, -CN, -OR5, -S(=0)R4, -S(=0)2R4, -OC R6R7, - 0C(=0)NR6R7, -P(=0)(R4)2, -P(=0)(0R5)2, -B 7, - S(=0)(=NRx)R5, -S(=0)(=NRx)NR6R7, -NR5S(
Figure imgf000041_0001
n some embodiments of a compound of Formula (IV), each R3a is independently deuterium, halogen, -CN, -OR5, - OC(=0)R4, -C(=0)OR5, -C(=0)NR6R7, -B(OR5)2, -S(=0)(=NRx)R5, G-G, heteroalkyl, heterocycloalkyl, or heteroaryl. In some embodiments of a compound of Formula (IV), each R3a is independently - OC(=0)R4, -C(=0)OR5, -OC(=0)OR5, -C(=0)NR6R7, -P(=0)(R4)2, -P(=0)(0R5)2, -B(OR5)2, - NR5C(=NRX)R5, -NR5 C(=NRX)NR6R7, -S(=0)(=NRx)R5, -S(=0)(=NRx)NR6R7, -NR5S(=0)2NR5C(=0)R5, or -NR5S(=0)(=NRx)R5 In some embodiments of a compound of Formula (IV), each R3a is independently -OC(=0)R4, -C(=0)OR5, -OC(=0)OR5, or -C(=0)NR6R7. In some embodiments of a compound of Formula (IV), each R3a is independently -P(=0)(R4)2, -P(=0)(0R5)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(=0)(=NRx)R5, -S(=0)(=NRx)NR6R7, -NR5S(=0)2NR5C(=0)R5, or -NR5S(=0)(=NRx)R5.
[00141] In some embodiments of a compound of Formula (IV), each R3b is independently deuterium, halogen, -CN, -ORb, G-G alkyl, G-G haloalkyl, or C i -G, deuteroalkyl. In some embodiments of a compound of Formula (IV), each R3b is independently deuterium, halogen, C i -G, alkyl, G-G haloalkyl, or G-G, deuteroalkyl.
[00142] In some embodiments of a compound of Formula (IV), each R4 is independently C i -G, alkyl, G-G alkenyl, G-G alkynyl, G-G haloalkyl, C i -G, 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 C i -G 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 C i -G, alkyl optionally substituted with one, two, or three R4a. In some embodiments of a compound of Formula (IV), each R4 is independently G-G alkyl. In some embodiments of a compound of Formula (IV), each R4 is independently G-G alkyl, G-G haloalkyl, or G-G deuteroalkyl.
[00143] In some embodiments of a compound of Formula (IV), each R4a is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, G-G alkyl, G-G 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.
[00144] In some embodiments of a compound of Formula (IV), each R5 is independently hydrogen, G- G alkyl, G-G haloalkyl, G-G 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, G-G 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 C i -G, alkyl optionally substituted with one, two, or three R5a. In some embodiments of a compound of Formula (IV), each R5 is independently C i -C , alkyl optionally substituted with one, two, or three R5a. In some embodiments of a compound of Formula (IV), each R5 is hydrogen or Ci-G, alkyl. In some embodiments of a compound of Formula (IV), each R5 is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C 1 -G, deuteroalkyl.
[00145] In some embodiments of a compound of Formula (IV), two R5 are taken together to form an optionally substituted heterocycloalkyl.
[00146] In some embodiments of a compound of Formula (IV), each R5a is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, C1-C6 alkyl, C 1 -G, 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(=0)(=NRx)Rb or -S(=0)(=NRx)NRcRd.
[00147] In some embodiments of a compound of Formula (IV), each R6 and R7 is independently hydrogen, Ci-Gs alkyl, C 1 -G, haloalkyl, C 1 -G, 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, Ci-Cs alkyl, C 1 -G, haloalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one, two, or three R"a. In some embodiments of a compound of Formula (IV), each R6 and R7 is independently hydrogen, G-G, alkyl, or C 1 -G, 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, C 1 -Co alkyl, C 1 -G, haloalkyl, or C 1 -G, deuteroalkyl.
[00148] In some embodiments of a compound of Formula (IV), each R6a is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, C 1 -G, alkyl, C 1 -G, 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(=0)(=NRx)Rb or -S(=0)(=NRx)NRcRd.
[00149] 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.
[00150] In some embodiments of a compound of Formula (IV), each R® is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, C1-C alkyl, C 1 -G, haloalkyl, C1-C6 hydroxyalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (IV), each R6b is independently C 1 -G, alkyl or Ci-C<5 haloalkyl. In some embodiments of a compound of Formula (IV), each R6b is independently Ci-Ce alkyl.
[00151] 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.
[00152] Diclosed herein is a compound of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure imgf000043_0001
Formula (V);
wherein:
R1 is hydrogen, deuterium, halogen, -CN, -ORb, -NRcRd, -NRbS(=0)2Ra, -C(=0)Ra, -C(=0)ORb, -
C(=0)NRcRd, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1 -G, haloalkyl, Ci-Ce deuteroalkyl, Ci-Ce hydroxyalkyl, C1-C6 aminoalkyl, or Ci-Ce heteroalkyl;
R3 is halogen, -CN, -OR5, -SR5, -S(=0)R4, -S(=0)2R4, -NO2, -NR6R7, -S(=0)2NR6R7, -C(=0)R4, -
Figure imgf000043_0002
haloalkyl, Ci-Ce deuteroalkyl, C 1 -C, hydroxyalkyl, Ci-Ce aminoalkyl, C 1 -G, 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(=0)R4, -S(=0)2R4, -NO2, -NR6R7,
Figure imgf000043_0003
G alkynyl, G-G haloalkyl, G-G deuteroalkyl, G-G hydroxyalkyl, C 1 -G, 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(=0)Ra, -C(=0)ORb, -C(=0)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, G-G alkynyl, G-G haloalkyl, G-G deuteroalkyl, G-G, hydroxyalkyl, C1-C6 aminoalkyl, C 1 -G, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
Rx is hydrogen, -NO2, -CN, or -S(=0)2Ra; each R4 is independently C i -G, alkyl, G-G alkenyl, G-G, alkynyl, C -C , haloalkyl, G-G, deuteroalkyl, G-G hydroxyalkyl, C -G, aminoalkyl, C -G, 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(=0)Ra, -C(=0)0Rb, -
C(=0)NRcRd, -NRbC(=NRx)Rb, -NRbC(=NRx)NRcRd, -S(=0)(=NRx)Rb, -S(=0)(=NRx)NRcRd, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, G-G haloalkyl, G-G deuteroalkyl, G-G hydroxyalkyl, C 1 -G, aminoalkyl, G-G heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R5 is independently hydrogen, G-G alkyl, G-G alkenyl, C2-C6 alkynyl, G-G haloalkyl, G-G deuteroalkyl, G-G hydroxyalkyl, G-G aminoalkyl, C 1 -G, 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(=0)Ra, -C(=0)0Rb, -
C(=0)NRcRd, -NRbC(=NRx)R\ -NRbC(=NRx)NRcRd, -S(=0)(=NRx)Rb, -S(=0)(=NRx)NRcRd, G-G alkyl, C -C alkenyl, G-G alkynyl, G-G haloalkyl, G-G deuteroalkyl, Ci-Ce hydroxyalkyl, G-G aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R6 and R7 is independently hydrogen, G-G alkyl, G-G, alkenyl, G-G alkynyl, G-G haloalkyl, G- G deuteroalkyl, G-G hydroxyalkyl, G-G aminoalkyl, G-G 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(=0)Ra, -C(=0)0Rb, -
C(=0)NRcRd, -NRbC(=NRx)Rb, -NRbC(=NRx)NRcRd, -S(=0)(=NRx)Rb, -S(=0)(=NRx)NRcRd, Ci-G alkyl, G-G alkenyl, G-G alkynyl, G-G haloalkyl, G-G deuteroalkyl, G-G hydroxyalkyl, G-G aminoalkyl, G-G 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, deutenum, halogen, -CN, -ORb, -NRcRd, -C(=0)Ra, -C(=0)0Rb, -
C(=0)NRcRd, G-G alkyl, G-G alkenyl, G-G alkynyl, G-G haloalkyl, G-G deuteroalkyl, G-G hydroxyalkyl, G-G aminoalkyl, G-G heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
X O OH
_ iS JL or _L ;
R8 is hydrogen, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=0)Ra, -C(=0)0Rb, G-G alkyl, G-G, alkenyl, G-G alkynyl, G-G haloalkyl, or G-G deuteroalkyl;
R9 is G-G alkyl, G-G alkenyl, G-G alkynyl, G-G haloalkyl, or G-G deuteroalkyl;
R10 is G-G alkyl, G-G alkenyl, G-G alkynyl, G-G haloalkyl, or G-G 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, C i -G, alkyl, C2-G5 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C 1 -G, deuteroalkyl, C 1 -C,, hydroxyalkyl, Ci-Ce aminoalkyl, or C 1 -G, 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(=0)Ra, -C(=0)0Rb, -C(=0)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C 1 -G, deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C 1 -G, heteroalkyl, cycloalkyl, or heterocycloalkyl;
R17 is hydrogen, -S(=0)Ra, -S(=0)2Ra, -S(=0)2NRcRd, -C(=0)Ra, -C(=0)0Rb, -C(=0)NRcRd, G-G, alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C 1 -G, deuteroalkyl, C1-C hydroxyalkyl, C 1 -G, aminoalkyl, C 1 -G, heteroalkyl, cycloalkyl, or heterocycloalkyl;
each Ra is independently C 1 -G, alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C 1 -G, deuteroalkyl, C1-C6 hydroxyalkyl, C 1 -G, aminoalkyl, C 1 -G, 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 C 1 -G, alkyl;
each Rb is independently hydrogen, C 1 -G, alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C 1 -G, deuteroalkyl, C 1 -G, hydroxyalkyl, C 1 -G, aminoalkyl, C 1 -G, 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 Ci- C6 alkyl; and
each Rc and Rd is independently hydrogen, C 1 -G, alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1 -G, haloalkyl, Ci- C5 deuteroalkyl, C 1 -G, hydroxyalkyl, Ci-C<5 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 C 1 -G, 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 Ci- C6 alkyl.
[00153] In some embodiments of a compound of Formula (V), R1 is -CN, Ci-Ce alkyl, C 1 -G, haloalkyl, or Ci-Ce deuteroalkyl. In some embodiments of a compound of Formula (V), R1 is -CN or Ci-C<5 haloalkyl. In some embodiments of a compound of Formula (V), R1 is Ci-Ce haloalkyl. In some embodiments of a compound of Formula (V), R1 is -CN.
[00154] 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.
[00155] In some embodiments of a compound of Formula (V), R9 is C 1 -G, 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-G5 alkyl.
[00156] In some embodiments of a compound of Formula (V), R10 is Ci-Ce 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 Ci-Ce alkyl. [00157] In some embodiments of a compound of Formula (V), R9 is C i -G, alkyl and R10 is C2-C6 alkynyl. In some embodiments of a compound of Formula (V), R10 is C 1 -G> alkyl and R9 is C2-G5 alkynyl.
X O
[00158] In some embodiments of a compound of Formula (V), is ~!L [n some embodiments of a
X OH
compound of Formula (Y), is— J— .
[00159] 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 (Y), R11 is hydrogen.
[00160] In some embodiments of a compound of Formula (V), R12 and R13 are independently hydrogen, C 1 -Co alkyl, or C 1 -C:, deuteroalkyl. In some embodiments of a compound of Formula (V), R12 and R13 are independently hydrogen or C 1 -G, alkyl. In some embodiments of a compound of Formula (V), R12 and R13 are independently hydrogen or C 1 -G, deuteroalkyl. In some embodiments of a compound of Formula (V), R12 and R13 are independently C 1 -G, alkyl.
[00161] 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 (Y), R12 and R13 are taken together to form a cycloalkyl substituted with 2-4 deuteriums.
[00162] 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.
[00163] In some embodiments of a compound of Formula (V), R17 is hydrogen, C 1 -G, alkyl, C 1 -G, haloalkyl, or C 1 -G, deuteroalkyl. In some embodiments of a compound of Formula (V), R17 is C 1 -G, alkyl.
[00164] In some embodiments of a compound of Formula (V), R3 is halogen, -CN, -OR5, -NR6R7, -
Figure imgf000046_0001
S(=0)(=NRx)NRsR7, -NR5S(=0)2NR5C(=0)R5, -NR5S(=0)(=NRX)R5, CI -G, alkyl, G-G, alkenyl, G-G, hydroxyalkyl, C 1 -G, 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(=0)(=NRx)R5, -S(=0)(=NRx)NR6R7, -NR5S(=0)2NR5C(=0)R5, or - NR5S (=0) (=NRX)R5.
[00165] In some embodiments of a compound of Formula (V), R3 is Ci-Cs alkyl optionally substituted with one, two, or three R3a. In some embodiments of a compound of Formula (V), R3 is C 1 -G, alkyl. [00166] In some embodiments of a compound of Formula (V), R3 is -C(=0)OR5.
[00167] In some embodiments of a compound of Formula (V), each R3a is independently deuterium, halogen, -CN, -OR5, -S(=0)R4, -S(=0)2R4, -OC 0)NR6R7, - 0C(=0)NR6R7, -P(=0)(R4)2, -P(=0)(0R5)2, -B R6R7, - S(=0)(=NRx)R5, -S(=0)(=NRx)NR6R7, -NR5S(
Figure imgf000047_0001
cycloalkyl, or heterocycloalkyl.
[00168] In some embodiments of a compound of Formula (V), each R3a is independently deuterium, halogen, -CN, -OR5, -S(=0)R4, -S(=0)2R4, -OC(=0)R4, -C(=0)OR5, -OC(=0)OR5, -C(=0)NR6R7, - 0C(=0)NR6R7, -P(=0)(R4)2, -P(=0)(0R5)2, -B(OR5)2, -NR5C(=NRX)R5, -NR5C(=NRX)NR6R7, - S(=0)(=NRx)R5, -S(=0)(=NRx)NR6R7, -NR5S(=0)2NR5C(=0)R5, or -NR5S(=0)(=NRx)R5. In some embodiments of a compound of Formula (V), each R3a is independently deuterium, halogen, -CN, -OR5, - OC(=0)R4, -C(=0)OR5, -C(=0)NR6R7, -B(OR5)2, -S(=0)(=NRx)R5, G-G, heteroalkyl, heterocycloalkyl, or heteroaryl. In some embodiments of a compound of Formula (V), each R3a is independently -
Figure imgf000047_0002
or -NR5S(=0)(=NRx)R5.In some embodiments of a compound of Formula (V), each R3a is independently - OC(=0)R4, -C(=0)OR5, -OC(=0)OR5, or -C(=0)NR6R7. In some embodiments of a compound of Formula (V), each R3a is independently -P(=0)(R4)2, -P(=0)(0R5)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(=0)(=NRx)R5, -S(=0)(=NRx)NR6R7, -NR5S(=0)2NR5C(=0)R5, or -NR5S(=0)(=NRx)R5.
[00169] In some embodiments of a compound of Formula (V), each R3b is independently deuterium, halogen, -CN, -ORb, C i -G, alkyl, G-G haloalkyl, or C i -G, deuteroalkyl. In some embodiments of a compound of Formula (Y), each R3b is independently deuterium, halogen, C i -G, alkyl, C i -G, haloalkyl, or C i -Co deuteroalkyl.
[00170] In some embodiments of a compound of Formula (V), each R4 is independently C i -G, alkyl, C2- C(, alkenyl, G-G, alkynyl, Ci-C(5 haloalkyl, C i -G, 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 G- C , 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 G-G alkyl optionally substituted with one, two, or three R4a. In some embodiments of a compound of Formula (V), each R4 is independently Ci-C<5 alkyl. In some embodiments of a compound of Formula (V), each R4 is independently G-G alkyl, C i -G, haloalkyl, or G-G, deuteroalkyl.
[00171] In some embodiments of a compound of Formula (V), each R4a is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, G-G alkyl, G-G 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.
[00172] In some embodiments of a compound of Formula (V), each R5 is independently hydrogen, G- G, alkyl, G-G haloalkyl, G-G 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, C i -G, 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 Ci- Ce alkyl optionally substituted with one, two, or three R5a. In some embodiments of a compound of Formula (V), each R5 is independently C i -G, 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-C alkyl, Ci-Ce haloalkyl, or C 1 -G, deuteroalkyl.
[00173] In some embodiments of a compound of Formula (V), two R5 are taken together to form an optionally substituted heterocycloalkyl.
[00174] In some embodiments of a compound of Formula (V), each R5a is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, C 1 -G, alkyl, C 1 -G, 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(=0)(=NRx)Rb or -S(=0)(=NRx)NRcRd.
[00175] In some embodiments of a compound of Formula (V), each R6 and R7 is independently hydrogen, Ci-Ce alkyl, C 1 -G, haloalkyl, Ci-Ce 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, Ci- C , alkyl, C 1 -G, haloalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and
heterocycloalkyl are independently optionally substituted with one, two, or three R"a. In some embodiments of a compound of Formula (V), each R6 and R7 is independently hydrogen, Ci-C<5 alkyl, or C 1 -Co 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 Ci-Ce alkyl. In some embodiments of a compound of Formula (V), each R6 and R7 is independently hydrogen, Ci-Ce alkyl, C 1 -G> haloalkyl, or C rG, deuteroalkyl.
[00176] In some embodiments of a compound of Formula (V), each R6a is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, C 1 -C, alkyl, C 1 -G, 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(=0)(=NRx)Rb or -S(=0)(=NRx)NRcRd.
[00177] 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. [00178] In some embodiments of a compound of Formula (V), each R6b is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, C 1 -C, alkyl, C 1 -G haloalkyl, C 1 -G, hydroxyalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (V), each R"b is independently C 1 -G, alkyl or G-G, haloalkyl. In some embodiments of a compound of Formula (V), each R6b is independently G-G alkyl.
[00179] In some embodiments of a compound of Formula (V), Rx is hydrogen, -N02, or -CN. In some embodiments of a compound of Formula (V), Rx is -N02 or -CN. In some embodiments of a compound of Formula (V), Rx is -CN.
[00180] Diclosed herein is a compound of Formula (VI), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure imgf000049_0001
Formula (VI);
wherein:
R1 is hydrogen, deuterium, halogen, -CN, -ORb, -NRcRd, -NRbS(=0)2Ra, -C(=0)Ra, -C(=0)0Rb, -
C(=0)NRcRd, Ci-Ce alkyl, C2-C<5 alkenyl, C2-Ce alkynyl, C 1 -G, haloalkyl, C 1 -G, deuteroalkyl, Ci-Ce hydroxyalkyl, C 1 -G, aminoalkyl, or C 1 -G, heteroalkyl;
R3 is halogen, -CN, -OR5, -SR5, -S(=0)R4, -S(=0)2R4, -N02, -NR6R7, -S(=0)2NR6R7, -C(=0)R4, -
Figure imgf000049_0002
haloalkyl, Ci-Ce deuteroalkyl, C 1 -C, hydroxyalkyl, Ci-Ce aminoalkyl, C 1 -G, 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(=0)R4, -S(=0)2R4, -N02, -NR6R7,
Figure imgf000049_0003
G alkynyl, G-G haloalkyl, Ci-Gs deuteroalkyl, G-G hydroxyalkyl, G-G 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(=0)Ra, -C(=0)0Rb, -C(=0)NRcRd, Ci-C<5 alkyl, C2-G5 alkenyl, C2-G5 alkynyl, C 1 -G, haloalkyl, Ci-Ce deuteroalkyl, Ci-Ce hydroxyalkyl, Ci-Ce aminoalkyl, C 1 -G, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
Rx is hydrogen, -NO2, -CN, or -S(=0)2Ra;
each R4 is independently Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1 -C haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C 1 -G, aminoalkyl, C 1 -G, 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(=0)Ra, -C(=0)0Rb, -
C(=0)NRcRd, -NRbC(=NRx)Rb, -NRbC(=NRx)NRcRd, -S(=0)(=NRx)Rb, -S(=0)(=NRx)NRcRd, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, Ci-Ce deuteroalkyl, C 1 -G, hydroxyalkyl, Ci-Ce aminoalkyl, Ci-Ce heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R5 is independently hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1 -G, haloalkyl, C 1 -G, deuteroalkyl, Ci-Ce hydroxyalkyl, Ci-Ce aminoalkyl, C 1 -G, 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(=0)Ra, -C(=0)0Rb, -
C(=0)NRcRd, -NRbC(=NRx)R\ -NRbC(=NRx)NRcRd, -S(=0)(=NRx)Rb, -S(=0)(=NRx)NRcRd, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1 -G, haloalkyl, C 1 -G, deuteroalkyl, C 1 -G, hydroxyalkyl, C 1 -G, aminoalkyl, C 1 -G, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R6 and R7 is independently hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1 -G, haloalkyl, Ci- C5 deuteroalkyl, C 1 -G, hydroxyalkyl, C 1 -CY, aminoalkyl, Ci-Ce 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(=0)Ra, -C(=0)0Rb, -
C(=0)NRcRd, -NRbC(=NRx)R\ -NRbC(=NRx)NRcRd, -S(=0)(=NRx)Rb, -S(=0)(=NRx)NRcRd, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1 -G, haloalkyl, C 1 -G, deuteroalkyl, C 1 -CV, hydroxyalkyl, C 1 -C , aminoalkyl, C 1 -G, 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(=0)Ra, -C(=0)0Rb, -
C(=0)NRcRd, C 1 -G, alkyl, C2-C6 alkenyl, C2-G5 alkynyl, C 1 -G, haloalkyl, C 1 -G, deuteroalkyl, C 1 -G, hydroxyalkyl, C 1 -G, aminoalkyl, Ci-Ce heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
X O OH
is—— or
Y1 and Y2 are independently hydrogen, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=0)Ra, -C(=0)0Rb, - C(=0)NRcRd, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, Ci-Ce deuteroalkyl, Ci-Ce hydroxyalkyl, C 1 -G, aminoalkyl, or Ci-Ce heteroalkyl; R8 is hydrogen, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=0)Ra, -C(=0)0Rb, C i -G, alkyl, G-G alkenyl, G-G alkynyl, G-G haloalkyl, or C 1 -G, deuteroalkyl;
R9 is G-G alkyl, G-G alkenyl, G-G alkynyl, C 1 -G, haloalkyl, or C 1 -G deuteroalkyl;
R10 is G-G alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1 -G, haloalkyl, or C 1 -G, 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, G-G alkyl, G-G alkenyl, C2-C6 alkynyl, G-G haloalkyl, G- G deuteroalkyl, C 1 -G, hydroxyalkyl, C 1 -G aminoalkyl, G-G heteroalkyl, cycloalkyl,
heterocycloalkyl, aryl, or heteroaryl; provided that R12 is not -CH3;
R13 is -OR19, -NR20R21, -S(=O)2NR20R21, -C(=0)R18, -0C(=0)R18, -C(=0)0R19, -0C(=0)0R19, - C(=O)NR20R21, -OC(=O)NR20R21, -NR19C(=O)NR20R21, -NR19C(=0)0R19, -NR19S(=O)2NR20R21, - NR19S(=0)2R18, -NR19C(=0)R18, G-G alkyl, G-G deuteroalkyl, G-G, hydroxyalkyl, G-G aminoalkyl, G-G 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(=0)R18, -S(=0)2R18, -NO2, - NR20R21, -S(=O)2NR20R21, -C(=0)R18, -0C(=0)R18, -C(=0)0R19, -0C(=0)0R19, -C(=O)NR20R21, - OC(=O)NR20R21, -NR19C(=O)NR20R21, -NR19C(=0)0R19, -NR19S(=O)2NR20R21, -NR19S(=0)2R18, - NR19C(=0)R18, -NR19C(=0)0R19, G-G alkyl, G-G alkenyl, G-G alkynyl, Ci-C6 haloalkyl, Ci-C6 deuteroalkyl, G-G hydroxyalkyl, C 1 -G, aminoalkyl, or G-G heteroalkyl;
each R18 is independently G-G alkyl,
Figure imgf000051_0001
alkenyl, G-G alkynyl, C 1 -G, haloalkyl, C 1 -G, deuteroalkyl, C1-C6 hydroxyalkyl, G-G aminoalkyl, C 1 -G, 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(=0)Ra, -C(=0)0Rb, -
C(=0)NRcRd, C 1 -G, alkyl, C2-C6 alkenyl, G-G, alkynyl, C 1 -C, haloalkyl, C 1 -G, deuteroalkyl, C 1 -G, hydroxyalkyl, Ci-Ce aminoalkyl, C 1 -G, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R19 is independently hydrogen, G-G alkyl, G-G alkenyl, G-G alkynyl, G-G, haloalkyl, G-G deuteroalkyl, G-G hydroxyalkyl, G-G aminoalkyl, G-G 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(=0)Ra, -C(=0)0Rb, -
C(=0)NRcRd, G-G alkyl, G-G alkenyl, G-G, alkynyl, G-G haloalkyl, G-G deuteroalkyl, C 1 -G, hydroxyalkyl, G-G aminoalkyl, G-G heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R20 and R21 are independently hydrogen, G-G alkyl, G-G alkenyl, G-G alkynyl, G-G haloalkyl, G-G deuteroalkyl, G-G hydroxyalkyl, G-G aminoalkyl, G-G 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(=0)Ru. -C(=0)0Rb, -
C(=0)NRcRd, C i -G, alkyl, G-G alkenyl, G-G alkynyl, G-G haloalkyl, C 1 -G deuteroalkyl, C 1 -G, hydroxyalkyl, G-G aminoalkyl, C 1 -G, 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(=0)Ra, -C(=0)0Rb, -
C(=0)NRcRd, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, G-G hydroxyalkyl, C 1 -G, aminoalkyl, C 1 -G, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R15 and R16 are independently hydrogen, -ORb, -NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1 -G, haloalkyl, G-G deuteroalkyl, C 1 -C, hydroxyalkyl, C 1 -G, aminoalkyl, or C 1 -G, 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(=0)Ra, -C(=0)0Rb, -C(=0)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1 -G, haloalkyl, G-G deuteroalkyl, G-G hydroxyalkyl, C1-C6 aminoalkyl, C 1 -G, heteroalkyl, cycloalkyl, or heterocycloalkyl;
each Ra is independently C 1 -G, alkyl, G-G alkenyl, G-G alkynyl, G-G haloalkyl, G-G deuteroalkyl, C1-C6 hydroxyalkyl, G-G aminoalkyl, G-G 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 C 1 -G, alkyl;
each Rb is independently hydrogen, C 1 -G, alkyl, G-G, alkenyl, G-G alkynyl, C 1 -G, haloalkyl, C 1 -G, deuteroalkyl, C 1 -G, hydroxyalkyl, C 1 -G, aminoalkyl, C 1 -G, 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 G- C5 alkyl; and
each Rc and Rd is independently hydrogen, C 1 -G, alkyl, G-G alkenyl, G-G alkynyl, C 1 -G, haloalkyl, G- G deuteroalkyl, C 1 -G, hydroxyalkyl, G-G aminoalkyl, C 1 -C, 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 C 1 -G, 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 deutenum, halogen, -OH, -NH2, or G- G alkyl.
[00181] In some embodiments of a compound of Formula (VI), Y1 and Y2 are independently hydrogen, deuterium, halogen, -ORb, C 1 -G, alkyl, C 1 -G, haloalkyl, or G-G 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 G-G alkyl. In some embodiments of a compound of Formula (VI), Y1 and Y2 are independently hydrogen. [00182] In some embodiments of a compound of Formula (VI), R12 is hydrogen, deuterium, -ORb, -NRcRd, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce deuteroalkyl, C i -C , hydroxyalkyl, or cycloalkyl; provided that R12 is not -CH3. In some embodiments of a compound of Formula (VI), R12 is hydrogen, deuterium, C i -G, alkyl, Ci-Ce haloalkyl, or Ci-Ce 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 Ci-Ce alkyl; provided that R12 is not -CH3. In some embodiments of a compound of Formula (VI), R12 is Ci-Ce alkyl; provided that R12 is not -CH3.
[00183] In some embodiments of a compound of Formula (VI), R13 is -NR20R21, -S(=O)2NR20R21, - C(=0)R18, -C(=0)OR19, -C(=O)NR20R21, -NR19C(=O)NR20R21, -NR19C(=0)0R19, -NR19S(=O)2NR20R21, - NR19S(=0)2R18, -NR19C(=0)R18, C I -C„ alkyl, C , -Ck deuteroalkyl, Ci-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(=0)R18, -C(=0)OR19, -C(=O)NR20R21, -NR19S(=O)2NR20R21, - NR19S(=0)2R18, -NR19C(=0)R18, Ci-Ce 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(=0)R18, - C(=0)OR19, -C(=O)NR20R21, -NR19S(=O)2NR20R21, -NR19S(=0)2R18, or -NR19C(=0)R18. In some embodiments of a compound of Formula (VI), R13 is -C(=O)NR20R21, -NR19S(=O)2NR20R21, - NR19S(=0)2R18, or -NR19C(=0)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(=0)R18. In some embodiments of a compound of Formula (VI), R13 is Ci-Ce 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.
[00184] In some embodiments of a compound of Formula (VI), each R13a is independently deuterium, halogen, -CN, -OR19, -NR20R21, -S(=O)2NR20R21, -C(=0)R18, -C(=0)OR19, -C(=O)NR20R21, - NR19C(=O)NR20R21, -NR19C(=0)0R19, -NR19S(=O)2NR20R21, -NR19S(=0)2R18, -NR19C(=0)R18, - NR19C(=0)0R19, Ci-Ce alkyl, Ci-C6 haloalkyl, Ci-Ce deuteroalkyl, Ci-Ce hydroxyalkyl, Ci-C6 aminoalkyl, or C i-C,, heteroalkyl. In some embodiments of a compound of Formula (VI), each R13a is independently deuterium, halogen, -CN, -OR19, -NR20R21, C i -G, alkyl, C i -CV, haloalkyl, Ci-Ce deuteroalkyl, Ci-C<¾ hydroxyalkyl, C i -G, aminoalkyl, or C i -C , heteroalkyl. In some embodiments of a compound of Formula (VI), each R13a is independently deuterium, halogen, -CN, -OR19, -NR20R21, Ci-Ce alkyl, Ci-C<¾ haloalkyl, or C i -C , deuteroalkyl. In some embodiments of a compound of Formula (VI), each R13a is independently -NR19S(=0)2R18 or -NR19C(=0)R18.
[00185] Diclosed herein is a compound of Formula (VII), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure imgf000054_0001
Formula (VII);
wherein:
R1 is hydrogen, deuterium, halogen, -CN, -ORb, -NRcRd, -NRbS(=0)2Ra, -C(=0)Ra, -C(=0)0Rb, -
C(=0)NRcRd, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-C6 haloalkyl, Ci-C6 deuteroalkyl, G-G, hydroxyalkyl, Ci-Ce aminoalkyl, or Ci-Ce heteroalkyl;
R3 is halogen, -CN, -OR5, -SR5, -S(=0)R4, -S(=0)2R4, -N02, -NR6R7, -S(=0)2NR6R7, -C(=0)R4, -
0C(=0)R4, -C(-0)0R\ -0C(-0)0R\ -C(=0)NR6R7, -0C(=0)NR¾7, -NR5C(=0)NR6R7, - NR5C(=0)0R5, -NR5S(=0)2NR6R7, -NR5S(=0)2R4, -NR5C(=0)R4, -P(=0)(R4)2, -P(=0)(0R5)2, - B(OR5)2, -NR5C(=NRX)R5, -NR5C(=NRX)NR6R7, -S(-0)(-NRX)R5. -S(=0)(=NRX)NR6R7, - NR5S(=0)2NR5C(=0)R5, -NR5S(=0)(=NRX)R5, CI -G, alkyl, G-G, alkenyl, G-G, alkynyl, C i-G, haloalkyl, C i -G, deuteroalkyl, C i -C,, hydroxyalkyl, Ci-Ce 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(=0)R4, -S(=0)2R4, -NO2, -NR6R7,
Figure imgf000054_0002
C5 alkynyl, C1-C6 haloalkyl, C i -G, deuteroalkyl, C i -C(, hydroxyalkyl, C i -G, 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(=0)Ra, -C(=0)0Rb, -C(=0)NRcRd, Ci-C<5 alkyl, C2-G, alkenyl, C2-G, alkynyl, Ci-Ce haloalkyl, C i -C(, deuteroalkyl, Ci-Ce hydroxyalkyl, C1-C6 aminoalkyl, Ci-Ce heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
Rx is hydrogen, -N02, -CN, or -S(=0)2Ra;
each R4 is independently Ci-Ce alkyl, C2-Ce alkenyl, C2-C alkynyl, Ci-Ce haloalkyl, G-G, deuteroalkyl, C1-C6 hydroxyalkyl, C i -G, aminoalkyl, Ci-Ce 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(=0)Ra, -C(=0)0Rb, -
C(=0)NRcRd, -NRbC(=NRx)Rb, -NRbC(=NRx)NRcRd, -S(=0)(=NRx)Rb, -S(=0)(=NRx)NRcRd, Ci-C6 alkyl, G-G alkenyl, G-G alkynyl, C 1 -G haloalkyl, G-G deuteroalkyl, C 1 -G hydroxyalkyl, G-G ammoalkyl, C -G heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R5 is independently hydrogen, C -G alkyl, G-G, alkenyl, G-G alkynyl, C -G, haloalkyl, C -G, deuteroalkyl, C -G, hydroxyalkyl, C -G, aminoalkyl, C -G, 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(=0)Ra, -C(=0)0Rb, -
C(=0)NRcRd, -NRbC(=NRx)Rb, -NRbC(=NRx)NRcRd, -S(=0)(=NRx)Rb, -S(=0)(=NRx)NRcRd, Ci-C6 alkyl, C -C alkenyl, G-G alkynyl, G-G haloalkyl, G-G deuteroalkyl, C -G, hydroxyalkyl, G-G aminoalkyl, C -G, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R6 and R7 is independently hydrogen, G-G alkyl, G-G alkenyl, G-G alkynyl, C -G, haloalkyl, G- G deuteroalkyl, G-G hydroxyalkyl, C -G, aminoalkyl, G-G 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(=0)Ra, -C(=0)0Rb, -
C(=0)NRcRd, -NRbC(=NRx)R\ -NRbC(=NRx)NRcRd, -S(=0)(=NRx)Rb, -S(=0)(=NRx)NRcRd, G-G alkyl, G-G alkenyl, G-G, alkynyl, G-G haloalkyl, G-G deuteroalkyl, G-G hydroxyalkyl, G-G aminoalkyl, G-G heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaiyl;
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 Rib is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=0)Ra, -C(=0)0Rb, -
C(=0)NRcRd, G-G alkyl, G-G alkenyl, G-G alkynyl, G-G haloalkyl, G-G deuteroalkyl, G-G hydroxyalkyl, G-G aminoalkyl, G-G heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
Figure imgf000055_0001
Y1 and Y2 are independently hydrogen, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=0)Ra, -C(=0)0Rb, - C(=0)NRcRd, G-G alkyl, G-G alkenyl, G-G alkynyl, G-G haloalkyl, G-G deuteroalkyl, G-G hydroxyalkyl, G-G aminoalkyl, or G-G heteroalkyl; provided that one of Y1 or Y2 is not hydrogen;
R8 is hydrogen, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=0)Ra, -C(=0)0Rb, G-G alkyl, G-G, alkenyl, G-G alkynyl, G-G haloalkyl, or G-G deuteroalkyl;
R9 is G-G alkyl, G-G alkenyl, G-G alkynyl, G-G haloalkyl, or G-G deuteroalkyl;
R10 is G-G alkyl, G-G alkenyl, G-G alkynyl, G-G haloalkyl, or G-G 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, G-G alkyl, G-G, alkenyl, G-G alkynyl, G-G haloalkyl, G- G deuteroalkyl, G-G hydroxyalkyl, G-G aminoalkyl, G-G heteroalkyl, cycloalkyl,
heterocycloalkyl, aryl, or heteroaryl; R13 is -OR19, -NR20R21, -S(=O)2NR20R21, -C(=0)R18, -0C(=0)R18, -C(=0)0R19, -0C(=0)0R19, - C(=O)NR20R21, -OC(=O)NR20R21, -NR19C(=O)NR20R21, -NR19C(=0)0R19, -NR19S(=O)2NR20R21, - NR19S(=0)2R18, -NR19C(=0)R18, G-G alkyl, Ci-C6 deuteroalkyl, G-G, hydroxyalkyl, Ci-C6 aminoalkyl, C i -G, 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(=0)R18, -S(=0)2R18, -N02, - NR20R21, -S(=O)2NR20R21, -C(=0)R18, -0C(=0)R18, -C(=0)0R19, -0C(=0)0R19, -C(=O)NR20R21, - OC(=O)NR20R21, -NR19C(=O)NR20R21, -NR19C(=0)0R19, -NR19S(=O)2NR20R21, -NR19S(=0)2R18, - NR19C(=0)R18, -NR19C(=0)0R19, G-G alkyl, G-G, alkenyl, C2-C6 alkynyl, Ci-C6 haloalkyl, G-G deuteroalkyl, C i -G, hydroxyalkyl, -C6 aminoalkyl, C i -G, heteroalkyl;
each R18 is independently G-G alkyl, C2-C6 alkenyl, G-G, alkynyl, C i -G, haloalkyl, C i -G, deuteroalkyl, -C6 hydroxyalkyl, C i -G, aminoalkyl, G-G 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(=0)Ra, -C(=0)0Rb, -
C(=0)NRcRd, C i -G, alkyl, G-G alkenyl, G-G alkynyl, G-G haloalkyl, G-G deuteroalkyl, G-G hydroxyalkyl, G-G aminoalkyl, G-G heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R19 is independently hydrogen, G-G alkyl, G-G alkenyl, G-G alkynyl, G-G haloalkyl, G-G deuteroalkyl, G-G hydroxyalkyl, G-G aminoalkyl, G-G 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(=0)Ra, -C(=0)0Rb, -
C(=0)NRcRd, C i -G, alkyl, G-G alkenyl, G-G, alkynyl, G-G haloalkyl, G-G deuteroalkyl, G-G hydroxyalkyl, G-G aminoalkyl, G-G heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R20 and R21 are independently hydrogen, G-G alkyl, G-G, alkenyl, G-G, alkynyl, G-G haloalkyl, G-G deuteroalkyl, G-G hydroxyalkyl, G-G aminoalkyl, G-G 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(=0)Ra, -C(=0)0Rb, -
C(=0)NRcRd, C i -G, alkyl, G-G alkenyl, G-G, alkynyl, G-G haloalkyl, G-G deuteroalkyl, G-G hydroxyalkyl, G-G aminoalkyl, G-G 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(=0)Ra, -C(=0)0Rb, -
C(=0)NRcRd, C i -G, alkyl, G-G alkenyl, G-G alkynyl, G-G haloalkyl, G-G deuteroalkyl, G-G hydroxyalkyl, G-G aminoalkyl, G-G heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R15 and R16 are independently hydrogen, -ORb, -NRcRd, G-G alkyl, G-G alkenyl, G-G alkynyl, G-G haloalkyl, G-G deuteroalkyl, G-G hydroxyalkyl, G-G aminoalkyl, or G-G 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(=0)Ru. -C(=0)0Rb, -C(=0)NRcRd, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C 1 -G, deuteroalkyl, Ci-Ce hydroxyalkyl, C1-C6 aminoalkyl, Ci-Ce heteroalkyl, cycloalkyl, or heterocycloalkyl;
each Ra is independently C1-C6 alkyl, C2-C alkenyl, C2-C6 alkynyl, C1-C haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C 1 -G, aminoalkyl, Ci-Ce 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 C 1 -G, alkyl;
each Rb is independently hydrogen, C 1 -G, alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C 1 -G, deuteroalkyl, C 1 -G, hydroxyalkyl, Ci-Ce aminoalkyl, C 1 -G, 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 G- Ce alkyl; and
each Rc and Rd is independently hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1 -G, haloalkyl, G- Ce deuteroalkyl, C 1 -G, hydroxyalkyl, C 1 -CY, aminoalkyl, C 1 -G, 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 G-G 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 G- C6 alkyl.
[00186] In some embodiments of a compound of Formula (VII), Y1 and Y2 are independently hydrogen, deuterium, halogen, -ORb, C 1 -G, alkyl, C 1 -G, haloalkyl, or C 1 -G, 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 Ci-Ce alkyl; provided that one of Y1 or Y2 is not hydrogen.
[00187] In some embodiments of a compound of Formula (VII), R12 is hydrogen, deuterium, -ORb, - NRcRd, Ci-Ce alkyl, C 1 -G, haloalkyl, Ci-Ce deuteroalkyl, G -G, hydroxyalkyl, or cycloalkyl. In some embodiments of a compound of Formula (VII), R12 is hydrogen, deuterium, G-G alkyl, C 1 -C, haloalkyl, or G-G 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 G-G alkyl.
[00188] In some embodiments of a compound of Formula (VII), R13 is -NR20R21, -S(=O)2NR20R21, - C(=0)R18, -C(=0)OR19, -C(=O)NR20R21, -NR19C(=O)NR20R21, -NR19C(=0)0R19, -NR19S(=O)2NR20R21, - NR19S(=0)2R18, -NR19C(=0)R18, G-G alkyl, G-G deuteroalkyl, G-G 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(=0)R18, -C(=0)0R19, -C(=O)NR20R21, -NR19S(=O)2NR20R21, - NR19S(=0)2R18, -NR19C(=0)R18, C I -G, 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(=0)R18, - C(=0)0R19, -C(=O)NR20R21, -NR19S(=O)2NR20R21, -NR19S(=0)2R18, or -NR19C(=0)R18. In some embodiments of a compound of Formula (VII), R13 is -C(=O)NR20R21, -NR19S(=O)2NR20R21, - NR19S(=0)2R18, or -NR19C(=0)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(=0)R18. In some embodiments of a compound of Formula (VII), R13 is Ci-Ce 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.
[00189] In some embodiments of a compound of Formula (VII), each R13a is independently deuterium, halogen, -CN, -OR19, -NR20R21, -S(=O)2NR20R21, -C(=0)R18, -C(=0)OR19, -C(=O)NR20R21, - NR19C(=O)NR20R21, -NR19C(=0)0R19, -NR19S(=O)2NR20R21, -NR19S(=0)2R18, -NR19C(=0)R18, - NR19C(=0)0R19, C 1 -G, alkyl, Ci-G, haloalkyl, Ci-Ce deuteroalkyl, Ci-G, hydroxyalkyl, C i-G, aminoalkyl, or Ci-Ce heteroalkyl. In some embodiments of a compound of Formula (VII), each R13a is independently deuterium, halogen, -CN, -OR19, -NR20R21, Ci-Ce alkyl, C 1 -G, haloalkyl, C 1 -G, deuteroalkyl, C1-C6 hydroxyalkyl, Ci-Ce aminoalkyl, or Ci-Ce heteroalkyl. In some embodiments of a compound of Formula (VII), each R13a is independently deuterium, halogen, -CN, -OR19, -NR20R21, C 1 -G, alkyl, Ci-Ce haloalkyl, or C 1 -G, deuteroalkyl. In some embodiments of a compound of Formula (VII), each R13a is independently -NR19S(=0)2R18 or -NR19C(=0)R18.
[00190] Diclosed herein is a compound of Formula (VIII), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure imgf000058_0001
Formula (VIII);
wherein:
R1 is hydrogen, deuterium, halogen, -CN, -ORb, -NRcRd, -NRbS(=0)2Ra, -C(=0)Ra, -C(=0)0Rb, -
C(=0)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, Ci-Ce deuteroalkyl, C1-C hydroxyalkyl, C 1 -G, aminoalkyl, or Ci-Cs heteroalkyl;
R3 is halogen, -CN, -OR5, -SR5, -S(=0)R4, -S(=0)2R4, -N02, -NR6R7, -S(=0)2NR6R7, -C(=0)R4, -
Figure imgf000058_0002
NR5S(=0)2NR5C(=0)R5, -NR5S(=0)(=NRX)R5, Ci-Ce alkyl, C2-C6 alkenyl, G-G, alkynyl, G-G haloalkyl, C i -G, deuteroalkyl, C i -C,, hydroxyalkyl, C i -G, aminoalkyl, C i -C(, 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(=0)R4, -S(=0)2R4, -N02, -NR6R7,
Figure imgf000059_0001
G, alkynyl, G-G haloalkyl, C i -G, deuteroalkyl, C i -C(, hydroxyalkyl, C i -G, aminoalkyl, G-G 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(=0)Ra, -C(=0)0Rb, -C(=0)NRcRd, C1-C6 alkyl, C2-G, alkenyl, C2-G, alkynyl, G-G haloalkyl, C1-C6 deuteroalkyl, G-G hydroxyalkyl, C1-C6 aminoalkyl, C 1 -G, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl,
Rx is hydrogen, -N02, -CN, or -S(=0)2Ra;
each R4 is independently C 1 -G, alkyl, G-G alkenyl, G-G alkynyl, C 1 -G, haloalkyl, G-G, deuteroalkyl, C1-C6 hydroxyalkyl, C 1 -G, aminoalkyl, C 1 -CV, 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(=0)Ra, -C(=0)0Rb, -
C(=0)NRcRd, -NRbC(=NRx)Rb, -NRbC(=NRx)NRcRd, -S(=0)(=NRx)Rb, -S(=0)(=NRx)NRcRd, Ci-C6 alkyl, G-G alkenyl, C2-G, alkynyl, C 1 -G, haloalkyl, C 1 -G, deuteroalkyl, C 1 -CV, hydroxyalkyl, C 1 -G, aminoalkyl, C 1 -G, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R5 is independently hydrogen, C 1 -G, alkyl, G-G, alkenyl, G-G, alkynyl, C 1 -G, haloalkyl, C 1 -G, deuteroalkyl, C 1 -G, hydroxyalkyl, C 1 -G, aminoalkyl, C 1 -G, 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(=0)Ra, -C(=0)0Rb, -
C(=0)NRcRd, -NRbC(=NRx)Rb, -NRbC(=NRx)NRcRd, -S(=0)(=NRx)Rb, -S(=0)(=NRx)NRcRd, Ci-C6 alkyl, G-G, alkenyl, G-G, alkynyl, C 1 -G, haloalkyl, C 1 -G, deuteroalkyl, C 1 -G, hydroxyalkyl, C 1 -G, aminoalkyl, C 1 -G, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R6 and R7 is independently hydrogen, C 1 -G, alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, G- G deuteroalkyl, C1-C6 hydroxyalkyl, G-G, aminoalkyl, C 1 -G, 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(=0)Ra, -C(=0)0Rb, -
C(=0)NRcRd, -NRbC(=NRx)Rb, -NRbC(=NRx)NRcRd, -S(=0)(=NRx)Rb, -S(=0)(=NRx)NRcRd, Ci-C6 alkyl, G-G alkenyl, G-G alkynyl, G-G haloalkyl, C 1 -G deuteroalkyl, G-G hydroxyalkyl, C 1 -C , aminoalkyl, C 1 -G, 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(=0)Ra, -C(=0)0Rb, -
C(=0)NRcRd, C 1 -G alkyl, C2-C6 alkenyl, C2-C6 alkynyl, G-G haloalkyl, G-G deuteroalkyl, G-G hydroxyalkyl, G-G aminoalkyl, G-G heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
Figure imgf000060_0001
Y1 and Y2 are independently hydrogen, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=0)Ra, -C(=0)0Rb, - C(=0)NRcRd, G-G alkyl, G-G alkenyl, G-G alkynyl, C 1 -G, haloalkyl, C 1 -G, deuteroalkyl, C 1 -G, hydroxyalkyl, C1-C6 aminoalkyl, or G-G heteroalkyl;
R8 is hydrogen, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=0)Ra, -C(=0)0Rb, C 1 -C , alkyl, G-G
alkenyl, G-G alkynyl, C 1 -G haloalkyl, or C 1 -G, deuteroalkyl;
R9 is G-G alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1 -G, haloalkyl, or C 1 -G, deuteroalkyl;
R10 is G-G alkyl, G-G alkenyl, G-G alkynyl, C 1 -G, haloalkyl, or C 1 -G, 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, C 1 -G alkyl, G-G, alkenyl, G-G alkynyl, C 1 -G, haloalkyl, G- G deuteroalkyl, G-G hydroxyalkyl, G-G aminoalkyl, G-G heteroalkyl, cycloalkyl,
heterocycloalkyl, aryl, or heteroaryl;
R13 is -CN, -OR19, -S(=O)2NR20R21, -0C(=0)R18, -0C(=0)0R19, -OC(=O)NR20R21, -NR19C(=0)0R19, G-G deuteroalkyl, G-G hydroxyalkyl, G-G aminoalkyl, G-G heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -CH2(cycloalkyl), -CH2(heterocycloalkyl), -CH2(aryl), or - ChhCheteroaryl); 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(=0)R18, -S(=0)2R18, -NO2, - NR20R21, -S(=O)2NR20R21, -C(=0)R18, -0C(=0)R18, -C(=0)0R19, -0C(=0)0R19, -C(=O)NR20R21, - OC(=O)NR20R21, -NR19C(=0)0R19, Ci-G alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-C6 haloalkyl, G-G deuteroalkyl, G-G hydroxyalkyl, G-G aminoalkyl, G-G heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R18 is independently G-G alkyl, G-G alkenyl, G-G alkynyl, C 1 -G, haloalkyl, G-G deuteroalkyl, G-G hydroxyalkyl, G-G aminoalkyl, G-G 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(=0)Ru. -C(=0)0Rb, -
C(=0)NRcRd, C i -G, alkyl, G-G alkenyl, G-G alkynyl, G-G haloalkyl, C 1 -G deuteroalkyl, C 1 -G, hydroxyalkyl, G-G aminoalkyl, C 1 -G, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R19 is independently hydrogen, C 1 -G, alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1 -G, haloalkyl, C 1 -G, deuteroalkyl, C1-C6 hydroxyalkyl, G-G 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(=0)Ra, -C(=0)0Rb, -
C(=0)NRcRd, C 1 -G alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1 -G, haloalkyl, C 1 -G deuteroalkyl, C1-C6 hydroxyalkyl, C 1 -G> aminoalkyl, C 1 -G, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R20 and R21 are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1 -G, haloalkyl, C1-C6 deuteroalkyl, C 1 -G, hydroxyalkyl, C 1 -G, aminoalkyl, C 1 -G, 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(=0)Ra, -C(=0)0Rb, -
C(=0)NRcRd, C 1 -G alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1 -G, haloalkyl, C 1 -G, deuteroalkyl, C 1 -G, hydroxyalkyl, C 1 -G, aminoalkyl, C 1 -G, 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(=0)Ra, -C(=0)0Rb, -
C(=0)NRcRd, G-G alkyl, G-G alkenyl, G-G alkynyl, C 1 -G, haloalkyl, C 1 -G, deuteroalkyl, C 1 -G, hydroxyalkyl, G-G aminoalkyl, C 1 -G heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R15 and R16 are independently hydrogen, -ORb, -NRcRd, C 1 -G, alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1 -G, haloalkyl, C 1 -G, deuteroalkyl, C 1 -C,, hydroxyalkyl, C 1 -G, aminoalkyl, or C 1 -G, 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(=0)Ra, -C(=0)ORb, -C(=0)NRcRd, G-G alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1 -G, haloalkyl, C 1 -G, deuteroalkyl, C 1 -Co hydroxyalkyl, G-G aminoalkyl, Ci-Ce heteroalkyl, cycloalkyl, or heterocycloalkyl;
each Ra is independently C 1 -G, alkyl, G-G alkenyl, G-G, alkynyl, C 1 -G, haloalkyl, C 1 -G, deuteroalkyl, G-G hydroxyalkyl, C 1 -G, aminoalkyl, C 1 -G, 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 C 1 -G, alkyl;
each Rb is independently hydrogen, C 1 -G, alkyl, G-G alkenyl, G-G alkynyl, C 1 -G, haloalkyl, C 1 -G, deuteroalkyl, G-G hydroxyalkyl, G-G aminoalkyl, G-G 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 G- G alkyl; and each Rc and Rd is independently hydrogen, C i -C(, alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, Ci- C5 deuteroalkyl, Ci-Ce hydroxyalkyl, C1-C6 aminoalkyl, Ci-Ce 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 Ci-Ce 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 Ci- C6 alkyl.
[00191] In some embodiments of a compound of Formula (VIII), Y1 and Y2 are independently hydrogen, deuterium, halogen, -ORb, Ci-Ce alkyl, C 1 -G, haloalkyl, or C 1 -G, 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 C 1 -G, alkyl. In some embodiments of a compound of Formula (VIII), Y1 and Y2 are hydrogen.
[00192] In some embodiments of a compound of Formula (VIII), R12 is hydrogen, deuterium, -ORb, - NRcRd, C 1 -G, alkyl, Ci-Ce haloalkyl, C 1 -G, deuteroalkyl, C 1 -G, hydroxyalkyl, or cycloalkyl. In some embodiments of a compound of Formula (VIII), R12 is hydrogen, deuterium, Ci-Ce alkyl, C1-C6 haloalkyl, or Ci-Ce 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 Ci-Ce alkyl. In some embodiments of a compound of Formula (VIII), R12 is C1-C6 alkyl.
[00193] In some embodiments of a compound of Formula (VIII), R13 is -CN.
[00194] In some embodiments of a compound of Formula (VIII), R13 is Ci-Ce 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.
[00195] 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.
[00196] In some embodiments of a compound of Formula (VIII), each R13a is independently deuterium, halogen, -CN, -OR19, -NR20R21, -S(=O)2NR20R21, -C(=0)R18, -C(=0)OR19, -C(=O)NR20R21, - NR19C(=0)0R19, C 1 -G, alkyl, G-G haloalkyl, G-G, deuteroalkyl, Ci-Ce hydroxyalkyl, Ci-C6 aminoalkyl, or C 1 -C,, heteroalkyl. In some embodiments of a compound of Formula (VIII), each R13a is independently deuterium, halogen, -CN, -OR19, -NR20R21, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce deuteroalkyl, Ci-Ce hydroxyalkyl, Ci-Ce aminoalkyl, or Ci-Ce heteroalkyl. In some embodiments of a compound of Formula (VIII), each R13a is independently deuterium, halogen, -CN, -OR19, -NR20R21, C i -C, alkyl, Ci-C<5 haloalkyl, or C 1 -G, deuteroalkyl.
[00197] In some embodiments of a compound of Formula (VIII), each R13a is independently oxo, -OR19, - NR20R21, -C(=0)R18, -C(=0)OR19, -C(=O)NR20R21, Ci-Ce alkyl, Ci-C6 haloalkyl, Ci-Ce deuteroalkyl, Ci- Ce hydroxyalkyl, Ci-Ce 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, C 1 -G, alkyl, C 1 -C, 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.
[00198] In some embodiments of a compound of Formula (VI)-(VIII), R1 is -CN, C 1 -G, alkyl, Ci-Ce haloalkyl, or Ci-Ce deuteroalkyl. In some embodiments of a compound of Formula (VI)-(VIII), R1 is -CN or Ci-Ce haloalkyl. In some embodiments of a compound of Formula (VI) -(VIII), R1 is C 1 -G, haloalkyl. In some embodiments of a compound of Formula (VI)-(VIII), R1 is -CN.
[00199] 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.
[00200] In some embodiments of a compound of Formula (VI)-(VIII), R9 is C 1 -G, alkyl or C2-C6 alkynyl. In some embodiments of a compound of Formula (VI)-(VIII), R9 is Ci-G, alkyl.
[00201] In some embodiments of a compound of Formula (VI)-(VIII), R10 is Ci-Ce alkyl or C2-C6 alkynyl. In some embodiments of a compound of Formula (VI)-(VIII), R10 is C 1 -G, alkyl.
[00202] In some embodiments of a compound of Formula (VI)-(VIII), R9 is C1-C6 alkyl and R10 is G-G, alkynyl. In some embodiments of a compound of Formula (VI)-(VIII), R10 is C 1 -G, alkyl and R9 is C2-C6 alkynyl.
X O
[00203] In some embodiments of a compound of Formula (VI)-(VIII),
Figure imgf000063_0001
is -M— . In some embodiments of a compound of Formula (
Figure imgf000063_0002
.
[00204] 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.
[00205] In some embodiments of a compound of Formula (VI)-(VIII), each R18 is independently C 1 -G, alkyl, G-G, alkenyl, C2-C6 alkynyl, C 1 -G, haloalkyl, C 1 -G, 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 C 1 -G, 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 C 1 -G, alkyl optionally substituted with one, two, or three R18a. In some embodiments of a compound of Formula (VI)-(VIII), each R18 is independently C 1 -G, alkyl. In some embodiments of a compound of Formula (VI)-(VIII), each R18 is independently C i -G, alkyl, Ci-Ce haloalkyl, or Ci-Ce deuteroalkyl.
[00206] In some embodiments of a compound of Formula (VI)-(VIII), each R18a is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, C i -G, alkyl, Ci-Ce 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.
[00207] In some embodiments of a compound of Formula (VI)-(VIII), each R19 is independently hydrogen, Ci-Gs alkyl, C i -G, haloalkyl, C i -G, 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, Ci-Ce 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 Ci-Ce alkyl optionally substituted with one, two, or three R19a. In some embodiments of a compound of Formula (VI)-(VIII), each R19 is independently Ci-Ce alkyl optionally substituted with one, two, or three R19a. In some embodiments of a compound of Formula (VI)-(VIII), each R19 is hydrogen or Ci-Gs alkyl. In some embodiments of a compound of Formula (YI)-(VIII), each R19 is independently hydrogen, Ci-Cs alkyl, Ci-Ce haloalkyl, or C i -C,, deuteroalkyl.
[00208] In some embodiments of a compound of Formula (VI)-(VIII), each R19a is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, C i -G, alkyl, Ci-Ce 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.
[00209] In some embodiments of a compound of Formula (VI)-(VIII), each R20 and R21 are independently hydrogen, Ci-Ce alkyl, C i -G, haloalkyl, Ci-Ce 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, Ci-Ce alkyl, C i -G, haloalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one, two, or three R"a. In some embodiments of a compound of Formula (VI)-(VIII), each R20 and R21 are independently hydrogen, Ci-Ce alkyl, or C i -G, 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 Ci-Ce alkyl. In some embodiments of a compound of Formula (VI)-(YIII), each R20 and R21 are independently hydrogen, C i -G, alkyl, C i -G, haloalkyl, or Ci-Ce deuteroalkyl.
[00210] In some embodiments of a compound of Formula (VI)-(VIII), each R20a is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, Ci-G; alkyl, Ci-Ce 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 (YI)-(VIII), each R20a is independently -S(=0)(=NRx)Rb or -S(=0)(=NRx)NRcRd.
[00211] 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.
[00212] In some embodiments of a compound of Formula (VI)-(VIII), each R20b is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, C1-C alkyl, C i -C( haloalkyl, Ci-Ce hydroxyalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (VI)-(VIII), each R20b is
independently C i -G, alkyl or Ci-Ce haloalkyl. In some embodiments of a compound of Formula (VI)- (VIII), each R20b is independently C i -G, alkyl.
[00213] In some embodiments of a compound of Formula (VI)-(VIII), R3 is halogen, -CN, -OR5, -NR6R7, -C(=0)R4, -OC(=0)R4, -C(=0)OR5, -C(=0)NR6R7, -0C(=0)NR6R7, -NR5C(=0)NR6R7, -NR5C(=0)0R5, -NR5S(=0)2R4, -NR5C(=0)R4, -NR5C(=NRX)R5, -NR5C(=NRX)NR6R7, -S(=0)(=NRX)R5, - S(=0)(=NRx)NR6R7, -NR5S(=0)2NR5C(=0)R5, -NR5S(=0)(=NRX)R5, Ci-Ce alkyl, G-G, alkenyl, G-G, hydroxyalkyl, Ci-Ce 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(=0)(=NRx)R5, -S(=0)(=NRx)NR6R7, -NR5S(=0)2NR5C(=0)R5, or - NR5S (=0) (=NRX)R5.
[00214] In some embodiments of a compound of Formula (VI)-(VIII), R3 is C1-C6 alkyl or -C(=0)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 C i -G, alkyl. In some embodiments of a compound of Formula (VI)-(VIII), R3 is -C(=0)OR5.
[00215] In some embodiments of a compound of Formula (VI)-(VIII), each R3a is independently deuterium, halogen, -CN, -OR5, -S(=0)R4, -S(=0)2R4, -OC(=0)R4, -C(=0)OR5, -OC(=0)OR5, - C(=0)NR6R7, -0C(=0)NR6R7, -P(=0)(R4)2, -P(=0)(0R5)2, -B(OR5)2, -NR5C(=NRX)R5, - NR5C(=NRX)NR6R7, -S(=0)(=NRx)R5, -S(=0)(=NRx)NR6R7, -NR5S(=0)2NR5C(=0)R5, - NR5S(=0)(=NRx)R5, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (VI)-(VIII), each R3a is independently deuterium, halogen, -CN, -OR5, -S(=0)R4, -S(=0)2R4, -OC(=0)R4,
Figure imgf000065_0001
or -NR5S(=0)(=NRx)R5. In some embodiments of a compound of Formula (VI)-(VIII), each R3a is independently deuterium, halogen, -CN, -OR5, -OC(=0)R4, -C(=0)OR5, -C(=0)NR6R7, -B(OR5)2, - S(=0)(=NRx)R5, C i -G, heteroalkyl, heterocycloalkyl, or heteroaryl. In some embodiments of a compound of Formula (VI)-(VIII), each R3a is independently -OC(=0)R4, -C(=0)OR5, -OC(=0)OR5, -C(=0)NR6R7, -P(=0)(R4)2, -P(=0)(0Rs)2, -B(OR5)2, -NR5C(=NRX)R5, -NR5C(=NRX)NR6R7, -S(=0)(=NRx)R5, - S(=0)(=NRx)NR6R7, -NR5S(=0)2NR5C(=0)R5, or -NR5S(=0)(=NRx)R5 In some embodiments of a compound of Formula (VI)-(VIII), each R3a is independently -OC(=0)R4, -C(=0)OR5, -OC(=0)OR5, or - C(=0)NR6R7. In some embodiments of a compound of Formula (VI)-(VIII), each R3a is independently - P(=0)(R4)2, -P(=0)(0R5)2, or -B(OR5)2. In some embodiments of a compound of Formula (VI)-(VIII), each R3a is independently -NR5C(=NRX)R5, -NR5C(=NRX)NRSR7, -S(=0)(=NRx)R5, -S(=0)(=NRx)NR6R7, -NR5S(=0)2NR5C(=0)R5, or -NR5S(=0)(=NRx)R5.
[00216] In some embodiments of a compound of Formula (VI)-(VIII), each R3b is independently deuterium, halogen, -CN, -ORb, G-G, alkyl, C i -CV, haloalkyl, or C1-C deuteroalkyl. In some
embodiments of a compound of Formula (VI)-(VIII), each R3b is independently deuterium, halogen, C i -G, alkyl, C1-C6 haloalkyl, or C i -G, deuteroalkyl.
[00217] In some embodiments of a compound of Formula (VI)-(VIII), each R4 is independently Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1 -G, haloalkyl, C 1 -G, 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 -Gs 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 C 1 -C,, alkyl optionally substituted with one, two, or three R4a. In some embodiments of a compound of Formula (VI)-(VIII), each R4 is independently C 1 -G, alkyl. In some embodiments of a compound of Formula (VI)-(VIII), each R4 is independently C 1 -G, alkyl, C 1 -G, haloalkyl, or G-G deuteroalkyl.
[00218] In some embodiments of a compound of Formula (VI)-(VIII), each R4a is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, G-G alkyl, C 1 -G, 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.
[00219] In some embodiments of a compound of Formula (VI)-(VIII), each R5 is independently hydrogen, C 1 -Co alkyl, C 1 -G, haloalkyl, C 1 -G, 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, C 1 -G, 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 G -G alkyl optionally substituted with one, two, or three R5a. In some embodiments of a compound of Formula (VI) -(VIII), each R5 is hydrogen or G-G alkyl. In some embodiments of a compound of Formula (VI)-(VIII), each R5 is independently hydrogen, G-G alkyl, C 1 -G, haloalkyl, or G-C<5 deuteroalkyl.
[00220] In some embodiments of a compound of Formula (VI)-(VIII), two R5 are taken together to form an optionally substituted heterocycloalkyl.
[00221] In some embodiments of a compound of Formula (VI)-(VIII), each R5a is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, G-G alkyl, C 1 -G, 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(=0)(=NRx)Rb or -S(=0)(=NRx)NRcRd.
[00222] In some embodiments of a compound of Formula (VI)-(VIII), each R6 and R7 is independently hydrogen, G-G alkyl, G-G haloalkyl, C i -G, 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, C i -G, 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, G-G alkyl, or C i -G, 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, G-G alkyl, C i -G, haloalkyl, or C i -G, deuteroalkyl.
[00223] In some embodiments of a compound of Formula (VI)-(VIII), each R6a is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, G-G alkyl, G-G 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(=0)(=NRx)Rb or -S(=0)(=NRx)NRcRd.
[00224] 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.
[00225] In some embodiments of a compound of Formula (VI)-(VIII), each R6b is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, C i -G, alkyl, C i -G, haloalkyl, Ci-Ce hydroxyalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (VI)-(VIII), each R6b is independently G-G alkyl or G-G haloalkyl. In some embodiments of a compound of Formula (VI)-(VIII), each R6b is independently G-G alkyl.
[00226] 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.
[00227] In some embodiments of a compound of Formula (VI)-(VIII), R15 and R16 are independently hydrogen, - alkyl, or G-G deuteroalkyl. In some embodiments of a compound of Formula (VI)- (VIII), R15 and R16 are independently hydrogen or G-G alkyl. In some embodiments of a compound of Formula (VI)-(VIII), R15 and R16 are independently hydrogen or G-G deuteroalkyl. In some
embodiments of a compound of Formula (VI)-(VIII), R15 and R16 are independently G-G alkyl.
[00228] 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 R"' are taken together to form a cycloalkyl substituted with 1 or 2 deuterium. In some embodiments of a compound of Formula (YI)-(VIII), R15 and R16 are taken together to form a cycloalkyl substituted with 2-4 deuteriums.
[00229] 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.
[00230] In some embodiments of a compound of Formula (I)-(VIII), each Ra is independently Ci-Ce alkyl, Ci-Ce haloalkyl, C i -G, deuteroalkyl, Ci-Ce hydroxyalkyl, C i -G, aminoalkyl, C i -G, 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 C i -G, alkyl In some embodiments of a compound of Formula (I)-(VIII), each Ra is independently G-G alkyl, G-G haloalkyl, C i -G deuteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one, two, or three deuterium, halogen, - OH, -NFF. or G-G alkyl. In some embodiments of a compound of Formula (I)-(VIII), each Ra is independently C i -G, alkyl, C i -G, haloalkyl, or C i -G, deuteroalkyl; wherein the alkyl are independently optionally substituted with one, two, or three deuterium, halogen, -OH, -NFF, or Oi-Ob alkyl. In some embodiments of a compound of Formula (I)-(VIII), each Ra is independently G-G alkyl optionally substituted with one, two, or three deuterium, halogen, -OH, -NFF. or G-G alkyl. In some embodiments of a compound of Formula (I)-(VIII), each Ra is independently G-G alkyl.
[00231] In some embodiments of a compound of Formula (I)-(VIII), each Rb is independently hydrogen, C i -G alkyl, C i -CV> haloalkyl, G-G deuteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one, two, or three deuterium, halogen, -OH, -NH2, or G-G, alkyl. In some embodiments of a compound of Formula (I)- (VIII), each Rb is independently hydrogen, C i -G, alkyl, C i -G, haloalkyl, or C1-C6 deuteroalkyl; wherein the alkyl are independently optionally substituted with one, two, or three deuterium, halogen, -OH, -NH2, or G-G alkyl. In some embodiments of a compound of Formula (I)-(VIII), each Rb is independently hydrogen or G-C<5 alkyl optionally substituted with one, two, or three deuterium, halogen, -OH, -NH2, or G-G alkyl. In some embodiments of a compound of Formula (I)-(VIII), each Rb is independently hydrogen or G-G 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 G-G alkyl.
[00232] In some embodiments of a compound of Formula (I)-(VIII), each Rc and Rd is independently hydrogen, C i -G, alkyl, -C6 haloalkyl, G-G deuteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one, two, or three deuterium, halogen, -OH, -NH2, or -C6 alkyl. In some embodiments of a compound of Formula (I)- (VIII), each Rc and Rd is independently hydrogen, C i -G, alkyl, C i -G, haloalkyl, or C i -G, deuteroalkyl; wherein the alkyl are independently optionally substituted with one, two, or three deuterium, halogen, - OH, -NH2, or C i -Co alkyl. In some embodiments of a compound of Formula (I)-(VIII), each Rc and Rd is independently hydrogen or Ci-Ce alkyl optionally substituted with one, two, or three deuterium, halogen, - OH, -NH2, or C i -C , alkyl. In some embodiments of a compound of Formula (I)-(VIII), each Rc and Rd is independently hydrogen or Ci-Ce 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.
[00233] 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 Ci-Ce alkyl.
[00234] Disclosed herein is a compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, selected from the group consisting of:
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0002
[00235] Disclosed herein is a compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, selected from the group consisting of:
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
ĭ72
Figure imgf000074_0001
Figure imgf000075_0001
[00236] Disclosed herein is a compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, selected from the group consisting of:
Figure imgf000076_0001
Figure imgf000077_0001
[00237] Disclosed herein is a compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, selected from the group consisting of:
Figure imgf000077_0002
Figure imgf000078_0001
Figure imgf000079_0001
Figure imgf000080_0001
[00238] Disclosed herein is a compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, selected from the group consisting of:
Figure imgf000080_0002
[00239] Disclosed herein is a compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, selected from the group consisting of:
Figure imgf000080_0003
Figure imgf000081_0001
[00240] Disclosed herein is a compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, selected from the group consisting of:
Figure imgf000081_0002
[00241] Disclosed herein is a compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, selected from the group consisting of:
Figure imgf000081_0003
[00242] Disclosed herein is a compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, selected from the group consisting of:
Figure imgf000081_0004
Further Forms of Compounds Disclosed Herein
Isomers/Stereoisomers
[00243] 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
[00244] 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 descnbed 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, 13 N, 180, 170, 31P, 32P, 35S, 18F, and 3SC1, 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.
[00245] In some embodiments, the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, biolumine scent labels, or chemiluminescent labels.
Pharmaceutically acceptable salts
[00246] 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.
[00247] 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.
[00248] 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-l,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-l,6-dioate, hydroxybenzoate, g-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2 -hydroxy ethane sulfonate, 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 xylene sulfonate.
[00249] 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, methane sulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2- hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo- [2.2.2]oct-2-ene-l-carboxylic acid, glucoheptonic acid, 4,4’-methylenebis-(3-hydroxy-2-ene-l-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.
[00250] 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+(CI-4 alkyl)4, and the like.
[00251] 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 quatemization of any basic nitrogen-containing groups they contain. In some embodiments, water or oil-soluble or dispersible products are obtained by such quatemization.
Solvates
[00252] 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.
[00253] 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
[00254] 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
[00255] 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, NI), TCI America (Portland, OR), Trans World Chemicals, Inc. (Rockville, MD), and Wako Chemicals USA, Inc. (Richmond, YA).
[00256] 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,“Modem
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)“Modem 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.
[00257] 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”, Yerlag Helvetica Chimica Acta, Zunch, 2002.
Pharmaceutical Compositions
[00258] 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)).
[00259] 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.
[00260] 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.
[00261] 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.
[00262] 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. [00263] 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 pg 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 pg to about 200 mg of the compound disclosed herein would be more commonly used, depending on a subject’s physiological response.
[00264] 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
[00265] The compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are useful in the treatment or prevention of inflammation or diseases associated with
inflammation.
[00266] Inflammation is a biological process that provides resistance to infectious or parasitic organisms and the repair of damaged tissue. Inflammation is commonly characterized by localized vasodilation, redness, swelling, and pain, the recruitment of leukocytes to the site of infection or injury, production of inflammatory cytokines such as TNF-a and IL-1, and production of reactive oxygen or nitrogen species such as hydrogen peroxide, superoxide, and peroxynitrite. In later stages of inflammation, tissue remodeling, angiogenesis, and scar formation (fibrosis) may occur as part of the wound healing process. Under normal circumstances, the inflammatory response is regulated and temporary and is resolved in an orchestrated fashion once the infection or injury has been dealt with adequately. However, acute inflammation can become excessive and life-threatening if regulatory mechanisms fail. Alternatively, inflammation can become chronic and cause cumulative tissue damage or systemic complications.
[00267] Many serious and intractable human diseases involve dysregulation of inflammatory processes, including diseases such as cancer, atherosclerosis, and diabetes, which were not traditionally viewed as inflammatory conditions. In the case of cancer, the inflammatory processes are associated with tumor formation, progression, metastasis, and resistance to therapy. Atherosclerosis, long viewed as a disorder of lipid metabolism, is now understood to be primarily an inflammatory condition, with activated macrophages playing an important role in the formation and eventual rapture of atherosclerotic plaques. Activation of inflammatory signaling pathways has also been shown to play a role in the development of insulin resistance, as well as in the peripheral tissue damage associated with diabetic hyperglycemia. Excessive production of reactive oxygen species and reactive nitrogen species such as superoxide, hydrogen peroxide, nitric oxide, and peroxynitrite is a hallmark of inflammatory conditions. Evidence of dysregulated peroxynitrite production has been reported in a wide variety of diseases.
[00268] Autoimmune diseases such as rheumatoid arthritis, lupus, psoriasis, and multiple sclerosis involve inappropriate and chronic activation of inflammatory processes in affected tissues, arising from dysfunction of self vs. non-self recognition and response mechanisms in the immune system. In neurodegenerative diseases such as Alzheimer's and Parkinson's diseases, neural damage is correlated with activation of microglia and elevated levels of pro -inflammatory proteins such as inducible nitric oxide synthase (iNOS). Chronic organ failure such as renal failure, heart failure, liver failure, and chronic obstructive pulmonary disease is closely associated with the presence of chronic oxidative stress and inflammation, leading to the development of fibrosis and eventual loss of organ function. Oxidative stress in vascular endothelial cells, which line major and minor blood vessels, can lead to endothelial dysfunction and is believed to be an important contributing factor in the development of systemic cardiovascular disease, complications of diabetes, chronic kidney disease, and other forms of organ failure, and a number of other aging -related diseases including degenerative diseases of the central nervous system and the retina.
[00269] Many other disorders involve oxidative stress and inflammation in affected tissues, including inflammatory bowel disease; inflammatory skin diseases; mucositis related to radiation therapy and chemotherapy; eye diseases such as uveitis, glaucoma, macular degeneration, and various forms of retinopathy; transplant failure and rejection; ischemia-reperfusion injury; chronic pain; degenerative conditions of the bones and joints including osteoarthritis and osteoporosis; asthma and cystic fibrosis; seizure disorders; and neuropsychiatric conditions including schizophrenia, depression, bipolar disorder, post-traumatic stress disorder, attention deficit disorders, autism-spectrum disorders, and eating disorders such as anorexia nervosa. Dysregulation of inflammatory signaling pathways is believed to be a major factor in the pathology of muscle wasting diseases including muscular dystrophy and various forms of cachexia.
[00270] A variety of life -threatening acute disorders also involve dysregulated inflammatory signaling, including acute organ failure involving the pancreas, kidneys, liver, or lungs, myocardial infarction or acute coronary syndrome, stroke, septic shock, trauma, severe bums, and anaphylaxis.
[00271] Many complications of infectious diseases also involve dysregulation of inflammatory responses. Although an inflammatory response can kill invading pathogens, an excessive inflammatory response can also be quite destructive and in some cases can be a primary source of damage in infected tissues.
Furthermore, an excessive inflammatory response can also lead to systemic complications due to overproduction of inflammatory cytokines such as TNF-a and IL-1. This is believed to be a factor in mortality arising from severe influenza, severe acute respiratory syndrome, and sepsis.
[00272] The aberrant or excessive expression of either iNOS or cyclooxygenase -2 (COX-2) has been implicated in the pathogenesis of many disease processes. NO is a potent mutagen and nitric oxide can activate COX-2. Furthermore, there is a marked increase in iNOS in rat colon tumors induced by the carcinogen azoxymethane.
[00273] In one aspect, compounds disclosed herein are characterized by their ability to inhibit the production of nitric oxide in macrophage-derived RAW 264.7 cells induced by exposure to g-interferon. They are further characterized by their ability to induce the expression of antioxidant proteins such as NQOl and reduce the expression of pro-inflammatory proteins such as COX-2 and inducible nitric oxide synthase (iNOS). These properties are relevant to the treatment of a wide array of diseases and disorders involving oxidative stress and dysregulation of inflammatory processes including cancer, complications from localized or total-body exposure to ionizing radiation, mucositis resulting from radiation therapy or chemotherapy, autoimmune diseases, cardiovascular diseases including atherosclerosis, ischemia- reperfusion injury, acute and chronic organ failure including renal failure and heart failure, respiratory diseases, diabetes and complications of diabetes, severe allergies, transplant rejection, graft-versus-host disease, neurodegenerative diseases, diseases of the eye and retina, acute and chronic pain, degenerative bone diseases including osteoarthritis and osteoporosis, inflammatory bowel diseases, dermatitis and other skin diseases, sepsis, bums, seizure disorders, and neuropsychiatric disorders.
[00274] In another aspect, compounds disclosed herein are used in preventing or treating tissue damage or organ failure, acute and chronic, resulting from oxidative stress exacerbated by inflammation. Examples of diseases that fall in this category include: heart failure, liver failure, transplant failure and rejection, renal failure, pancreatitis, fibrotic lung diseases (cystic fibrosis, COPD, and idiopathic pulmonary fibrosis, among others), diabetes (including complications), atherosclerosis, ischemia- reperfusion injury, glaucoma, stroke, autoimmune disease, autism, macular degeneration, and muscular dystrophy.
[00275] In some embodiments, the compounds disclosed herein are generally applied to the treatment of inflammatory conditions, such as sepsis, dermatitis, autoimmune disease, and osteoarthritis. In one aspect, the compounds disclosed herein are used to treat inflammatory pain and/or neuropathic pain, for example, by inducing Nrf2 and/or inhibiting NF-KB.
[00276] In some embodiments, the compounds disclosed herein are used in the treatment and prevention of diseases such as cancer, inflammation, Alzheimer's disease, Parkinson's disease, multiple sclerosis, autism, amyotrophic lateral sclerosis, Huntington's disease, autoimmune diseases such as rheumatoid arthritis, lupus, Crohn's disease, and psoriasis, inflammatory bowel disease, other diseases whose pathogenesis is believed to involve excessive production of either nitric oxide or prostaglandins, and pathologies involving oxidative stress alone or oxidative stress exacerbated by inflammation.
[00277] In some embodiments, the compounds disclosed herein are used in the treatment and prevention of diseases such as NASH. In some embodiments, the compounds disclosed herein are used in the treatment and prevention of diseases such as irritable bowel disease. In some embodiments, the compounds disclosed herein are used in the treatment and prevention of diabetic nephropathy. In some embodiments, the compounds disclosed herein are used in the treatment and prevention of chronic kidney disease.
[00278] In one aspect, the compounds disclosed herein are used to control the production of pro- inflammatory cytokines within the cell by selectively activating regulatory cysteine residues (RCRs) on proteins that regulate the activity of redox- sensitive transcription factors. Activation of RCRs by cyPGs has been shown to initiate a pro-resolution program in which the activity of the antioxidant and cytoprotective transcription factor Nrf2 is potently induced and the activities of the pro -oxidant and pro- inflammatory transcription factors NF-kB and the STATs are suppressed. In some embodiments, this increases the production of antioxidant and reductive molecules (NQO l, HO-1, SOD1, g-GCS) and decreases oxidative stress and the production of pro- oxidant and pro-inflammatory molecules (iNOS, COX-2, TNF-a). In some embodiments, the compounds disclosed herein cause the cells that host the inflammatory event to revert to a non-inflammatory state by promoting the resolution of inflammation and limiting excessive tissue damage to the host.
Combination Therapy
[00279] 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.
[00280] 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.
[00281] 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.
[00282] 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.
[00283] 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.
[00284] 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.
[00285] 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.
[00286] 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).
[00287] 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.
[00288] 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
Intermediate 1: (2S,4aS,6aR,6bS,8aR,12aS,14aR,14bS)-ll-cyano-2,4a,6a,6b,9,9,12a- heptamethyl- 10,14-dioxo-l,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b-octadecahydropicene-2-carboxylic acid
Figure imgf000092_0001
Step 1: benzyl (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-hydroxy-2,4a,6a,6b,9,9,12a- heptamethyl-13-oxo-l,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,ll,12,12a,12b,13,14b-icosahydropicene-2- carboxylate (IB)
Figure imgf000092_0002
[00289] To a stirred solution of glycyrrhetnic acid (1A) (470 g, 1.0 mol) in dimethyl formamide (3 L) was added powdered potassium carbonate (414 g, 3.0 mol) at 0 °C followed by slow addition of benzyl bromide (205 g, 1.2 mol). After completion of addition, the reaction mixture was allowed to warm to room temperature and stirred for 12 h. The reaction was quenched by addition of water (5 L) and filtered. The residue was washed with water (2 L) and dried on vacuum to obtain IB (500 g, 89%) as a white solid, which was used directly for the next step without further purifications.
Step 2: benzyl (2S,4aS,6aS,6bR,8aR,10S,12aR,12bR,14bR)-10-hydroxy-2,4a,6a,6b,9,9,12a- heptamethyl-l,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,ll,12,12a,12b,13,14b-icosahydropicene-2-carboxylate
(1C)
Figure imgf000093_0001
[00290] Compound (IB) (250 g, 446 mmol) and zinc powder (583 g, 8.9 mol) were dissolved in EtOH (3 L), then concentrated hydrochloric acid (1.5 L) was added to the mixture slowly at 0 °C. After completion of addition, the reaction was stirred for 12 h at room temperature. Then the reaction mixture was filtered, extracted with methylene chloride (3 L x 3), and the organics were dried over Na2S04 and the solvent was removed to give crude product, which was purified by flash chromatography to afford 1C (180 g, 74%) as a white solid. ¾ NMR (400 MHz, CDC13) 7.42 - 7.27 (m, 5H), 5.23 - 5.04 (m, 3H), 3.24-3.19 (m, 1H), 2.06 - 1.93 (m, 2H), 1.93 - 1.82 (m, 4H), 1.82 - 1.70 (m, 1H), 1.69 - 1.49 (m, 7H), 1.49 - 1.36 (m, 3H), 1.37 - 1.21 (m, 5H), 1.14 (s, 3H), 1.13 (s, 3H), 0.99 (s, 3H), 0.95 (s, 3H), 0.93 (s, 3H), 0.92 - 0.82 (m, 2H), 0.79 (s, 3H), 0.74 (s, 3H).
Step 3: benzyl (2S,4aS,6aS,6bR,8aR,12aR,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-10- oxo- l,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,12b,13,14b-octadecahydropicene-2-carboxylate (ID)
Figure imgf000093_0002
[00291] To a stirred suspension of 1C (55 g, 100 mmol) obtained above in anhydrous dimethyl sulfoxide (400 mL) was added iodoxybenzoic acid (112 g, 0.4 mol) and fluorobenzene (25 mL). The resulting suspension was heated to 85 °C under nitrogen for 24 hours. After the completion of the reaction, it was quenched with 20% aqueous sodium thiosulfate (500 mL). The resulting mixture was extracted with methylene chloride (4 x 500 mL), the combined organic extracts were washed with saturated NaHCO, (500 mL) and brine (500 mL), and dried over NaiSCL. The solvent was removed to give the crude product as yellowish solid, which was subjected to flash column chromatography to give pure ID (43 g, 78%) as a white solid.
Step 4: benzyl (2S,4aS,6aR,6bR,8aR,12aR,12bR,14aR,14bS)-2,4a,6a,6b,9,9,12a-heptamethyl- 10,14- dioxo-l -icosahydropicene-2-carboxylate (IE)
Figure imgf000093_0003
Figure imgf000093_0004
[00292] To a stirred solution of ID (43 g, 78 mmol) in methylene chloride (400 mL) was slowly added m- chloroperbenzoic acid (20.4 g, 85% purity, 100 mmol) at 0 °C. After the completion of addition, the reaction was allowed to warm to room temperature and kept stirring for 24 hours. After the completion of the reaction, the reaction mixture was diluted with methylene chloride (300 mL), and the resulting mixture was washed with 20% aqueous sodium thiosulfate (2 x 300 mL), 10% potassium carbonate (2 x 300 mL), and brine (300 mL). The organics were dried over Na2SC>4 and the solvent was removed to give crude product IE as yellowish solid, which was used directly for the next step without further purifications.
Step 5: benzyl (2S,4aS,6aR,6bS,8aR,12aR,14aR,14bS)-ll-bromo-2,4a,6a,6b,9,9,12a-heptamethyl - 10,14-dioxo-l,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b-octadecahydropicene-2-carboxylate (IF)
Figure imgf000094_0001
[00293] To the solution of IE obtained above in acetic acid (200 mL) was added dropwise hydrobromic acid (4.5 mL, 39 mmol) at room temperature. The reaction mixture was then heated to 35 °C, and bromine (10 mL, 0.2 mol) was thus added dropwise. The resulting reaction mixture was kept stirring for another 3 h. After completion of the reaction, the acid was removed under vacuum. And the residue was then quenched with 20% aqueous sodium thiosulfate (200 mL), and extracted with methylene chloride (4 x 200 mL). The combined organic extracts were washed with saturated sodium bicarbonate (2 x 200 mL), brine (l x 200 mL), and dried over NaiSCL. The residue was subjected to flash column chromatography to give pure IF (14.8 g, 30% from ID) as a yellowish solid. LC-MS (ESI) m/z: 635.3/637.3 [M+H]+. ¾ NMR (400 MHz, CDCL) d 7.83 (s, 1H), 7.50 (d, J= 7.2 Hz, 2H), 7.43 - 7.28 (m, 3H), 6.04 (s, 1H), 5.20 (q, J = 12.5 Hz, 2H), 3.04 (d, J= 4.7 Hz, 1H), 2.37 - 2.25 (m, 1H), 2.14-2.08 (m, 1H), 2.05 - 1.90 (m, 2H), 1.90 - 1.65 (m, 5H), 1.59-1.50 (m, 2H), 1.48 (s, 3H), 1.46 (s, 3H), 1.36 - 1.28 (m, 2H), 1.26 (s, 3H), 1.26-1.20 (m, 1H), 1.19 (s, 3H), 1.13 (s, 3H), 1.10-1.06(m, 1H), 1.01 (s, 3H), 0.97-0.91 (m, 1H), 0.90 (s, 3H).
Step 6: benzyl (2S,4aS,6aR,6bS,8aR,12aS,14aR,14bS)-ll-cyano-2,4a,6a,6b,9,9,12a-heptamethyl- 10,14-dioxo-l,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b-octadecahydropicene-2-carboxylate (1G)
Figure imgf000094_0002
[00294] To a stirred solution of IF (14.8 g, 23.3 mmol) in anhydrous dimethyl formamide (150 mL) was added copper (I) cyanide (3.1 g, 35 mmol) and potassium iodide (0.77 g, 4.7 mmol), and the resulting reaction mixture was heated to 120°C for 24 h. After the completion of reaction, it was cooled to room temperature, quenched with water (300 mL), and diluted with ethyl acetate (300 mL). The organic phase was washed with saturated NaHCCL (2 c 200 mL), brine (200 mL), and dried over NazSCL. Removal of solvent and the residue was subjected to flash column chromatography to give pure 1G (10.4 g, 77%) as a yellowish solid. LC-MS (ESI) m/z: 582.4 [M+H]+
Step 7: (2S,4aS,6aR,6bS,8aR,12aS,14aR,14bS)-ll-cyano-10-hydroxy-2,4a,6a,6b,9,9,12a- heptamethyl-14-oxo-l,2,3,4,4a,5,6,6a,6b,7,8,8a,9,12,12a,14,14a,14b-octadecahydropicene-2- carboxylic acid (1H)
Figure imgf000095_0001
[00295] To a stirred solution of 1G (10.4 g, 18 mmol) dissolved in THF(l00 mL), palladium carbon (2 g) was added and the mixture was stirred for 6 h under hydrogen atmosphere. After completion of the reaction, the mixture was filtered and concentrated under reduced pressure to obtain 1H as a brown solid, which was used directly for the next step without further purifications.
LC-MS (ESI) m/z: 494.3 [M+H]+
Step 7: (2S,4aS,6aR,6bS,8aR,12aS,14aR,14bS)-ll-cyano-2,4a,6a,6b,9,9,12a-heptamethyl- 10,14- dioxo-l,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b-octadecahydropicene-2-carboxylic acid (intermediate 1)
Figure imgf000095_0002
[00296] A solution of 1H obtained above and DDQ (4.1 g, 18 mmol) in dry toluene (80 mL) was heated under reflux for 30 min. After completion of the reaction, the mixture was filtered and concentrated under reduced pressure. The residue was subjected to flash column chromatography to give pure intermediate 1 (10.4 g, 77%) as a yellowish solid. LC-MS (ESI) m/z: 492.3 [M+H]+. ¾ NMR (400 MHz, CDCL) d 8.07 (s, 1H), 6.06 (s, 1H), 3.18 (d, J= 4.5 Hz, 1H), 2.26-2.19 (m, 2H), 2.03 - 1.70 (m, 6H), 1.70 - 1.53 (m, 3H), 1.52 (s, 3H), 1.50 (s, 3H), 1.43 - 1.30 (m, 2H), 1.30 - 1.23 (m, 5H), 1.20 (s, 3H), 1.18 (s, 3H), 1.13- 1.08(m, 1H), 1.02 (s, 3H), 0.99 (s, 3H).
Intermediate 2: tert-butyl (((4aS,6aR,6bS,8aR,12aS,14aR,14bS)-ll-cyano-2,2,6a,6b,9,9,12a- heptamethyl-10,14-dioxo-l,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b-hexadecahydropicen-4a(2i/)- yl)methyl)carbamate
Figure imgf000096_0002
[00297] To a solution of oleanolic acid 2A (92 g, 0.2 mol) in DMF (500 mL) were successively added HATU (91.2 g, 0.24 mol) and Et3N (41 g, 0.4 mol). The reaction mixture was stirred at room temperature for 0.5 h, then the mixture was added NH3 (42 mL, 7M in MeOH) and stirred at room temperature for 3 h. The mixture was diluted with water (1 L) and filtered. The residue was washed with water (1 L) and dried on vacuum to obtain 2B as a white solid, which was used directly for the next step without further purifications. LC-MS (ESI) m/z 456.4 [M+H]+
Step 2: (3S,4aR,6aR,6bS,8aS,12aS,14aR,14bR)-8a-(aminomethyl)-4,4,6a,6b,ll,ll,14b- heptamethyl- l,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,ll,12,12a,14,14a,14b-icosahydropicen-3-ol (2C)
Figure imgf000096_0001
[00298] To a solution of 2B (90 g, 197 mmol) in THF (600 mL) were added LiAlH4 (30 g, 0.79 mol) in portion under 0°C. Then the reaction mixture was heated to 60 °C for 4 h. After the completion of the reaction, it was allowed to cool to 0°C, the mixture was quenched successively with water (30 mL), 15% NaOH (60 mL) and water (90 mL). The mixture was filtered and filtrate was dried over Na2S04. The solvent was removed to give the crude product 2C as white solid, which was used directly for the next step without further purifications. LC-MS (ESI) m/z 442.4 [M+H]+
Step 3: tert-butyl (((4aS,6aS,6bR,8aR,12aR,12bR,14bS)-10-hydroxy-2,2,6a,6b,9,9,12a- heptamethyl- l,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,ll,12,12a,12b,13,14b-icosahydropicen-4a-yl)methyl)carbamate (2D)
Figure imgf000097_0001
[00299] To a stirred suspension of 2C (80 g, 0.18 mol) obtained above in DCM (500 mL) was added EhN (36.4 g, 0.36 mol). The resulting suspension was added dropwise Di-tert-butyl pyrocarbonate (47 g in 200 ml DCM). After the completion of the reaction, the solvent was removed to give the crude product, which was subjected to flash column chromatography to give pure 2D (72 g, 73%) as a white solid.
Step 4: tert-butyl (((4aS,6aS,6bR,8aR,12aR,12bR,14bS)-2,2,6a,6b,9,9,12a-heptamethyl-10-oxo- l,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,12b,13,14b-octadecahydropicen-4a-yl)methyl)carbamate (2E)
Figure imgf000097_0002
[00300] To a stirred suspension of 2D (36 g, 66 mmol) obtained above in anhydrous dimethyl sulfoxide (250 mL) was added iodoxybenzoic acid (55.8 g, 0.2 mol) and fluorobenzene (15 mL). The resulting suspension was heated to 85°C under nitrogen for 24 h. After the completion of the reaction, it was quenched with 20% aqueous sodium thiosulfate (300 mL). The resulting mixture was extracted with methylene chloride (4 x 300 mL), the combined organic extracts were washed with saturated NaHCCL (300 mL) and brine (300 mL), and dried over Na2SC>4. The solvent was removed to give the crude product, which was subjected to flash column chromatography to give pure 2E (27 g, 76%) as a white solid. LC-MS (ESI) m/z 438.4 [M-Boc+H]+
Step 5: tert-butyl (((4aS,6aR,6bR,8aR,12aR,14aR,14bS)-2,2,6a,6b,9,9,12a-heptamethyl-10,14- dioxo- l,3,4,5,6,6a,6b,7,8,8a,9,10,12a,12b,13,14,14a,14b-octadecahydropicen-4a(2iT)-yl)methyl)carbamate
(2F)
Figure imgf000097_0003
[00301] To a stirred solution of 2E (27 g, 50 mmol) in methylene chloride (300 mL) was slowly added mchloroperbenzoic acid (14.2 g, 70 mmol) at 0 °C. Afterthe completion of addition, the reaction was allowed to warm to room temperature and kept stirring for 24 hours. After the completion of the reaction, the reaction mixture was diluted with methylene chloride (300 mL), and the resulting mixture was washed with 20% aqueous sodium thiosulfate (3 x 200 mL), 10% potassium carbonate (2 x 200 mL), and brine (200 mL). The organics were dried over Na2S04 and the solvent was removed to give crude mixture of 2F and 2G as yellowish solid, which was used directly for the next step without further purifications.
Step 6: tert-butyl (((4aS,6aR,6bS,8aR,12aR,14aR,14bS)-ll-bromo-2,2,6a,6b,9,9,12a-heptamethyl - 10,14-dioxo-l,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b-hexadecahydropicen-4a(2i/)- yl)methyl)carbamate (2H)
Figure imgf000098_0001
[00302] To the solution of 2F and 2G obtained above in acetic acid (150 mL) was added dropwise hydrobromic acid (2.9 mL, 25 mmol) at room temperature. The reaction mixture was then heated to 35°C, and bromine (6.2 mL, 0.12 mol) was thus added dropwise. The resulting reaction mixture was kept stirring for another 3 h. After completion of the reaction, the acid was removed under vacuum. And the residue was then quenched with 20% aqueous sodium thiosulfate (100 mL), and extracted with methylene chloride (4 x 100 mL). The combined organic extracts were washed with saturated sodium bicarbonate (2 x 200 mL), brine (1 x 200 mL), and dried over Na2S04. The solvent was added Et3N (10 1 g, 0.1 mol). The resulting suspension was added dropwise Di-tert-butyl pyrocarbonate (15.3 g in 100 ml DCM). After the completion of the reaction, the solvent was removed to give the crude product, which was subjected to flash column chromatography to give pure 2H (14.1 g) as a yellowish solid. LC-MS (ESI) m/z = 574.2/ 576.2 [M-tBu+H]+.
Step 7: tert-butyl (((4aS,6aR,6bS,8aR,12aS,14aR,14bS)-ll-cyano-2,2,6a,6b,9,9,12a-heptamethyl - 10,14-dioxo-l,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b-hexadecahydropicen-4a(2/7)- yl)methyl)ca
Figure imgf000098_0002
[00303] To a solution 2H (0.63 g, 1 mmol) in DMF (20 mL) under argon was successively added K4[Fe(CN)5] (0.18 g, 0.5 mmol), sodium Carbonate (0.98 g, 3.0 mmol) and then Pd(OAc)2 (58 mg, 0.1 mmol). The reaction mixture was heated at 110°C for 3 h. After cooling to room temperature, the mixture was diluted with water and EtOAc. The organic layer was separated and the aqueous layer extracted with EtOAc. The combined organic layers were then washed with water and brine, dried over Na2S04, filtered, and concentrated in vacuo. The residue was purified by flash chromatography to afford intermediate 2 (0.19 g, 35%) as a yellow solid. LC-MS (ESI) m/z 521.2 [M-tBu+H]+. 'H NMR (400 MHz, CDCL) d 8.03 (s, 1H), 5.97 (s, 1H), 4.62 (s, 1H), 3.28-3.24 (m, 1H), 3.18 (d, J = 4.1 Hz, 1H), 3.10-3.04 (m, 1H), 2.23 (s, 1H), 2.04 - 1.90 (m, 2H), 1.90 - 1.66 (m, 4H), 1.63-1.57 (m, 2H), 1.56 (s, 3H), 1.55-1.51 (m, 1H), 1.51 (s, 3H), 1.450-1.46 (m, 1H), 1.42 (s, 9H), 1.36-1.30 (m, 1H), 1.29 (s, 2H), 1.28 - 1.24 (m, 3H), 1.24 - 1.19 (m, 1H), 1.19-1.04 (m, 2H), 1.14 - 1.03 (m, 1H), 1.01 (s, 3H), 0.93 (s, 3H), 0.87 (s, 3H).
Intermediate 3: (4aR,6aS,6bR,8aS,llS,12aS,12bR,14bS)-ll-amino-4,4,6a,6b,8a,ll,14b- heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,ll,12,12a,12b,13,14b-octadecahydropicene-2- carbonitrile
Figure imgf000099_0001
Step 1: (2S,4aS,6aR,6bS,8aR,12aS,14aR,14bS)-ll-cyano-2,4a,6a,6b,9,9,12a-heptamethyl -10,14- dioxo-l,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b-octadecahydropicene-2-carbonyl azide (3A)
Figure imgf000099_0002
[00304] To a stirred solution of intermediate 1 (2.0 g, 4.1 mmol), DPPA (3.0 g, 12 mmol) in toluene (10 mL) at 0 °C was added Et3N (4.1 g, 41.0 mmol) under nitrogen. The resulting solution was stirred at room temperature for 3 hours. Upon consumption of the starting material, the reaction mixture was diluted with EtOAc and washed with brine (20 mL). The organic layer was dried (ISfeSCE), filtered and concentrated under reduced pressure. The crude product was purified by flash silica chromatography to afford 3A (1.4 g, 67%) as a white solid.
Step 2: (4aR,6aS,6bR,8aS,llS,12aS,12bR,14bS)-ll-amino-4,4,6a,6b,8a,ll,14b-heptamethyl -3,13- dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,ll,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile
(intermediate 3)
Figure imgf000099_0003
[00305] A solution of 3A (1.4 g, 2.7 mmol) in toluene (10 mL) was heated to 80°C. The resulting solution was stirred at 80°C for 3 h. The reaction mixture was concentrated under reduced pressure. The crude product was dissolved in MeOH (10 mL), and was added concentrated hydrochloric acid (2 mL) at 0°C, The resulting solution was stirred at room temperature for 3 hours. Upon consumption of the starting material, the reaction mixture was diluted with EtOAc (20 mL) and washed with saturated NaHC03 (20 mL). The organic layer was dried (Na2S04), filtered and concentrated under reduced pressure. The crude product was purified by flash silica chromatography to afford intermediate 3 (1.2 g, 91%) as a white solid. LC-MS (ESI): m/z = 463.3 [M+H] +.
Example 1 : (4aR,6aS,6bR,8aS,llS,12aS,12bR,14bS)-4,4,6a,6b,8a,ll,14b-heptamethyl-ll-(5- methyl-l,3,4-oxadiazol-2-yl)-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11 2,12a,12b,13,14b- octadecahydropicene-2-carbonitrile (compound 1)
Figure imgf000100_0001
Step 1: (2S,4aS,6aR,6bS,8aR,12aS,14aR,14bS)-N'-acetyl-ll-cyano-2,4a,6a,6b,9,9,12a- heptamethyl-
10,14-dioxo-l,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b-octadecahydropicene-2-carbohydrazide
(la)
[00306] To a solution of intermediate 1 (5.5 g, 11 mmol) in DMF (56 mL) was added HATU (5.1 g, 13 mmol), Triethylamine (9.4 mL, 68 mmol) and Acetohydrazide (0.99 g, 13 mmol). The reaction mixture was stirred at room temperature for 2 h, washed with water (150 mL), and extracted with DCM (2x 150 mL). The combined organic layers were dried over Na2SC>4, concentrated in vacuo. The residue was purified by flash chromatography to afford la (5.0 g, 82%) as a yellow powder. LC-MS (ESI): m/z =548.4 [M+H] +.
Step 2: (4aR,6aS,6bR,8aS,llS,12aS,12bR,14bS)-4,4,6a,6b,8a,ll,14b-heptamethyl-ll-(5-methyl - l,3,4-oxadiazol-2-yl)-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,ll,12,12a,12b,13,14b- octadecahydropicene-2-carbonitrile (compound 1)
[00307] To a solution of la (5 g, 9.1 mmol) in DCM (45 mL) was added N1,N1,N6,N6-tetramethylhexane- 1, 6-diamine (3.1 g, 18.3 mmol) and TsCI (3.5 g, 18.3 mmol). The reaction mixture was stirred at room temperature overnight, washed with water (50 mL), and extracted with EA (2x50 mL). The combined organic layers were dried over Na2S04, concentrated in vacuo. The residue was purified by
chromatography to afford compound 1 (3 g, 62%) as a white solid. LC-MS (ESI): m/z =530.3 [M+H] + ¾ NMR (400 MHz, CDCf) d 8.02 (s, 1H), 5.99 (s, 1H), 3.04 (d, 1H), 2.59 (s, 3H), 2.32 - 2.20 (m, 2H), 2.01 - 1.68 (m, 10H), 1.62 - 1.53 (m, 2H), 1.50 (s, 3H), 1.47 (s, 3H), 1.42 - 1.34 (m, 1H), 1.27 (s, 6H), 1.18 (s, 3H), 1.17 - 1.09 (m, 1H), 1.02 (s, 3H), 0.92 (s, 3H).
Example 2 : (2S,4aS,6aR,6bS,8aR,12aS,14aR,14bS)-2,4a,6a,6b,9,9,12a-heptamethyl-10,14- dioxo- l,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b-octadecahydropicene-2,ll-dicarbonitrile (compound 2)
Figure imgf000101_0001
Step 1: (2S,4aS,6aR,6bS,8aR,12aS,14aR,14bS)-ll-cyano-2,4a,6a,6b,9,9,12a-heptamethyl-10,14 - dioxo-l,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b-octadecahydropicene-2-carboxamide (2a)
[00308] To a solution of intermediate 1 (0.160 g, 0.325 mmol), HATU (0.148 g, 0.390 mmol) and TEA (0.066 g, 0.65 mmol) in DCM (5 mL) was added NH4CI (0.052 g, 0.976 mmol) at 25 °C. The reaction mixture was stirred for 2 h, washed with water (20 mL), and extracted with DCM (2x 10 mL). The combined organic layers were dried over Na2SC>4, concentrated in vacuo. The residue was used to next step directly.
LC-MS (ESI): m/z =491.4 [M+H] +.
Step 2: (2S,4aS,6aR,6bS,8aR,12aS,14aR,14bS)-2,4a,6a,6b,9,9,12a-heptamethyl- 10,14-dioxo- l,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b-octadecahydropicene-2,ll-dicarbonitrile (compound 2)
[00309] To a solution of 2a (0.12 g, 0.245 mmol) in MeCN (5 mL) was added POCL (0.375 g, 2.45 mmol) at 0°C. The reaction mixture was warmed to room temperature and then refluxed for 2 h, washed with water (20 mL), and extracted with DCM (2x 10 mL). The combined organic layers were dried over NazSCL, concentrated in vacuo. The residue was purified by flash chromatography to afford compound 2 (0.034 g, 34.6%) as a white solid. LC-MS (ESI): m/z =473.4 [M+H] +.
¾ NMR (400 MHz, CDCh) 5 8.04 (s, 1H), 6.04 (s, 1H), 3.17 (d, 1H), 2.41 (d, 1H), 2.12 - 2.04 (m, 1H), 1.95 - 1.66 (m, 8H), 1.60 (d, 1H), 1.52 (s, 5H), 1.51 - 1.48 (m, 1H), 1.46 (d, 1H), 1.42 (d, 1H), 1.32 (d, 4H), 1.26 (s, 3H), 1.18 (s, 3H), 1.16 - 1.09 (m, 1H), 1.06 (s, 3H), 1.00 (d, 1H), 0.96 (s, 3H).
Example 3 : 2-cyano-l-(((4aS,6aR,6bS,8aR,12aS,14aR,14bS)-ll-cyano-2,2,6a,6b,9,9,12a- heptamethyl-10,14-dioxo-l,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b-hexadecahydropicen-4a(2f/)- yl)methyl)-3-methylguanidine (compound 3)
Figure imgf000101_0002
Step 1: (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-(aminomethyl)-4,4,6a,6b,ll,ll,14b-heptamethyl - 3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,ll,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile (3a)
[00310] A solution of intermediate 2 (0.15 g, 0.26 mmol) and trifluoroacetic acid (3 mL) in DCM (10 mL) was stirred at room temperature for 0.5 h. Solvent was evaporated, and the crude product was partitioned between water and DCM. The aqueous layer was basified with NaHC03 and extracted with DCM. Combined organic layers were washed with brine, dried over sodium sulfate, filtered, and evaporated to give 3a (0.12 g, 100%) that was used in the next step without further purification. LC-MS (ESI) m/z 477.3 [M+H]+.
Step 2 : 2-cyano-l-(((4aS,6aR,6bS,8aR,12aS,14aR,14bS)-ll-cyano-2,2,6a,6b,9,9,12a- heptamethyl- 10,14-dioxo-l,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b-hexadecahydropicen-4a(2i/)-yl)methyl)-3- methylguanidine (compound 3)
[00311] To a solution of 3a (0.10 g, 0.21 mmol) in MeOH (10 mL) was added
bis(methylsulfanyl)methylenecyanamide (44 mg, 0.30 mmol), and stirred overnight at 30 °C. Then methanamine in EtOH (1.0 mL, 2.0 mmol) was added to the reaction mixture. After another 20 h, the reaction mixture was concentrated in vacuo. The residue was purified by chromatography on silica gel (PE: EA= 1/1 to 1/2) to afford compound 3 (20 mg, 20%) as a pale yellow solid. LC-MS (ESI): m/z =558.4 [M+H]+
Example 4: A ,-cyano-N-(((4aS,6aR,6bS,8aR,12aS,14aR,14bS)-ll-cyano-2,2,6a,6b,9,9,12a- heptamethyl-10,14-dioxo-l,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b-hexadecahydropicen-4a(2f/)- yl)methyl)acetimidamide (compound 4)
Figure imgf000102_0001
[00312] To a solution of 3a (0.12 g, 0.26 mmol) in MeOH (5 mL) was added ethyl N-cyanoacetimidate (0.5mL). The reaction mixture was stirred for 8 h. After the completion of the reaction, the mixture was concentrated in vacuo. The residue was purified by flash chromatography to afford Compound 4 (35 mg) as a yellow solid. LC-MS (ESI): m/z 543.4 [M+H]+. ¾ NMR (400 MHz, CDCL) S 8.05 (s, 1H), 6.01-5.96 (m, 2H), 3.75-3.70 (m, 1H), 3.23-3.18 (m, 1H), 3.10 (d, J = 4.6 Hz, 1H), 2.37 (s, 3H), 2.26-2.22 (m, 1H), 2.08 - 1.67 (m, 6H), 1.63 (s, 3H), 1.60-1.56 (m, 1H), 1.55 (s, 3H), 1.51 (s, 3H), 1.46-1.40 (m, 1H), 1.35- 1.28 (m, 2H), 1.27 (s, 3H), 1.19 (s, 3H), 1.14-1.08 (m, 1H), 1.01 (s, 3H), 0.98-0.93 (m, 1H)0.92 (s, 3H), 0.89 (s, 3H).
Example 5 : Ar-((4aS,6aR,6bS,8aR,12aS,14aR,14bS)-ll-cyano-2,2,6a,6b,9,9,12a-heptamethyl- 10,14- dioxo-l,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b-hexadecahydropicen-4a(2i/)-yl)-2-((ls)-/V-cyano-S- methylsulfinimidoyl)acetamide (compound 5)
Figure imgf000103_0001
Step 1: /V-((4aS,6aR,6bS,8aR,12aS,14aR,14bS)-ll-cyano-2,2,6a,6b,9,9,12a-heptamethyl -10,14 - dioxo-l,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b-hexadecahydropicen-4a(2i/)-yl)-2- (methylthio)acetamide (5b)
[00313] To a solution of 5a (0.30 g, 0.65 mmol) and TEA (0.20 g, 1.9 mmol) in DCM (5 mL) was added 2-(methylthio)acetyl chloride (0.12 g, 0.97 mmol) at 0°C. The reaction mixture was warmed to room temperature and stirred for 2 h, washed with water (20 mL), and extracted with DCM (2x 10 mL). The combined organic layers were dried over Na2SC>4, concentrated in vacuo. The residue was purified by flash chromatography to afford 5b (0.21 g, 59%) as a white solid. LC-MS (ESI): m/z =551.3 [M+H] +. Step 2: /V-((4aS,6aR,6bS,8aR,12aS,14aR,14bS)-ll-cyano-2,2,6a,6b,9,9,12a-heptamethyl-10,14 - dioxo-l,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b-hexadecahydropicen-4a(2i/)-yl)-2-((E)-iV- cyano-S- methylsulfinimidoyl)acetamide (compound 5)
[00314] To a solution of 5a (0.17 g, 0.31 mmol) and NLLCN (0.20 g, 1.9 mmol) in DCM (3 mL) was added PhI(OAc)2 (0.10 g, 0.34 mmol) at 0°C. The reaction mixture was warmed to room temperature and stirred for 2 h, washed with water (20 mL), and extracted with DCM (2x 10 mL). The combined organic layers were dried over lNfeSCL, concentrated in vacuo. The residue was purified by flash chromatography to afford compound 5 (0.11 g, 60%) as a white solid. LC-MS (ESI): m/z =591.3 [M+Hj f'HNMR (400 MHz, CDCL) S 8.64 (s, 1H), 7.97 (d, 1H), 6.23 (s, 1H), 4.11 (d, 1H), 4.00 (t, 1H), 3.11 (s, 1H), 2.83- 2.50 (m, 4H), 2.07-0.94 (m, 33H), 0.86 (s, 3H).
Example 6 : (4aR,6aS,6bR,8aS,llS,12aS,12bR,14bS)-4,4,6a,6b,8a,ll,14b-heptamethyl-ll- (oxazol- 2-yl)-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,ll,12,12a,12b,13,14b-octadecahydropicene-2- carbonitrile (compound 6)
Figure imgf000104_0001
Step 1: (2S,4aS,6aR,6bS,8aR,12aS,14aR,14bS)-ll-cyano-N-(2-hydroxyethyl)-2,4a,6a,6b,9,9, 12a- heptamethyl-10,14-dioxo-l,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b-octadecahydropicene-2- carboxamide (6a)
[00315] To a solution of intermediate 1 (0.12 g, 0.24 mmol) in DMF (500 mL) were successively added HATU (0.15 g, 0.36 mmol) and EtsN (41 mg, 0.4 mmol). The reaction mixture was stirred at room temperature for 0.5 h, and the mixture was added 2-aminoethanol (60 mg, 1 mmol) and stirred at room temperature for 3h. The mixture was diluted with water and EtOAc. The organic layer was separated and the aqueous layer extracted with EtOAc. The combined organic layers were then washed with water and brine, dried over Na2S04, filtered and concentrated in vacuo. The residue was purified by flash chromatography to afford 6a (0.11 g, 84%) as a yellow solid. LC-MS (ESI): m/z 535.4 [M+H]+
Step 2: (2S,4aS,6aR,6bS,8aR,12aS,14aR,14bS)-ll-cyano-2,4a,6a,6b,9,9,12a-heptamethyl-10,14- dioxo-A/-(2-oxoethyl)-l,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b-octadecahydropicene-2- carboxamide (6b)
[00316] A solution of 6a (0.11 g, 0.2 mmol) in DCM (10 mL) was added DMP (0.42 g, 1 mmol) and stirred at room temperature for 1 h. The mixture was quenched with aqueous NaHCO, and extracted with DCM. Combined organic layers were washed with brine, dried over sodium sulfate, filtered, and evaporated to give 6b (90 mg, 82%) that was used in the next step without further purification. LC-MS (ESI) m/z 533.4 [M+H]+
Step 3: (4aR,6aS,6bR,8aS,llS,12aS,12bR,14bS)-4,4,6a,6b,8a,ll,14b-heptamethyl-ll-(oxazol -2-yl)- 3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,ll,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile (compound 6)
[00317] A solution of 6b (90 mg, 0.17 mmol) in THF (10 mL) was added Burgess reagent (0.13 g, 0.51 mmol), the mixture was stirred in microwave at 110°C for 1 h. Then the mixture was concentrated in vacuo. The residue was purified by flash chromatography to afford Compound 6 (32 mg, 37%) as a yellow solid. LC-MS (ESI): m/z 515.4 [M+H]+. ¾ NMR (400 MHz, CDCT) d 8.04 (s, 1H), 7.72 (s, 1H), 7.15 (s, 1H), 6.00 (s, 1H), 3.05 (d, J= 4.7 Hz, 1H), 2.49 - 2.21 (m, 3H), 2.02 - 1.71 (m, 7H), 1.65 - 1.52 (m, 3H), 1.50 (s, 3H), 1.46 (s, 3H), 1.45-1.35(m, , 1H), 1.27 (s, 3H), 1.26 (s, 3H), 1.18 (s, 3H), 1.16 - 1.09 (m, 1H), 1.04 (s, 3H), 1.03-0.94 (m, 1H), 0.90 (s, 3H). Example 7 : (4aR,6aS,6bR,8aS,llS,12aS,12bR,14bS)-4,4,6a,6b,8a,ll,14b-heptamethyl-ll-(5- methyloxazol-2-yl)-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,ll,12,12a,12b,13,14b- octadecahydropicene-2-carbonitrile (compound 7)
Figure imgf000105_0001
Step 1: (2S,4aS,6aR,6bS,8aR,12aS,14aR,14bS)-ll-cyano-2,4a,6a,6b,9,9,12a-heptamethyl-10,14- dioxo-N-(prop-2-yn-l-yl)-l,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b-octadecahydropicene-2- carboxamide (7a)
[00318] To a stirred solution of intermediate 1 (0.50 g, 1.00 mmol), HATU(0.58g, 1.50 mmol) and prop- 2-yn-l-amine (0.07 g, 1.2 mmol) in DCM (10 mL) at room temperature was added DIPEA (0.4 g, 3.0 mmol) under nitrogen. The resulting solution was stirred at room temperature overnight. Upon consumption of the starting material, the reaction mixture was diluted with EtOAc and washed with brine (20 mL). The organic layer was dried (Na2SC>4), filtered and concentrated under reduced pressure. The crude product was purified by flash silica chromatography to afford 7a (0.48 g, 89%) as a white solid. LC-MS (ESI): m/z = 529.3 [M+H] +.
Step 2: (4aR,6aS,6bR,8aS,llS,12aS,12bR,14bS)-4,4,6a,6b,8a,ll,14b-heptamethyl-ll-(5- methyl oxazol-2-yl)-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,ll,12,12a,12b,13,14b-octadecahydropicene-2- carbonitrile (compound 7)
[00319] To a solution of 7a (0.43 g, 0 81 mmol) in DCM (10 mL) was added AuCL (49 mg, 0.16 mmol) under nitrogen. The resulting solution was stirred at room temperature overnight and concentrated under reduced pressure. The crude product was purified by flash silica chromatography to afford compound 7 (114 mg, 26%) as a white solid. LC-MS (ESI): m/z = 529.4 [M+H] +. ¾ NMR (400 MHz, CDCL) d 8.02 (s, 1H), 7.00 (d, 1H), 6.03 (s, 1H), 3.05 (d, 1H), 2.43 (m, 4H), 2.27 (m, 1H), 2.04 - 1.67 (m, 7H), 1.66 - 1.36 (m, 11H), 1.28 (m, 6H), 1.24 - 1.10 (m, 4H), 1.04 (m, 4H), 0.91 (s, 3H).
Example 8: (4aR,6aS,6bR,8aS,llS,12aS,12bR,14bS)-4,4,6a,6b,8a,ll,14b-heptamethyl-3,13- dioxo- ll-(3-phenyl-lH-l,2,4-triazol-5-yl)-3,4,4a,5,6,6a,6b,7,8,8a,9,10,ll,12,12a,12b,13,14b- octadecahydropicene-2-carbonitrile (compound 8)
Figure imgf000105_0002
[00320] To a stirred solution of intermediate 1 (50 mg,0.10 mmol), HATU (50 mg, 0.13 mmol) and benzimidamide hydrochloride (21 mg, 0.13 mmol) in DCM (4 mL) at room temperature was added DIPEA (53 mg, 0.41mmol) under nitrogen. The resulting solution was stirred at room temperature for 4 hours. Upon consumption of the starting material, hydrazine hydrochloride (56 mg, 0.81 mmol) and acetic acid (12 mg, 0.20 mmol) were added to the reaction mixture that heated to reflux for 5 h. After consumption of intermediate, the reaction mixture was diluted with EtOAc and washed with saturated NaHCCE (20 mL). The organic layer was dried (MgSCft), filtered and concentrated under reduced pressure. The crude product was purified by flash silica chromatography to afford compound 8 (11.7 mg, 20%) as a white solid. LC-MS (ESI): m/z = 591.3 [M+H] +. H NMR (400 MHz, CDC13) S 8.15 (d, 2H), 8.07 (s, 1H), 7.49 - 7.33 (m, 3H), 6.12 (s, 1H), 3.12 (d, 1H), 2.23 (s, 1H), 2.05 (m, 3H), 1.89 (d, 2H), 1.83 (s, 3H), 1.68 - 1.60 (m, 3H), 1.55 (s, 3H), 1.52 (s, 3H), 1.42 - 1.36 (m, 4H), 1.27 (m, 4H), 1.23 - 1.11 (m, 6H), 1.05 (s, 3H), 0.90 (s, 3H).
Example 9 : (4aR,6aS,6bR,8aS,llS,12aS,12bR,14bS)-4,4,6a,6b,8a,ll,14b-heptamethyl-ll-(l,3,4- oxadiazol-2-yl)-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,ll,12,12a,12b,13,14b-octadecahydropicene-2- carbonitrile (compound 9)
Figure imgf000106_0001
Step 1: (2S,4aS,6aR,6bS,8aR,12aS,14aR,14bS)-ll-cyano-/V-formyl-2,4a,6a,6b,9,9,12a-hepta methyl-
10,14-dioxo-l,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b-octadecahydropicene-2-carbohydrazide
(9a)
[00321] To a stirred solution of intermediate 1(1.30 g, 2.60 mmol), HATU(1.20 g, 3.20 mmol) and formylhydrazine (0.21 g, 3.40 mmol) in DCM (10 mL) at room temperature was added DIPEA (1.0 g,
7.91 mmol) under nitrogen. The resulting solution was stirred at room temperature overnight. Upon consumption of the starting material, the reaction mixture was diluted with EtOAc and washed o with brine (20 mL). The organic layer was dried (MgSO. , filtered and concentrated under reduced pressure. The crude product was purified by flash silica chromatography to afford 9a (1.1 g, 78%) as a white solid. LC-MS (ESI): m/z = 534.3 [M+H] +.
Step 2: (4aR,6aS,6bR,8aS,llS,12aS,12bR,14bS)-4,4,6a,6b,8a,ll,14b-heptamethyl-ll-(l,3,4- oxadiazol-2-yl)-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,ll,12,12a,12b,13,14b-octadecahydropicene-2- carbonitrile (compound 9)
[00322] To a solution of 9a (1.10 g, 2.06 mmol) in DCM (5 mL) was added TsCI (0.79 g, 4.12 mmol) and N^N^N^N'+tetramethylhexane-l, 6-diamine (0.98 g, 6.18 mmol). The reaction mixture was stirred at room temperature overnight, the reaction mixture was diluted with EtOAc and washed with saturated NH4C1 solution (20 mL). The organic layer was dried (Na3S04), filtered and concentrated under reduced pressure. The crude product was purified by flash silica chromatography to afford compound 9 (170 mg, 16%) as a white solid. LC-MS (ESI): m/z =516.3 [M+H] +. ¾ NMR (400 MHz, CDCL) 0 8.44 (s, 1H), 8.03 (s, 1H), 5.99 (s, 1H), 3.04 (d, 1H), 2.33 (m, 2H), 2.02 - 1.76 (m, 7H), 1.71 - 1.53 (m, 6H), 1.49 (d, 5H), 1.40 (d, 1H), 1.28 (d, 6H), 1.21 - 1.09 (m, 4H), 1.02 (d, 3H), 0.91 (s, 3H).
Example 10 : (4aR,6aS,6bR,8aS,llS,12aS,12bR,14bS)-4,4,6a,6b,8a,ll,14b-heptamethyl-3,13- dioxo- ll-(5-(trifluoromethyl)-l,3,4-oxadiazol-2-yl)-3,4,4a,5,6,6a,6b,7,8,8a,9,10,ll,12,12a,12b,13,14b- octadecahydropicene-2-carbonitrile (compound 10)
Figure imgf000107_0001
Step 1: (2S,4aS,6aR,6bS,8aR,12aS,14aR,14bS)-ll-cyano-2,4a,6a,6b,9,9,12a-heptamethyl-10,14 - dioxo-l,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b-octadecahydropicene-2-carbohydrazide (10a)
[00323] To a solution of intermediate 1 (0.3 g, 0.56 mmol) in 1,4-dioxane (10 mL) was added concentrated hydrochloric acid (1 mL) . The resulting solution was stirred at room temperature overnight. Upon consumption of the starting material, the reaction mixture was diluted with EtOAc (20 mL) and washed with saturated NaHCCL solution (20 mL). The organic layer was dried (NaiSCL), filtered and concentrated under reduced pressure. The crude product was purified by flash silica chromatography to afford 10a (0.2 g, 67%) as a white solid. LC-MS (ESI): m/z = 506.3 [M+H] +.
Step 2: (2S,4aS,6aR,6bS,8aR,12aS,14aR,14bS)-ll-cyano-2,4a,6a,6b,9,9,12a-heptamethyl-10,14 - dioxo-/V-(2,2,2-trifluoroacetyl)-l,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b-octadecahydropicene- 2-carbohydrazide (10b)
[00324] To a solution of 10a (0.50 g, 1.0 mmol) and TEA (0.300 g, 3.0 mmol) in DCM (25 mL) was added TFAA (0.310 g, 1.5 mmol) at 25 °C. The reaction mixture was stirred for 2 h, washed with water (20 mL), and extracted with DCM (2x 10 mL). The combined organic layers were dried over Na2S04, concentrated in vacuo. The residue was used to next step directly. LC-MS (ESI): m/z =602.3 [M+H] +.
Step 3: (4aR,6aS,6bR,8aS,llS,12aS,12bR,14bS)-4,4,6a,6b,8a,ll,14b-heptamethyl-3,13-dioxo- ll-(5- (trifluoromethyl)-l,3,4-oxadiazol-2-yl)-3,4,4a,5,6,6a,6b,7,8,8a,9,10,ll?12,12a,12b,13,14b- octadecahydropicene-2-carbonitrile (compound 10)
To a solution of 10b (0.200 g, 0.332 mmol) and N^N^N'blSf-tetramethylhexane-l, 6-diamine (0.115 g, 0.665 mmol) in DCM (10 mL) was added TsCI (0.127 g, 0.665 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 16 h, washed with water (20 mL), and extracted with DCM (2x 10 mL). The combined organic layers were dned over NazSCL, concentrated in vacuo. The residue was purified by flash chromatography to afford compound 10 (0.040 g, 20.6%) as a white solid. LC-MS (ESI): m/z =584.4 [M+H] +. ¾ NMR (400 MHz, CDCL) d 8.02 (s, 1H), 6.03 (s, 1H), 3.05 (d, 1H), 2.32 (d, 2H), 1.78-1.75 (m, 6H), 1.68 - 1.56 (m, 3H), 1.55 - 1.39 (m, 7H), 1.34 (s, 3H), 1.27 (s, 5H), 1.20 - 1.11 (m, 4H), 1.04 (d, 4H), 0.93 (s, 3H).
Example 11 : (4aR,6aS,6bR,8aS,llS,12aS,12bR,14bS)-4,4,6a,6b,8a,ll,14b-heptamethyl-ll- morpholino-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,ll,12,12a,12b,13,14b-octadecahydropicene-2- carbonitrile (compound 11)
Figure imgf000108_0001
[00325] To a solution of intermediate 3 (0.100 g, 0.216 mmol) and K2CO3 (0.090 g, 0.648 mmol) in MeCN (5 mL) was added l-bromo-2-(2-bromoethoxy)ethane (0.060 g, 0.259 mmol) at 25 °C. The reaction mixture was stirred at 90 °C for 4 h, washed with water (20 mL), and extracted with DCM (2x 10 mL). The combined organic layers were dried over Na2S04, concentrated in vacuo. The residue was purified by flash chromatography to afford compound 11 (0.040 g, 34.7%) as a white solid. LC-MS (ESI): m/z =533.5 [M+H] +. 'H NMR (400 MHz, CDCL) d 8.02 (s, 1H), 5.95 (s, 1H), 3.73 (s, 4H), 3.06 (d, 1H), 2.44-2.42 (m, 3H), 2.03 - 1.92 (m, 1H), 1.92 - 1.85 (m, 1H), 1.85 - 1.75 (m, 6H), 1.75 - 1.55 (m, 4H), 1.49 (d, 6H), 1.28 - 1.23 (m, 4H), 1.21 - 1.15 (m, 4H), 1.13 (s, 1H), 1.11 - 1.03 (m, 1H), 0.98 (t, 6H), 0.92-0.90 (m, 1H), 0.80 (s, 3H).
Example 12 : (4aR,6aS,6bR,8aS,llS,12aS,12bR,14bS)-4,4,6a,6b,8a,ll,14b-heptamethyl-3,13- dioxo- ll-(2-oxopyrrolidin-l-yl)-3,4,4a,5,6,6a,6b,7,8,8a,9,10,ll,12,12a,12b,13,14b-octadecahydropicene-2- carbonitrile (compound 12)
Figure imgf000108_0002
Step 1: 4-chloro-/V-((2S,4aS,6aR,6bS,8aR,12aS,14aR,14bS)-ll-cyano-2,4a,6a,6b,9,9,12a- heptamethyl-10,14-dioxo-l,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b-octadecahydropicen-2- yl)butanamide (12a) [00326] To a stirred solution of intermediate 3 (0.18 g, 0.18 mmol) in THF (5 mL) at 0 °C was added EtsN (0.2 g, 1.9 mmol), 4-chlorobutanoyl chloride (0.11 g, 0.78 mmol) under nitrogen. The resulting solution was stirred at room temperature for 2 hours. Upon consumption of the starting material, the reaction mixture was diluted with EtOAc and washed with brine (20 mL). The organic layer was dried (Na2SC>4), filtered and concentrated under reduced pressure. The crude product was purified by flash silica chromatography to afford 12a (0.1 g, 45%) as a white solid. LC-MS (ESI): m/z = 567.3[M+H] +.
Step 2: (4aR,6aS,6bR,8aS,llS,12aS,12bR,14bS)-4,4,6a,6b,8a,ll,14b-heptamethyl-3,13-dioxo- ll-(2- oxopyrrolidin-l-yl)-3,4,4a,5,6,6a,6b,7,8,8a,9,10,ll,12,12a,12b,13,14b-octadecahydropicene-2- carbonitrile (compound 12)
[00327] To a stirred solution of 12a (0.10 g, 0.18 mmol) in THF (5 mL) at 0 °C was added (50% w/w) NaH (21 mg, 0.88 mmol) under nitrogen. The resulting solution was stirred at room temperature for 1 hour. The reaction mixture was diluted with EtOAc and washed with brine (10 mL). The organic layer was dried over Na2S04, filtered and concentrated under reduced pressure. The crude product was purified by flash silica chromatography to afford compound 12 (24 mg, 26%) as a white solid. LC-MS (ESI): m/z = 531.4 [M+H] +. ¾ NMR (400 MHz, CDCb) d 8.03 (s, 1H), 5.98 (s, 1H), 4.06 (m, 1H), 3.28 (m, 2H), 3.11 (d, 1H), 2.49 - 2.23 (m, 2H), 2.05 - 1.77 (m, 10H), 1.67 (s, 3H), 1.58 (m, 2H), 1.50 (d, 6H), 1.39 - 1.23 (m, 8H), 1.20 (d, 3H), 1.14 (s, 3H), 1.03 - 0.94 (m, 3H).
Example 13 : (4aR,6aS,6bR,8aS,llS,12aS,12bR,14bS)-4,4,6a,6b,8a,ll,14b-heptamethyl-3,13 -dioxo- ll-(2-oxooxazolidin-3-yl)-3,4,4a,5,6,6a,6b,7,8,8a,9,10,ll,12,12a,12b,13,14b-octadecahydropicene-2- carbonitrile (compound 13)
Figure imgf000109_0001
Step 1: (2S,4aS,6aR,6bS,8aR,12aS,14aR,14bS)-ll-cyano-2,4a,6a,6b,9,9,12a-heptamethyl-10,14 - dioxo-l,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b-octadecahydropicene-2-carbonyl azide (13a)
[00328] To a solution of intermediate 1 (1.0 g, 2.0 mmol) and TEA (0.62 g, 6.0 mmol) in Toluene (20 mL) was added DPPA (0.84 g, 0.259 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 2 h, washed with water (20 mL), and extracted with EA (2x20 mL). The combined organic layers were dried over Na2S04, concentrated in vacuo. The residue was purified by flash chromatography to afford compound 13a (0.80 g, 76%) as a white solid Step 2: 2-bromoethyl ((2S,4aS,6aR,6bS,8aR,12aS,14aR,14bS)-ll-cyano-2,4a,6a,6b,9,9,12a- heptamethyl-10,14-dioxo-l,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b-octadecahydropicen-2- yl)carbamate (13b)
[00329] To a solution of 13a (0.220 g, 0.426 mmol) in Toluene (20 mL) was added 2-bromoethan-l-ol (0.213 g, 1.70 mmol) at 25 °C. The reaction mixture was stirred at 110 °C for 2 h, washed with water (20 mL), and extracted with EA (2x20 mL). The combined organic layers were dried over NaiSCL.
concentrated in vacuo. The residue was purified by flash chromatography to afford compound 13b (0.120 g, 46%) as a white solid. LC-MS (ESI): m/z =613.3 [M+H] +.
Step 3: (4aR,6aS,6bR,8aS,llS,12aS,12bR,14bS)-4,4,6a,6b,8a,ll,14b-heptamethyl-3,13-dioxo -ll-(2- oxooxazolidin-3-yl)-3,4,4a,5,6,6a,6b,7,8,8a,9,10,ll,12,12a,12b,13,14b-octadecahydropicene-2- carbonitrile (compound 13)
[00330] To a solution of 13b (0.070 g, 0.11 mmol) in THF (5 mL) was added NaH (0.02 g, 0.46 mmol) at 0 °C The reaction mixture was stirred at 25 °C for 2 h, washed with water (20 mL), and extracted with EA (2x20 mL). The combined organic layers were dried over Na2SC>4, concentrated in vacuo. The residue was purified by flash chromatography to afford compound 13 (0.025 g, 41%) as a white solid.
LC-MS (ESI): m/z =533.4 [M+H] +. ¾ NMR (400 MHz, CDCL) S 8.02 (s, 1H), 5.97 (s, 1H), 4.35 - 4.14 (m, 3H), 3.58 - 3.48 (m, 1H), 3.12 (d, 1H), 3.05-3.01 (m, 1H), 2.07 - 2.00 (m, 1H), 1.98 - 1.87 (m, 2H), 1.87 - 1.71 (m, 5H), 1.66-1.64 (m, 2H), 1.55 (s, 3H), 1.51 (s, 3H), 1.40 - 1.24 (m, 9H), 1.21 - 1.10 (m, 7H), 1.00 (m, 7H).
Example 14 : (4aR,6aS,6bR,8aR,llS,12aS,12bR,14bS)-ll-((l,3,4-oxadiazol-2-yl)methyl)-4,4, 6a,6b,8a,ll,14b-heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,ll,12,12a,12b,13,14b- octadecahydropicene-2-carbonitrile (compound 14)
Figure imgf000111_0001
Step 1: (2S,4aS,6aS,6bR,8aR,10S,12aR,14bR)-methyl-10-((tert-butyldimethylsilyl)oxy) -2, 4a, 6a, 6b,9,9,12a-heptamethyl-l,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,ll,12,12a,12b,13,14b-icosahydropicene-2- carboxylate (14b)
[00331] To a solution of 14a (10.0 g, 21.3 mmol) in DCM (500 mL) was added 2, 6-lutidine (22.8 g, 21.3 mmol) at - 60 °C for 0.5 h and added Trifluoromethanesulfonic acid tert-butyldimethylsilyl ester (28.7 g, 106.4 mmol) for another 5 h at this temperature. The mixture was diluted with EA (1000 mL), washed with water (2 c 500 mL) and brine (1 x250 mL), dried with Na2SC>4 and concentrated. The crude product was purified by flash chromatography to afford the title compound 14b (7.8 g, 63%) as a white solid. LC- MS (ESI): m/z =585.3 [M+H] +.
Step 2: ((2S,4aS,6aS,6bR,8aR,10S,12aR,14bR)-10-((tert-butyldimethylsilyl)oxy)-2,4a,6a,6b, 9,9,12a- heptamethyl-l,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,ll,12,12a,12b,13,14b-icosahydropicen-2-yl)methanol
(14c) [00332] To a solution of 14b (6.3 g, 10.6 mmol) in THF (50 mL) was added Lithium aluminium hydride (2.0 g, 53.0 mmol) at 0 °C for 3 h . The mixture was added water (2 mL) and then added sodium hydroxide (15%, 2 mL) and water (6 mL) at 0 °C. The mixture was fdtered and the fdtrate was diluted with EA (200 mL), washed with water (2x200 mL) and brine (1 ^250 mL), dried with Na2S04 and concentrated. The crude product was purified by flash chromatography to afford the title compound 14c (4 g, 70.1%) as a yellow oil. LC-MS (ESI): m/z =557.3 [M+H] +.
Step 3: ((2S,4aS,6aS,6bR,8aR,10S,12aR,14bR)-10-((tert-butyldimethylsilyl)oxy)-2,4a,6a,6b, 9,9,12a- heptamethyl-l,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,ll,12,12a,12b,13,14b-icosahydropicen-2-yl)methyl 4- methylbenzenesulfonate (14d)
[00333] To a solution of 14c (4.0 g, 7.0 mmol) in DCM (50 mL) was added tosyl chloride (2.7 g, 14.1 mmol) and triethylamine (3 mL) and DMAP (0.08 g, 0.07 mmol), then the reaction mixture was stirred for 8 h at room temperature. The reaction mixture was then poured into crashed ice, and extracted with ethyl acetate (2x 100 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel to give the compound 14d (2.7 g, 52.9%).
LC-MS (ESI): m/z =711.3 [M+H]+.
Step 4: 2-((2S,4aR,6aS,6bR,8aR,10S,12aR,14bR)-10-((tert-butyldimethylsilyl)oxy)-2,4a,6a,6b, 9,9,12a-heptamethyl-l,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,ll,12,12a,12b,13,14b-icosahydropicen-2- yl) acetonitrile (14e)
[00334] To a solution of 14d (2.7 g, 3.7 mmol) in dimethyl sulfoxide (100 mL) was added potassium cyanide (1.2 g, 18.6 mmol). The reaction mixture was heated at 120 °C for 24 h. After cooling to room temperature, the mixture was diluted with water and EtOAc. The organic layer was separated and the aqueous layer extracted with EtOAc. The combined organic layers were then washed with water and brine, dried over NazSCL, filtered, and concentrated in vacuo. The residue was purified by flash chromatography to afford 14e (1.5 g, 70%) as a yellow solid.
Step 5: 2-((2S,4aR,6aS,6bR,8aR,10S,12aR,14bR)-10-((tert-butyldimethylsilyl)oxy)-2,4a,6a,6b, 9,9,12a-heptamethyl-l,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,ll,12,12a,12b,13,14b-icosahydropicen-2- yl)acetaldehyde (14f)
[00335] To a solution of 14e (1.8 g, 3.2 mmol) in DCM (20 mL) was added Dibal (2.4 mL, 2 M, 4.8 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 6 h, quenched with saturated solution of sodium potassium tartrate, extracted with DCM (2x20 mL). The combined organic layers were dried over NazSCL, concentrated in vacuo. The residue was purified by flash chromatography to afford 14f (1.1 g, 64%) as a white solid. ¾ NMR (400 MHz, CDCL) d 9.81 (t, 1H), 5.15 (t, 1H), 3.17-3.13 (m, 1H), 2.36- 2.33 (m, 2H), 2.00-0.72 (m, 53H), 0.00 (t, 6H).
Step 6: 2-((2S,4aR,6aS,6bR,8aR,10S,12aR,14bR)-10-((tert-butyldimethylsilyl)oxy)-2,4a,6a,6b, 9,9,12a-heptamethyl-l,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,ll,12,12a,12b,13,14b-icosahydropicen-2- yl)acetic acid (14g)
[00336] To a solution of 14f (1.1 g, 2.0 mmol) in t-BuOH (10 mL) was added DCM (10 mL), ¾0 (2 mL), 2-methylbut-2-ene (0.46 g, 4.6 mmol) and NaH2P04 (0.5 g, 4.5 mmol). The mixture was added NaCICL
- I l l - (0.27g, 4.0 mmol) at 0 °C. The reaction mixture was warmed to room temperature and stirred for 3 h, quenched with water (20 mL), and extracted with DCM (2x20 mL). The combined organic layers were dried over Na2S04, concentrated in vacuo. The residue was purified by flash chromatography to afford 14g (1.0 g, 85%) as a white solid. 'H NMR (400 MHz, CDC13) d 5.21 (t, 1H), 3.21-3.17 (m, 1H), 2.41-
2.30 (m, 2H), 1.40-0.75 (m, 53H), 0.04 (t, 6H).
Step 7: methyl 2-((2S,4aR,6aS,6bR,8aR,10S,12aR,14bR)-10-hydroxy-2,4a,6a,6b,9,9,12a-hepta methyl-l,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,ll,12,12a,12b,13,14b-icosahydropicen-2-yl)acetate (14h)
[00337] To a solution of 14g (2.5 g, 4.3 mmol) in MeOH (30 mL) was added SOCL (1.0 g, 8.6 mmol). The reaction mixture was stirred at 40°C for 3 h, washed with NaHCCL (sat.aq, 30 mL) to PH = 8-9, and extracted with DCM (2x20 mL). The combined organic layers were dried over Na2SC>4, concentrated in vacuo. The residue was purified by flash chromatography to afford 14h (1.2 g, 58%) as a white solid.
¾ NMR (400 MHz, CDCL) d 5.21 (t, 1H), 3.65 (s, 3H), 3.24-3.20 (m, 1H), 2.40-2.26 (m, 2H), 1.40- 0.75 (m, 44H).
Step 8: methyl 2-((2S,4aR,6aS,6bR,8aR,12aR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-10- oxo-1,2, 3,4,4a,5,6,6a,6b,7,8,8a,9,10,ll,12,12a,12b,13,14b-icosahydropicen-2-yl)acetate (14i)
[00338] To a solution of 14h (2.0 g, 4.1 mmol) and PhF (1 mL) in DMSO (20 mL) was added IBX (4.6 g, 17.0 mmol). The reaction mixture was stirred at 85°C overnight, washed with Na2S20- (sat.aq, 30 mL), NaHCO; (sat.aq, 30 mL), and extracted with EA (2x20 mL). The combined organic layers were dried over Na2SC>4, concentrated in vacuo to afford 14i (2.0 g, crude) as a yellow oil used in next step.
Step 9: methyl 2-((2S,4aR,6aS,6bR,8aR,12aR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-10- oxo- l,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,12b,13,14b-octadecahydropicen-2-yl)acetate (14j)
[00339] To a solution of 14i (2.0 g, 4.1 mmol) and PhF (1 mL) in DMSO (20 mL) was added IBX (2.3 g, 8.2 mmol). The reaction mixture was stirred at 85°C overnight, washed with Na2S203 (sat.aq, 30 mL), NaHCO; (sat.aq, 30 mL), and extracted with EA (2x20 mL). The combined organic layers were dried over Na2S04, concentrated in vacuo. The residue was purified by flash chromatography to afford 14j (1.2 g, 60%) as a yellow oil. Ή NMR (400 MHz, CDCL) d 7.03(d, 1H), 5.80(d, 1H), 5.29(t, 1H), 3.66 (s, 3H), 2.38-2.29 (m, 2H), 1.67-0.80 (m, 40H).
Step 10: methyl 2-((2S,4aR,6aR,6bR,8aR,12aR,14aR,14bS)-2,4a,6a,6b,9,9,12a-heptamethyl- 10,14- dioxo-l,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,12b,13,14,14a,14b-icosahydropicen-2-yl)acetate (14k)
[00340] To a solution of 14j (1.2 g, 2.5 mmol) in DCM (30 mL) was added m- CPBA (0.9 g, 5.0 mmol). The reaction mixture was stirred at 30°C overnight, washed with Na2S203 (sat.aq, 30 mL), and extracted with DCM (2x20 mL). The combined organic layers were dried over Na2SC>4, concentrated in vacuo. The residue was purified by flash chromatography to afford 14k (0.95 g, 77%) as a white solid.
¾ NMR (400 MHz, CDCL) 6.93 (d, 1H), 5.83 (d, 1H), 3.73 (s, 3H), 2.85 (d, 1H), 2.45-
2.31 (m, 4H), 1.98-0.95 (m, 38H).
Step 11: methyl 2-((2S,4aR,6aR,6bS,8aR,12aR,14aR,14bS)-ll-bromo-2,4a,6a,6b,9,9,12a- heptamethyl-10,14-dioxo-l,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b-octadecahydropicen-2- yl)acetate (141) [00341] To a solution of 14k (0.5 g, 1.0 mmol) and HBr (36 mg, 0.4 mmol) in AcOH (5 mL) was added dropwise Br2 (0.37 g, 2.3 mmol). The reaction mixture was stirred at room temperature for 1.5 h, washed with Na2S2C>3 (sat.aq, 20 mL), and extracted with DCM (2x30 mL). The combined organic layers were dried over Na2S04, concentrated in vacuo. The residue was purified by flash chromatography to afford 141 (0.45 g, 78%) as a white solid. LC-MS (ESI): m/z =573.3 [M+H] +.
Step 12: methyl 2-((2S,4aR,6aR,6bS,8aR,12aS,14aR,14bS)-ll-cyano-2,4a,6a,6b,9,9,12a- heptamethyl-10,14-dioxo-l,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b-octadecahydropicen-2- yl)acetate (14m)
[00342] To a solution of 141 (0.35 g, 0.6 mmol) in DMF (5 mL) was added Na2CC>3 (0.12 g, 1.2 mmol), potassium ferrocyanide trihyrate (0.15 g, 0.4 mmol) and Pd(OAc)2 (27 mg, 0.1 mmol). The reaction mixture was stirred under N2 atmosphere at 110°C for 5 h, washed with water (20 mL), and extracted with EA (2x30 mL). The combined organic layers were dried over Na2S04, concentrated in vacuo. The residue was purified by flash chromatography to afford 14m (0.10 g, 32%) as a white solid. LC-MS (ESI): m/z =520.3 [M+H] +.
Step 13: 2-((2S,4aR,6aR,6bS,8aR,12aS,14aR,14bS)-ll-cyano-2,4a,6a,6b,9,9,12a-heptamethyl- 10,14- dioxo-l,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b-octadecahydropicen-2-yl)acetic acid (14n)
[00343] To a solution of 14m (0.27 g, 0.5 mmol) in CH3OH (3 mL), THF (3 mL) and H20 (3 mL) was added NaOH (0.21 g, 5.2 mmol). The reaction mixture was stirred at 50°C overnight, added dropwise HC1 (1 N aq.) until PH = 5-6, extracted with EA (2x30 mL). The combined organic layers were dried over Na2S04, concentrated in vacuo to afford 14n (0.26 g, 99%) as a white solid. LC-MS (ESI): m/z =506.3 [M+H] +.
Step 14: 2-((2S,4aR,6aR,6bS,8aR,12aS,14aR,14bS)-ll-cyano-2,4a,6a,6b,9,9,12a-heptamethyl -10,14- dioxo-l,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b-octadecahydropicen-2-yl)-Ar'- formylacetohydrazide (14o)
[00344] To a solution of 14n (0.26 g, 0.5 mmol) in DCM (5 mL) was added formylhydrazine (42 mg, 0.7 mmol), DIPEA (0.2 g, 1.6 mmol) and HATU (0.26 g, 0.7 mmol). The reaction mixture was stirred at room temperature overnight, washed with water (20 mL), and extracted with DCM (2x20 mL). The combined organic layers were dned over Na2S04, concentrated in vacuo. The residue was purified by flash chromatography to afford 14o (0.16 g, 55%) as a white solid. LC-MS (ESI): m/z =548.4 [M+H] +.
Step 15: (4aR,6aS,6bR,8aR,llS,12aS,12bR,14bS)-ll-((l,3,4-oxadiazol-2-yl)methyl)-4,4,
6a,6b,8a,ll,14b-heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,ll,12,12a,12b,13,14b- octadecahydropicene-2-carbonitrile (compound 14)
[00345] To a solution of 14o (0.16 g, 0.3 mmol) in CH3CN (5 mL) was added DIPEA (0.11 g, 0.9 mmol) and TsCl (0.17 g, 0.9 mmol). The reaction mixture was stirred at room temperature for 2 h, washed with water (20 mL), and extracted with EA (2x20 mL). The combined organic layers were dried over Na2SC>4, concentrated in vacuo. The residue was purified by HPLC to afford compound 14 (23 mg, 15%) as a white solid. LC-MS (ESI): m/z =530.3 [M+H] +. ¾ NMR (400 MHz, CDCL) S 8.40 (s, 1H), 8.03 (s, 1H), 5.99 (s, 1H), 3.17-3.11 (m, 2H), 2.89- 2.86 (m, 1H), 2.28-2.23 (m, 1H), 2.25-0.97 (m, 36H). Example 15 : (4aR,6aS,6bR,8aS,llS,12aS,12bR,14bS)-4,4,6a,6b,8a,ll,14b-heptamethyl-ll-(3- methyl-l,2,4-oxadiazol-5-yl)-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,ll,12,12a,12b,13,14b- octadecahydropicene-2-carbonitrile (compound 15)
Figure imgf000115_0001
Step 1: (2S,4aS,6aR,6bS,8aR,12aS,14aR,14bS)-ll-cyano-A-(( )-l-(hydroxyiinino)ethyl)-2,4a,6a, 6b,9,9,12a-heptamethyl-10,14-dioxo-l,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b- octadecahydropicene-2-carboxamide (15a)
[00346] To a stirred solution of intermediate 1 (0.50 g, 1.00 mmol), HATU (0.50 g, 1.20 mmol)and N'- hydroxyacetamidine (0.10 g, 2.0 mmol) in DCM (10 mL) at room temperature was added DIPEA (0.4 g, 3.0 mmol) under nitrogen. The resulting solution was stirred at room temperature overnight. Upon consumption of the starting material, the reaction mixture was diluted with EtOAc and washed with brine (20 mU). The organic layer was dried (NazSCL), filtered and concentrated under reduced pressure. The crude product was purified by flash silica chromatography to afford 15a (0.75 g, 100%) as a white solid. LC-MS (ESI): m/z = 548.4 [M+H] +.
Step 2: (4aR,6aS,6bR,8aS,llS,12aS,12bR,14bS)-4,4,6a,6b,8a,ll,14b-heptamethyl-ll-(3-methyl - l,2,4-oxadiazol-5-yl)-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,ll,12,12a,12b,13,14b- octadecahydropicene-2-carbonitrile (compound 15)
[00347] To a solution of 15a (0.70 g, 1.3 mmol) in toluene (13.5 mL) was added EtOAc (1.5 mL). The reaction mixture was stirred at l20°C for 4 h, and concentrated under reduced pressure. The crude product was purified by flash silica chromatography to afford compound 15 (100 mg, 15%) as a white solid. LC- MS (ESI): m/z = 530.3 [M+H] +. ¾ NMR (400 MHz, CDCL) d 8.06 (s, 1H), 6.04 (s, 1H), 3.08 (d, 1H), 2.54 - 2.34 (m, 4H), 2.20 (m, 1H), 2.07 (m, 1H), 2.00 - 1.67 (m, 6H), 1.64 - 1.34 (m, 11H), 1.28 (m, 6H), 1.20 - 1.10 (m, 4H), 1.09 - 0.95 (m, 4H), 0.91 (s, 3H).
Example 16 : (4aR,6aS,6bR,8aS,llS,12aS,12bR,14bS)-ll-(5-cyclopropyl-l,3,4-oxadiazol-2-yl) - 4,4,6a,6b,8a,ll,14b-heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,ll,12,12a,12b,13,14b- octadecahydropicene-2-carbonitrile (compound 16)
Figure imgf000115_0002
[00348] The title compound was prepared by the method substantially similar to that mentioned in compound 9, using cyclopropanecarbohydrazide to afford compound 16 as a white solid. LC-MS (ESI): m/z =556.4 [M+H] +. ¾ NMR (400 MHz, CDCE) d 8.03 (s, 1H), 6.03 (s, 1 H), 3.03 (d, 1H), 2.28 (m, 3H), 1.99 -1.65 (m, 8H), 1.63-1.44 (m, 10H), 1.38 (d, 1H), 1.30-1.09 (m, 13H), 1.00 (d, 4H), 0.90 (s, 3H).
Example 17 : (4aR,6aS,6bR,8aS,llS,12aS,12bR,14bS)-4,4,6a,6b,8a,ll,14b-heptamethyl-3,13 -dioxo- ll-(4H-l,2,4-triazol-4-yl)-3,4,4a,5,6,6a,6b,7,8,8a,9,10,ll,12,12a,12b,13,14b-octadecahydropicene-2- carbonitrile (compound 17)
Figure imgf000116_0001
[00349] To a solution of Triethoxymethane (0.080 g, 0.54 mmol) and formohydrazide (0.032 g, 0.54 mmol) in MeOH (5 mL) was added intermediate 3 (50 mg, 0.1 lmmol). The reaction mixture was stirred at 80 °C for 20 h, washed with water (20 mL), and extracted with DCM (2* 10 mL). The combined organic layers were dried over Na2SC>4, concentrated in vacuo. The residue was purified by flash chromatography to afford compound 17 (0.023 g, 41%) as a white solid. LC-MS (ESI): m/z =515.4 [M+H] +. 1 H NMR (400 MHz, CDC13) d 9.47 (s, 2H), 8.04 (s, 1H), 6.08 (s, 1H), 3.15 (d, 1H), 2.51 (d, 1H), 2.41 (d, 1H), 2.00 (s, 1H), 2.00 - 1.71 (m, 9H), 1.62 (d, 1H), 1.54 (d, 9H), 1.27 (d, 4H), 1.20 (s, 4H), 1.13 (d, 1H), 1.03 (s, 3H), 0.90 (d, 3H).
Example 18 : (4aR,6aS,6bR,8aS,llS,12aS,12bR,14bS)-ll-(2,5-dioxopyrrolidin-l-yl)-4,4,6a,6b, 8a,ll,14b-heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,ll,12,12a,12b,13,14b- octadecahydropicene-2-carbonitrile (compound 18)
Figure imgf000116_0002
[00350] A solution of intermediate 3 (100 mg, 0.21 mmol) in o-xylene (10 mL) was heated to 150°C. The resulting solution was stirred at 150°C for 7 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The crude product was purified by flash silica chromatography to afford compound 18 (12 mg, 10 %) as a white solid. LC-MS (ESI): m/z = 545.3[M+H] +. ¾ NMR (400 MHz, CDCE) d 8.03 (s, 1H), 6.06 (s, 1H), 3.09 (t, 3H), 2.77 - 2.65 (m, 3H), 2.63 - 2.51 (m, 4H),
1.85 (m, 6H), 1.58 (d, 1H), 1.46 (t, 6H), 1.41 - 1.30 (m, 5H), 1.25 (d, 4H), 1.21 - 1.09 (m, 4H), 1.00 (t, 6H). Example 19: 5-((2S,4aS,6aR,6bS,8aR,12aS,14aR,14bS)-ll-cyano-2,4a,6a,6b,9,9,12a-heptameth yl- 10,14-dioxo-l,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b-octadecahydropicen-2-yl)-/V-cyclopropyl- l,3,4-oxadiazole-2-carboxamide (compound 19)
Figure imgf000117_0001
Step 1: methyl2-(2-((2S,4aS,6aR,6bS,8aR,12aS,14aR,14bS)-ll-cyano-2,4a,6a,6b,9,9,12a- heptamethyl-10,14-dioxo-l,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b-octadecahydropicene-2- carbonyl)hydrazineyl)-2-oxoacetate (19a)
[00351] To a solution of 10a (0.25 g, 0.49 mmol) and TEA (0.15 g, 1.5 mmol) in DCM (10 mL) was added methyl 2-chloro-2-oxoacetate (0.13 g, 0.99 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 2 h, washed with water (20 mL), and extracted with DCM (2x20 mL). The combined organic layers were concentrated in vacuo. The residue was used to next step directly.
Step 2: methyl 5-((2S,4aS,6aR,6bS,8aR,12aS,14aR,14bS)-ll-cyano-2,4a,6a,6b,9,9,12a-heptamethyl- 10,14-dioxo-l,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b-octadecahydropicen-2-yl)-l,3,4- oxadiazole-2-carboxylate (19b)
[00352] To a solution of 19a (0.28 g, 0.47 mmol) and N1,N1,N6,N6-tetramethylhexane-l, 6-diamine (0.16 g, 0.94 mmol) in DCM (10 mL) was added 4-methylbenzenesulfonyl chloride (0.18 g, 0.94 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 16 h, washed with water (20 mL), and extracted with DCM (2x20 mL). The combined organic layers were concentrated in vacuo. The residue was used to next step directly. LC-MS (ESI): m/z =574.3 [M+H] +.
Step 3: 5-((2S,4aS,6aR,6bS,8aR,12aS,14aR,14bS)-ll-cyano-2,4a,6a,6b,9,9,12a-heptamethyl- 10,14- dioxo-l,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b-octadecahydropicen-2-yl)-/V-cyclopropyl-l,3,4- oxadiazole-2-carboxamide (compound 19)
[00353] To a solution of 19b (0.20 g, 0.35 mmol) in MeOH (5 mL) was added cyclopropanamine (0.030 g, 0.52 mmol) at 25 °C. The reaction mixture was stirred at 85 °C for 4 h, washed with water (20 mL), and extracted with DCM (2x20 mL). The combined organic layers were dried over Na2S04, concentrated in vacuo. The residue was purified by flash chromatography to afford compound 19 (0.012 g, 5.7%) as a white solid. LC-MS (ESI): m/z =599.4 [M+H] +. ¾ NMR (400 MHz, CDCh) d 8.07 (s, 1H), 7.55 (d, 1H), 6.03 (s, 1H), 3.07 - 2.97 (m, 2H), 2.41 - 2.23 (m, 2H), 1.99 - 1.69 (m, 8H), 1.67 - 1.55 (m, 4H), 1.55 - 1.45 (m, 6H), 1.45 - 1.36 (m, 1H), 1.35 - 1.23 (m, 6H), 1.22 - 1.10 (m, 4H), 1.02 (d, 4H), 0.95 - 0.86 (m, 4H), 0.82 - 0.72 (m, 2H).
Example 20: (4aR,6aS,6bR,8aS,llS,12aS,12bR,14bS)-ll-(3-hydroxypyrrolidin-l-yl)-4,4,6a,6b, 8a,ll,14b-heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,ll,12,12a,12b,13,14b- octadecahydropicene-2-carbonitrile (compound 20)
Figure imgf000118_0001
[00354] To a solution of intermediate 3 (0.25 g, 0.54 mmol) in CLLCN (10 mL) was added 1,4- dibromobutan-2-ol (0.25 g, 1.08 mmol), potassium bicarbonateat (0.27 g, 2.70 mmol). The reaction mixture was heated to reflux for 7 h, after cooling to room temperature, the reaction mixture washed with water (20 mL), and extracted with DCM (2x20 mL). The combined organic layers were dried over NazSCL, concentrated in vacuo. The residue was purified by flash chromatography to afford compound 20 (20 mg, 6.9%) as a white solid. LC-MS (ESI): m/z =533.3 [M+H] +.
Example 21: (4aR,6aS,6bR,8aS,llS,12aS,12bR,14bS)-4,4,6a,6b,8a,ll,14b-heptamethyl-3,13- dioxo- ll-(pyrrolidin-l-yl)-3,4,4a,5,6,6a,6b,7,8,8a,9,10,ll,12,12a,12b,13,14b-octadecahydropicene-2- carbonitrile (compound 21)
Figure imgf000118_0002
[00355] The title compound was prepared by the method substantially similar to that mentioned in compound 20, using l,4-dibromobutane to afford compound 21 (19 mg, 5.7%) as a white solid. LC-MS (ESI): m/z =517.4 [M+H] +.
Example 23: (4aR,6aS,6bR,8aS,llS,12aS,12bR,14bS)-ll-(5-((S)-l-hydroxyethyl)-l,3,4- oxadiazol-2- yl)-4,4,6a,6b,8a,ll,14b-heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,ll,12,12a,12b,13,14b- octadecahydropicene-2-carbonitrile (compound 23)
Figure imgf000119_0001
Step 1: (S)-l-(5-((2S,4aS,6aR,6bS,8aR,12aS,14aR,14bS)-ll-cyano-2,4a,6a,6b,9,9,12a- heptamethyl- 10,14-dioxo-l,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b-octadecahydropicen-2-yl)-l,3,4- oxadiazol-2-yl)ethyl acetate (23a)
[00356] 23a was prepared by the method substantially similar to that mentioned in compound 1, using (S)-2-acetoxypropanoic acid to afford compound 23a (62 mg, 62%) as a white solid.
LC-MS (ESI): m/z =602.4 [M+H] +.
Step 2: (4aR,6aS,6bR,8aS,llS,12aS,12bR,14bS)-ll-(5-((S)-l-hydroxyethyl)-l,3,4-oxadiazol -2-yl)- 4,4,6a,6b,8a,ll,14b-heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,ll,12,12a,12b,13,14b- octadecahydropicene-2-carbonitrile (compound 23)
[00357] To a solution of 23a (62 mg, 0.10 mmol) in MeOH (5mL), ¾0 (1 mL) was added Potassium hydroxide (1 lm g, 0.19 mmol). The reaction mixture was stirred at room temperature for 4 h. the reaction mixture washed with water (20 mL), and extracted with DCM (2x20 mL). The combined organic layers were dried over Na SO-. concentrated in vacuo. The residue was purified by flash chromatography to afford compound 23 (18 mg, 32.3%) as a white solid. LC-MS (ESI): m/z =560.3 [M+H] +.
Example 24 : 5-((2S,4aS,6aR,6bS,8aR,12aS,14aR,14bS)-ll-cyano-2,4a,6a,6b,9,9,12a- heptamethyl- 10,14-dioxo-l,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b-octadecahydropicen-2-yl)-N-methyl- l,3,4-oxadiazole-2-carboxamide (compound 24)
Figure imgf000119_0002
[00358] To a solution of 19b (0.05 g, 0.087 mmol) in MeOH (2 mL) was added methanamine (0.011 g, 0.35 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 4 h, washed with water (10 mL), and extracted with DCM (2x 10 mL). The combined organic layers were dried over Na2S04, concentrated in vacuo. The residue was purified by flash chromatography to afford compound 24 (3.0 mg, 6.0%) as a white solid. LC-MS (ESI): m/z =573.3 [M+H]+. ¾ NMR (400 MHz, CDCL) d 8.07 (s, 1H), 7.52 (d, 1H), 6.07 (s, 1H), 3.08 (t, 3H), 2.38 (d, 1H), 2.34 - 2.26 (m, 1H), 1.97 - 1.72 (m, 8H), 1.64-1.60 (m, , 4H), 1.56 - 1.50 (m, 4H), 1.48 (s, 3H), 1.45 - 1.39 (m, 1H), 1.33 (s, 3H), 1.28 (s, 3H), 1.19 (s, 3H), 1.16 (d, 1H), 1.06 - 1.01 (m, 3H), 0.90 (d, 3H). Example 25 : 5-((2S,4aS,6aR,6bS,8aR,12aS,14aR,14bS)-ll-cyano-2,4a,6a,6b,9,9,12a- heptamethyl- 10,14-dioxo-l,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b-octadecahydropicen-2-yl)-l,3,4- oxadiazole-2-carboxamide (compound 25)
Figure imgf000120_0001
Step 1: 2-(2-((2S,4aS,6aR,6bS,8aR,12aS,14aR,14bS)-ll-cyano-2,4a,6a,6b,9,9,12a- heptamethyl- 10,14-dioxo-l,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b-octadecahydropicene-2- carbonyl)hydrazinyl)-2-oxoacetamide (25a)
[00359] To a solution of intermediate 1 (0.100 g, 0.203 mmol), HATU(0.093 g, 0.244 mmol) and DIPEA (0.080 g, 0.61 mmol) in DCM (10 mL) was added 2-hydrazinyl-2-oxoacetamide (0.031g, 0.305 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 2 h, washed with water (20 mL), and extracted with DCM (2x20 mL). The combined organic layers were concentrated in vacuo. The residue was used to next step directly.
Step 2: 5-((2S,4aS,6aR,6bS,8aR,12aS,14aR,14bS)-ll-cyano-2,4a,6a,6b,9,9,12a- heptamethyl-10,14- dioxo-l,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b-octadecahydropicen-2-yl)-l,3,4-oxadiazole-2- carboxamide (25)
[00360] To a solution of 25a (0.10 g, 0.17 mmol) and N1,N1,N6,N6-tetramethylhexane-l, 6-diamine (0.059 g, 0.35 mmol) in DCM (5 mL) was added 4-methylbenzenesulfonyl chloride (0.66 g, 0.35 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 16 h, washed with water (20 mL), extracted with DCM (2x20 mL). The combined organic layers were concentrated in vacuo. The residue was purified by flash chromatography to afford compound 25 (0.030 g, 31%) as a white solid. LC-MS (ESI): m/z =559.4 [M+H]+. ¾NMR (400 MHz, CDC13) d 8.07 (s, 1H), 7.54 (s, 1H), 6.40 (s, 1H), 6.09 (s, 1H), 3.07 (d, 1H), 2.38-2.32 (m, 2H), 1.92-1.88 (m, 3H), 1.85 - 1.73 (m, 4H), 1.64-1.60 (m, 4H), 1.53 (d, J = 6.2 Hz, 3H), 1.48 (s, 3H), 1.44 - 1.38 (m, 1H), 1.34 (s, 3H), 1.27 (s, 3H), 1.20 - 1.13 (m, 4H), 1.04 (d, 4H), 0.91 (s, 3H).
Example 26 : (4aR,6aS,6bR,8aS,llS,12aS,14bS)-ll-(3-hydroxyazetidin-l-yl)-4,4, 6a,6b,8a,ll,14b- heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,ll,12,12a,12b,13,14b-octadecahydropicene-2- carbonitrile(compound 26)
Figure imgf000121_0001
[00361] To a solution of intermediate 3 (50 mg, 0.11 mmol) in i-PrOH (2 mL) was added 2-(chloro methyl)oxirane (11 mg, 0.1 1 mmol). The reaction mixture was stirred at 50 °C overnight and concentrated in vacuo. The residue was added CH3CN (5 mL), Et3N (27 mg, 0.27 mmol). The reaction mixture was refluxed for 4 h. The reaction mixture was washed with water (20 mL), extracted with DCM (2x20 mL). The combined organic layers were dried over Na2S04, concentrated in vacuo. The residue was purified by flash chromatography to afford compound 26 (16 mg, 34.3%) as a white solid. LC-MS (ESI): m/z =519.4 [M+H] +. ¾ NMR (400 MHz, CDC13) d 8.06 (s, 1H), 6.03 (s, 1H), 4.64 - 3.80 (m, 5H), 3.14 (s, 1H), 2.19 (d, 2H), 2.09 - 0.75 (m, 35H).
Example 27 : (4aR,6aS,6bR,8aS,llS,12aS,12bR,14bS)-ll-(5-amino-l,3,4-oxadiazol-2-yl)-4,4, 6a,6b,8a,ll,14b-heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,ll,12,12a,12b,13,14b- octadecahydropicene-2-carbonitrile (compound 27)
Figure imgf000121_0002
[00362] To a solution of 10a (50 mg, 0.10 mmol) in MeOH (2 mL) was added cyanogen bromide (21 mg, 0.20 mmol). The reaction mixture was stirred at room temperature overnight and washed with water (20 mL), extracted with DCM (2x20 mL). The combined organic layers were dried over NaiSCL. concentrated in vacuo. The residue was purified by flash chromatography to afford compound 27 (2.7 mg, 5.1%) as a white solid. LC-MS (ESI): m/z =531.3 [M+H] +. ¾ NMR (400 MHz, CDC13) d 8.02 (s, 1H), 5.99 (s, 1H), 3.07 (m, 1H), 1.82 (m, 8H), 1.67 - 1.37 (m, 10H), 1.39 - 1.23 (m, 9H), 1.21 - 1.09 (m, 4H), 1.01 (m, 6H).
Example A: Nitric Oxide Assays
Nitric Oxide Assay
[00363] Raw 264.7 cells were seeded in 96-well plates at a density of 30, 000 cells per well in
DMEM+10%FBS and incubated overnight. The next day, cell media was replaced by DMEM+2%FBS. Cells were pretreated with DMSO or test compounds (top dose lOOnM, 1:4 serial dilution, 10-point) for 2 hours and then treated with recombinant mouse IFNy (R&D, Cat# 485 -MI- 100) at a final concentration of lOng/ml for 24 hours. Nitrite levels were measured in culture media as a surrogate for nitric oxide using the Griess Reagent System (Promega, Cat# G2930). Cell viability was determined using CellTiter Glo reagents (Promega, Cat#G7572). The nitrite levels were adjusted to live cell numbers and inhibition percentage was calculated. The inhibition percentage was then plotted against compound concentration, and IC50 values were calculated using four-parameter algorithm in Graphpad Prism.
NQOl activity assay
[00364] Raw264.7 cells were seeded in DMEM+10%FBS in 96-well plates at a density of 10, 000 cells per well. 6 hours after plating, cells were treated with DMSO or test compounds (top dose lOOnM, 1:4 serial dilution, 8-point) for 48 hours. NQOl activity was then detected in cell lysates using NQOl activity assay kit (Abeam, Cat#abl84867). NQOl activity was then plotted against compound concentration, and EC50 values were calculated using four-parameter algorithm in Graphpad Prism.
Figure imgf000122_0001
A < 10 nM
10 nM < B < 100 nM
100 nM < C < 1 mM
Example B: CYP450 enzyme inhibition:
[00365] The inhibition potential of test compounds towards major drug metabolizing CYP450 enzymes was studied in liver microsomes of CD-I mouse, Sprague Dawley rat, Beagle dog, cynomolgus monkey, and human. The inhibition of CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 was assessed using CYP450 specific probe reactions in a cocktail incubation. Seven concentrations of test compounds (0.05, 0.15, 0.5, 1.5, 5, 15, and 50mM) were evaluated. In addition, known inhibitors for each probe reaction were included as positive controls and incubated at a single concentration above their respective IC50. The IC50 data (in nM) for each test compound in each species were summarized in the following table.
Figure imgf000123_0001
Example C: Metabolic Stability of Test Compounds in Mouse, Rat, Dog, Monkey, and Human Liver Microsomes:
[00366] The metabolic stability of test compounds was examined in CD-I mouse, Sprague Dawley rat, Beagle dog, cynomolgus monkey, and human liver microsomes. Test compound (final concentration 1 mM) was mixed with diluted liver microsomes from each of the 5 species and a small aliquot was taken at 0, 5, 10, 20, 30, and 60 minutes for LC/MS/MS analysis. Intrinsic clearance and half-life were calculated.
Figure imgf000123_0002
Figure imgf000124_0001
Figure imgf000124_0002
Example D: Pharmacokinetic studies in Sprague Dawley rats:
[00367] The pharmacokinetics oftest compounds was evaluated in male SD rats when administered via oral gavage and IV injection. For oral dosing, compound was formulated in 0.5% methylcellulose and administered at doses of 5 mg/kg (3 rats per dose level) and volume of 10 mL/kg. For IV dosing, compound was formulated in 5% DMSO/5% Solutol/90% saline and administered to 3 rats at a dose of 1 mg/kg and a volume of 5 mL/kg. The rats were fasted overnight before administration. Plasma samples were collected predose and at 0.5, 1, 3, 6, 9, 12, and 24 hours postdose. The samples were analyzed by LC/MS/MS and the concentration of test compound at each timepoint was determined by linear regression. Pharmacokinetic parameters were calculated from the plasma concentrations using Pheonix
WinNonlin. The PK results were summarized in the following table.
Figure imgf000124_0003
Figure imgf000125_0001
Example E: Pharmaceutical Compositions
Example El: Parenteral Composition
[00368] To prepare a parenteral pharmaceutical composition suitable for administration by injection, 100 mg of a water-soluble salt of a compound described herein is dissolved in DMSO and then mixed with 10 mL of 0.9% sterile saline. The mixture is incorporated into a dosage unit form suitable for administration by injection.
Example E2: Oral Composition
[00369] To prepare a pharmaceutical composition for oral delivery, 100 mg of a compound described herein is mixed with 750 mg of starch. The mixture is incorporated into an oral dosage unit for, such as a hard gelatin capsule, which is suitable for oral administration.
Example E3: Sublingual (Hard Lozenge) Composition
[00370] To prepare a pharmaceutical composition for buccal delivery, such as a hard lozenge, mix 100 mg of a compound described herein, with 420 mg of powdered sugar mixed, with 1.6 mL of light com syrup, 2.4 mL distilled water, and 0.42 mL mint extract. The mixture is gently blended and poured into a mold to form a lozenge suitable for buccal administration.
[00371] 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 compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure imgf000126_0001
Formula (III);
wherein:
R1 is hydrogen, deuterium, halogen, -CN, -ORb, -NRcRd, -NRbS(=0)2Ra, -C(=0)Ra, -C(=0)0Rb, - C(=0)NRcRd, C -C , alkyl, C2-CV, alkenyl, C2-G, alkynyl, C -Ck, haloalkyl, C -C , deuteroalkyl, Ci- C(, hydroxyalkyl, Ci-Ce aminoalkyl, or C -C heteroalkyl;
R3 is N-linked heterocycloalkyl, N-linked heteroaryl, -P(=0)(R4)2, -P(=0)(0R5)2, -B(OR5)2, - R5, -
Figure imgf000126_0002
-cycloalkyl, -Z-O- heterocycloalkyl, -Z-O-aryl, -Z-O-heteroaryl, -Z-NR5-cycloalkyl, -Z -NR5 -heterocycloalkyl, -Z- NR5-aryl, -Z -NR5 -heteroaryl, -Y(Ci-C6alkylene)S(=0)R4, -Y(Ci-C6alkylene)S(=0)2R4, -Y(Ci-
Figure imgf000126_0003
C6alkenylene)cycloalkyl, -Y(C2-C6alkenylene)heterocycloalkyl, -Y(C2-C6alkenylene)aryl, -Y(C2- G>alkcnylcnc)hctcroaryl. -(Ci-C5alkylene)0P(=0)(0R5)2, -(C i -G,alkylcnc)0(C i - C ,alkylcnc)0P(=0)(0R5)2. or -(Ci-C6alkylene)0P(=0)(0R5)[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(=0)Ra, -C(=0)0Rb, - C(=0)NRcRd, C i -C(, alkyl, C2-G, alkenyl, C2-C(, alkynyl, C i -C(, haloalkyl, C i -C , deuteroalkyl, Ci- C , hydroxyalkyl, C i -C aminoalkyl, or C -C heteroalkyl;
Y is a bond, -0-, -S-, or -NRb-;
Z is a bond or Ci-C , alkylene: Rx is hydrogen, -NO2, -CN, or -S(=0)2Ra;
each R4 is independently C1-G5 alkyl, Cri-G, alkenyl, C2-C6 alkynyl, Ci-C<5 haloalkyl, Ci-Ce
deuteroalkyl, Ci-Ce hydroxyalkyl, C 1 -G, aminoalkyl, C 1 -G, 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(=0)Ra, -C(=0)0Rb, - C(=0)NRcRd, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C1-C deuteroalkyl, G- G, hydroxyalkyl, Ci-Ce aminoalkyl, Ci-Ce heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R5 is independently hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, G-G, alkynyl, C 1 -G, haloalkyl, C 1 -G, deuteroalkyl, Ci-Ce hydroxyalkyl, Ci-Ce aminoalkyl, Ci-Ce 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(=0)Ra, -C(=0)0Rb, - C(=0)NRcRd, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1 -G, haloalkyl, Ci-Ce deuteroalkyl, Ci- C e hydroxyalkyl, Ci-Ce aminoalkyl, Ci-Ce heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R6 and R7 is independently hydrogen, Ci-Ce alkyl, G-Ce alkenyl, G-Ce alkynyl, C 1 -G, haloalkyl, Ci-Ce deuteroalkyl, G-G hydroxyalkyl, C 1 -G, aminoalkyl, C 1 -G, 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(=0)Ra, -C(=0)0Rb, - C(=0)NRcRd, C 1 -C(, alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1 -G, haloalkyl, C 1 -G, deuteroalkyl, G- G, hydroxyalkyl, C 1 -G, aminoalkyl, C 1 -G, 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(=0)Ra, -C(=0)0Rb, - C(=0)NRcRd, C 1 -C(, alkyl, G-G alkenyl, G-G alkynyl, C 1 -G, haloalkyl, C 1 -C, deuteroalkyl, G- G, hydroxyalkyl, C 1 -G, aminoalkyl, C 1 -G, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
X O OH
1S JL or ;
R8 is hydrogen, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=0)Ra, -C(=0)0Rb, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1 -G, haloalkyl, or C 1 -Co, deuteroalkyl; R9 is Ci-C<5 alkyl, C2-C6 alkenyl, C2-G5 alkynyl, C 1 -G> haloalkyl, or C 1 -G> deuteroalkyl;
R10 is C 1 -G, alkyl, C2-C6 alkenyl, G-G, alkynyl, C 1 -C , haloalkyl, or C 1 -G, deuteroalkyl;
R11 is hydrogen, deuterium, halogen, or -ORb;
or R3 and R1 1 are taken together to form an optionally substituted cycloalkyl or an optionally
substituted heterocycloalkyl;
R12 and R13 are independently hydrogen, -ORb, -NRcRd, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci- C haloalkyl, C 1 -G, deuteroalkyl, C1-C6 hydroxyalkyl, C 1 -C,, aminoalkyl, or C1-C 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(=0)Ra, -C(=0)0Rb, -
C(=0)NRcRd, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-C6 haloalkyl, G-G, deuteroalkyl, Ci- G, hydroxyalkyl, C1-C6 aminoalkyl, C 1 -G, heteroalkyl, cycloalkyl, or heterocycloalkyl;
R15 and R16 are independently hydrogen, -ORb, -NRcRd, C 1 -G, alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci- G, haloalkyl, C 1 -G, deuteroalkyl, C1-C6 hydroxyalkyl, C 1 -C,, aminoalkyl, or C 1 -G, 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(=0)Ra, -C(=0)ORb, -
C(=0)NRcRd, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1 -G, haloalkyl, Ci-Ce deuteroalkyl, Ci- G, hydroxyalkyl, C1-C6 aminoalkyl, C 1 -G, heteroalkyl, cycloalkyl, or heterocycloalkyl;
each Ra is independently C1-G5 alkyl, G-G, alkenyl, CG-Cr, alkynyl, C 1 -CV> haloalkyl, G-G
deuteroalkyl, G-G hydroxyalkyl, C 1 -G, aminoalkyl, C 1 -G, 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 C 1 -G, alkyl;
each Rb is independently hydrogen, C 1 -G, alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1 -G, haloalkyl, G-G deuteroalkyl, C 1 -G, hydroxyalkyl, C 1 -G, aminoalkyl, C 1 -G, 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 G-G, alkyl; and
each Rc and Rd is independently hydrogen, G-G alkyl, C2-C6 alkenyl, G-G alkynyl, C 1 -G, haloalkyl, C 1 -G, deuteroalkyl, G-G hydroxyalkyl, C 1 -G, aminoalkyl, C 1 -G, 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 C 1 -G, 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 G-G alkyl.
2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: R1 is -CN, Ci-Ce alkyl, C i -G, haloalkyl, or Ci-Ce deuteroalkyl.
3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
R1 is -CN.
4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt, solvate, or
stereoisomer thereof, wherein:
R8 is hydrogen or deuterium.
5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt, solvate, or
stereoisomer thereof, wherein:
R8 is hydrogen.
6 The compound of any one of claims 1-5, or a pharmaceutically acceptable salt, solvate, or
stereoisomer thereof, wherein:
R9 is Ci-Ce alkyl.
7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt, solvate, or
stereoisomer thereof, wherein:
R10 is Ci-Ce alkyl.
8 The compound of any one of claims 1-7, or a pharmaceutically acceptable salt, solvate, or
stereoisomer thereof, wherein:
Figure imgf000129_0001
9. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, solvate, or
stereoisomer thereof, wherein:
R11 is hydrogen.
10 The compound of any one of claims 1-9, or a pharmaceutically acceptable salt, solvate, or
stereoisomer thereof, wherein:
R12 and R13 are independently hydrogen, Ci-Ce alkyl, or Ci-C<5 deuteroalkyl.
11 The compound of any one of claims 1-10, or a pharmaceutically acceptable salt, solvate, or
stereoisomer thereof, wherein:
R12 and R13 are independently Ci-Ce alkyl.
12 The compound of any one of claims 1-11, or a pharmaceutically acceptable salt, solvate, or
stereoisomer thereof, wherein:
R15 and R16 are independently hydrogen, Ci-Ce alkyl, or C1-C6 deuteroalkyl.
13. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt, solvate, or
stereoisomer thereof, wherein:
R15 and R16 are independently Ci-Ce alkyl.
14 The compound of any one of claims 1-13, or a pharmaceutically acceptable salt, solvate, or
stereoisomer thereof, wherein:
R3 is -P(=0)(R4)2, -P(=0)(0R5)2, -Y(Ci-C6alkylene)P(=0)(R4)2, -Y(Ci-C6alkylene)P(=0)(0R5)2, - B(OR5)2, -Y(Ci-C6alkylene)B(OR5)2, -S(=0)R4, -S(=0)2R4, -Y(Ci-C6alkylene)S(=0)R4, -Y(Ci- C6alkylene)S(=0)2R4, -NR5C(=NRX)R5, -NR5C(=NRX)NR6R7, -Y(Ci-C6alkylene)NR5C(=NRx)R5, -Y(Ci-C6alkylene)NR5C(=NRx)NR6R7, -NR5C(=0)(Ci-C6alkylene)S(=NRx)NR6R7, - NR5C(=0)(Ci-C6alkylene)S(=NRx)R5, -S(=0)(=NRx)R5, -S(=0)(=NRx)NR6R7, - NR5S(=0)2NR5C(=0)R5, -NR5S(=0)(=NRX)R5, -Y(Ci-C6alkylene)S(=0)(=NRx)R5, -Y(Ci- C6alkylene)S(=0)(=NRx)NR6R7, -Y(Ci-C6alkylene)NR5S(=0)2NR5C(=0)R5, -Y(Ci- C6alkylene)NR5S(=0)(=NRx)R5, a N-linked heterocycloalkyl, or a N-linked heteroaryl.
15. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt, solvate, or
stereoisomer thereof, wherein:
R3 is -P(=0)(R4)2, -P(=0)(0R5)2, -Y(Ci-C6alkylene)P(=0)(R4)2, -Y(Ci-C6alkylene)P(=0)(0R5)2, - B(OR5)2, -Y(Ci-C6alkylene)B(OR5)2, -S(=0)R4, -S(=0)2R4, -Y(Ci-C6alkylene)S(=0)R4, -Y(Ci- C6alkylene)S(=0)2R4, -NR5C(=NRX)R5, -NR5C(=NRX)NR6R7, -Y(Ci-C6alkylene)NR5C(=NRx)R5, -Y( C i -Cealky lene)NR5 C (=NRX)NR6R7, -S(=0)(=NRx)R5, -S(=0)(=NRx)NR6R7, - NR5S(=0)2NR5C(=0)R5, -NR5S(=0)(=NRX)R5, -Y(Ci-C6alkylene)S(=0)(=NRx)R5, -Y(Ci- C6alkylene)S(=0)(=NRx)NR6R7, -Y(Ci-C6alkylene)NR5S(=0)2NR5C(=0)R5, -Y(Ci- C6alkylene)NR5S(=0)(=NRx)R5, a N-linked heterocycloalkyl, or a N-linked heteroaryl.
16. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt, solvate, or
stereoisomer thereof, wherein:
R3 is -P(=0)(R4)2, -P(=0)(0R5)2, -Y(Ci-C6alkylene)P(=0)(R4)2, or -Y(Ci- C6alkylene)P(=0)(0R5)2.
17. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt, solvate, or
stereoisomer thereof, wherein:
R3 is -B(OR5)2 or -Y(Ci-C6alkylene)B(OR5)2.
18. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt, solvate, or
stereoisomer thereof, wherein:
R3 is -S(=0)R4, -S(=0)2R4, -Y(Ci-C6alkylene)S(=0)R4, or -Y(Ci-C6alkylene)S(=0)2R4.
19. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt, solvate, or
stereoisomer thereof, wherein:
Figure imgf000130_0001
20. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt, solvate, or
stereoisomer thereof, wherein:
R3 is -Y(Ci-C6alkylene)NR5C(=NRx)R5 or -Y(Ci-C6alkylene)NR5C(=NRx)NR6R7.
21. The compound of any one of claims 1 - 13 , or a pharmaceutically acceptable salt, solvate , or
stereoisomer thereof, wherein:
Figure imgf000130_0002
22. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt, solvate, or
stereoisomer thereof, wherein: R3 is -NR5 C(=0)(C i - alkylene) S (=NRX)NR6R7 or -NR5C(=0)(G-C6alkylene)S(=NRx)R5.
23. The compound 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 compound of any one of claims 1-21, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
Y is a bond.
25. The compound of any one of claims 1-24, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
Rx is -CN.
26. The compound of any one of claims 1-25, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
each R4 is independently Ci-Ce alkyl, C i -G, haloalkyl, or C i -G, deuteroalkyl.
27. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
each R5 is independently hydrogen, Ci-G alkyl, C i-G, haloalkyl, or Ci-G, deuteroalkyl.
28. The compound 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 compound of any one of claims 1-28, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
each R6 and R7 is independently hydrogen, G-G alkyl, C i -G, haloalkyl, or C i -G, deuteroalkyl.
30. The compound of any one of claim 1, or a pharmaceutically acceptable salt, solvate, or
stereoisomer thereof, wherein the compound is:
Figure imgf000131_0001
Figure imgf000132_0001
Figure imgf000133_0001
Figure imgf000134_0001
31. A compound of Formula (VIII), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure imgf000134_0002
Formula (VIII);
wherein:
R1 is hydrogen, deuterium, halogen, -CN, -ORb, -NRcRd, -NRbS(=0)2Ra, -C(=0)Ra, -C(=0)0Rb, -
C(=0)NRcRd, C i -G, alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C i -G, haloalkyl, C i -G, deuteroalkyl, C1-C6 hydroxyalkyl, C i -G, aminoalkyl, or Ci-Ce heteroalkyl;
R3 is halogen, -CN, -OR5, -SR5, -S(=0)R4, -S(=0)2R4, -N02, -NR6R7, -S(=0)2NR¾7, -C(=0)R4, -
Figure imgf000134_0004
haloalkyl, Ci-Ce deuteroalkyl, C i -G, hydroxyalkyl, C i -G, aminoalkyl, C i -G, 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(=0)R4, -S(=0)2R4, -N02, -NR6R7,
Figure imgf000134_0003
S(=0)(=NRx)NR>R7, -NR5S(=0)2NR5C(=0)R5, -NR5S(=0)(=NRX)R5, G-G alkyl, G-G alkenyl, C2- C5 alkynyl, G-G haloalkyl, C 1 -G, deuteroalkyl, G-G hydroxyalkyl, C 1 -G, aminoalkyl, G-G 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(=0)Ra, -C(=0)0Rb, -C(=0)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, G-G haloalkyl, C 1 -G deuteroalkyl, G-G hydroxyalkyl, C1-C6 aminoalkyl, G-G heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
Rx is hydrogen, -N02, -CN, or -S(=0)2Ra;
each R4 is independently C 1 -G, alkyl, C2-G, alkenyl, C2-C , alkynyl, G-G haloalkyl, C i-G, deuteroalkyl, C1-C6 hydroxyalkyl, G-G aminoalkyl, C 1 -G, 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(=0)Ra, -C(=0)0Rb, -
C(=0)NRcRd, -NRbC(=NRx)Rb, -NRbC(=NRx)NRcRd, -S(=0)(=NRx)Rb, -S(=0)(=NRx)NRcRd, G-G alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1 -G, haloalkyl, G-G deuteroalkyl, C 1 -CV, hydroxyalkyl, C 1 -G, aminoalkyl, C 1 -G, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R5 is independently hydrogen, G-G alkyl, G-G alkenyl, G-G, alkynyl, C 1 -G, haloalkyl, C 1 -G, deuteroalkyl, C 1 -G, hydroxyalkyl, G-G aminoalkyl, C 1 -G, 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(=0)Ra, -C(=0)0Rb, -
C(=0)NRcRd, -NRbC(=NRx)Rb, -NRbC(=NRx)NRcRd, -S(=0)(=NRx)Rb, -S(=0)(=NRx)NRcRd, Ci-C6 alkyl, G-G, alkenyl, G-G, alkynyl, C 1 -G, haloalkyl, C 1 -G deuteroalkyl, C 1 -G, hydroxyalkyl, C 1 -G, aminoalkyl, C 1 -G, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R6 and R7 is independently hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, G-G alkynyl, C 1 -G, haloalkyl, G- G deuteroalkyl, C 1 -G, hydroxyalkyl, C1-C6 aminoalkyl, C 1 -G, 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 Rba is independently oxo, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=0)Ra, -C(=0)0Rb, -
C(=0)NRcRd, -NRbC(=NRx)Rb, -NRbC(=NRx)NRcRd, -S(=0)(=NRx)Rb, -S(=0)(=NRx)NRcRd, Ci-C6 alkyl, G-G, alkenyl, G-G, alkynyl, C 1 -G, haloalkyl, C 1 -G, deuteroalkyl, C 1 -G, hydroxyalkyl, C 1 -G, aminoalkyl, C 1 -G, 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(=0)Ra, -C(=0)0Rb, -
C(=0)NRcRd, C 1 -G, alkyl, C2-C6 alkenyl, C2-C6 alkynyl, G-G haloalkyl, G-G deuteroalkyl, G-G hydroxyalkyl, C 1 -G, aminoalkyl, C 1 -G, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; X O OH
-1L is JL or JL ;
Y1 and Y2 are independently hydrogen, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=0)Ra, -C(=0)0Rb, - C(=0)NRcRd, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, Ci-C6 deuteroalkyl, C , -CY, hydroxyalkyl, Ci-Ce aminoalkyl, or C 1 -CY-, heteroalkyl;
R8 is hydrogen, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=0)Ra, -C(=0)0Rb, Ci-Ce alkyl, CY-CY, alkenyl, CY-CY, alkynyl, C 1 -CY, haloalkyl, or C 1 -CY, deuteroalkyl;
R9 is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1 -CY, haloalkyl, or C’ 1 -CY, deuteroalkyl;
R10 is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1 -CY, haloalkyl, or C 1 -CY, 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, C 1 -CY, alkyl, CY-CY, alkenyl, C2-G, alkynyl, C -G, haloalkyl, Ci- C(5 deuteroalkyl, C 1 -CY, hydroxyalkyl, Ci-Ce aminoalkyl, Ci-Ce heteroalkyl, cycloalkyl,
heterocycloalkyl, aryl, or heteroaryl;
R13 is -CN, -OR19, -S(=O)2NR20R21, -0C(=0)R18, -0C(=0)0R19, -OC(=O)NR20R21, -NR19C(=0)0R19,
C1-C6 deuteroalkyl, C i -CY, hydroxyalkyl, C1-C6 aminoalkyl, Ci-Ce 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(=0)R18, -S(=0)2R18, -N02, - NR20R21, -S(-0)2NR2,IR21. -C(-0)R18. -0C(=0)R18, -C(=0)0R19, -0C(=0)0R19, -C(=O)NR20R21, - OC(=O)NR20R21, -NR19C(=0)0R19, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-C6 haloalkyl, CY-CY, deuteroalkyl, Ci-Ce hydroxyalkyl, C i -CY, aminoalkyl, Ci-Ce heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R18 is independently Ci-Cs alkyl, CY-CY, alkenyl, G-G alkynyl, C i -CY, haloalkyl, C i -CY, deuteroalkyl, C1-C6 hydroxyalkyl, Ci-Ce aminoalkyl, C 1 -G, 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(=0)Ra, -C(=0)0Rb, -
C(=0)NRcRd, C 1 -CY, alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1 -G, haloalkyl, C 1 -CY, deuteroalkyl, C1-C6 hydroxyalkyl, C 1 -CY, aminoalkyl, C 1 -G, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R19 is independently hydrogen, Ci-Ce alkyl, CY-CY, alkenyl, C2-C6 alkynyl, C 1 -CY, haloalkyl, Ci-Ce deuteroalkyl, Ci-Ce hydroxyalkyl, Ci-Ce aminoalkyl, C 1 -CY, 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(=0)Ra, -C(=0)0Rb, -
C(=0)NRcRd, C 1 -CY, alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 1 -CY, haloalkyl, C 1 -CY, deuteroalkyl, Ci-Ce hydroxyalkyl, C 1 -CY, aminoalkyl, C 1 -CY, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R20 and R21 are independently hydrogen, C i -G, alkyl, G-G alkenyl, G-G alkynyl, G-G haloalkyl, G-G deuteroalkyl, C 1 -G hydroxyalkyl, G-G aminoalkyl, G-G 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(=0)Ra, -C(=0)0Rb, -
C(=0)NRcRd, C 1 -G, alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1 -G, haloalkyl, G-G deuteroalkyl, C 1 -G, hydroxyalkyl, C 1 -G aminoalkyl, C 1 -G 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(=0)Ra, -C(=0)0Rb, -
C(=0)NRcRd, G-G alkyl, G-G alkenyl, C2-C6 alkynyl, G-G haloalkyl, Ci-C6 deuteroalkyl, G-G, hydroxyalkyl, G-G aminoalkyl, C 1 -G, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R15 and R16 are independently hydrogen, -ORb, -NRcRd, G-G alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1 -G haloalkyl, G-G deuteroalkyl, C 1 -C,, hydroxyalkyl, G-G aminoalkyl, or C 1 -G 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(=0)Ra, -C(=0)0Rb, -C(=0)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1 -G, haloalkyl, C 1 -G, deuteroalkyl, C i-G, hydroxyalkyl, C1-C6 aminoalkyl, C 1 -G, heteroalkyl, cycloalkyl, or heterocycloalkyl;
each Ra is independently C 1 -G, alkyl, C2-C6 alkenyl, C2-C6 alkynyl, G-G haloalkyl, C 1 -G, deuteroalkyl, G-G hydroxyalkyl, G-G aminoalkyl, C 1 -G, 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, C 1 -G, alkyl, G-G, alkenyl, G-G, alkynyl, C 1 -G, haloalkyl, C 1 -G, deuteroalkyl, C 1 -G, hydroxyalkyl, C 1 -G, aminoalkyl, C 1 -G, 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 G- G alkyl; and
each Rc and Rd is independently hydrogen, C 1 -G, alkyl, G-G alkenyl, G-G alkynyl, G-G, haloalkyl, G- G deuteroalkyl, G-G hydroxyalkyl, G-G aminoalkyl, G-G, 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 G-G 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 G- G alkyl.
32. The compound of claim 31, or a pharmaceutically acceptable salt, solvate, or stereoisomer
thereof, wherein:
R1 is -CN, G-G alkyl, G-G haloalkyl, or G-G deuteroalkyl.
33. The compound of claim 31 or 32, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
R1 is -CN.
34. The compound of any one of claims 31-33, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
R8 is hydrogen.
35. The compound of any one of claims 31-34, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
R9 is Ci-Ce alkyl.
36. The compound of any one of claims 31-35, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
R10 is Ci-Ce alkyl.
37. The compound of any one of claims 31-36, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
Figure imgf000138_0001
38. The compound of any one of claims 31-37, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
Y1 and Y2 are hydrogen.
39. The compound of any one of claims 31-38, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
R11 is hydrogen, halogen, or -OH.
40. The compound of any one of claims 31-39, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
R11 is hydrogen.
41. The compound of any one of claims 31-40, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
R12 is hydrogen, Ci-Ce alkyl, or C1-C6 deuteroalkyl.
42. The compound of any one of claims 31-41, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
R12 is Ci-Ce alkyl.
43. The compound of any one of claims 31-42, 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.
44. The compound of any one of claims 31-43, 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.
45. The compound of any one of claims 31-44, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
R13 is heteroaryl optionally substituted with one, two, or three R13a.
46. The compound of any one of claims 31-45, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
R13 is heterocycloalkyl optionally substituted with one, two, or three R13a.
47. The compound of any one of claims 31-46, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
each R13a is independently oxo, -OR19, -NR20R21, -C(=0)R18, -C(=0)0R19, -C(=O)NR20R21, Ci-C6 alkyl, Ci-Ce haloalkyl, Ci-Ce deuteroalkyl, C i -G, hydroxyalkyl, Ci-Ce aminoalkyl, C i -G> heteroalkyl, or aryl.
48. The compound of any one of claims 31-47, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
each R13a is independently oxo, -OR19, -NR20R21, -C(=O)NR20R21, Ci-Ce alkyl, C i -G> haloalkyl, Ci-Ce hydroxyalkyl, or aryl.
49. The compound of any one of claims 31-48, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
each R13a is independently -OR19, -NR20R21, or -C(=O)NR20R21.
50. The compound of any one of claims 31-49, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
R15 and R16 are independently hydrogen, Ci-Ce alkyl, or G-G, deuteroalkyl.
51. The compound of any one of claims 31-50, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
R15 and R16 are independently C i -G, alkyl.
52. The compound of any one of claims 31-51, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
R3 is G-G alkyl or -C(=0)OR5.
53. The compound of any one of claims 31-52, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
R3 is Ci-Ce alkyl.
54. The compound of claim 31, or a pharmaceutically acceptable salt, solvate, or stereoisomer
thereof, wherein the compound is:
Figure imgf000140_0001
Figure imgf000141_0001
55. A pharmaceutical composition comprising a therapeutically effective amount of the compound of any one of claims 1-54, and a pharmaceutically acceptable excipient.
56. A method for treating a disease in a mammal comprising administering to the mammal a
therapeutically effective amount of the compound of any one of claims 1-54, or the
pharmaceutical composition of claim 55.
57. The methof of claim 56, wherein the disease is an inflammatory disease.
58. The methof of claim 56, wherein the disease is diabetic nephropathy or chronic kidney disease.
59. The methof of claim 56, wherein the disease is chronic obstructive pulmonary disease (COPD) or inflammatory bowel disease (IBD).
60. The methof of claim 56, wherein the disease is nonalcoholic steatohepatitis (NASH).
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021127480A1 (en) * 2019-12-19 2021-06-24 Reata Pharmaceuticals, Inc. Synthetic triterpenoids with nitrogen-based substituents at c-17 and methods of use thereof
WO2022126129A1 (en) * 2020-12-11 2022-06-16 Reata Pharmaceuticals, Inc. Synthetic triterpenoids for use in therapy
WO2022155614A1 (en) * 2021-01-18 2022-07-21 Reata Pharmaceuticals, Inc. Synthetic ursolic acid derivatives and methods of use thereof

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009129546A1 (en) * 2008-04-18 2009-10-22 Reata Pharmaceuticals, Inc. Antioxidant inflammation modulators: oleanolic acid derivatives with amino and other modifications at c-17
US20120238767A1 (en) * 2008-04-18 2012-09-20 Xin Jiang Antioxidant inflammation modulators: novel derivatives of oleanolic acid
WO2014040056A1 (en) * 2012-09-10 2014-03-13 Reata Pharmaceuticals, Inc. C17-heteroaryl derivatives of oleanolic acid and methods of use thereof
US20150080465A1 (en) * 2013-08-23 2015-03-19 Reata Pharmaceuticals, Inc. Methods of treating and preventing endothelial dysfunction using bardoxolone methyl or analogs thereof
US20150148384A1 (en) * 2012-06-15 2015-05-28 Reata Pharmaceuticals, Inc. A-ring epoxidized triterpenoid-based anti-inflammation modulators and methods of use thereof

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103619866B (en) * 2011-03-11 2016-06-22 里亚塔医药公司 The derivant of C4-monomethyl triterpenoid and using method thereof
US20140073700A1 (en) * 2012-09-10 2014-03-13 Abbvie Inc. Glycyrrhetinic acid derivatives and methods of use thereof

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009129546A1 (en) * 2008-04-18 2009-10-22 Reata Pharmaceuticals, Inc. Antioxidant inflammation modulators: oleanolic acid derivatives with amino and other modifications at c-17
US20120238767A1 (en) * 2008-04-18 2012-09-20 Xin Jiang Antioxidant inflammation modulators: novel derivatives of oleanolic acid
US20150148384A1 (en) * 2012-06-15 2015-05-28 Reata Pharmaceuticals, Inc. A-ring epoxidized triterpenoid-based anti-inflammation modulators and methods of use thereof
WO2014040056A1 (en) * 2012-09-10 2014-03-13 Reata Pharmaceuticals, Inc. C17-heteroaryl derivatives of oleanolic acid and methods of use thereof
US20150080465A1 (en) * 2013-08-23 2015-03-19 Reata Pharmaceuticals, Inc. Methods of treating and preventing endothelial dysfunction using bardoxolone methyl or analogs thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP3856755A4 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021127480A1 (en) * 2019-12-19 2021-06-24 Reata Pharmaceuticals, Inc. Synthetic triterpenoids with nitrogen-based substituents at c-17 and methods of use thereof
WO2022126129A1 (en) * 2020-12-11 2022-06-16 Reata Pharmaceuticals, Inc. Synthetic triterpenoids for use in therapy
WO2022155614A1 (en) * 2021-01-18 2022-07-21 Reata Pharmaceuticals, Inc. Synthetic ursolic acid derivatives and methods of use thereof

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