WO2020157069A1 - Composés amino hétérocycliques et leurs utilisations - Google Patents

Composés amino hétérocycliques et leurs utilisations Download PDF

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WO2020157069A1
WO2020157069A1 PCT/EP2020/052053 EP2020052053W WO2020157069A1 WO 2020157069 A1 WO2020157069 A1 WO 2020157069A1 EP 2020052053 W EP2020052053 W EP 2020052053W WO 2020157069 A1 WO2020157069 A1 WO 2020157069A1
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optionally substituted
alkyl
compound
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David Harrison
Roderick Alan Porter
Jane E. SCANLON
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Nodthera Ltd
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Nodthera Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/10—Anti-acne agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D249/14—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
    • C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
    • C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D251/14—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom
    • C07D251/22—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom to two ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D261/18—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/48—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/10—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
    • C07D271/113—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen

Definitions

  • the present disclosure relates to amino heterocyclic derivatives, prodrugs, and pharmaceutically acceptable salts thereof, which may possess inflammasome inhibitory activity and are accordingly useful in methods of treatment of the human or animal body.
  • the present disclosure also relates to processes for the preparation of these compounds, to pharmaceutical compositions comprising them and to their use in the treatment of disorders in which
  • inflammasome activity is implicated, such as inflammatory, autoinflammatory, autoimmune and oncological diseases.
  • IL-1 interleukin-1
  • monocytes monocytes
  • fibroblasts and other components of the innate immune system like dendritic cells.
  • IL-1 is involved in a variety of cellular activities, including cell proliferation, differentiation and apoptosis (Seth L. al. Rev. Immunol. 2009. 27:621-68).
  • NLR proteins are divided into four NLR subfamilies according to their N- terminal domains.
  • NLRA contains a CARD-AT domain
  • NLRB contains a BIR domain
  • NLRC contains a CARD domain
  • NLRP contains a pyrin domain.
  • Multiple NLR family members are associated with inflammasome formation.
  • inflammasome activation appears to have evolved as an important component of host immunity to pathogens, the NLRP3 inflammasome is unique in its ability activate in response to endogenous sterile danger signals. Many such sterile signals have been elucidated, and their formation is associated with specific disease states. For example, uric acid crystals found in gout patients are effective triggers of NLRP3 activation. Similarly, cholesterol crystals found in atherosclerotic patients can also promote NLRP3 activation. Recognition of the role of sterile danger signals as NLRP3 activators led to IL-1 and IL-18 being implicated in a diverse range of pathophysiological indications including metabolic, physiologic, inflammatory, hematologic and immunologic disorders. [005] The disclosure arises from a need to provide further compounds for the specific modulation of NLRP3 -dependent cellular processes. In particular, compounds with improved physicochemical, pharmacological and pharmaceutical properties to existing compounds are desirable.
  • the present disclosure provides, inter alia , a compound of Formula (I):
  • X is O or N 4;
  • Ri is C3-C16 cycloalkyl or C5-C10 aryl, wherein the C3-C16 cycloalkyl or C5-C10 aryl is optionally substituted with one or more Ris; wherein each Ris is independently C1-C6 alkyl, Ci- Ce haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or halo;
  • R2 is 5- to 10-membered heteroaryl or 4- to 8-membered heterocycloalkyl, wherein the 5- to 10-membered heteroaryl or 4- to 8-membered heterocycloalkyl is optionally substituted with one or more C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, Ci- Ce haloalkoxy, halo, -CN, -OH, -NH2, -NH(CI-C 6 alkyl), -N(CI-C 6 alkyl)2, oxo, -C(0)R2S, - C(0)OR2S, or -C(0)N(R2S) 2 ;
  • each R 2 S is independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, or 4- to 8-membered heterocycloalkyl;
  • R3 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C7 cycloalkyl; wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C7 cycloalkyl is optionally substituted with one or more C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C7 cycloalkyl, halo, -CN, -OH, -NH2, -NH(CI-C6 alkyl), -N(CI-C6 alkyl)2, or oxo; and
  • Ri is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl; wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C7 cycloalkyl is optionally substituted with one or more C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C7 cycloalkyl, halo, -CN, -OH, -NH2, -NH(Ci-C6 alkyl), -N(CI-C 6 alkyl)2, or oxo.
  • the present disclosure provides, inter alia , a compound of Formula (F):
  • Ri is C3-C1 6 cycloalkyl or C5-C1 0 aryl, wherein the C3-C1 6 cycloalkyl or C5-C1 0 aryl is optionally substituted with one or more Ris; wherein each Ris is independently C1-C 6 alkyl, Ci- Ce haloalkyl, C1-C 6 alkoxy, C1-C 6 haloalkoxy, or halo;
  • R2 is 5- to 10-membered heteroaryl or 4- to 8-membered heterocycloalkyl, wherein the 5- to 10-membered heteroaryl or 4- to 8-membered heterocycloalkyl is optionally substituted with one or more C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, Ci- Ce haloalkoxy, halo, -CN, -OH, -NH2, -NH(CI-C 6 alkyl), -N(CI-C 6 alkyl)2, oxo, -C(0)R2S, - C(0)0R2S, or -C(0)N(R2S) 2 ;
  • each R 2S is independently H, C1-C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, C 3 -C7 cycloalkyl, or 4- to 8-membered heterocycloalkyl;
  • R3 is H, C1-C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, or C 3 -C7 cycloalkyl; wherein C1-C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, or C 3 -C7 cycloalkyl is optionally substituted with one or more C1-C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, C1-C 6 haloalkyl, C1-C 6 alkoxy, C1-C 6 haloalkoxy, C 3 -C7 cycloalkyl, halo, -CN, -OH, -NH2, -NH(CI-C6 alkyl), -N(CI-C6 alkyl)2, or oxo.
  • the present disclosure provides a compound obtainable by, or obtained by, a method for preparing a compound as described herein.
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.
  • the present disclosure provides an intermediate as described herein, being suitable for use in a method for preparing a compound as described herein (e.g., the intermediate is selected from the intermediates described in Examples 1-9).
  • the present disclosure provides a method of inhibiting inflammasome (e.g., the NLRP3 inflammasome) activity (e.g., in vitro or in vivo), comprising contacting a cell with an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof.
  • inflammasome e.g., the NLRP3 inflammasome
  • a pharmaceutically acceptable salt thereof e.g., in vitro or in vivo
  • the present disclosure provides a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.
  • the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in inhibiting inflammasome (e.g., the NLRP3 inflammasome) activity (e.g., in vitro or in vivo).
  • inflammasome e.g., the NLRP3 inflammasome
  • activity e.g., in vitro or in vivo.
  • the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating or preventing a disease or disorder disclosed herein.
  • the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for inhibiting inflammasome (e.g., the NLRP3 inflammasome) activity (e.g., in vitro or in vivo).
  • inflammasome e.g., the NLRP3 inflammasome
  • activity e.g., in vitro or in vivo.
  • the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.
  • the present disclosure provides a method of preparing a compound of the present disclosure.
  • the present disclosure provides a method of preparing a compound, comprising one or more steps described herein.
  • IL-1 interleukin-1
  • monocytes monocytes
  • fibroblasts and other components of the innate immune system like dendritic cells, involved in a variety of cellular activities, including cell proliferation, differentiation and apoptosis (Seth L. al. Rev. Immunol. 2009. 27:621-68).
  • Cytokines from the IL-1 family are highly active and, as important mediators of inflammation, primarily associated with acute and chronic inflammation (Sims J. et al. Nature Reviews Immunology 10, 89-102 (February 2010)).
  • the overproduction of IL-1 is considered to be a mediator of some autoimmune and autoinflammatory diseases.
  • Autoinflammatory diseases are characterised by recurrent and unprovoked inflammation in the absence of autoantibodies, infection, or antigen-specific T lymphocytes.
  • Proinflammatory cytokines of the IL-1 superfamily include IL-1 a, IL-Ib, IL-18, and IL- 36a, b, l and are produced in response to pathogens and other cellular stressors as part of a host innate immune response. Unlike many other secreted cytokines, which are processed and released via the standard cellular secretory apparatus consisting of the endoplasmic reticulum and Golgi apparatus, IL-1 family members lack leader sequences required for endoplasmic reticulum entry and thus are retained intracellularly following translation. In addition, IL-Ib, IL- 18, and IL-36a, b, l are synthesised as procytokines that require proteolytic activation to become optimal ligands for binding to their cognate receptors on target cells.
  • an inflammasome is responsible for activating the proforms of IL-1 b and IL- 18 and for release of these cytokines extracellularly.
  • An inflammasome complex typically consists of a sensor molecule, such as an NLR (Nucleotide-Oligerimisation Domain (NOD)-like receptor), an adaptor molecule ASC (Apoptosis-associated speck-like protein containing a CARD (Caspase Recruitment Domain)) and procaspase-1.
  • NLR Nucleotide-Oligerimisation Domain
  • ASC Apoptosis-associated speck-like protein containing a CARD (Caspase Recruitment Domain)
  • PAMPs pathogen-associated molecule patterns
  • DAMPs danger associated molecular patterns
  • PAMPs include molecules such as peptidoglycan, viral DNA or RNA and bacterial DNA or RNA.
  • DAMPs consist of a wide range of endogenous or exogenous sterile triggers including monosodium urate crystals, silica, alum, asbestos, fatty acids, ceramides, cholesterol crystals and aggregates of beta-amyloid peptide.
  • inflammasome sensors detecting and responding to specific molecular danger signals.
  • NLR proteins are divided into four NLR subfamilies according to their N- terminal domains.
  • NLRA contains a CARD-AT domain
  • NLRB contains a BIR domain
  • NLRC contains a CARD domain
  • NLRP contains a pyrin domain.
  • Multiple NLR family members are associated with inflammasome formation including NLRPl, NLRP3, NLRP6, NLRP7, NLRP12 and NLRC4 (IPAF).
  • active caspase-1 In addition to proteolytic activation of pro-IL-Ib and pro-IL-18, active caspase-1 also triggers a form of inflammatory cell death known as pyroptosis through cleavage of gasdermin- D. Pyroptosis allows the mature forms of IL-Ib and IL-18 to be externalised along with release of alarmin molecules (compounds that promote inflammation and activate innate and adaptive immunity) such as high mobility group box 1 protein (HMGB1), IL-33, and IL-la.
  • HMGB1 high mobility group box 1 protein
  • IL-33 interleukin-33
  • IL-la interleukin-la
  • uric acid crystals found in gout patients are effective triggers of NLRP3 activation.
  • cholesterol crystals found in atherosclerotic patients can also promote NLRP3 activation.
  • IL-Ib and IL-18 Recognition of the role of sterile danger signals as NLRP3 activators led to IL-Ib and IL-18 being implicated in a diverse range of pathophysiological indications including metabolic, physiologic, inflammatory, hematologic and immunologic disorders.
  • a link to human disease is best exemplified by discovery that mutations in the NLRP3 gene which lead to gain-of-function confer a range of autoinflammatory conditions collectively known as cryopyrin-associated periodic syndromes (CAPS) including familial cold
  • NLRP3 autoinflammatory syndrome
  • MFS Muckle-Wells syndrome
  • NOMID Neonatal onset multisystem inflammatory disease
  • sterile mediator-induced activation of NLRP3 has been implicated in a wide range of disorders including joint degeneration (gout, rheumatoid arthritis, osteoarthritis), cardiometabolic (type 2 diabetes, atherosclerosis, hypertension), Central Nervous System (Alzheimer’s Disease, Parkinson’s disease, multiple sclerosis), gastrointestinal (Crohn’s disease, ulcerative colitis), lung (chronic obstructive pulmonary disease (COPD), asthma, idiopathic pulmonary fibrosis) and liver (fibrosis, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis (NASH)). It is further believed that NLRP3 activation promotes kidney inflammation and thus contributes to chronic kidney disease (CKD).
  • CKD chronic kidney disease
  • IL-1 receptor antagonists anakinra
  • canakinumab is licensed for CAPS, Tumor Necrosis Factor Receptor Associated Periodic Syndrome (TRAPS),
  • Hyperimmunoglobulin D Syndrome HIDS/Mevalonate Kinase Deficiency (MKD), Familial Mediterranean Fever (FMF) and gout.
  • HIDS Hyperimmunoglobulin D Syndrome
  • MKD Mevalonate Kinase Deficiency
  • FMF Familial Mediterranean Fever
  • Glyburide for example, is a specific inhibitor of NLRP3 activation, albeit at micromolar concentrations which are unlikely attainable in vivo.
  • Non-specific agents such as parthenolide, Bay 11-7082, and 3, 4-methyl enedioxy-P-nitrostyrene are reported to impair NLRP3 activation but are expected to possess limited therapeutic utility due to their sharing of a common structural feature consisting of an olefin activated by substitution with an electron withdrawing group; this can lead to undesirable formation of covalent adducts with protein bearing thiol groups.
  • a number of natural products for example b-hydroxybutyrate,
  • sulforaphane, quercetin, and salvianolic acid also are reported to suppress NLRP3 activation.
  • effectors/modulators of other molecular targets have been reported to impair NLRP3 activation including agonists of the G-protein coupled receptor TGR5, an inhibitor of sodium-glucose co-transport epigliflozin, the dopamine receptor antagonist A-68930, the serotonin reuptake inhibitor fluoxetine, fenamate non-steroidal anti-inflammatory drugs, and the b-adrenergic receptor blocker nebivolol. Utility of these molecules as therapeutics for the chronic treatment of NLRP3 -dependent inflammatory disorders remains to be established.
  • the disclosure relates to compounds useful for the specific modulation of NLRP3- dependent cellular processes.
  • compounds with improved physicochemical, pharmacological and pharmaceutical properties to existing NLRP3 -modulating compounds are desired.
  • “alkyl”,“Ci, C 2, C 3 , C 4 , Cs or Ce alkyl” or“Ci-C e alkyl” is intended to include Ci, C2, C 3 , Cr, C5 or Ce straight chain (linear) saturated aliphatic hydrocarbon groups and C3, C 4 , C5 or Ce branched saturated aliphatic hydrocarbon groups.
  • C r C 6 alkyl is intends to include C C 2 , C 3 , C 4 , C 5 and C 6 alkyl groups.
  • alkyl examples include, moieties having from one to six carbon atoms, such as, but not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl or n-hexyl.
  • a straight chain or branched alkyl has six or fewer carbon atoms (e.g ., C1-C6 for straight chain, C3-C6 for branched chain), and in another embodiment, a straight chain or branched alkyl has four or fewer carbon atoms.
  • the term“optionally substituted alkyl” refers to unsubstituted alkyl or alkyl having designated substituents replacing one or more hydrogen atoms on one or more carbons of the hydrocarbon backbone.
  • substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino), acylamino
  • alkylsulphinyl sulphonato, sulphamoyl, sulphonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.
  • alkenyl includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double bond.
  • alkenyl includes straight chain alkenyl groups (e.g ., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl), and branched alkenyl groups.
  • a straight chain or branched alkenyl group has six or fewer carbon atoms in its backbone (e.g ., C2-C6 for straight chain, C3-C6 for branched chain).
  • C2-C6 includes alkenyl groups containing two to six carbon atoms.
  • C3-C6 includes alkenyl groups containing three to six carbon atoms.
  • optionally substituted alkenyl refers to unsubstituted alkenyl or alkenyl having designated substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms.
  • substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,
  • aryloxycarbonyloxy carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulphydryl, alkylthio, arylthio, thiocarboxylate, sulphates, alkylsulphinyl, sulphonato, sulphamoyl, sulphonamido, nitro, trifluoromethyl, cyano, heterocyclyl, alkylaryl, or
  • alkynyl includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one triple bond.
  • “alkynyl” includes straight chain alkynyl groups (e.g ., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl), and branched alkynyl groups.
  • a straight chain or branched alkynyl group has six or fewer carbon atoms in its backbone (e.g ., Cri-O, for straight chain, C3-C6 for branched chain).
  • C2-C6 includes alkynyl groups containing two to six carbon atoms.
  • the term“C3- C6” includes alkynyl groups containing three to six carbon atoms.
  • “C2-C6 alkenylene linker” or“C2-C6 alkynylene linker” is intended to include C2, C3, C4, C5 or Ce chain (linear or branched) divalent unsaturated aliphatic hydrocarbon groups.
  • C 2 -C 6 alkenylene linker is intended to include C2, C3, C4, C5 and Ce alkenylene linker groups.
  • optionally substituted alkynyl refers to unsubstituted alkynyl or alkynyl having designated substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms.
  • substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,
  • aryloxycarbonyloxy carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulphydryl, alkylthio, arylthio, thiocarboxylate, sulphates,
  • alkylsulphinyl sulphonato, sulphamoyl, sulphonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.
  • optionally substituted moieties include both the unsubstituted moieties and the moieties having one or more of the designated substituents.
  • substituted heterocycloalkyl includes those substituted with one or more alkyl groups, such as 2,2,6,6-tetramethyl-piperidinyl and 2,2,6,6-tetramethyl-l,2,3,6-tetrahydropyridinyl.
  • cycloalkyl refers to a saturated or partially unsaturated hydrocarbon monocyclic or polycyclic (e.g., fused, bridged, or spiro rings) system having 3 to 30 carbon atoms (e.g., C3-C12, C3-C10, or C3-C8).
  • cycloalkyl examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,2,3,4-tetrahydronaphthalenyl, and adamantyl.
  • polycyclic cycloalkyl only one of the rings in the cycloalkyl needs to be non aromatic.
  • the cycloalkyl is hexahydroindacenyl.
  • cycloalkyl is hexahydroindacenyl.
  • heterocycloalkyl refers to a saturated or partially unsaturated 3-8 membered monocyclic, 7-12 membered bicyclic (fused, bridged, or spiro rings), or 11-14 membered tricyclic ring system (fused, bridged, or spiro rings) having one or more heteroatoms (such as O, N, S, P, or Se), e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or e.g. , 1, 2, 3, 4, 5, or 6 heteroatoms, independently selected from the group consisting of nitrogen, oxygen and sulphur, unless specified otherwise.
  • heteroatoms such as O, N, S, P, or Se
  • heterocycloalkyl groups include, but are not limited to, piperidinyl, piperazinyl, pyrrolidinyl, dioxanyl, tetrahydrofuranyl, isoindolinyl, indolinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, oxiranyl, azetidinyl, oxetanyl, thietanyl, 1,2,3,6-tetrahydropyridinyl, tetrahydropyranyl, dihydropyranyl, pyranyl, morpholinyl, tetrahydrothiopyranyl, 1,4-diazepanyl, 1,4-oxazepanyl, 2-oxa-5- azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-o
  • aryl includes groups with aromaticity, including
  • aryl includes both monovalent species and divalent species. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl and the like. Conveniently, an aryl is phenyl.
  • heteroaryl is intended to include a stable 5- or 6-membered monocyclic or 8-, 9-, 10-, 11- or 12-membered bicyclic aromatic heterocyclic ring which consists of carbon atoms and one or more heteroatoms, e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or e.g. , 1, 2, 3, 4, 5, or 6 heteroatoms, independently selected from the group consisting of nitrogen, oxygen and sulphur.
  • the nitrogen atom may be substituted or
  • N and NR unsubstituted
  • R is H or other substituents, as defined.
  • heteroaryl groups examples include pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, 1,3,4-oxadiazole, 4/7- 1,2, 4-triazole, pyridine, pyrazine, pyridazine, pyrimidine, 1,3,5-triazine, and the like.
  • Heteroaryl groups can also be fused or bridged with alicyclic or heterocyclic rings, which are not aromatic so as to form a multicyclic system (e.g., 4,5,6,7-tetrahydrobenzo[c]isoxazolyl).
  • aryl and“heteroaryl” include multicyclic aryl and heteroaryl groups, e.g., tricyclic, bicyclic, e.g., naphthalene, benzoxazole, benzodi oxazole, benzothiazole, benzoimidazole, benzothiophene, quinoline, isoquinoline, naphthrydine, indole, benzofuran, purine, benzofuran, deazapurine, indolizine.
  • multicyclic aryl and heteroaryl groups e.g., tricyclic, bicyclic, e.g., naphthalene, benzoxazole, benzodi oxazole, benzothiazole, benzoimidazole, benzothiophene, quinoline, isoquinoline, naphthrydine, indole, benzofuran, purine, benzofuran, deazapurine, indolizine.
  • cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring can be substituted at one or more ring positions (e.g., the ring-forming carbon or heteroatom such as N) with such
  • alkyl alkenyl, alkynyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl,
  • alkylthiocarbonyl phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including
  • Aryl and heteroaryl groups can also be fused or bridged with alicyclic or heterocyclic rings, which are not aromatic so as to form a multi cyclic system (e.g ., tetralin, methylenedioxyphenyl such as benzo[d][l,3]dioxole-5-yl).
  • alicyclic or heterocyclic rings which are not aromatic so as to form a multi cyclic system (e.g ., tetralin, methylenedioxyphenyl such as benzo[d][l,3]dioxole-5-yl).
  • the term“substituted,” means that any one or more hydrogen atoms on the designated atom is replaced with a selection from the indicated groups, provided that the designated atom’s normal valency is not exceeded, and that the substitution results in a stable compound.
  • 2 hydrogen atoms on the atom are replaced.
  • Keto substituents are not present on aromatic moieties.
  • “Stable compound” and“stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • any variable e.g ., R
  • its definition at each occurrence is independent of its definition at every other occurrence.
  • R e.g ., R
  • the group may optionally be substituted with up to two R moieties and R at each occurrence is selected independently from the definition of R.
  • substituents and/or variables are permissible, but only if such combinations result in stable compounds.
  • the term“hydroxy” or“hydroxyl” includes groups with an -OH or -O .
  • halo refers to fluoro, chloro, bromo and iodo.
  • haloalkyl or“haloalkoxyl” refers to an alkyl or alkoxyl substituted with one or more halogen atoms.
  • optionally substituted haloalkyl refers to unsubstituted haloalkyl having designated substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms.
  • substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,
  • aryloxycarbonyloxy carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulphydryl, alkylthio, arylthio, thiocarboxylate, sulphates,
  • alkylsulphinyl sulphonato, sulphamoyl, sulphonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.
  • alkoxy or“alkoxyl” includes substituted and unsubstituted alkyl, alkenyl and alkynyl groups covalently linked to an oxygen atom.
  • alkoxy groups or alkoxyl radicals include, but are not limited to, methoxy, ethoxy, isopropyloxy, propoxy, butoxy and pentoxy groups.
  • substituted alkoxy groups include halogenated alkoxy groups.
  • the alkoxy groups can be substituted with groups such as alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,
  • aryloxycarbonyloxy carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulphydryl, alkylthio, arylthio, thiocarboxylate, sulphates,
  • halogen substituted alkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy and trichloromethoxy.
  • the expressions“one or more of A, B, or C,”“one or more A, B, or C,” “one or more of A, B, and C,”“one or more A, B, and C,”“selected from the group consisting of A, B, and C”,“selected from A, B, and C”, and the like are used interchangeably and all refer to a selection from a group consisting of A, B, and/or C, i.e., one or more As, one or more Bs, one or more Cs, or any combination thereof, unless indicated otherwise.
  • compositions are described as having, including, or comprising specific components, it is contemplated that compositions also consist essentially of, or consist of, the recited components. Similarly, where methods or processes are described as having, including, or comprising specific process steps, the processes also consist essentially of, or consist of, the recited processing steps. Further, it should be understood that the order of steps or order for performing certain actions is immaterial so long as the invention remains operable. Moreover, two or more steps or actions can be conducted simultaneously.
  • any description of a method of treatment includes use of the compounds to provide such treatment or prophylaxis as is described herein, as well as use of the compounds to prepare a medicament to treat or prevent such condition.
  • the treatment includes treatment of human or non-human animals including rodents and other disease models.
  • the term“subject” is interchangeable with the term“subject in need thereof’, both of which refer to a subject having a disease or having an increased risk of developing the disease.
  • A“subject” includes a mammal.
  • the mammal can be e.g ., a human or appropriate non-human mammal, such as primate, mouse, rat, dog, cat, cow, horse, goat, camel, sheep or a pig.
  • the subject can also be a bird or fowl.
  • the mammal is a human.
  • a subject in need thereof can be one who has been previously diagnosed or identified as having a disease or disorder disclosed herein.
  • a subject in need thereof can also be one who is suffering from a disease or disorder disclosed herein.
  • a subject in need thereof can be one who has an increased risk of developing such disease or disorder relative to the population at large (i.e., a subject who is predisposed to developing such disorder relative to the population at large).
  • a subject in need thereof can have a refractory or resistant a disease or disorder disclosed herein (i.e., a disease or disorder disclosed herein that does not respond or has not yet responded to treatment).
  • the subject may be resistant at start of treatment or may become resistant during treatment.
  • the subject in need thereof received and failed all known effective therapies for a disease or disorder disclosed herein.
  • the subject in need thereof received at least one prior therapy.
  • the term“treating” or“treat” describes the management and care of a patient for the purpose of combating a disease, condition, or disorder and includes the administration of a compound of the present disclosure, or a pharmaceutically acceptable salt, polymorph or solvate thereof, to alleviate the symptoms or complications of a disease, condition or disorder, or to eliminate the disease, condition or disorder.
  • the term“treat” can also include treatment of a cell in vitro or an animal model.
  • references to“treating” or“treatment” include the alleviation of established symptoms of a condition.“Treating” or “treatment” of a state, disorder or condition therefore includes: (1) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a human that may be afflicted with the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition, (2) inhibiting the state, disorder or condition, i.e., arresting, reducing or delaying the development of the disease or a relapse thereof (in case of maintenance treatment) or at least one clinical or subclinical symptom thereof, or (3) relieving or attenuating the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.
  • a compound of the present disclosure can or may also be used to prevent a relevant disease, condition or disorder, or used to identify suitable candidates for such purposes.
  • the term“preventing,”“prevent,” or“protecting against” describes reducing or eliminating the onset of the symptoms or complications of such disease, condition or disorder.
  • compositions comprising any compound described herein in combination with at least one pharmaceutically acceptable excipient or carrier.
  • the term“pharmaceutical composition” is a formulation containing the compounds of the present disclosure in a form suitable for administration to a subject.
  • the pharmaceutical composition is in bulk or in unit dosage form.
  • the unit dosage form is any of a variety of forms, including, for example, a capsule, an IV bag, a tablet, a single pump on an aerosol inhaler or a vial.
  • the quantity of active ingredient (e.g ., a formulation of the disclosed compound or salt, hydrate, solvate or isomer thereof) in a unit dose of composition is an effective amount and is varied according to the particular treatment involved.
  • active ingredient e.g ., a formulation of the disclosed compound or salt, hydrate, solvate or isomer thereof
  • the dosage will also depend on the route of administration.
  • routes of administration A variety of routes are contemplated, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalational, buccal, sublingual, intrapleural, intrathecal, intranasal, and the like.
  • Dosage forms for the topical or transdermal administration of a compound of this disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that are required.
  • the term“pharmaceutically acceptable” refers to those compounds, anions, cations, materials, compositions, carriers, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • the term“pharmaceutically acceptable excipient” means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes excipient that is acceptable for veterinary use as well as human pharmaceutical use.
  • A“pharmaceutically acceptable excipient” as used in the specification and claims includes both one and more than one such excipient.
  • routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., ingestion), inhalation, transdermal (topical), and transmucosal administration.
  • Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulphite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates, and agents for the adjustment of tonicity such as sodium chloride or dextrose.
  • the pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide.
  • the parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.
  • a compound or pharmaceutical composition of the disclosure can be administered to a subject in many of the well-known methods currently used for chemotherapeutic treatment.
  • a compound of the disclosure may be injected into the blood stream or body cavities or taken orally or applied through the skin with patches.
  • the dose chosen should be sufficient to constitute effective treatment but not so high as to cause unacceptable side effects.
  • the state of the disease condition (e.g., a disease or disorder disclosed herein) and the health of the patient should preferably be closely monitored during and for a reasonable period after treatment. Therapeutically effective amounts for a given situation can be determined by routine experimentation that is within the skill and judgment of the clinician.
  • A“therapeutically effective amount” means the amount of a compound that, when administered to a mammal for treating a disease, is sufficient to effect such treatment for the disease.
  • the “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated.
  • the term“effective amount”, refers to an amount of a pharmaceutical agent to treat, ameliorate, or prevent an identified disease or condition, or to exhibit a detectable therapeutic or inhibitory effect.
  • the effect can be detected by any assay method known in the art.
  • the precise effective amount for a subject will depend upon the subject’s body weight, size, and health; the nature and extent of the condition; and the therapeutic or combination of therapeutics selected for administration. Effective amounts for a given situation can be determined by routine experimentation that is within the skill and judgment of the clinician.
  • the therapeutically effective amount can be estimated initially either in cell culture assays, e.g ., of neoplastic cells, or in animal models, usually rats, mice, rabbits, dogs, or pigs. It is to be understood that, for any compound, the effective amount can be estimated initially either in cell culture assays, e.g., of neoplastic cells, or in animal models, usually rats, mice, rabbits, dogs, or pigs. The animal model may also be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans.
  • Therapeutic/prophylactic efficacy and toxicity may be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., EDso (the dose therapeutically effective in 50% of the population) and LDso (the dose lethal to 50% of the population).
  • the dose ratio between toxic and therapeutic effects is the therapeutic index, and it can be expressed as the ratio, LD50/ED50.
  • Pharmaceutical compositions that exhibit large therapeutic indices are preferred. The dosage may vary within this range depending upon the dosage form employed, sensitivity of the patient, and the route of administration.
  • Dosage and administration are adjusted to provide sufficient levels of the active agent(s) or to maintain the desired effect.
  • Factors which may be taken into account include the severity of the disease state, general health of the subject, age, weight, and gender of the subject, diet, time and frequency of administration, drug combination(s), reaction sensitivities, and
  • Long-acting pharmaceutical compositions may be administered every 3 to 4 days, every week, or once every two weeks depending on half-life and clearance rate of the particular formulation.
  • compositions containing active compounds of the present disclosure may be manufactured in a manner that is generally known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or lyophilising processes.
  • Pharmaceutical compositions may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers comprising excipients and/or auxiliaries that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Of course, the appropriate formulation is dependent upon the route of administration chosen.
  • compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion.
  • suitable carriers include physiological saline, bacteriostatic water, Cremophor ELTM (BASF, Parsippany, N. J.) or phosphate buffered saline (PBS).
  • the composition must be sterile and should be fluid to the extent that easy syringeability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof.
  • the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like.
  • isotonic agents for example, sugars, polyalcohols such as mannitol and sorbitol, and sodium chloride in the composition.
  • Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.
  • Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilisation.
  • dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above.
  • methods of preparation are vacuum drying and freeze-drying that yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • Oral compositions generally include an inert diluent or an edible pharmaceutically acceptable carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition.
  • the tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
  • a binder such as microcrystalline cellulose, gum tragacanth or gelatin
  • an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch
  • a lubricant such as magnesium stearate or Sterotes
  • a glidant such as colloidal silicon dioxide
  • the compounds are delivered in the form of an aerosol spray from pressured container or dispenser, which contains a suitable propellant, e.g ., a gas such as carbon dioxide, or a nebuliser.
  • a suitable propellant e.g ., a gas such as carbon dioxide, or a nebuliser.
  • Systemic administration can also be by transmucosal or transdermal means.
  • penetrants appropriate to the barrier to be permeated are used in the formulation.
  • penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives.
  • Transmucosal administration can be accomplished through the use of nasal sprays or
  • the active compounds are formulated into ointments, salves, gels, or creams as generally known in the art.
  • the active compounds can be prepared with pharmaceutically acceptable carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems.
  • pharmaceutically acceptable carriers such as a controlled release formulation, including implants and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides,
  • polyglycolic acid collagen, polyorthoesters, and polylactic acid.
  • Methods for preparation of such formulations will be apparent to those skilled in the art.
  • the materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc.
  • Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,811.
  • Dosage unit form refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • the specification for the dosage unit forms of the disclosure are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved.
  • the dosages of the pharmaceutical compositions used in accordance with the disclosure vary depending on the agent, the age, weight, and clinical condition of the recipient patient, and the experience and judgment of the clinician or practitioner administering the therapy, among other factors affecting the selected dosage.
  • the dose should be sufficient to result in slowing, and preferably regressing, the symptoms of the disease or disorder disclosed herein and also preferably causing complete regression of the disease or disorder.
  • Dosages can range from about 0.01 mg/kg per day to about 5000 mg/kg per day. In preferred aspects, dosages can range from about 1 mg/kg per day to about 1000 mg/kg per day.
  • the dose will be in the range of about 0.1 mg/day to about 50 g/day; about 0.1 mg/day to about 25 g/day; about 0.1 mg/day to about 10 g/day; about 0.1 mg to about 3 g/day; or about 0.1 mg to about 1 g/day, in single, divided, or continuous doses (which dose may be adjusted for the patient’s weight in kg, body surface area in m 2 , and age in years).
  • An effective amount of a pharmaceutical agent is that which provides an objectively identifiable improvement as noted by the clinician or other qualified observer. Improvement in survival and growth indicates regression.
  • the term“dosage effective manner” refers to amount of an active compound to produce the desired biological effect in a subject or cell.
  • compositions can be included in a container, pack, or dispenser together with instructions for administration.
  • the term“pharmaceutically acceptable salts” refer to derivatives of the compounds of the present disclosure wherein the parent compound is modified by making acid or base salts thereof.
  • pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like.
  • the pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • such conventional non toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from 2-acetoxybenzoic, 2-hydroxyethane sulphonic, acetic, ascorbic, benzene sulphonic, benzoic, bicarbonic, carbonic, citric, edetic, ethane disulphonic, 1,2-ethanesulphonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromic, hydrochloric, hydroiodic, hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulphonic, maleic, malic, mandelic, methane sulphonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic,
  • the pharmaceutically acceptable salt is a sodium salt, a potassium salt, a calcium salt, a magnesium salt, a diethylamine salt, a choline salt, a meglumine salt, a benzathine salt, a tromethamine salt, an ammonia salt, an arginine salt, or a lysine salt.
  • cyclopentane propionic acid pyruvic acid, malonic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, 4-chlorobenzenesulphonic acid, 2-naphthalenesulphonic acid, 4-toluenesulphonic acid, camphanic acid, camphorsulphonic acid, 4-methylbicyclo-[2.2.2]-oct-2-ene-l -carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, muconic acid, and the like.
  • the present disclosure also encompasses salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine,
  • the ratio of the compound to the cation or anion of the salt can be 1 : 1, or any ratio other than 1 : 1, e.g., 3: 1, 2: 1, 1 :2, or 1 :3.
  • the compounds, or pharmaceutically acceptable salts thereof are administered orally, nasally, transdermally, pulmonary, inhalationally, buccally, sublingually, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally and parenterally.
  • the compound is administered orally.
  • One skilled in the art will recognise the advantages of certain routes of administration.
  • the dosage regimen utilising the compounds is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed.
  • An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the condition.
  • Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions.
  • the compounds will be present in such pharmaceutical compositions in amounts sufficient to provide the desired dosage amount in the range described herein.
  • compounds may be drawn with one particular configuration for simplicity. Such particular configurations are not to be construed as limiting the disclosure to one or another isomer, tautomer, regioisomer or stereoisomer, nor does it exclude mixtures of isomers, tautomers, regioisomers or stereoisomers; however, it will be understood that a given isomer, tautomer, regioisomer or stereoisomer may have a higher level of activity than another isomer, tautomer, regioisomer or stereoisomer.
  • the present disclosure provides, inter alia , a compound of Formula (I):
  • X is O or NR4
  • Ri is C3-C16 cycloalkyl or C5-C10 aryl, wherein the C3-C16 cycloalkyl or C5-C10 aryl is optionally substituted with one or more Ris; wherein each Ris is independently C1-C6 alkyl, Ci- Ce haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or halo;
  • R2 is 5- to 10-membered heteroaryl or 4- to 8-membered heterocycloalkyl, wherein the 5- to 10-membered heteroaryl or 4- to 8-membered heterocycloalkyl is optionally substituted with one or more C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, Ci- Ce haloalkoxy, halo, -CN, -OH, -NH2, -NH(CI-C 6 alkyl), -N(CI-C 6 alkyl)2, oxo, -C(0)R2S, - C(0)OR2S, or -C(0)N(R2S) 2 ;
  • each R 2 S is independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, or 4- to 8-membered heterocycloalkyl;
  • R3 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C7 cycloalkyl; wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C7 cycloalkyl is optionally substituted with one or more C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C7 cycloalkyl, halo, -CN, -OH, -NH2, -NH(CI-C6 alkyl), -N(CI-C6 alkyl)2, or oxo; and
  • Ri is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl; wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C7 cycloalkyl is optionally substituted with one or more C1-C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, C1-C 6 haloalkyl, C1-C 6 alkoxy, C1-C 6 haloalkoxy, C3-C7 cycloalkyl, halo, -CN, -OH, -NH2, -NH(CI-C6 alkyl), -N(CI-C6 alkyl)2, or oxo.
  • the present disclosure provides, inter alia , a compound of Formula (G):
  • Ri is C3-C1 6 cycloalkyl or C5-C1 0 aryl, wherein the C3-C1 6 cycloalkyl or C5-C1 0 aryl is optionally substituted with one or more Ris; wherein each Ris is independently C1-C 6 alkyl, Ci- Ce haloalkyl, C1-C 6 alkoxy, C1-C 6 haloalkoxy, or halo;
  • R 2 is 5- to 10-membered heteroaryl or 4- to 8-membered heterocycloalkyl, wherein the 5- to 10-membered heteroaryl or 4- to 8-membered heterocycloalkyl is optionally substituted with one or more C1-C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, C1-C 6 haloalkyl, C1-C 6 alkoxy, Ci- Ce haloalkoxy, halo, -CN, -OH, -NH2, -NH(CI-C6 alkyl), -N(CI-C6 alkyl)2, oxo, -C(0)R2S, - C(0)OR2S, or -C(0)N(R 2S ) 2 ;
  • each R 2S is independently H, C1-C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, C 3 -C7 cycloalkyl, or 4- to 8-membered heterocycloalkyl;
  • R 3 is H, C1-C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, or C 3 -C7 cycloalkyl; wherein C1-C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, or C 3 -C7 cycloalkyl is optionally substituted with one or more C1-C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, C1-C 6 haloalkyl, C1-C 6 alkoxy, C1-C 6 haloalkoxy, C 3 -C7 cycloalkyl, halo, -CN, -OH, -NH2, -NH(Ci-C6 alkyl), -N(CI-C6 alkyl)2, or oxo.
  • the present disclosure provides, inter alia , a compound of Formula (I):
  • X is O or NR4
  • Ri is C 3 -C1 6 cycloalkyl or C5-C1 0 aryl, wherein the C 3 -C1 6 cycloalkyl or C5-C1 0 aryl is optionally substituted with one or more Ris; wherein each Ris is independently C1-C 6 alkyl, Ci- Ce haloalkyl, C1-C 6 alkoxy, C1-C 6 haloalkoxy, or halo;
  • R 2 is 5- to 10-membered heteroaryl or 4- to 8-membered heterocycloalkyl, wherein the 5- to 10-membered heteroaryl or 4- to 8-membered heterocycloalkyl is optionally substituted with one or more C1-C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, C1-C 6 haloalkyl, C1-C 6 alkoxy, Ci- Ce haloalkoxy, halo, -CN, -OH, -NH2, -NH(CI-C6 alkyl), -N(CI-C6 alkyl)2,
  • R 3 is H, C1-C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, or C3-C7 cycloalkyl; wherein C1-C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, or C3-C7 cycloalkyl is optionally substituted with one or more C1-C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, C1-C 6 haloalkyl, C1-C 6 alkoxy, C1-C 6 haloalkoxy, C3-C7 cycloalkyl, halo, -CN, -OH, -NH2, -NH(CI-C6 alkyl), -N(CI-C6 alkyl)2, or oxo; and
  • R 4 is H, C1-C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, or C 3 -C7 cycloalkyl ; wherein the Ci- Ce alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, or C 3 -C7 cycloalkyl is optionally substituted with one or more C1-C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, C1-C 6 haloalkyl, C1-C 6 alkoxy, C1-C 6 haloalkoxy, C 3 -C7 cycloalkyl, halo, -CN, -OH, -NH2, -NH(Ci-C6 alkyl), -N(CI-C6 alkyl)2, or oxo.
  • the present disclosure provides, inter alia , a compound of Formula (G):
  • Ri is C 3 -C1 6 cycloalkyl or C5-C1 0 aryl, wherein the C 3 -C1 6 cycloalkyl or C5-C1 0 aryl is optionally substituted with one or more Ris; wherein each Ris is independently C1-C 6 alkyl, Ci- Ce haloalkyl, C1-C 6 alkoxy, C1-C 6 haloalkoxy, or halo;
  • R 2 is 5- to 10-membered heteroaryl or 4- to 8-membered heterocycloalkyl, wherein the 5- to 10-membered heteroaryl or 4- to 8-membered heterocycloalkyl is optionally substituted with one or more C1-C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, C1-C 6 haloalkyl, C1-C 6 alkoxy, Ci- Ce haloalkoxy, halo, -CN, -OH, -NH2, -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl) 2 , -C(0)R 2 s, - C(0)OR2S, or -C(0)N(R 2S ) 2 ;
  • each R 2S is independently H, C1-C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, C 3 -C7 cycloalkyl, or 4- to 8-membered heterocycloalkyl;
  • R 3 is H, C1-C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, or C 3 -C7 cycloalkyl; wherein C1-C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, or C 3 -C7 cycloalkyl is optionally substituted with one or more C1-C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, C1-C 6 haloalkyl, C1-C 6 alkoxy, C1-C 6 haloalkoxy, C 3 -C7 cycloalkyl, halo, -CN, -OH, -NH2, -NH(Ci-C6 alkyl), -N(CI-C6 alkyl)2, or oxo.
  • X, Ri, Ris, R2, R2 S , R J , and R4 can each be, where applicable, selected from the groups described herein, and any group described herein for any of X, Ri, Ris, R2, R2 S , R J , and R4 can be combined, where applicable, with any group described herein for one or more of the remainder of X, Ri, Ris, R2, R2 S , R J , and R 4 .
  • X is O or NR 4 .
  • X is O.
  • X is NR 4 .
  • Ri is C3-C16 cycloalkyl or C5-C10 aryl, wherein the C3-C16 cycloalkyl or C5-C10 aryl is optionally substituted with one or more Ris.
  • Ri is C3-C16 cycloalkyl optionally substituted with one or more Ris.
  • Ri is C3-C8 monocyclic cycloalkyl or Cs-Ci 6 polycyclic cycloalkyl, wherein the C3-C8 monocyclic cycloalkyl or Cs-Ci 6 polycyclic cycloalkyl is optionally substituted with one or more Ris.
  • Ri is C3-C7 monocyclic cycloalkyl or Cs-Ci 6 polycyclic cycloalkyl, wherein the C3-C8 monocyclic cycloalkyl or Cs-Ci 6 polycyclic cycloalkyl is optionally substituted with one or more Ris.
  • Ri is C3-C7 monocyclic cycloalkyl, C9-C10 bicyclic cycloalkyl, or C12-C16 tricyclic cycloalkyl, wherein the C3-C7 monocyclic cycloalkyl, C9-C10 bicyclic cycloalkyl, or C12-C16 tricyclic cycloalkyl is optionally substituted with one or more Ris.
  • Ri is C3-C7 monocyclic cycloalkyl.
  • Ri is C3-C7 monocyclic cycloalkyl optionally substituted with one or more Ris.
  • Ri is C3-C7 monocyclic saturated cycloalkyl optionally substituted with one or more Ris.
  • Ri is C5-C7 monocyclic partially saturated cycloalkyl optionally substituted with one or more Ris.
  • Ri is C6-C10 bicyclic cycloalkyl.
  • Ri is C6-C10 bicyclic cycloalkyl optionally substituted with one or more Ris.
  • Ri is C6-C10 bicyclic saturated cycloalkyl optionally substituted with one or more Ris.
  • Ri is C6-C10 bicyclic partially saturated cycloalkyl optionally substituted with one or more Ris.
  • Ri is C12-C16 tricyclic cycloalkyl.
  • Ri is C12-C16 tricyclic cycloalkyl optionally substituted with one or more Ris.
  • Ri is C12-C16 tricyclic saturated cycloalkyl optionally substituted with one or more Ris.
  • Ri is C12-C16 tricyclic partially unsaturated cycloalkyl optionally substituted with one or more Ris.
  • Ri is Cs-Ci 6 polycyclic cycloalkyl.
  • Ri is Cs-Ci 6 polycyclic cycloalkyl substituted with one or more
  • Ri is 2,3-dihydro- l 7-indenyl optionally substituted with one or more Ris.
  • Ri is 2,3-dihydro-l//-indenyl.
  • Ri is 2,3-dihydro-l 7-in deny 1 optionally substituted with one, two, or three substituents independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or halo.
  • Ri is unsubstituted 2,3-dihydro- l /7-indenyl
  • Ri is hexahydroindacenyl optionally substituted with one or more Ris.
  • Ri is hexahydroindacenyl.
  • n and n a each independently are 0, 1, 2, or 3.
  • n and n a each independently are 0, 1, 2, or 3.
  • n and n a each independently are 0, 1, 2, or 3.
  • Ri is na , wherein n and n a each independently are 0,
  • Ris is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or halo.
  • Ris is C1-C6 alkyl, C1-C6 haloalkyl
  • Ci-Ce alkoxy C1-C6 haloalkoxy, or halo.
  • Ri is hexahydroindacenyl optionally substituted with one, two, three, or four substituents independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or halo.
  • Ri is unsubstituted hexahydroindacenyl.
  • Ri is C5-C10 aryl.
  • Ri is C5-C 10 aryl optionally substituted with one or more Ris.
  • Ri is C5-C 10 aryl substituted with one or more Ris.
  • Ri is C5-C6 monocyclic aryl.
  • Ri is C5-C6 monocyclic aryl optionally substituted with one or more Ris.
  • Ri is C5-C6 monocyclic aryl substituted with one or more Ris.
  • Ri is phenyl
  • Ri is phenyl optionally substituted with one or more Ris.
  • Ri is phenyl substituted with one or more Ris.
  • Ri is phenyl substituted with one Ris.
  • Ri is phenyl substituted with two Ris.
  • Ri is phenyl substituted with three Ris.
  • Ri is phenyl substituted with four Ris.
  • Ri is phenyl substituted with five Ris.
  • Ri is phenyl substituted with one or more substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, and -CF3.
  • Ri is phenyl optionally substituted with C1-C6 alkyl (e.g. linear or branched).
  • Ri is phenyl optionally substituted with halo.
  • Ri is phenyl optionally substituted with one, two, or three substituents independently selected from Cl and F.
  • Ri is phenyl optionally substituted with C1-C6 alkoxy.
  • Ri is phenyl optionally substituted with one, two, or three substituents independently selected C1-C6 haloalkoxy.
  • At least one Ris is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or halo.
  • At least one Ris is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or halo.
  • At least one Ris is C1-C6 alkyl, C1-C6 haloalkyl, or halo.
  • At least one Ris is C1-C6 alkyl or halo.
  • At least one Ris is C1-C6 alkyl or C1-C6 haloalkyl.
  • At least one Ris is C1-C6 alkyl (e.g. linear or branched).
  • At least one Ris is methyl. In some embodiments, at least one Ris is ethyl. In some embodiments, at least one Ris is propyl. In some embodiments, at least one Ris is butyl. In some embodiments, at least one Ris is pentyl. In some embodiments, at least one Ris is hexyl. In some embodiments, at least one Ris is isopropyl. In some embodiments, at least one Ris is isobutyl. In some embodiments, at least one Ris is isopentyl. In some embodiments, at least one Ris is isohexyl. In some embodiments, at least one Ris is secbutyl. In some embodiments, at least one Ris is secpentyl. In some embodiments, at least one Ris is sechexyl. In some embodiments, at least one Ris is tertbutyl.
  • At least one Ris is C1-C6 haloalkyl (e.g . methyl, ethyl, propyl, butyl, pentyl, or hexyl substituted with one or more halogen).
  • At least one Ris is -CH2F, -CHF2, -CF3.
  • At least one Ris is -CH2F. In some embodiments, at least one Ris is -CHF2. In some embodiments, at least one Ris is -CF3.
  • At least one Ris is C1-C6 alkoxy or C1-C6 haloalkoxy.
  • At least one Ris is C1-C6 alkoxy.
  • At least one Ris is methoxy. In some embodiments, at least one Ris is ethoxy. In some embodiments, at least one Ris is propoxy. In some embodiments, at least one Ris is butoxy. In some embodiments, at least one Ris is pentoxy. In some embodiments, at least one Ris is hexoxy.
  • At least one Ris is C1-C6 haloalkoxy (e.g. methoxy, ethoxy, propoxy, butoxy, pentoxy, or hexoxy substituted with one or more halogen).
  • At least one Ris is halomethoxy. In some embodiments, at least one Ris is haloethoxy. In some embodiments, at least one Ris is halopropoxy. In some embodiments, at least one Ris is halobutoxy. In some embodiments, at least one Ris is halopentoxy. In some embodiments, at least one Ris is halohexoxy.
  • At least one Ris is -OCF3.
  • At least one Ris is -OCH2CF3.
  • At least one Ris is halo.
  • At least one Ris is F, Cl, Br, or I.
  • At least one Ris is F or Cl.
  • At least one Ris is F.
  • At least one Ris is Cl.
  • R2 is 5- to 10-membered heteroaryl or 4- to 8-membered heterocycloalkyl, wherein the 5- to 10-membered heteroaryl or 4- to 8-membered heterocycloalkyl is optionally substituted with one or more C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, -CN, -OH, -NH2, -NH(CI-C 6 alkyl), -N(CI-C 6 alkyl)2, oxo, -C(0)R2S, -C(0)0R2S, or -C(0)N(R2s)2.
  • R2 is 5- to 10-membered heteroaryl or 4- to 8-membered heterocycloalkyl; wherein the 5- to 10-membered heteroaryl or 4- to 8-membered
  • heterocycloalkyl is optionally substituted with one or more C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, -CN, -OH, -NH2, -NH(CI-C 6 alkyl), -N(CI-C 6 alkyl)2, or oxo.
  • R2 is 5- to 10- membered heteroaryl.
  • R2 is 5- to 10-membered heteroaryl optionally substituted with one or more C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, -CN, -OH, -NH2, -NH(CI-C 6 alkyl), -N(CI-C 6 alkyl)2, oxo, -C(0)R2S, - C(0)0R 2S , or -C(0)N(R2S)2.
  • R2 is 5- to 10-membered heteroaryl optionally substituted with one or more C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, -CN, -OH, -NH2, -NH(Ci-C 6 alkyl), -N(CI-C 6 alkyl)2, or oxo.
  • R2 is 5- to 10-membered heteroaryl optionally substituted with one or more C1-C6 alkyl. In some embodiments, R2 is optionally substituted with one or more C2-C6 alkenyl. In some embodiments, R2 is 5- to 10-membered heteroaryl optionally substituted with one or more C2-C6 alkynyl. In some embodiments, R2 is 5- to 10-membered heteroaryl optionally substituted with one or more C1-C6 haloalkyl. In some embodiments, R2 is 5- to 10- membered heteroaryl optionally substituted with one or more C1-C6 alkoxy. In some
  • R2 is 5- to 10-membered heteroaryl optionally substituted with one or more C1-C6 haloalkoxy. In some embodiments, R2 is 5- to 10-membered heteroaryl optionally substituted with one or more halo. In some embodiments, R2 is 5- to 10-membered heteroaryl optionally substituted with one or more -CN. In some embodiments, R2 is 5- to 10-membered heteroaryl optionally substituted with one or more -OH. In some embodiments, R2 is 5- to 10-membered heteroaryl optionally substituted with one or more -NH2. In some embodiments, R2 is 5- to 10- membered heteroaryl optionally substituted with one or more -NH(Ci-C 6 alkyl).
  • R2 is 5- to 10-membered heteroaryl optionally substituted with one or more - N(CI-C 6 alkyl)2. In some embodiments, R2 is 5- to 10-membered heteroaryl optionally substituted with one or more oxo.
  • R2 is 5-membered heteroaryl.
  • R2 is 5-membered heteroaryl optionally substituted with one or more C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, -CN, -OH, -NH2, -NH(CI-C 6 alkyl), -N(CI-C 6 alkyl)2, oxo, -C(0)R2S, - C(0)0R 2S , or -C(0)N(R2S)2.
  • R2 is 5-membered heteroaryl optionally substituted with one or more C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, -CN, -OH, -NH2, -NH(CI-C 6 alkyl), -N(CI-C 6 alkyl)2, or oxo.
  • R2 is 5-membered heteroaryl optionally substituted with one or more C1-C6 alkyl. In some embodiments, R2 is 5-membered heteroaryl optionally substituted with one or more C2-C6 alkenyl. In some embodiments, R2 is 5-membered heteroaryl optionally substituted with one or more C2-C6 alkynyl. In some embodiments, R2 is 5-membered heteroaryl optionally substituted with one or more C1-C6 haloalkyl. In some embodiments, R2 is 5- membered heteroaryl optionally substituted with one or more C1-C6 alkoxy. In some
  • R2 is 5-membered heteroaryl optionally substituted with one or more C1-C6 haloalkoxy. In some embodiments, R2 is 5-membered heteroaryl optionally substituted with one or more halo. In some embodiments, R2 is 5-membered heteroaryl optionally substituted with one or more -CN. In some embodiments, R2 is 5-membered heteroaryl optionally substituted with one or more -OH. In some embodiments, R2 is 5-membered heteroaryl optionally substituted with one or more -NH2. In some embodiments, R2 is 5-membered heteroaryl optionally substituted with one or more -NH(Ci-C 6 alkyl).
  • R2 is 5- membered heteroaryl optionally substituted with one or more -N(CI-C 6 alkyl)2. In some embodiments, R2 is 5-membered heteroaryl optionally substituted with one or more oxo.
  • R2 is 5-membered heteroaryl optionally substituted with one or more -C(0)R 2 s, -C(0)OR 2S , or -C(0)N(R 2 s)2.
  • R2 is 5-membered heteroaryl optionally substituted with one or more -C(0)R2S.
  • R2 is 5-membered heteroaryl optionally substituted with one or more -C(0)-(4- to 8-membered heterocycloalkyl).
  • R 2 is 5-membered heteroaryl optionally substituted with one or more -C(0)0R2S.
  • R 2 is 5-membered heteroaryl optionally substituted with one or more -C(0)N(R2s)2.
  • R 2 is 6-membered heteroaryl.
  • R 2 is 6-membered heteroaryl optionally substituted with one or more C1-C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, C1-C 6 haloalkyl, C1-C 6 alkoxy, C1-C 6 haloalkoxy, halo, -CN, -OH, -NH2, -NH(CI-C6 alkyl), -N(CI-C6 alkyl)2, oxo, -C(0)R2S, - C(0)0R 2S , or -C(0)N(R2S)2.
  • R 2 is 6-membered heteroaryl optionally substituted with one or more C1-C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, C1-C 6 haloalkyl, C1-C 6 alkoxy, C1-C 6 haloalkoxy, halo, -CN, -OH, -NH2, -NH(CI-C6 alkyl), -N(CI-C6 alkyl)2, or oxo.
  • R 2 is 6-membered heteroaryl optionally substituted with one or more C1-C 6 alkyl. In some embodiments, R 2 is 6-membered heteroaryl optionally substituted with one or more C2-C 6 alkenyl. In some embodiments, R 2 is 6-membered heteroaryl optionally substituted with one or more C2-C 6 alkynyl. In some embodiments, R 2 is 6-membered heteroaryl optionally substituted with one or more C1-C 6 haloalkyl. In some embodiments, R 2 is 6- membered heteroaryl optionally substituted with one or more C1-C 6 alkoxy. In some
  • R 2 is 6-membered heteroaryl optionally substituted with one or more C1-C 6 haloalkoxy. In some embodiments, R 2 is 6-membered heteroaryl optionally substituted with one or more halo. In some embodiments, R 2 is 6-membered heteroaryl optionally substituted with one or more -CN. In some embodiments, R 2 is 6-membered heteroaryl optionally substituted with one or more -OH. In some embodiments, R 2 is 6-membered heteroaryl optionally substituted with one or more -NH2. In some embodiments, R 2 is 6-membered heteroaryl optionally substituted with one or more -NH(Ci-C6 alkyl).
  • R 2 is 6- membered heteroaryl optionally substituted with one or more -N(CI-C6 alkyl)2. In some embodiments, R 2 is 6-membered heteroaryl optionally substituted with one or more oxo.
  • R 2 is 7-membered heteroaryl.
  • R 2 is 7-membered heteroaryl optionally substituted with one or more C1-C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, C1-C 6 haloalkyl, C1-C 6 alkoxy, C1-C 6 haloalkoxy, halo, -CN, -OH, -NH2, -NH(CI-C6 alkyl), -N(CI-C6 alkyl)2, oxo, -C(0)R2S, - C(0)0R 2S , or -C(0)N(R2S)2.
  • R 2 is 7-membered heteroaryl optionally substituted with one or more C1-C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, C1-C 6 haloalkyl, C1-C 6 alkoxy, C1-C 6 haloalkoxy, halo, -CN, -OH, -NH2, -NH(CI-C6 alkyl), -N(CI-C6 alkyl)2, or oxo.
  • R 2 is 7-membered heteroaryl optionally substituted with one or more C1-C 6 alkyl. In some embodiments, R 2 is 7-membered heteroaryl optionally substituted with one or more C2-C 6 alkenyl. In some embodiments, R 2 is 7-membered heteroaryl optionally substituted with one or more C2-C 6 alkynyl. In some embodiments, R 2 is 7-membered heteroaryl optionally substituted with one or more C1-C 6 haloalkyl. In some embodiments, R 2 is 7- membered heteroaryl optionally substituted with one or more C1-C 6 alkoxy. In some
  • R 2 is 7-membered heteroaryl optionally substituted with one or more C1-C 6 haloalkoxy. In some embodiments, R 2 is 7-membered heteroaryl optionally substituted with one or more halo. In some embodiments, R 2 is 7-membered heteroaryl optionally substituted with one or more -CN. In some embodiments, R 2 is 7-membered heteroaryl optionally substituted with one or more -OH. In some embodiments, R 2 is 7-membered heteroaryl optionally substituted with one or more -NH2. In some embodiments, R 2 is 7-membered heteroaryl optionally substituted with one or more -NH(Ci-C6 alkyl).
  • R 2 is 7- membered heteroaryl optionally substituted with one or more -N(CI-C6 alkyl)2. In some embodiments, R 2 is 7-membered heteroaryl optionally substituted with one or more oxo.
  • R 2 is 8-membered heteroaryl.
  • R 2 is 8-membered heteroaryl optionally substituted with one or more C1-C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, C1-C 6 haloalkyl, C1-C 6 alkoxy, C1-C 6 haloalkoxy, halo, -CN, -OH, -NH2, -NH(Ci-C6 alkyl), -N(CI-C6 alkyl)2, oxo, -C(0)R2S, - C(0)0R 2S , or -C(0)N(R2S)2.
  • R 2 is 8-membered heteroaryl optionally substituted with one or more C1-C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, C1-C 6 haloalkyl, C1-C 6 alkoxy, C1-C 6 haloalkoxy, halo, -CN, -OH, -NH2, -NH(Ci-C6 alkyl), -N(CI-C6 alkyl)2, or oxo.
  • R 2 is 8-membered heteroaryl optionally substituted with one or more C1-C 6 alkyl. In some embodiments, R 2 is 8-membered heteroaryl optionally substituted with one or more C2-C 6 alkenyl. In some embodiments, R 2 is 8-membered heteroaryl optionally substituted with one or more C2-C 6 alkynyl. In some embodiments, R 2 is 8-membered heteroaryl optionally substituted with one or more C1-C 6 haloalkyl. In some embodiments, R 2 is 8- membered heteroaryl optionally substituted with one or more C1-C 6 alkoxy. In some
  • R 2 is 8-membered heteroaryl optionally substituted with one or more C1-C 6 haloalkoxy. In some embodiments, R 2 is 8-membered heteroaryl optionally substituted with one or more halo. In some embodiments, R 2 is 8-membered heteroaryl optionally substituted with one or more -CN. In some embodiments, R 2 is 8-membered heteroaryl optionally substituted with one or more -OH. In some embodiments, R 2 is 8-membered heteroaryl optionally substituted with one or more -NH2. In some embodiments, R 2 is 8-membered heteroaryl optionally substituted with one or more -NH(CI-C6 alkyl).
  • R 2 is 8- membered heteroaryl optionally substituted with one or more -N(CI-C6 alkyl)2. In some embodiments, Rs is 8-membered heteroaryl optionally substituted with one or more oxo.
  • R 2 is 9-membered heteroaryl.
  • R 2 is 9-membered heteroaryl optionally substituted with one or more C1-C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, C1-C 6 haloalkyl, C1-C 6 alkoxy, C1-C 6 haloalkoxy, halo, -CN, -OH, -NH2, -NH(CI-C6 alkyl), -N(CI-C6 alkyl)2, oxo, -C(0)R2S, - C(0)0R 2S , or -C(0)N(R2S)2.
  • R 2 is 9-membered heteroaryl optionally substituted with one or more C1-C 6 alkyl. In some embodiments, R 2 is 9-membered heteroaryl optionally substituted with one or more C2-C 6 alkenyl. In some embodiments, R 2 is 9-membered heteroaryl optionally substituted with one or more C2-C 6 alkynyl. In some embodiments, R 2 is 9-membered heteroaryl optionally substituted with one or more C1-C 6 haloalkyl. In some embodiments, R 2 is 9- membered heteroaryl optionally substituted with one or more C1-C 6 alkoxy. In some
  • R 2 is 9-membered heteroaryl optionally substituted with one or more C1-C 6 haloalkoxy. In some embodiments, R 2 is 9-membered heteroaryl optionally substituted with one or more halo. In some embodiments, R 2 is 9-membered heteroaryl optionally substituted with one or more -CN. In some embodiments, R 2 is 9-membered heteroaryl optionally substituted with one or more -OH. In some embodiments, R 2 is 9-membered heteroaryl optionally substituted with one or more -NH2. In some embodiments, R 2 is 9-membered heteroaryl optionally substituted with one or more -NH(Ci-C6 alkyl).
  • R 2 is 9- membered heteroaryl optionally substituted with one or more -N(CI-C 6 alkyl)2. In some embodiments, Rs is 9-membered heteroaryl optionally substituted with one or more oxo.
  • R2 is 10-membered heteroaryl.
  • R2 is 10-membered heteroaryl optionally substituted with one or more C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, -CN, -OH, -NH2, -NH(CI-C 6 alkyl), -N(CI-C 6 alkyl)2, oxo, -C(0)R2S, - C(0)0R 2S , or -C(0)N(R2S)2.
  • R2 is 10-membered heteroaryl optionally substituted with one or more C1-C6 alkyl. In some embodiments, R2 is 10-membered heteroaryl optionally substituted with one or more C2-C6 alkenyl. In some embodiments, R2 is 10-membered heteroaryl optionally substituted with one or more C2-C6 alkynyl. In some embodiments, R2 is 10-membered heteroaryl optionally substituted with one or more C1-C6 haloalkyl. In some embodiments, R2 is 10-membered heteroaryl optionally substituted with one or more C1-C6 alkoxy.
  • R2 is 10-membered heteroaryl optionally substituted with one or more C1-C6 haloalkoxy. In some embodiments, R2 is 10-membered heteroaryl optionally substituted with one or more halo. In some embodiments, R2 is 10-membered heteroaryl optionally substituted with one or more -CN. In some embodiments, R2 is 10-membered heteroaryl optionally substituted with one or more -OH. In some embodiments, R2 is 10-membered heteroaryl optionally substituted with one or more -NH2. In some embodiments, R2 is 10-membered heteroaryl optionally substituted with one or more -NH(CI-C 6 alkyl). In some embodiments, R2 is 10- membered heteroaryl optionally substituted with one or more -N(CI-C 6 alkyl)2. In some embodiments, Rs is 10-membered heteroaryl optionally substituted with one or more oxo.
  • R2 is 4- to 8-membered heterocycloalkyl.
  • R2 is 4- to 8-membered heterocycloalkyl heteroaryl optionally substituted with one or more C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, -CN, -OH, -NH2, -NH(Ci-C 6 alkyl), -N(CI-C 6 alkyl)2, oxo, - C(0)R2S, -C(0)OR2S, or -C(0)N(R2S)2.
  • R2 is 4- to 8-membered heterocycloalkyl optionally substituted with one or more C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, Ci- Ce haloalkoxy, halo, -CN, -OH, -NH2, -NH(Ci-C 6 alkyl), -N(CI-C 6 alkyl)2, or oxo.
  • R 2 is 4- to 8-membered heterocycloalkyl optionally substituted with one or more C1-C 6 alkyl.
  • R 2 is 4- to 8-membered heterocycloalkyl optionally substituted with one or more C2-C 6 alkenyl. In some embodiments, R 2 is 4- to 8- membered heterocycloalkyl optionally substituted with one or more C2-C 6 alkynyl. In some embodiments, R 2 is 4- to 8-membered heterocycloalkyl optionally substituted with one or more C1-C 6 haloalkyl. In some embodiments, R 2 is 4- to 8-membered heterocycloalkyl optionally substituted with one or more C1-C 6 alkoxy. In some embodiments, R 2 is 4- to 8-membered heterocycloalkyl optionally substituted with one or more C1-C 6 haloalkoxy. In some embodiments,
  • R 2 is 4- to 8-membered heterocycloalkyl optionally substituted with one or more halo. In some embodiments, R 2 is 4- to 8-membered heterocycloalkyl optionally substituted with one or more -CN. In some embodiments, R 2 is 4- to 8-membered heterocycloalkyl optionally substituted with one or more -OH. In some embodiments, R 2 is 4- to 8-membered
  • R 2 is 4- to 8-membered heterocycloalkyl optionally substituted with one or more -NH2.
  • R 2 is 4- to 8-membered heterocycloalkyl optionally substituted with one or more -NH(CI-C6 alkyl).
  • R 2 is 4- to 8-membered heterocycloalkyl optionally substituted with one or more - N(CI-C6 alkyl)2.
  • R 2 is 4- to 8-membered heterocycloalkyl optionally substituted with one or more oxo.
  • R 2 is 4-membered heterocycloalkyl.
  • R 2 is 4-membered heterocycloalkyl heteroaryl optionally substituted with one or more C1-C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, C1-C 6 haloalkyl, C1-C 6 alkoxy, C1-C 6 haloalkoxy, halo, -CN, -OH, -NH2, -NH(CI-C6 alkyl), -N(CI-C6 alkyl)2, oxo, - C(0)R2S, -C(0)OR2S, or -C(0)N(R2S)2.
  • R 2 is 4-membered heterocycloalkyl optionally substituted with one or more C1-C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, C1-C 6 haloalkyl, C1-C 6 alkoxy, C1-C 6 haloalkoxy, halo, -CN, -OH, -NH2, -NH(CI-C6 alkyl), -N(CI-C6 alkyl)2, or oxo.
  • R 2 is 4-membered heterocycloalkyl optionally substituted with one or more C1-C 6 alkyl. In some embodiments, R 2 is 4-membered heterocycloalkyl optionally substituted with one or more C2-C 6 alkenyl. In some embodiments, R 2 is 4-membered heterocycloalkyl optionally substituted with one or more C2-C 6 alkynyl. In some embodiments, R 2 is 4-membered heterocycloalkyl optionally substituted with one or more C1-C 6 haloalkyl. In some embodiments, R 2 is 4-membered heterocycloalkyl optionally substituted with one or more C1-C 6 alkoxy.
  • R 2 is 4-membered heterocycloalkyl optionally substituted with one or more C1-C 6 haloalkoxy. In some embodiments, R 2 is 4-membered heterocycloalkyl optionally substituted with one or more halo. In some embodiments, R 2 is 4-membered heterocycloalkyl optionally substituted with one or more -CN. In some embodiments, R 2 is 4- membered heterocycloalkyl optionally substituted with one or more -OH. In some embodiments, R 2 is 4-membered heterocycloalkyl optionally substituted with one or more -NH2.
  • R 2 is 4-membered heterocycloalkyl optionally substituted with one or more - NH(CI-C6 alkyl). In some embodiments, R 2 is 4-membered heterocycloalkyl optionally substituted with one or more -N(CI-C6 alkyl)2. In some embodiments, R 2 is 4-membered heterocycloalkyl optionally substituted with one or more oxo.
  • R 2 is 5-membered heterocycloalkyl.
  • R 2 is 5-membered heterocycloalkyl heteroaryl optionally substituted with one or more C1-C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, C1-C 6 haloalkyl, C1-C 6 alkoxy, C1-C 6 haloalkoxy, halo, -CN, -OH, -NH2, -NH(CI-C6 alkyl), -N(CI-C6 alkyl)2, oxo, - C(0)R2S, -C(0)OR2S, or -C(0)N(R2S)2.
  • R 2 is 5-membered heterocycloalkyl optionally substituted with one or more C1-C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, C1-C 6 haloalkyl, C1-C 6 alkoxy, C1-C 6 haloalkoxy, halo, -CN, -OH, -NH2, -NH(CI-C6 alkyl), -N(CI-C6 alkyl)2, or oxo.
  • R 2 is 5-membered heterocycloalkyl optionally substituted with one or more C1-C 6 alkyl. In some embodiments, R 2 is 5-membered heterocycloalkyl optionally substituted with one or more C2-C 6 alkenyl. In some embodiments, R 2 is 5-membered
  • R 2 is 5-membered heterocycloalkyl optionally substituted with one or more C2-C 6 alkynyl.
  • R 2 is 5-membered heterocycloalkyl optionally substituted with one or more C1-C 6 haloalkyl.
  • R 2 is 5-membered heterocycloalkyl optionally substituted with one or more C1-C 6 alkoxy.
  • R 2 is 5-membered heterocycloalkyl optionally substituted with one or more C1-C 6 haloalkoxy.
  • R 2 is 5-membered heterocycloalkyl optionally substituted with one or more halo.
  • R 2 is 5-membered heterocycloalkyl optionally substituted with one or more -CN. In some embodiments, R 2 is 5- membered heterocycloalkyl optionally substituted with one or more -OH. In some embodiments, R 2 is 5-membered heterocycloalkyl optionally substituted with one or more -NH2. In some embodiments, R 2 is 5-membered heterocycloalkyl optionally substituted with one or more - NH(CI-C6 alkyl). In some embodiments, R 2 is 5-membered heterocycloalkyl optionally substituted with one or more -N(CI-C6 alkyl)2. In some embodiments, R 2 is 5-membered heterocycloalkyl optionally substituted with one or more oxo.
  • R 2 is 6-membered heterocycloalkyl.
  • R 2 is 6-membered heterocycloalkyl heteroaryl optionally substituted with one or more C1-C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, C1-C 6 haloalkyl, C1-C 6 alkoxy, C1-C 6 haloalkoxy, halo, -CN, -OH, -NH2, -NH(CI-C6 alkyl), -N(CI-C6 alkyl)2, oxo, - C(0)R2S, -C(0)OR2S, or -C(0)N(R2S)2.
  • R 2 is 6-membered heterocycloalkyl optionally substituted with one or more C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, -CN, -OH, -NH2, -NH(CI-C6 alkyl), -N(CI-C6 alkyl)2, or oxo.
  • R 2 is 6-membered heterocycloalkyl optionally substituted with one or more C1-C 6 alkyl. In some embodiments, R 2 is 6-membered heterocycloalkyl optionally substituted with one or more C2-C 6 alkenyl. In some embodiments, R 2 is 6-membered
  • R 2 is 6-membered heterocycloalkyl optionally substituted with one or more C2-C 6 alkynyl.
  • R 2 is 6-membered heterocycloalkyl optionally substituted with one or more C1-C 6 haloalkyl.
  • R 2 is 6-membered heterocycloalkyl optionally substituted with one or more C1-C 6 alkoxy.
  • R 2 is 6-membered heterocycloalkyl optionally substituted with one or more C1-C 6 haloalkoxy.
  • R 2 is 6-membered heterocycloalkyl optionally substituted with one or more halo.
  • R 2 is 6-membered heterocycloalkyl optionally substituted with one or more -CN. In some embodiments, R 2 is 6- membered heterocycloalkyl optionally substituted with one or more -OH. In some embodiments, R 2 is 6-membered heterocycloalkyl optionally substituted with one or more -NH2. In some embodiments, R 2 is 6-membered heterocycloalkyl optionally substituted with one or more - NH(CI-C6 alkyl). In some embodiments, R 2 is 6-membered heterocycloalkyl optionally substituted with one or more -N(CI-C6 alkyl)2. In some embodiments, R 2 is 6-membered heterocycloalkyl optionally substituted with one or more oxo.
  • R 2 is 7-membered heterocycloalkyl.
  • R 2 is 7-membered heterocycloalkyl heteroaryl optionally substituted with one or more C1-C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, C1-C 6 haloalkyl, C1-C 6 alkoxy, C1-C 6 haloalkoxy, halo, -CN, -OH, -NH2, -NH(CI-C6 alkyl), -N(CI-C6 alkyl)2, oxo, - C(0)R2S, -C(0)0R2S, or -C(0)N(R2S)2.
  • R 2 is 7-membered heterocycloalkyl optionally substituted with one or more C1-C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, C1-C 6 haloalkyl, C1-C 6 alkoxy, C1-C 6 haloalkoxy, halo, -CN, -OH, -NH2, -NH(CI-C6 alkyl), -N(CI-C6 alkyl)2, or oxo.
  • R 2 is 7-membered heterocycloalkyl optionally substituted with one or more C1-C 6 alkyl. In some embodiments, R 2 is 7-membered heterocycloalkyl optionally substituted with one or more C2-C 6 alkenyl. In some embodiments, R 2 is 7-membered
  • R 2 is 7-membered heterocycloalkyl optionally substituted with one or more C2-C 6 alkynyl.
  • R 2 is 7-membered heterocycloalkyl optionally substituted with one or more C1-C 6 haloalkyl.
  • R 2 is 7-membered heterocycloalkyl optionally substituted with one or more C1-C 6 alkoxy.
  • R 2 is 7-membered heterocycloalkyl optionally substituted with one or more C1-C 6 haloalkoxy.
  • R 2 is 7-membered heterocycloalkyl optionally substituted with one or more halo.
  • R 2 is 7-membered heterocycloalkyl optionally substituted with one or more -CN. In some embodiments, R 2 is 7- membered heterocycloalkyl optionally substituted with one or more -OH. In some embodiments, R 2 is 7-membered heterocycloalkyl optionally substituted with one or more -NH2. In some embodiments, R 2 is 7-membered heterocycloalkyl optionally substituted with one or more - NH(CI-C6 alkyl). In some embodiments, R 2 is 7-membered heterocycloalkyl optionally substituted with one or more -N(CI-C6 alkyl)2. In some embodiments, R 2 is 7-membered heterocycloalkyl optionally substituted with one or more oxo.
  • R 2 is 8-membered heterocycloalkyl.
  • R 2 is 8-membered heterocycloalkyl heteroaryl optionally substituted with one or more C1-C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, C1-C 6 haloalkyl, C1-C 6 alkoxy, C1-C 6 haloalkoxy, halo, -CN, -OH, -NH2, -NH(Ci-C6 alkyl), -N(CI-C6 alkyl)2, oxo, - C(0)R2S, -C(0)OR2S, or -C(0)N(R2S)2.
  • R 2 is 8-membered heterocycloalkyl optionally substituted with one or more C1-C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, C1-C 6 haloalkyl, C1-C 6 alkoxy, C1-C 6 haloalkoxy, halo, -CN, -OH, -NH2, -NH(Ci-C6 alkyl), -N(CI-C6 alkyl)2, or oxo.
  • R 2 is 8-membered heterocycloalkyl optionally substituted with one or more C1-C 6 alkyl. In some embodiments, R 2 is 8-membered heterocycloalkyl optionally substituted with one or more C2-C 6 alkenyl. In some embodiments, R 2 is 8-membered heterocycloalkyl optionally substituted with one or more C2-C 6 alkynyl. In some embodiments, R 2 is 8-membered heterocycloalkyl optionally substituted with one or more C1-C 6 haloalkyl. In some embodiments, R 2 is 8-membered heterocycloalkyl optionally substituted with one or more C1-C 6 alkoxy.
  • R 2 is 8-membered heterocycloalkyl optionally substituted with one or more C1-C 6 haloalkoxy. In some embodiments, R 2 is 8-membered heterocycloalkyl optionally substituted with one or more halo. In some embodiments, R 2 is 8-membered heterocycloalkyl optionally substituted with one or more -CN. In some embodiments, R 2 is 8- membered heterocycloalkyl optionally substituted with one or more -OH. In some embodiments, R 2 is 8-membered heterocycloalkyl optionally substituted with one or more -NH2.
  • R 2 is 8-membered heterocycloalkyl optionally substituted with one or more - NH(CI-C 6 alkyl). In some embodiments, R 2 is 8-membered heterocycloalkyl optionally substituted with one or more -N(CI-C 6 alkyl)2. In some embodiments, R 2 is 8-membered heterocycloalkyl optionally substituted with one or more oxo.
  • R 2 is furanyl
  • R 2 is furanyl optionally substituted with one or more C1-C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, C1-C 6 haloalkyl, C1-C 6 alkoxy, C1-C 6 haloalkoxy, halo, -CN, -OH, -NH 2 , -NH(CI-C 6 alkyl), -N(Ci-Ce alkyl) 2 , oxo, -C(0)R 2 s, -C(0)OR 2 s, or -C(0)N(R 2 s)2.
  • R 2 is furanyl optionally substituted with one or more C1-C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, C1-C 6 haloalkyl, C1-C 6 alkoxy, C1-C 6 haloalkoxy, halo, -CN, -OH, -NH2, -NH(CI-C 6 alkyl), -N(CI-C 6 alkyl)2, or oxo.
  • R 2 is furanyl optionally substituted with one or more C1-C 6 alkyl. In some embodiments, R 2 is furanyl optionally substituted with one or more methyl. In some embodiments, R 2 is furanyl optionally substituted with one or more ethyl. In some embodiments, R 2 is furanyl optionally substituted with one or more propyl. In some embodiments, R 2 is furanyl optionally substituted with one or more butyl. In some embodiments, R 2 is furanyl optionally substituted with one or more pentyl. In some embodiments, R 2 is furanyl optionally substituted with one or more hexyl.
  • R 2 is furanyl optionally substituted with one or more isopropyl. In some embodiments, R 2 is furanyl optionally substituted with one or more isobutyl. In some embodiments, R 2 is furanyl optionally substituted with one or more isopentyl. In some embodiments, R 2 is furanyl optionally substituted with one or more isohexyl. In some embodiments, R 2 is furanyl optionally substituted with one or more secbutyl. In some embodiments, R 2 is furanyl optionally substituted with one or more secpentyl. In some embodiments, R 2 is furanyl optionally substituted with one or more sechexyl. In some embodiments, R 2 is furanyl optionally substituted with one or more tertbutyl.
  • R 2 is furanyl optionally substituted with one or more C2-C 6 alkenyl. In some embodiments, R 2 is furanyl optionally substituted with one or more C2-C 6 alkynyl.
  • R 2 is furanyl optionally substituted with one or more C1-C 6 haloalkyl. In some embodiments, R 2 is furanyl optionally substituted with one or more halomethyl. In some embodiments, R 2 is furanyl optionally substituted with one or more haloethyl. In some embodiments, R 2 is furanyl optionally substituted with one or more halopropyl. In some embodiments, R 2 is furanyl optionally substituted with one or more halobutyl. In some embodiments, R 2 is furanyl optionally substituted with one or more halopentyl. In some embodiments, R 2 is furanyl optionally substituted with one or more halohexyl.
  • R 2 is furanyl optionally substituted with one or more C1-C 6 alkoxy. In some embodiments, R 2 is furanyl optionally substituted with one or more methoxy. In some embodiments, R 2 is furanyl optionally substituted with one or more ethoxy. In some embodiments, R 2 is furanyl optionally substituted with one or more propoxy. In some embodiments, R 2 is furanyl optionally substituted with one or more butoxy. In some
  • R 2 is furanyl optionally substituted with one or more pentoxy. In some embodiments, R 2 is furanyl optionally substituted with one or more hexoxy.
  • R 2 is furanyl optionally substituted with one or more C1-C 6 haloalkoxy. In some embodiments, R 2 is furanyl optionally substituted with one or more halomethoxy. In some embodiments, R 2 is furanyl optionally substituted with one or more haloethoxy. In some embodiments, R 2 is furanyl optionally substituted with one or more halopropoxy. In some embodiments, R 2 is furanyl optionally substituted with one or more halobutoxy. In some embodiments, R 2 is furanyl optionally substituted with one or more halopentoxy. In some embodiments, R 2 is furanyl optionally substituted with one or more halohexoxy.
  • R 2 is furanyl optionally substituted with one or more halo. In some embodiments, R 2 is furanyl optionally substituted with one or more F, Cl, Br, or I. In some embodiments, R 2 is furanyl optionally substituted with one or more F or Cl. In some embodiments,
  • R 2 is furanyl optionally substituted with one or more F. In some embodiments, R 2 is furanyl optionally substituted with one or more Cl.
  • R 2 is furanyl optionally substituted with one or more -CN. In some embodiments, R 2 is furanyl optionally substituted with one or more -OH. In some embodiments, R 2 is furanyl optionally substituted with one or more -NH2.
  • R 2 is furanyl optionally substituted with one or more -NH(CI-C 6 alkyl). In some embodiments, R 2 is furanyl optionally substituted with one or more -NH(methyl). In some embodiments, R 2 is furanyl optionally substituted with one or more -NH(ethyl). In some embodiments, R 2 is furanyl optionally substituted with one or more -NH(propyl). In some embodiments, R 2 is furanyl optionally substituted with one or more -NH(butyl). In some embodiments, R 2 is furanyl optionally substituted with one or more -NH(pentyl). In some embodiments, R 2 is furanyl optionally substituted with one or more -NH(hexyl).
  • R 2 is furanyl optionally substituted with one or more -N(CI-C 6 alkyl)2.
  • R 2 is furanyl optionally substituted with one or more oxo.
  • R 2 is oxazolyl
  • R 2 is oxazolyl optionally substituted with one or more C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, -CN, -OH, -NH 2 , -NH(CI-C 6 alkyl), -N(Ci-Ce alkyl) 2 , oxo, -C(0)R 2 s, -C(0)OR 2 s, or -C(0)N(R 2 s)2.
  • R 2 is oxazolyl optionally substituted with one or more C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, -CN, -OH, -NH 2 , -NH(CI-C 6 alkyl), -N(Ci-Ce alkyl) 2 , or oxo.
  • R 2 is oxazolyl optionally substituted with one or more C1-C6 alkyl. In some embodiments, R 2 is oxazolyl optionally substituted with one or more methyl. In some embodiments, R 2 is oxazolyl optionally substituted with one or more ethyl. In some embodiments, R 2 is oxazolyl optionally substituted with one or more propyl. In some embodiments, R 2 is oxazolyl optionally substituted with one or more butyl. In some
  • R 2 is oxazolyl optionally substituted with one or more pentyl. In some embodiments, R 2 is oxazolyl optionally substituted with one or more hexyl. In some embodiments, R 2 is oxazolyl optionally substituted with one or more isopropyl. In some embodiments, R 2 is oxazolyl optionally substituted with one or more isobutyl. In some embodiments, R 2 is oxazolyl optionally substituted with one or more isopentyl. In some embodiments, R 2 is oxazolyl optionally substituted with one or more isohexyl.
  • R 2 is oxazolyl optionally substituted with one or more secbutyl. In some embodiments, R 2 is oxazolyl optionally substituted with one or more secpentyl. In some embodiments, R 2 is oxazolyl optionally substituted with one or more sechexyl. In some embodiments, R 2 is oxazolyl optionally substituted with one or more tertbutyl.
  • R 2 is oxazolyl optionally substituted with one or more C2-C 6 alkenyl. In some embodiments, R 2 is oxazolyl optionally substituted with one or more C2-C 6 alkynyl.
  • R 2 is oxazolyl optionally substituted with one or more C1-C 6 haloalkyl. In some embodiments, R 2 is oxazolyl optionally substituted with one or more halomethyl. In some embodiments, R 2 is oxazolyl optionally substituted with one or more haloethyl. In some embodiments, R 2 is oxazolyl optionally substituted with one or more halopropyl. In some embodiments, R 2 is oxazolyl optionally substituted with one or more halobutyl. In some embodiments, R 2 is oxazolyl optionally substituted with one or more halopentyl. In some embodiments, R 2 is oxazolyl optionally substituted with one or more halohexyl.
  • R 2 is oxazolyl optionally substituted with one or more C1-C 6 alkoxy. In some embodiments, R 2 is oxazolyl optionally substituted with one or more methoxy. In some embodiments, R 2 is oxazolyl optionally substituted with one or more ethoxy. In some embodiments, R 2 is oxazolyl optionally substituted with one or more propoxy. In some embodiments, R 2 is oxazolyl optionally substituted with one or more butoxy. In some embodiments, R 2 is oxazolyl optionally substituted with one or more pentoxy. In some embodiments, R 2 is oxazolyl optionally substituted with one or more hexoxy.
  • R 2 is oxazolyl optionally substituted with one or more C1-C 6 haloalkoxy. In some embodiments, R 2 is oxazolyl optionally substituted with one or more halomethoxy. In some embodiments, R 2 is oxazolyl optionally substituted with one or more haloethoxy. In some embodiments, R 2 is oxazolyl optionally substituted with one or more halopropoxy. In some embodiments, R 2 is oxazolyl optionally substituted with one or more halobutoxy. In some embodiments, R 2 is oxazolyl optionally substituted with one or more halopentoxy. In some embodiments, R 2 is oxazolyl optionally substituted with one or more halohexoxy.
  • R 2 is oxazolyl optionally substituted with one or more halo. In some embodiments, R 2 is oxazolyl optionally substituted with one or more F, Cl, Br, or I. In some embodiments, R 2 is oxazolyl optionally substituted with one or more F or Cl. In some embodiments, R 2 is oxazolyl optionally substituted with one or more F. In some embodiments,
  • R2 is oxazolyl optionally substituted with one or more Cl.
  • R 2 is oxazolyl optionally substituted with one or more -CN. In some embodiments, R 2 is oxazolyl optionally substituted with one or more -OH. In some embodiments, R 2 is oxazolyl optionally substituted with one or more -NH2.
  • R 2 is oxazolyl optionally substituted with one or more -NH(CI-C 6 alkyl). In some embodiments, R 2 is oxazolyl optionally substituted with one or more - NH(methyl). In some embodiments, R 2 is oxazolyl optionally substituted with one or more - NH(ethyl). In some embodiments, R 2 is oxazolyl optionally substituted with one or more - NH(propyl). In some embodiments, R 2 is oxazolyl optionally substituted with one or more - NH(butyl).
  • R 2 is oxazolyl optionally substituted with one or more - NH(pentyl). In some embodiments, R 2 is oxazolyl optionally substituted with one or more - NH(hexyl).
  • R 2 is oxazolyl optionally substituted with one or more -N(CI-C6 alkyl)2.
  • R 2 is oxazolyl optionally substituted with one or more oxo.
  • R 2 is isoxazolyl
  • R 2 is isoxazolyl optionally substituted with one or more C1-C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, C1-C 6 haloalkyl, C1-C 6 alkoxy, C1-C 6 haloalkoxy, halo, -CN, -OH, -NH2, -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl) 2 , oxo, -C(0)R 2 s, -C(0)OR 2 s, or -C(0)N(R 2 s)2.
  • R 2 is isoxazolyl optionally substituted with one or more C1-C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, C1-C 6 haloalkyl, C1-C 6 alkoxy, C1-C 6 haloalkoxy, halo, -CN, -OH, -NH 2 , -NH(CI-C 6 alkyl), -N(Ci-Ce alkyl) 2 , or oxo.
  • R 2 is isoxazolyl optionally substituted with one or more C1-C 6 alkyl. In some embodiments, R 2 is isoxazolyl optionally substituted with one or more methyl. In some embodiments, R 2 is isoxazolyl optionally substituted with one or more ethyl. In some embodiments, R 2 is isoxazolyl optionally substituted with one or more propyl. In some embodiments, R 2 is isoxazolyl optionally substituted with one or more butyl. In some
  • R 2 is isoxazolyl optionally substituted with one or more pentyl. In some embodiments, R 2 is isoxazolyl optionally substituted with one or more hexyl. In some embodiments, R 2 is isoxazolyl optionally substituted with one or more isopropyl. In some embodiments, R 2 is isoxazolyl optionally substituted with one or more isobutyl. In some embodiments, R 2 is isoxazolyl optionally substituted with one or more isopentyl. In some embodiments, R 2 is isoxazolyl optionally substituted with one or more isohexyl.
  • R 2 is isoxazolyl optionally substituted with one or more secbutyl. In some embodiments, R 2 is isoxazolyl optionally substituted with one or more secpentyl. In some embodiments, R 2 is isoxazolyl optionally substituted with one or more sechexyl. In some embodiments, R 2 is isoxazolyl optionally substituted with one or more tertbutyl. [0275] In some embodiments, R 2 is isoxazolyl optionally substituted with one or more C2-C 6 alkenyl. In some embodiments, R 2 is isoxazolyl optionally substituted with one or more C2-C 6 alkynyl.
  • R 2 is isoxazolyl optionally substituted with one or more C1-C 6 haloalkyl. In some embodiments, R 2 is isoxazolyl optionally substituted with one or more halomethyl. In some embodiments, R 2 is isoxazolyl optionally substituted with one or more haloethyl. In some embodiments, R 2 is isoxazolyl optionally substituted with one or more halopropyl. In some embodiments, R 2 is isoxazolyl optionally substituted with one or more halobutyl. In some embodiments, R 2 is isoxazolyl optionally substituted with one or more halopentyl. In some embodiments, R 2 is isoxazolyl optionally substituted with one or more halohexyl.
  • R 2 is isoxazolyl optionally substituted with one or more C1-C 6 alkoxy. In some embodiments, R 2 is isoxazolyl optionally substituted with one or more methoxy. In some embodiments, R 2 is isoxazolyl optionally substituted with one or more ethoxy. In some embodiments, R 2 is isoxazolyl optionally substituted with one or more propoxy. In some embodiments, R 2 is isoxazolyl optionally substituted with one or more butoxy. In some embodiments, R 2 is isoxazolyl optionally substituted with one or more pentoxy. In some embodiments, R 2 is isoxazolyl optionally substituted with one or more hexoxy.
  • R 2 is isoxazolyl optionally substituted with one or more C1-C 6 haloalkoxy. In some embodiments, R 2 is isoxazolyl optionally substituted with one or more halomethoxy. In some embodiments, R 2 is isoxazolyl optionally substituted with one or more haloethoxy. In some embodiments, R 2 is isoxazolyl optionally substituted with one or more halopropoxy. In some embodiments, R 2 is isoxazolyl optionally substituted with one or more halobutoxy. In some embodiments, R 2 is isoxazolyl optionally substituted with one or more halopentoxy. In some embodiments, R 2 is isoxazolyl optionally substituted with one or more halohexoxy.
  • R 2 is isoxazolyl optionally substituted with one or more halo. In some embodiments, R 2 is isoxazolyl optionally substituted with one or more F, Cl, Br, or I. In some embodiments, R 2 is isoxazolyl optionally substituted with one or more F or Cl. In some embodiments, R 2 is isoxazolyl optionally substituted with one or more F. In some embodiments, R 2 is isoxazolyl optionally substituted with one or more Cl. [0280] In some embodiments, R 2 is isoxazolyl optionally substituted with one or more -CN. In some embodiments, R 2 is isoxazolyl optionally substituted with one or more -OH. In some embodiments, R 2 is isoxazolyl optionally substituted with one or more -NH2.
  • R 2 is isoxazolyl optionally substituted with one or more -NH(Ci- Ce alkyl). In some embodiments, R 2 is isoxazolyl optionally substituted with one or more - NH(methyl). In some embodiments, R 2 is isoxazolyl optionally substituted with one or more - NH(ethyl). In some embodiments, R 2 is isoxazolyl optionally substituted with one or more - NH(propyl). In some embodiments, R 2 is isoxazolyl optionally substituted with one or more - NH(butyl).
  • R 2 is isoxazolyl optionally substituted with one or more - NH(pentyl). In some embodiments, R 2 is isoxazolyl optionally substituted with one or more - NH(hexyl).
  • R 2 is isoxazolyl optionally substituted with one or more -N(CI-C 6 alkyl)2.
  • R 2 is isoxazolyl optionally substituted with one or more oxo.
  • R 2 is thiazolyl
  • R 2 is thiazolyl optionally substituted with one or more C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, -CN, -OH, -NH 2 , -NH(CI-C 6 alkyl), -N(Ci-Ce alkyl) 2 , oxo, -C(0)R 2 s, -C(0)OR 2 s, or -C(0)N(R 2 s)2.
  • R 2 is thiazolyl optionally substituted with one or more C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, -CN, -OH, -NH2, -NH(CI-C 6 alkyl), -N(Ci-Ce alkyl) 2 , or oxo.
  • R 2 is thiazolyl optionally substituted with one or more C1-C6 alkyl. In some embodiments, R 2 is thiazolyl optionally substituted with one or more methyl. In some embodiments, R 2 is thiazolyl optionally substituted with one or more ethyl. In some embodiments, R 2 is thiazolyl optionally substituted with one or more propyl. In some
  • R 2 is thiazolyl optionally substituted with one or more butyl.
  • R 2 is thiazolyl optionally substituted with one or more pentyl.
  • R 2 is thiazolyl optionally substituted with one or more hexyl. In some embodiments, R 2 is thiazolyl optionally substituted with one or more isopropyl. In some embodiments, R 2 is thiazolyl optionally substituted with one or more isobutyl. In some embodiments, R 2 is thiazolyl optionally substituted with one or more isopentyl. In some embodiments, R 2 is thiazolyl optionally substituted with one or more isohexyl. In some embodiments, R 2 is thiazolyl optionally substituted with one or more secbutyl. In some embodiments, R 2 is thiazolyl optionally substituted with one or more secpentyl. In some embodiments, R 2 is thiazolyl optionally substituted with one or more sechexyl. In some embodiments, R 2 is thiazolyl optionally substituted with one or more tertbutyl.
  • R 2 is thiazolyl optionally substituted with one or more C2-C 6 alkenyl. In some embodiments, R 2 is thiazolyl optionally substituted with one or more C2-C 6 alkynyl.
  • R 2 is thiazolyl optionally substituted with one or more C1-C 6 haloalkyl. In some embodiments, R 2 is thiazolyl optionally substituted with one or more halomethyl. In some embodiments, R 2 is thiazolyl optionally substituted with one or more haloethyl. In some embodiments, R 2 is thiazolyl optionally substituted with one or more halopropyl. In some embodiments, R 2 is thiazolyl optionally substituted with one or more halobutyl. In some embodiments, R 2 is thiazolyl optionally substituted with one or more halopentyl. In some embodiments, R 2 is thiazolyl optionally substituted with one or more halohexyl.
  • R 2 is thiazolyl optionally substituted with one or more C1-C 6 alkoxy. In some embodiments, R 2 is thiazolyl optionally substituted with one or more methoxy. In some embodiments, R 2 is thiazolyl optionally substituted with one or more ethoxy. In some embodiments, R 2 is thiazolyl optionally substituted with one or more propoxy. In some embodiments, R 2 is thiazolyl optionally substituted with one or more butoxy. In some embodiments, R 2 is thiazolyl optionally substituted with one or more pentoxy. In some embodiments, R 2 is thiazolyl optionally substituted with one or more hexoxy.
  • R 2 is thiazolyl optionally substituted with one or more C1-C 6 haloalkoxy. In some embodiments, R 2 is thiazolyl optionally substituted with one or more halomethoxy. In some embodiments, R 2 is thiazolyl optionally substituted with one or more haloethoxy. In some embodiments, R 2 is thiazolyl optionally substituted with one or more halopropoxy. In some embodiments, R 2 is thiazolyl optionally substituted with one or more halobutoxy. In some embodiments, R2 is thiazolyl optionally substituted with one or more halopentoxy. In some embodiments, R2 is thiazolyl optionally substituted with one or more halohexoxy.
  • R2 is thiazolyl optionally substituted with one or more halo. In some embodiments, R2 is thiazolyl optionally substituted with one or more F, Cl, Br, or I. In some embodiments, R2 is thiazolyl optionally substituted with one or more F or Cl. In some embodiments, R2 is thiazolyl optionally substituted with one or more F. In some embodiments, R 2 is thiazolyl optionally substituted with one or more Cl.
  • R2 is thiazolyl optionally substituted with one or more -CN. In some embodiments, R2 is thiazolyl optionally substituted with one or more -OH. In some embodiments, R2 is thiazolyl optionally substituted with one or more -NH2.
  • R2 is thiazolyl optionally substituted with one or more -NH(Ci- Ce alkyl). In some embodiments, R2 is thiazolyl optionally substituted with one or more - NH(methyl). In some embodiments, R2 is thiazolyl optionally substituted with one or more - NH(ethyl). In some embodiments, R2 is thiazolyl optionally substituted with one or more - NH(propyl). In some embodiments, R2 is thiazolyl optionally substituted with one or more - NH(butyl). In some embodiments, R2 is thiazolyl optionally substituted with one or more - NH(pentyl). In some embodiments, R2 is thiazolyl optionally substituted with one or more - NH(hexyl).
  • R2 is thiazolyl optionally substituted with one or more -N(CI-C 6 alkyl)2.
  • R2 is thiazolyl optionally substituted with one or more oxo.
  • R2 is thiazolyl optionally substituted with one or more -C(0)R2S,
  • R2 is thiazolyl optionally substituted with one or more -C(0)R2S.
  • R2 is thiazolyl optionally substituted with one or more -C(0)-(4- to 8-membered heterocycloalkyl).
  • R2 is or , wherein * denotes an attachment of R2 to the adjacent nitrogen atom, and ** denotes an attachment of R2 to the adjacent carbon atom.
  • R2 is 1,3,4-oxadizolyl.
  • R2 is 1,3,4-oxadizolyl optionally substituted with one or more Ci- Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, - CN, -OH, -NH2, -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl) 2 , oxo, -C(0)R 2 s, -C(0)OR 2 s, or - C(0)N(R2S)2.
  • R2 is 1,3,4-oxadizolyl optionally substituted with one or more Ci- Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, - CN, -OH, -NH 2 , -NH(CI-C 6 alkyl), -N(Ci-Ce alkyl) 2 , or oxo.
  • R2 is 1,3,4-oxadizolyl optionally substituted with one or more Ci- Ce alkyl. In some embodiments, R2 is 1,3,4-oxadizolyl optionally substituted with one or more methyl. In some embodiments, R2 is 1,3,4-oxadizolyl optionally substituted with one or more ethyl. In some embodiments, R2 is 1,3,4-oxadizolyl optionally substituted with one or more propyl. In some embodiments, R2 is 1,3,4-oxadizolyl optionally substituted with one or more butyl.
  • R2 is 1,3,4-oxadizolyl optionally substituted with one or more pentyl. In some embodiments, R2 is 1,3,4-oxadizolyl optionally substituted with one or more hexyl. In some embodiments, R2 is 1,3,4-oxadizolyl optionally substituted with one or more isopropyl. In some embodiments, R2 is 1,3,4-oxadizolyl optionally substituted with one or more isobutyl. In some embodiments, R2 is 1,3,4-oxadizolyl optionally substituted with one or more isopentyl.
  • R2 is 1,3,4-oxadizolyl optionally substituted with one or more isohexyl. In some embodiments, R2 is 1,3,4-oxadizolyl optionally substituted with one or more secbutyl. In some embodiments, R2 is 1,3,4-oxadizolyl optionally substituted with one or more secpentyl. In some embodiments, R2 is 1,3,4-oxadizolyl optionally substituted with one or more sechexyl. In some embodiments, R2 is 1,3,4-oxadizolyl optionally substituted with one or more tertbutyl.
  • R2 is 1,3,4-oxadizolyl optionally substituted with one or more C2- Ce alkenyl. In some embodiments, R2 is 1,3,4-oxadizolyl optionally substituted with one or more C2-C6 alkynyl.
  • R2 is 1,3,4-oxadizolyl optionally substituted with one or more Ci- Ce haloalkyl. In some embodiments, R2 is 1,3,4-oxadizolyl optionally substituted with one or more halomethyl. In some embodiments, R2 is 1,3,4-oxadizolyl optionally substituted with one or more haloethyl. In some embodiments, R2 is 1,3,4-oxadizolyl optionally substituted with one or more halopropyl. In some embodiments, R2 is 1,3,4-oxadizolyl optionally substituted with one or more halobutyl.
  • R2 is 1,3,4-oxadizolyl optionally substituted with one or more halopentyl. In some embodiments, R2 is 1,3,4-oxadizolyl optionally substituted with one or more halohexyl.
  • R2 is 1,3,4-oxadizolyl optionally substituted with one or more Ci- Ce alkoxy. In some embodiments, R2 is 1,3,4-oxadizolyl optionally substituted with one or more methoxy. In some embodiments, R2 is 1,3,4-oxadizolyl optionally substituted with one or more ethoxy. In some embodiments, R2 is 1,3,4-oxadizolyl optionally substituted with one or more propoxy. In some embodiments, R2 is 1,3,4-oxadizolyl optionally substituted with one or more butoxy. In some embodiments, R2 is 1,3,4-oxadizolyl optionally substituted with one or more pentoxy. In some embodiments, R2 is 1,3,4-oxadizolyl optionally substituted with one or more hexoxy.
  • R2 is 1,3,4-oxadizolyl optionally substituted with one or more Ci- Ce haloalkoxy. In some embodiments, R2 is 1,3,4-oxadizolyl optionally substituted with one or more halomethoxy. In some embodiments, R2 is 1,3,4-oxadizolyl optionally substituted with one or more haloethoxy. In some embodiments, R2 is 1,3,4-oxadizolyl optionally substituted with one or more halopropoxy. In some embodiments, R2 is 1,3,4-oxadizolyl optionally substituted with one or more halobutoxy.
  • R2 is 1,3,4-oxadizolyl optionally substituted with one or more halopentoxy. In some embodiments, R2 is 1,3,4-oxadizolyl optionally substituted with one or more halohexoxy.
  • R2 is 1,3,4-oxadizolyl optionally substituted with one or more halo. In some embodiments, R2 is 1,3,4-oxadizolyl optionally substituted with one or more F, Cl, Br, or I. In some embodiments, R2 is 1,3,4-oxadizolyl optionally substituted with one or more F or Cl. In some embodiments, R2 is 1,3,4-oxadizolyl optionally substituted with one or more F. In some embodiments, R2 is 1,3,4-oxadizolyl optionally substituted with one or more Cl.
  • R2 is 1,3,4-oxadizolyl optionally substituted with one or more - CN. In some embodiments, R2 is 1,3,4-oxadizolyl optionally substituted with one or more -OH. In some embodiments, R2 is 1,3,4-oxadizolyl optionally substituted with one or more -NH2.
  • R2 is 1,3,4-oxadizolyl optionally substituted with one or more - NH(CI-C 6 alkyl). In some embodiments, R2 is 1,3,4-oxadizolyl optionally substituted with one or more -NH(methyl). In some embodiments, R2 is 1,3,4-oxadizolyl optionally substituted with one or more -NH(ethyl). In some embodiments, R2 is 1,3,4-oxadizolyl optionally substituted with one or more -NH(propyl). In some embodiments, R2 is 1,3,4-oxadizolyl optionally substituted with one or more -NH(butyl).
  • R2 is 1,3,4-oxadizolyl optionally substituted with one or more -NH(pentyl). In some embodiments, R2 is 1,3,4-oxadizolyl optionally substituted with one or more -NH(hexyl).
  • R2 is 1,3,4-oxadizolyl optionally substituted with one or more - N(Ci-Ce alkyl) 2.
  • R2 is 1,3,4-oxadizolyl optionally substituted with one or more oxo.
  • R2 is , wherein * denotes an attachment of R2 to the adjacent nitrogen atom, and ** denotes an attachment of R2 to the adjacent carbon atom.
  • R2 is 477-1,2,4-triazolyl.
  • R2 is 4/7- 1 ,2,4-triazolyl optionally substituted with one or more C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, -CN, -OH, -NH 2 , -NH(Ci-C 6 alkyl), -N(Ci-Ce alkyl) 2 , oxo, -C(0)R 2 s, -C(0)OR 2 s, or - C(0)N(R2S)2.
  • R2 is 477-1,2,4-triazolyl optionally substituted with one or more C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, -CN, -OH, -NH2, -NH(Ci-C 6 alkyl), -N(Ci-Ce alkyl) 2 , or oxo.
  • R2 is 477-1,2,4-triazolyl optionally substituted with one or more C1-C6 alkyl. In some embodiments, R2 is 477-1,2,4-triazolyl optionally substituted with one or more methyl. In some embodiments, R2 is 477-1,2,4-triazolyl optionally substituted with one or more ethyl. In some embodiments, R2 is 4/7- 1 ,2,4-triazolyl optionally substituted with one or more propyl. In some embodiments, R2 is 477-1,2,4-triazolyl optionally substituted with one or more butyl.
  • R2 is 477-1,2,4-triazolyl optionally substituted with one or more pentyl. In some embodiments, R2 is 477-1,2,4-triazolyl optionally substituted with one or more hexyl. In some embodiments, R2 is 477-1,2,4-triazolyl optionally substituted with one or more isopropyl. In some embodiments, R2 is 477-1,2,4-triazolyl optionally substituted with one or more isobutyl. In some embodiments, R2 is 477-1,2,4-triazolyl optionally substituted with one or more isopentyl.
  • R2 is 477-1,2,4-triazolyl optionally substituted with one or more isohexyl. In some embodiments, R2 is 477-1,2,4-triazolyl optionally substituted with one or more secbutyl. In some embodiments, R2 is 477-1,2,4-triazolyl optionally substituted with one or more secpentyl. In some embodiments, R2 is 477-1,2,4-triazolyl optionally substituted with one or more sechexyl. In some embodiments, R2 is 477-1,2,4-triazolyl optionally substituted with one or more tertbutyl.
  • R2 is 477-1,2,4-triazolyl optionally substituted with one or more C2-C6 alkenyl. In some embodiments, R2 is 477-1,2,4-triazolyl optionally substituted with one or more C2-C6 alkynyl.
  • R2 is 477-1,2,4-triazolyl optionally substituted with one or more C1-C6 haloalkyl. In some embodiments, R2 is 477-1,2,4-triazolyl optionally substituted with one or more halomethyl. In some embodiments, R2 is 477-1,2,4-triazolyl optionally substituted with one or more haloethyl. In some embodiments, R2 is 477-1,2,4-triazolyl optionally substituted with one or more halopropyl. In some embodiments, R2 is 477-1,2,4-triazolyl optionally substituted with one or more halobutyl.
  • R2 is 477-1,2,4-triazolyl optionally substituted with one or more halopentyl. In some embodiments, R2 is 477-1,2,4-triazolyl optionally substituted with one or more halohexyl.
  • R2 is 477-1,2,4-triazolyl optionally substituted with one or more C1-C6 alkoxy. In some embodiments, R2 is 477-1,2,4-triazolyl optionally substituted with one or more methoxy. In some embodiments, R2 is 477-1,2,4-triazolyl optionally substituted with one or more ethoxy. In some embodiments, R2 is 477-1,2,4-triazolyl optionally substituted with one or more propoxy. In some embodiments, R2 is 477-1,2,4-triazolyl optionally substituted with one or more butoxy.
  • R2 is 477-1,2,4-triazolyl optionally substituted with one or more pentoxy. In some embodiments, R2 is 4/7- 1 ,2,4-triazolyl optionally substituted with one or more hexoxy.
  • R2 is 477-1,2,4-triazolyl optionally substituted with one or more C1-C6 haloalkoxy. In some embodiments, R2 is 477-1,2,4-triazolyl optionally substituted with one or more halomethoxy. In some embodiments, R2 is 477-1,2,4-triazolyl optionally substituted with one or more haloethoxy. In some embodiments, R2 is 477-1,2,4-triazolyl optionally substituted with one or more halopropoxy. In some embodiments, R2 is 477-1,2,4-triazolyl optionally substituted with one or more halobutoxy.
  • R2 is 477-1,2,4-triazolyl optionally substituted with one or more halopentoxy. In some embodiments, R2 is 477-1,2,4- triazolyl optionally substituted with one or more halohexoxy.
  • R2 is 477-1,2,4-triazolyl optionally substituted with one or more halo. In some embodiments, R2 is 477-1,2,4-triazolyl optionally substituted with one or more F, Cl, Br, or I. In some embodiments, R2 is 477-1,2,4-triazolyl optionally substituted with one or more F or Cl. In some embodiments, R2 is 477-1,2,4-triazolyl optionally substituted with one or more F. In some embodiments, R2 is 477-1,2,4-triazolyl optionally substituted with one or more Cl.
  • R2 is 477-1,2,4-triazolyl optionally substituted with one or more - CN. In some embodiments, R2 is 477-1,2,4-triazolyl optionally substituted with one or more - OH. In some embodiments, R2 is 477-1,2,4-triazolyl optionally substituted with one or more - NH2.
  • R2 is 477-1,2,4-triazolyl optionally substituted with one or more - NH(CI-C 6 alkyl). In some embodiments, R2 is 477-1,2,4-triazolyl optionally substituted with one or more -NH(methyl). In some embodiments, R2 is 477-1,2,4-triazolyl optionally substituted with one or more -NH(ethyl). In some embodiments, R2 is 477-1,2,4-triazolyl optionally substituted with one or more -NH(propyl). In some embodiments, R2 is 477-1,2,4-triazolyl optionally substituted with one or more -NH(butyl).
  • R2 is 477-1,2,4-triazolyl optionally substituted with one or more -NH(pentyl). In some embodiments, R2 is 477-1,2,4- triazolyl optionally substituted with one or more -NH(hexyl).
  • R2 is 477-1,2,4-triazolyl optionally substituted with one or more - N(Ci-Ce alkyl) 2.
  • R 2 is 4/7- 1 ,2,4-triazolyl optionally substituted with one or more oxo.
  • R 2 is pyridinyl
  • R 2 is pyridinyl optionally substituted with one or more C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, -CN, -OH, -NH2, -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl) 2 , oxo, -C(0)R 2 s, -C(0)OR 2 s, or -C(0)N(R 2 s)2.
  • R 2 is pyridinyl optionally substituted with one or more C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, -CN, -OH, -NH 2 , -NH(CI-C 6 alkyl), -N(Ci-Ce alkyl) 2 , or oxo.
  • R 2 is pyridinyl optionally substituted with one or more C1-C6 alkyl. In some embodiments, R 2 is pyridinyl optionally substituted with one or more methyl. In some embodiments, R 2 is pyridinyl optionally substituted with one or more ethyl. In some embodiments, R 2 is pyridinyl optionally substituted with one or more propyl. In some
  • R 2 is pyridinyl optionally substituted with one or more butyl.
  • R 2 is pyridinyl optionally substituted with one or more pentyl.
  • R 2 is pyridinyl optionally substituted with one or more hexyl.
  • R 2 is pyridinyl optionally substituted with one or more isopropyl. In some embodiments, R 2 is pyridinyl optionally substituted with one or more isobutyl. In some embodiments, R 2 is pyridinyl optionally substituted with one or more isopentyl. In some embodiments, R 2 is pyridinyl optionally substituted with one or more isohexyl. In some embodiments, R 2 is pyridinyl optionally substituted with one or more secbutyl. In some embodiments, R 2 is pyridinyl optionally substituted with one or more secpentyl. In some embodiments, R 2 is pyridinyl optionally substituted with one or more sechexyl. In some embodiments, R 2 is pyridinyl optionally substituted with one or more tertbutyl.
  • R 2 is pyridinyl optionally substituted with one or more C2-C6 alkenyl. In some embodiments, R 2 is pyridinyl optionally substituted with one or more C2-C6 alkynyl. [0335] In some embodiments, R 2 is pyridinyl optionally substituted with one or more C1-C 6 haloalkyl. In some embodiments, R 2 is pyridinyl optionally substituted with one or more halomethyl. In some embodiments, R 2 is pyridinyl optionally substituted with one or more haloethyl. In some embodiments, R 2 is pyridinyl optionally substituted with one or more halopropyl.
  • R 2 is pyridinyl optionally substituted with one or more halobutyl. In some embodiments, R 2 is pyridinyl optionally substituted with one or more halopentyl. In some embodiments, R 2 is pyridinyl optionally substituted with one or more halohexyl.
  • R 2 is pyridinyl optionally substituted with one or more C1-C 6 alkoxy. In some embodiments, R 2 is pyridinyl optionally substituted with one or more methoxy. In some embodiments, R 2 is pyridinyl optionally substituted with one or more ethoxy. In some embodiments, R 2 is pyridinyl optionally substituted with one or more propoxy. In some embodiments, R 2 is pyridinyl optionally substituted with one or more butoxy. In some embodiments, R 2 is pyridinyl optionally substituted with one or more pentoxy. In some embodiments, R 2 is pyridinyl optionally substituted with one or more hexoxy.
  • R 2 is pyridinyl optionally substituted with one or more C1-C 6 haloalkoxy. In some embodiments, R 2 is pyridinyl optionally substituted with one or more halomethoxy. In some embodiments, R 2 is pyridinyl optionally substituted with one or more haloethoxy. In some embodiments, R 2 is pyridinyl optionally substituted with one or more halopropoxy. In some embodiments, R 2 is pyridinyl optionally substituted with one or more halobutoxy. In some embodiments, R 2 is pyridinyl optionally substituted with one or more halopentoxy. In some embodiments, R 2 is pyridinyl optionally substituted with one or more halohexoxy.
  • R 2 is pyridinyl optionally substituted with one or more halo. In some embodiments, R 2 is pyridinyl optionally substituted with one or more F, Cl, Br, or I. In some embodiments, R 2 is pyridinyl optionally substituted with one or more F or Cl. In some embodiments, R 2 is pyridinyl optionally substituted with one or more F. In some embodiments, R 2 is pyridinyl optionally substituted with one or more Cl.
  • R 2 is pyridinyl optionally substituted with one or more -CN. In some embodiments, R 2 is pyridinyl optionally substituted with one or more -OH. In some embodiments, R 2 is pyridinyl optionally substituted with one or more -NH2. [0340] In some embodiments, R 2 is pyridinyl optionally substituted with one or more -NH(Ci- Ce alkyl). In some embodiments, R 2 is pyridinyl optionally substituted with one or more - NH(methyl). In some embodiments, R 2 is pyridinyl optionally substituted with one or more - NH(ethyl).
  • R 2 is pyridinyl optionally substituted with one or more - NH(propyl). In some embodiments, R 2 is pyridinyl optionally substituted with one or more - NH(butyl). In some embodiments, R 2 is pyridinyl optionally substituted with one or more - NH(pentyl). In some embodiments, R 2 is pyridinyl optionally substituted with one or more - NH(hexyl).
  • R 2 is pyridinyl optionally substituted with one or more -N(CI-C 6 alkyl)2.
  • R 2 is pyridinyl optionally substituted with one or more oxo.
  • R 2 is pyrimidinyl
  • R 2 is pyrimidinyl optionally substituted with one or more C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, -CN, -OH, -NH2, -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl) 2 , oxo, -C(0)R 2 s, -C(0)OR 2 s, or -C(0)N(R 2 s)2.
  • R 2 is pyrimidinyl optionally substituted with one or more C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, -CN, -OH, -NH 2 , -NH(CI-C 6 alkyl), -N(Ci-Ce alkyl) 2 , or oxo.
  • R 2 is pyrimidinyl optionally substituted with one or more C1-C6 alkyl. In some embodiments, R 2 is pyrimidinyl optionally substituted with one or more methyl.
  • R 2 is pyrimidinyl optionally substituted with one or more ethyl. In some embodiments, R 2 is pyrimidinyl optionally substituted with one or more propyl. In some embodiments, R 2 is pyrimidinyl optionally substituted with one or more butyl. In some embodiments, R 2 is pyrimidinyl optionally substituted with one or more pentyl. In some embodiments, R 2 is pyrimidinyl optionally substituted with one or more hexyl. In some embodiments, R 2 is pyrimidinyl optionally substituted with one or more isopropyl. In some embodiments, R 2 is pyrimidinyl optionally substituted with one or more isobutyl.
  • R 2 is pyrimidinyl optionally substituted with one or more isopentyl. In some embodiments, R 2 is pyrimidinyl optionally substituted with one or more isohexyl. In some embodiments, R 2 is pyrimidinyl optionally substituted with one or more secbutyl. In some embodiments, R 2 is pyrimidinyl optionally substituted with one or more secpentyl. In some embodiments, R 2 is pyrimidinyl optionally substituted with one or more sechexyl. In some embodiments, R 2 is pyrimidinyl optionally substituted with one or more tertbutyl.
  • R 2 is pyrimidinyl optionally substituted with one or more C2-C 6 alkenyl. In some embodiments, R 2 is pyrimidinyl optionally substituted with one or more C2-C 6 alkynyl.
  • R 2 is pyrimidinyl optionally substituted with one or more C1-C 6 haloalkyl. In some embodiments, R 2 is pyrimidinyl optionally substituted with one or more halomethyl. In some embodiments, R 2 is pyrimidinyl optionally substituted with one or more haloethyl. In some embodiments, R 2 is pyrimidinyl optionally substituted with one or more halopropyl. In some embodiments, R 2 is pyrimidinyl optionally substituted with one or more halobutyl. In some embodiments, R 2 is pyrimidinyl optionally substituted with one or more halopentyl. In some embodiments, R 2 is pyrimidinyl optionally substituted with one or more halohexyl.
  • R 2 is pyrimidinyl optionally substituted with one or more C1-C 6 alkoxy. In some embodiments, R 2 is pyrimidinyl optionally substituted with one or more methoxy. In some embodiments, R 2 is pyrimidinyl optionally substituted with one or more ethoxy. In some embodiments, R 2 is pyrimidinyl optionally substituted with one or more propoxy. In some embodiments, R 2 is pyrimidinyl optionally substituted with one or more butoxy. In some embodiments, R 2 is pyrimidinyl optionally substituted with one or more pentoxy. In some embodiments, R 2 is pyrimidinyl optionally substituted with one or more hexoxy.
  • R 2 is pyrimidinyl optionally substituted with one or more C1-C 6 haloalkoxy. In some embodiments, R 2 is pyrimidinyl optionally substituted with one or more halomethoxy. In some embodiments, R 2 is pyrimidinyl optionally substituted with one or more haloethoxy. In some embodiments, R 2 is pyrimidinyl optionally substituted with one or more halopropoxy. In some embodiments, R 2 is pyrimidinyl optionally substituted with one or more halobutoxy. In some embodiments, R 2 is pyrimidinyl optionally substituted with one or more halopentoxy. In some embodiments, R2 is pyrimidinyl optionally substituted with one or more halohexoxy.
  • R2 is pyrimidinyl optionally substituted with one or more halo. In some embodiments, R2 is pyrimidinyl optionally substituted with one or more F, Cl, Br, or I. In some embodiments, R2 is pyrimidinyl optionally substituted with one or more F or Cl. In some embodiments, R2 is pyrimidinyl optionally substituted with one or more F. In some embodiments,
  • R2 is pyrimidinyl optionally substituted with one or more Cl.
  • R2 is pyrimidinyl optionally substituted with one or more -CN.
  • R2 is pyrimidinyl optionally substituted with one or more -OH. In some embodiments, R2 is pyrimidinyl optionally substituted with one or more -NH2.
  • R2 is pyrimidinyl optionally substituted with one or more - NH(CI-C 6 alkyl). In some embodiments, R2 is pyrimidinyl optionally substituted with one or more -NH(methyl). In some embodiments, R2 is pyrimidinyl optionally substituted with one or more -NH(ethyl). In some embodiments, R2 is pyrimidinyl optionally substituted with one or more -NH(propyl). In some embodiments, R2 is pyrimidinyl optionally substituted with one or more -NH(butyl). In some embodiments, R2 is pyrimidinyl optionally substituted with one or more -NH(pentyl). In some embodiments, R2 is pyrimidinyl optionally substituted with one or more -NH(hexyl).
  • R2 is pyrimidinyl optionally substituted with one or more -N(Ci- C 6 alkyl)2.
  • R2 is pyrimidinyl optionally substituted with one or more oxo.
  • R2 is or , wherein * denotes an attachment of R2 to the adjacent nitrogen atom, and ** denotes an attachment of R2 to the adjacent carbon atom.
  • R2 is 1,3,5-triazinyl.
  • R2 is 1,3,5-triazinyl optionally substituted with one or more Ci- Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, - CN, -OH, -NH2, -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl) 2 , oxo, -C(0)R 2 s, -C(0)OR 2 s, or - C(0)N(R2S)2.
  • R2 is 1,3,5-triazinyl optionally substituted with one or more Ci- Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, - CN, -OH, -NH2, -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl) 2 , or oxo.
  • R2 is 1,3,5-triazinyl optionally substituted with one or more Ci- Ce alkyl. In some embodiments, R2 is 1,3,5-triazinyl optionally substituted with one or more methyl. In some embodiments, R2 is 1,3,5-triazinyl optionally substituted with one or more ethyl. In some embodiments, R2 is 1,3,5-triazinyl optionally substituted with one or more propyl. In some embodiments, R2 is 1,3,5-triazinyl optionally substituted with one or more butyl. In some embodiments, R2 is 1,3,5-triazinyl optionally substituted with one or more pentyl.
  • R2 is 1,3,5-triazinyl optionally substituted with one or more hexyl. In some embodiments, R2 is 1,3,5-triazinyl optionally substituted with one or more isopropyl. In some embodiments, R2 is 1,3,5-triazinyl optionally substituted with one or more isobutyl. In some embodiments, R2 is 1,3,5-triazinyl optionally substituted with one or more isopentyl. In some embodiments, R2 is 1,3,5-triazinyl optionally substituted with one or more isohexyl. In some embodiments, R2 is 1,3,5-triazinyl optionally substituted with one or more secbutyl.
  • R2 is 1,3,5-triazinyl optionally substituted with one or more secpentyl. In some embodiments, R2 is 1,3,5-triazinyl optionally substituted with one or more sechexyl. In some embodiments, R2 is 1,3,5-triazinyl optionally substituted with one or more tertbutyl.
  • R2 is 1,3,5-triazinyl optionally substituted with one or more C2- Ce alkenyl. In some embodiments, R2 is 1,3,5-triazinyl optionally substituted with one or more C2-C6 alkynyl.
  • R2 is 1,3,5-triazinyl optionally substituted with one or more Ci- Ce haloalkyl. In some embodiments, R2 is 1,3,5-triazinyl optionally substituted with one or more halomethyl. In some embodiments, R2 is 1,3,5-triazinyl optionally substituted with one or more haloethyl. In some embodiments, R2 is 1,3,5-triazinyl optionally substituted with one or more halopropyl. In some embodiments, R2 is 1,3,5-triazinyl optionally substituted with one or more halobutyl.
  • R2 is 1,3,5-triazinyl optionally substituted with one or more halopentyl. In some embodiments, R2 is 1,3,5-triazinyl optionally substituted with one or more halohexyl.
  • R2 is 1,3,5-triazinyl optionally substituted with one or more Ci- Ce alkoxy. In some embodiments, R2 is 1,3,5-triazinyl optionally substituted with one or more methoxy. In some embodiments, R2 is 1,3,5-triazinyl optionally substituted with one or more ethoxy. In some embodiments, R2 is 1,3,5-triazinyl optionally substituted with one or more propoxy. In some embodiments, R2 is 1,3,5-triazinyl optionally substituted with one or more butoxy. In some embodiments, R2 is 1,3,5-triazinyl optionally substituted with one or more pentoxy. In some embodiments, R2 is 1,3,5-triazinyl optionally substituted with one or more hexoxy.
  • R2 is 1,3,5-triazinyl optionally substituted with one or more Ci- Ce haloalkoxy. In some embodiments, R2 is 1,3,5-triazinyl optionally substituted with one or more halomethoxy. In some embodiments, R2 is 1,3,5-triazinyl optionally substituted with one or more haloethoxy. In some embodiments, R2 is 1,3,5-triazinyl optionally substituted with one or more halopropoxy. In some embodiments, R2 is 1,3,5-triazinyl optionally substituted with one or more halobutoxy. In some embodiments, R2 is 1,3,5-triazinyl optionally substituted with one or more halopentoxy. In some embodiments, R2 is 1,3,5-triazinyl optionally substituted with one or more halohexoxy.
  • R2 is 1,3,5-triazinyl optionally substituted with one or more halo. In some embodiments, R2 is 1,3,5-triazinyl optionally substituted with one or more F, Cl, Br, or I. In some embodiments, R2 is 1,3,5-triazinyl optionally substituted with one or more F or Cl. In some embodiments, R2 is 1,3,5-triazinyl optionally substituted with one or more F. In some embodiments, R2 is 1,3,5-triazinyl optionally substituted with one or more Cl.
  • R2 is 1,3,5-triazinyl optionally substituted with one or more -CN. In some embodiments, R2 is 1,3,5-triazinyl optionally substituted with one or more -OH. In some embodiments, R2 is 1,3,5-triazinyl optionally substituted with one or more -NH2.
  • R2 is 1,3,5-triazinyl optionally substituted with one or more - NH(CI-C 6 alkyl). In some embodiments, R2 is 1,3,5-triazinyl optionally substituted with one or more -NH(methyl). In some embodiments, R2 is 1,3,5-triazinyl optionally substituted with one or more -NH(ethyl). In some embodiments, R2 is 1,3,5-triazinyl optionally substituted with one or more -NH(propyl). In some embodiments, R2 is 1,3,5-triazinyl optionally substituted with one or more -NH(butyl).
  • R2 is 1,3,5-triazinyl optionally substituted with one or more -NH(pentyl). In some embodiments, R2 is 1,3,5-triazinyl optionally substituted with one or more -NH(hexyl). [0369] In some embodiments, R2 is 1,3,5-triazinyl optionally substituted with one or more - N(Ci-Ce alky 1) 2.
  • R2 is 1,3,5-triazinyl optionally substituted with one or more oxo.
  • R2 is -C(0)R2S, -C(0)OR.2S, or -C(0)N(R.2s)2.
  • R2 is -C(0)R.2S.
  • R2 is -C(0)OR.2S.
  • R2 is -C(0)N(R.2s)2.
  • each R2 S is independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, or 4- to 8-membered heterocycloalkyl.
  • each R2 S is independently H.
  • each R2 S is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, or 4- to 8-membered heterocycloalkyl.
  • each R2 S is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C7 cycloalkyl.
  • each R2 S is independently C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl.
  • each R2 S is independently C1-C6 alkyl. [0383] In some embodiments, each R2 S is independently methyl. In some embodiments, each R2 S is independently ethyl. In some embodiments, each R2 S is independently propyl. In some embodiments, each R2 S is independently butyl. In some embodiments, each R2 S is independently pentyl. In some embodiments, each R2 S is independently hexyl. In some embodiments, each R2 S is independently isopropyl. In some embodiments, at least one I is independently isobutyl. In some embodiments, at least one R2 S is independently isopentyl. In some embodiments, at least one R2 S is independently isohexyl. In some embodiments, at least one R2 S is independently secbutyl. In some embodiments, at least one R2 S is independently secpentyl. In some
  • At least one R2 S is independently sechexyl. In some embodiments, at least one R2 S is independently tertbutyl.
  • each R2 S is independently C2-C 6 alkenyl.
  • each R2 S is independently C2 alkenyl. In some embodiments, each R2 S is independently C3 alkenyl. In some embodiments, each R2 S is independently C4 alkenyl. In some embodiments, each R2 S is independently C5 alkenyl. In some embodiments, each R2 S is independently Ce alkenyl.
  • each R2 S is independently C2-C 6 alkynyl.
  • each R2 S is independently C2 alkynyl. In some embodiments, each R2 S is independently C3 alkynyl. In some embodiments, each R2 S is independently C4 alkynyl. In some embodiments, each R2 S is independently C5 alkynyl. In some embodiments, each R2 S is independently Ce alkynyl.
  • each R2 S is independently C 3 -C7 cycloalkyl.
  • each R2 S is independently cyclopropyl. In some embodiments, each R2 S is independently cyclobutyl. In some embodiments, each R2 S is independently cyclopentyl. In some embodiments, each R2 S is independently cyclohexyl. In some embodiments,
  • each R2 S is independently cycloheptyl. In some embodiments, each R2 S is independently cyclooctyl. In some embodiments, each R2 S is independently cyclopentenyl. In some embodiments, each R2 S is independently cyclohexenyl. In some embodiments, each R2 S is independently cycloheptenyl.
  • each R2 S is independently 4- to 8-membered heterocycloalkyl.
  • each R2 S is independently 4-membered heterocycloalkyl. In some embodiments, each R2 S is independently 5-membered heterocycloalkyl. In some embodiments, each R2 S is independently 6-membered heterocycloalkyl. In some embodiments, each R2 S is independently 7-membered heterocycloalkyl. In some embodiments, each R2 S is independently 8-membered heterocycloalkyl.
  • R is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C7 cycloalkyl; wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C7 cycloalkyl is optionally substituted with one or more C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C7 cycloalkyl, halo, -CN, -OH, -NH2, -NH(CI-C6 alkyl), -N(CI-C6 alkyl)2, or oxo.
  • R 3 is H.
  • R 3 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C7 cycloalkyl; wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C7 cycloalkyl is optionally substituted with one or more C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C7 cycloalkyl, halo, -CN, -OH, -NH2, -NH(CI-C6 alkyl), -N(CI-C6 alkyl)2, or oxo.
  • R 3 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C7 cycloalkyl.
  • R 3 is C1-C6 alkyl.
  • R 3 is methyl. In some embodiments, R 3 is ethyl. In some embodiments, R 3 is propyl. In some embodiments, R 3 is butyl. In some embodiments, R 3 is pentyl. In some embodiments, R 3 is hexyl. In some embodiments, R 3 is isopropyl. In some embodiments, at least one R 3 IS isobutyl. In some embodiments, at least one R 3 is isopentyl. In some embodiments, at least one R3 is isohexyl. In some embodiments, at least one R3 IS secbutyl. In some embodiments, at least one R 3 is secpentyl. In some embodiments, at least one R 3 is sechexyl. In some embodiments, at least one R 3 is tertbutyl.
  • R3 is C1-C6 alkyl optionally substituted with one or more C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C7 cycloalkyl, halo, -CN, -OH, -NH2, -NH(CI-C6 alkyl), -N(CI-C6 alkyl)2, or oxo.
  • R 3 is C1-C6 alkyl optionally substituted with one or more C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl.
  • R3 is C1-C6 alkyl optionally substituted with one or more C1-C6 alkyl. [0401] In some embodiments, R3 is C1-C6 alkyl optionally substituted with one or more C2-C6 alkenyl.
  • R is C1-C6 alkyl optionally substituted with one or more C2-C6 alkynyl.
  • R3 is C1-C6 alkyl optionally substituted with one or more C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy.
  • R is C1-C6 alkyl optionally substituted with one or more C1-C6 haloalkyl.
  • R is C1-C6 alkyl optionally substituted with one or more C1-C6 alkoxy.
  • R is C1-C6 alkyl optionally substituted with one or more C1-C6 haloalkoxy.
  • R is C1-C6 alkyl optionally substituted with one or more halo, - CN, -OH, -NH2, or oxo.
  • R is C1-C6 alkyl optionally substituted with one or more halo.
  • R is C1-C6 alkyl optionally substituted with one or more F, Cl, Br, or I.
  • R is C1-C6 alkyl optionally substituted with one or more F or Cl.
  • R is C1-C6 alkyl optionally substituted with one or more F.
  • R is C1-C6 alkyl optionally substituted with one or more Cl.
  • R is C1-C6 alkyl optionally substituted with one or more -CN.
  • R is C1-C6 alkyl optionally substituted with one or more -OH.
  • R is C1-C6 alkyl optionally substituted with one or more -NH2.
  • R is C1-C6 alkyl optionally substituted with one or more oxo.
  • R is C1-C6 alkyl optionally substituted with one or more - NH(Ci-Ce alkyl), or -N(Ci-Ce alkyl) 2.
  • R is C1-C6 alkyl optionally substituted with one or more - NH(Ci-Ce alkyl).
  • R is C1-C6 alkyl optionally substituted with one or more -N(Ci- Ce alky 1)2.
  • R3 is methyl optionally substituted with one or more C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C7 cycloalkyl, halo, -CN, -OH, -NH2, -NH(CI-C6 alkyl), -N(CI-C6 alkyl)2, or oxo.
  • R3 is methyl optionally substituted with one or more C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C7 cycloalkyl.
  • R3 is methyl optionally substituted with one or more C1-C6 alkyl.
  • R3 is methyl optionally substituted with one or more C2-C6 alkenyl.
  • R3 is methyl optionally substituted with one or more C2-C6 alkynyl.
  • R3 is methyl optionally substituted with one or more C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy.
  • R3 is methyl optionally substituted with one or more C1-C6 haloalkyl.
  • R3 is methyl optionally substituted with one or more C1-C6 alkoxy.
  • R3 is methyl optionally substituted with one or more C1-C6 haloalkoxy.
  • R3 is methyl optionally substituted with one or more C3-C7 cycloalkyl.
  • R3 is methyl optionally substituted with one or more halo, -CN, - OH, -NH2, or oxo.
  • R3 is methyl optionally substituted with one or more halo.
  • R3 is methyl optionally substituted with one or more F, Cl, Br, or I.
  • R3 is methyl optionally substituted with one or more F or Cl.
  • R3 is methyl optionally substituted with one or more F.
  • R3 is methyl optionally substituted with one or more Cl.
  • R3 is methyl optionally substituted with one or more -CN.
  • R3 is methyl optionally substituted with one or more -OH.
  • R3 is methyl optionally substituted with one or more -NH2. [0439] In some embodiments, R3 is methyl optionally substituted with one or more oxo.
  • R is methyl optionally substituted with one or more -NH(CI-C 6 alkyl), or -N(CI-C 6 alkyl)2.
  • R is methyl optionally substituted with one or more -NH(CI-C 6 alkyl).
  • R is methyl optionally substituted with one or more -N(CI-C 6 alkyl)2.
  • R is ethyl optionally substituted with one or more C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C7 cycloalkyl, halo, -CN, -OH, -NH2, -NH(CI-C6 alkyl), -N(CI-C6 alkyl)2, or oxo.
  • R3 is ethyl optionally substituted with one or more C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C7 cycloalkyl.
  • R3 is ethyl optionally substituted with one or more C1-C6 alkyl.
  • R3 is ethyl optionally substituted with one or more C2-C6 alkenyl.
  • R3 is ethyl optionally substituted with one or more C2-C6 alkynyl.
  • R3 is ethyl optionally substituted with one or more C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy.
  • R3 is ethyl optionally substituted with one or more C1-C6 haloalkyl.
  • R3 is ethyl optionally substituted with one or more C1-C6 alkoxy.
  • R3 is ethyl optionally substituted with one or more C1-C6 haloalkoxy.
  • R3 is ethyl optionally substituted with one or more C3-C7 cycloalkyl.
  • R3 is ethyl optionally substituted with one or more halo, -CN, - OH, -NH2, or oxo.
  • R3 is ethyl optionally substituted with one or more halo.
  • R3 is ethyl optionally substituted with one or more F, Cl, Br, or I.
  • R3 is ethyl optionally substituted with one or more F or Cl.
  • R3 is ethyl optionally substituted with one or more F.
  • R3 is ethyl optionally substituted with one or more Cl. [0459] In some embodiments, R3 is ethyl optionally substituted with one or more -CN.
  • R is ethyl optionally substituted with one or more -OH.
  • R is ethyl optionally substituted with one or more -NH2.
  • R is ethyl optionally substituted with one or more oxo.
  • R is ethyl optionally substituted with one or more -NH(CI-C 6 alkyl), or -N(CI-C 6 alkyl)2.
  • R is ethyl optionally substituted with one or more -NH(CI-C 6 alkyl).
  • R is ethyl optionally substituted with one or more -N(CI-C 6 alkyl)2.
  • R is isopropyl optionally substituted with one or more C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C7 cycloalkyl, halo, -CN, -OH, -NH2, -NH(CI-C6 alkyl), -N(CI-C6 alkyl)2, or oxo.
  • R3 is isopropyl optionally substituted with one or more C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl.
  • R3 is isopropyl optionally substituted with one or more C1-C6 alkyl.
  • R3 is isopropyl optionally substituted with one or more C2-C6 alkenyl.
  • R3 is isopropyl optionally substituted with one or more C2-C6 alkynyl.
  • R3 is isopropyl optionally substituted with one or more C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy.
  • R3 is isopropyl optionally substituted with one or more C1-C6 haloalkyl.
  • R3 is isopropyl optionally substituted with one or more C1-C6 alkoxy.
  • R3 is isopropyl optionally substituted with one or more C1-C6 haloalkoxy.
  • R3 is isopropyl optionally substituted with one or more halo, - CN, -OH, -NH2, or oxo. [0476] In some embodiments, R3 is isopropyl optionally substituted with one or more halo.
  • R is isopropyl optionally substituted with one or more F, Cl, Br, or I.
  • R is isopropyl optionally substituted with one or more F or Cl.
  • R is isopropyl optionally substituted with one or more F.
  • R is isopropyl optionally substituted with one or more Cl.
  • R is isopropyl optionally substituted with one or more -CN.
  • R is isopropyl optionally substituted with one or more -OH.
  • R is isopropyl optionally substituted with one or more -NH2.
  • R is isopropyl optionally substituted with one or more oxo.
  • R is isopropyl optionally substituted with one or more -NH(Ci-
  • R is isopropyl optionally substituted with one or more -NH(Ci- Ce alkyl).
  • R is isopropyl optionally substituted with one or more -N(CI-C 6 alkyl)2.
  • R is C2-C6 alkenyl.
  • R is C2-C6 alkenyl optionally substituted with one or more C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C7 cycloalkyl, halo, -CN, -OH, -NH2, -NH(CI-C6 alkyl), -N(CI-C6 alkyl) 2 , or oxo.
  • R3 is C2-C6 alkenyl optionally substituted with one or more C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl.
  • R3 is C2-C6 alkenyl optionally substituted with one or more C1-C6 alkyl.
  • R3 is C2-C6 alkenyl optionally substituted with one or more C2-C6 alkenyl.
  • R3 is C2-C6 alkenyl optionally substituted with one or more C2-C6 alkynyl.
  • R3 is C2-C6 alkenyl optionally substituted with one or more C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy. [0495] In some embodiments, R3 is C2-C6 alkenyl optionally substituted with one or more C1-C6 haloalkyl.
  • R is C2-C6 alkenyl optionally substituted with one or more C1-C6 alkoxy.
  • R3 is C2-C6 alkenyl optionally substituted with one or more C1-C6 haloalkoxy.
  • R is C2-C6 alkenyl optionally substituted with one or more halo, -CN, -OH, -NH2, or oxo.
  • R is C2-C6 alkenyl optionally substituted with one or more halo.
  • R is C2-C6 alkenyl optionally substituted with one or more F, Cl, Br, or I.
  • R is C2-C6 alkenyl optionally substituted with one or more F or Cl.
  • R is C2-C6 alkenyl optionally substituted with one or more F.
  • R is C2-C6 alkenyl optionally substituted with one or more Cl.
  • R is C2-C6 alkenyl optionally substituted with one or more -CN.
  • R is C2-C6 alkenyl optionally substituted with one or more -OH.
  • R is C2-C6 alkenyl optionally substituted with one or more -NH2.
  • R is C2-C6 alkenyl optionally substituted with one or more oxo.
  • R is C2-C6 alkenyl optionally substituted with one or more - NH(Ci-Ce alkyl), or -N(Ci-Ce alkyl) 2.
  • R is C2-C6 alkenyl optionally substituted with one or more - NH(Ci-Ce alkyl).
  • R is C2-C6 alkenyl optionally substituted with one or more - N(Ci-Ce alkyl) 2.
  • R is C2-C6 alkynyl.
  • R is C2-C6 alkynyl optionally substituted with one or more Ci- Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C7 cycloalkyl, halo, -CN, -OH, -NH2, -NH(Ci-C6 alkyl), -N(CI-C 6 alkyl)2, or oxo.
  • R3 is C2-C6 alkynyl optionally substituted with one or more Ci- Ce alkyl, C2-C6 alkenyl, or C2-C6 alkynyl. [0514] In some embodiments, R3 is C2-C6 alkynyl optionally substituted with one or more Ci- Ce alkyl.
  • R is C2-C6 alkynyl optionally substituted with one or more C2- Ce alkenyl.
  • R 3 is C2-C6 alkynyl optionally substituted with one or more C2- Ce alkynyl.
  • R is C2-C6 alkynyl optionally substituted with one or more Ci- Ce haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy.
  • R is C2-C6 alkynyl optionally substituted with one or more Ci- Ce haloalkyl.
  • R is C2-C6 alkynyl optionally substituted with one or more Ci- Ce alkoxy.
  • R is C2-C6 alkynyl optionally substituted with one or more Ci- Ce haloalkoxy.
  • R is C2-C6 alkynyl optionally substituted with one or more halo, -CN, -OH, -NH2, or oxo.
  • R is C2-C6 alkynyl optionally substituted with one or more halo.
  • R is C2-C6 alkynyl optionally substituted with one or more F, Cl, Br, or I.
  • R is C2-C6 alkynyl optionally substituted with one or more F or Cl.
  • R is C2-C6 alkynyl optionally substituted with one or more F.
  • R is C2-C6 alkynyl optionally substituted with one or more Cl.
  • R is C2-C6 alkynyl optionally substituted with one or more -CN.
  • R is C2-C6 alkynyl optionally substituted with one or more -OH.
  • R is C2-C6 alkynyl optionally substituted with one or more - NH 2.
  • R is C2-C6 alkynyl optionally substituted with one or more oxo.
  • R is C2-C6 alkynyl optionally substituted with one or more - NH(Ci-Ce alkyl), or -N(Ci-Ce alkyl) 2.
  • R3 is C2-C6 alkynyl optionally substituted with one or more - NH(Ci-Ce alkyl).
  • R is C2-C6 alkynyl optionally substituted with one or more - N(Ci-Ce alkyl) 2.
  • R3 is methyl, ethyl, or isopropyl.
  • R is C3-C7 cycloalkyl.
  • R 3 is C3-C7 cycloalkyl optionally substituted with one or more C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3- Ci cycloalkyl, halo, -CN, -OH, -NH2, -NH(CI-C6 alkyl), -N(CI-C6 alkyl)2, or oxo.
  • R3 is C3-C7 cycloalkyl optionally substituted with one or more C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl.
  • R3 is C3-C7 cycloalkyl optionally substituted with one or more Ci-Ce alkyl.
  • R 3 is C3-C7 cycloalkyl optionally substituted with one or more C2-C6 alkenyl.
  • R3 is C3-C7 cycloalkyl optionally substituted with one or more C2-C6 alkynyl.
  • R3 is C3-C7 cycloalkyl optionally substituted with one or more C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy.
  • R3 is C3-C7 cycloalkyl optionally substituted with one or more C1-C6 haloalkyl.
  • R3 is C3-C7 cycloalkyl optionally substituted with one or more C1-C6 alkoxy.
  • R3 is C3-C7 cycloalkyl optionally substituted with one or more C1-C6 haloalkoxy.
  • R 3 is C3-C7 cycloalkyl optionally substituted with one or more C3-C7 cycloalkyl.
  • R3 is C3-C7 cycloalkyl optionally substituted with one or more halo, -CN, -OH, -NH2, or oxo.
  • R 3 is C3-C7 cycloalkyl optionally substituted with one or more halo.
  • R3 is C3-C7 cycloalkyl optionally substituted with one or more F, Cl, Br, or I.
  • R3 is C3-C7 cycloalkyl optionally substituted with one or more F or Cl.
  • R3 is C3-C7 cycloalkyl optionally substituted with one or more F.
  • R3 is C3-C7 cycloalkyl optionally substituted with one or more Cl.
  • R3 is C3-C7 cycloalkyl optionally substituted with one or more - CN.
  • R3 is C3-C7 cycloalkyl optionally substituted with one or more - OH.
  • R3 is C3-C7 cycloalkyl optionally substituted with one or more - NH2.
  • R3 is C3-C7 cycloalkyl optionally substituted with one or more oxo.
  • R3 is C3-C7 cycloalkyl optionally substituted with one or more - NH(Ci-Ce alkyl), or -N(Ci-Ce alkyl) 2.
  • R3 is C3-C7 cycloalkyl optionally substituted with one or more - NH(Ci-Ce alkyl).
  • R3 is C3-C7 cycloalkyl optionally substituted with one or more - N(Ci-Ce alkyl) 2.
  • R4 is H, C1-C6 alkyl, C 2 -C6 alkenyl, C 2 -C6 alkynyl, or C3-C7 cycloalkyl ; wherein the C1-C6 alkyl, C 2 -C6 alkenyl, C 2 -C6 alkynyl or C3-C7 cycloalkyl is optionally substituted with one or more C1-C6 alkyl, C 2 -C6 alkenyl, C 2 -C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C7 cycloalkyl, halo, -CN, -OH, -NH 2 , -NH(CI-C6 alkyl), -N(CI-C6 alkyl) 2 , or oxo.
  • R4 is H.
  • R4 is C1-C6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or C3-C7 cycloalkyl; wherein the C1-C6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or C3-C7 cycloalkyl is optionally substituted with one or more C1-C6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C1-C6 haloalkyl, C1-C 6 alkoxy, C1-C 6 haloalkoxy, C3-C7 cycloalkyl, halo, -CN, -OH, -NH2, -NH(CI-C6 alkyl), -N(CI-C6 alkyl)2, or oxo.
  • R 4 is C1-C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, or C3-C7 cycloalkyl.
  • R 4 is C1-C 6 alkyl.
  • R 4 is methyl. In some embodiments, R 4 is ethyl. In some embodiments, R 4 is propyl. In some embodiments, R 4 is butyl. In some embodiments, R 4 is pentyl. In some embodiments, R 4 is hexyl. In some embodiments, R 4 is isopropyl. In some embodiments, at least one R 4 IS isobutyl. In some embodiments, at least one R 4 is isopentyl. In some embodiments, at least one R 4 is isohexyl. In some embodiments, at least one Ri is secbutyl. In some embodiments, at least one R 4 is secpentyl. In some embodiments, at least one R 4 is sechexyl. In some embodiments, at least one R 4 is tertbutyl.
  • R 4 is C1-C 6 alkyl optionally substituted with one or more C1-C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, C1-C 6 haloalkyl, C1-C 6 alkoxy, C1-C 6 haloalkoxy, C 3 -C7 cycloalkyl, halo, -CN, -OH, -NH2, -NH(CI-C6 alkyl), -N(CI-C6 alkyl)2, or oxo.
  • R 4 is C1-C 6 alkyl optionally substituted with one or more C1-C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, or C 3 -C7 cycloalkyl.
  • R 4 is C1-C 6 alkyl optionally substituted with one or more C1-C 6 alkyl.
  • R 4 is C1-C 6 alkyl optionally substituted with one or more C2-C 6 alkenyl.
  • R 4 is C1-C 6 alkyl optionally substituted with one or more C2-C 6 alkynyl.
  • R 4 is C1-C 6 alkyl optionally substituted with one or more C1-C 6 haloalkyl, C1-C 6 alkoxy, C1-C 6 haloalkoxy, or C 3 -C7 cycloalkyl.
  • R 4 is C1-C 6 alkyl optionally substituted with one or more C1-C 6 haloalkyl.
  • R 4 is C1-C 6 alkyl optionally substituted with one or more C1-C 6 alkoxy.
  • R 4 is C1-C 6 alkyl optionally substituted with one or more C1-C 6 haloalkoxy.
  • R4 is C1-C6 alkyl optionally substituted with one or more C3-C7 cycloalkyl.
  • R4 is C1-C6 alkyl optionally substituted with one or more halo, - CN, -OH, -NH2, or oxo.
  • R4 is C1-C6 alkyl optionally substituted with one or more halo.
  • R4 is C1-C6 alkyl optionally substituted with one or more F, Cl,
  • R4 is C1-C6 alkyl optionally substituted with one or more F or Cl.
  • R4 is C1-C6 alkyl optionally substituted with one or more F.
  • R4 is C1-C6 alkyl optionally substituted with one or more Cl.
  • R4 is C1-C6 alkyl optionally substituted with one or more -CN.
  • R4 is C1-C6 alkyl optionally substituted with one or more -OH.
  • R4 is C1-C6 alkyl optionally substituted with one or more -NH2.
  • R4 is C1-C6 alkyl optionally substituted with one or more oxo.
  • R4 is C1-C6 alkyl optionally substituted with one or more -
  • R4 is C1-C6 alkyl optionally substituted with one or more - NH(Ci-Ce alkyl).
  • R4 is C1-C6 alkyl optionally substituted with one or more -N(Ci- Ce alky 1)2.
  • R4 is C2-C6 alkenyl.
  • R4 is C2-C6 alkenyl optionally substituted with one or more C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C7 cycloalkyl, C1-C6 haloalkoxy, halo, -CN, -OH, -NH2, -NH(Ci-C6 alkyl), -N(CI-C 6 alkyl)2, or oxo.
  • R4 is C2-C6 alkenyl optionally substituted with one or more C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C7 cycloalkyl.
  • R4 is C2-C6 alkenyl optionally substituted with one or more C1-C6 alkyl.
  • R4 is C2-C6 alkenyl optionally substituted with one or more C2-C6 alkenyl.
  • R4 is C2-C6 alkenyl optionally substituted with one or more C2-C6 alkynyl.
  • R4 is C2-C6 alkenyl optionally substituted with one or more C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy.
  • R4 is C2-C6 alkenyl optionally substituted with one or more C1-C6 haloalkyl.
  • R4 is C2-C6 alkenyl optionally substituted with one or more C1-C6 alkoxy.
  • R4 is C2-C6 alkenyl optionally substituted with one or more C1-C6 haloalkoxy.
  • R4 is C2-C6 alkenyl optionally substituted with one or more C3-C7 cycloalkyl.
  • R4 is C2-C6 alkenyl optionally substituted with one or more halo, -CN, -OH, -NH2, or oxo.
  • R4 is C2-C6 alkenyl optionally substituted with one or more halo.
  • R4 is C2-C6 alkenyl optionally substituted with one or more F, Cl, Br, or I.
  • R4 is C2-C6 alkenyl optionally substituted with one or more F or Cl.
  • R4 is C2-C6 alkenyl optionally substituted with one or more F.
  • R4 is C2-C6 alkenyl optionally substituted with one or more Cl.
  • R4 is C2-C6 alkenyl optionally substituted with one or more -CN.
  • R4 is C2-C6 alkenyl optionally substituted with one or more -OH.
  • R4 is C2-C6 alkenyl optionally substituted with one or more -NH2.
  • R4 is C2-C6 alkenyl optionally substituted with one or more oxo.
  • R4 is C2-C6 alkenyl optionally substituted with one or more - NH(Ci-Ce alkyl), or -N(Ci-Ce alkyl) 2.
  • R4 is C2-C6 alkenyl optionally substituted with one or more - NH(Ci-Ce alkyl).
  • R4 is C2-C6 alkenyl optionally substituted with one or more - N(Ci-Ce alky 1) 2.
  • R4 is C2-C6 alkynyl.
  • R4 is C2-C6 alkynyl optionally substituted with one or more Ci- Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C7 cycloalkyl, halo, -CN, -OH, -NH2, -NH(CI-C6 alkyl), -N(CI-C6 alkyl)2, or oxo.
  • R4 is C2-C6 alkynyl optionally substituted with one or more Ci- Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C7 cycloalkyl.
  • R4 is C2-C6 alkynyl optionally substituted with one or more Ci- C 6 alkyl.
  • R4 is C2-C6 alkynyl optionally substituted with one or more C2- Ce alkenyl.
  • R4 is C2-C6 alkynyl optionally substituted with one or more C2- Ce alkynyl.
  • R4 is C2-C6 alkynyl optionally substituted with one or more Ci- Ce haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy.
  • R4 is C2-C6 alkynyl optionally substituted with one or more Ci- Ce haloalkyl.
  • R4 is C2-C6 alkynyl optionally substituted with one or more Ci- Ce alkoxy.
  • R4 is C2-C6 alkynyl optionally substituted with one or more Ci- Ce haloalkoxy.
  • R4 is C2-C6 alkynyl optionally substituted with one or more C3- C7 cycloalkyl.
  • R4 is C2-C6 alkynyl optionally substituted with one or more halo, -CN, -OH, -NH2, or oxo.
  • R4 is C2-C6 alkynyl optionally substituted with one or more halo.
  • R4 is C2-C6 alkynyl optionally substituted with one or more F, Cl,
  • R4 is C2-C6 alkynyl optionally substituted with one or more F or Cl.
  • R4 is C2-C6 alkynyl optionally substituted with one or more F.
  • R4 is C2-C6 alkynyl optionally substituted with one or more Cl.
  • R4 is C2-C6 alkynyl optionally substituted with one or more -CN.
  • R4 is C2-C6 alkynyl optionally substituted with one or more -OH.
  • R4 is C2-C6 alkynyl optionally substituted with one or more -
  • R4 is C2-C6 alkynyl optionally substituted with one or more oxo.
  • R4 is C2-C6 alkynyl optionally substituted with one or more -
  • R4 is C2-C6 alkynyl optionally substituted with one or more - NH(Ci-Ce alkyl).
  • R4 is C2-C6 alkynyl optionally substituted with one or more - N(Ci-Ce alkyl) 2.
  • R4 is C3-C7 cycloalkyl.
  • R4 is C3-C7 cycloalkyl optionally substituted with one or more C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3- Ci cycloalkyl, halo, -CN, -OH, -NH2, -NH(CI-C6 alkyl), -N(CI-C6 alkyl)2, or oxo.
  • R4 is C3-C7 cycloalkyl optionally substituted with one or more C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C7 cycloalkyl.
  • R4 is C3-C7 cycloalkyl optionally substituted with one or more Ci-Ce alkyl.
  • R4 is C3-C7 cycloalkyl optionally substituted with one or more C2-C6 alkenyl.
  • R4 is C3-C7 cycloalkyl optionally substituted with one or more C2-C6 alkynyl.
  • R4 is C3-C7 cycloalkyl optionally substituted with one or more C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy.
  • R4 is C3-C7 cycloalkyl optionally substituted with one or more C1-C6 haloalkyl.
  • R4 is C3-C7 cycloalkyl optionally substituted with one or more C1-C6 alkoxy.
  • R4 is C3-C7 cycloalkyl optionally substituted with one or more C1-C6 haloalkoxy. [0646] In some embodiments, R4 is C3-C7 cycloalkyl optionally substituted with one or more C3-C7 cycloalkyl.
  • R4 is C3-C7 cycloalkyl optionally substituted with one or more halo, -CN, -OH, -NH2, or oxo.
  • R4 is C3-C7 cycloalkyl optionally substituted with one or more halo.
  • R4 is C3-C7 cycloalkyl optionally substituted with one or more F, Cl, Br, or I.
  • R4 is C3-C7 cycloalkyl optionally substituted with one or more F or Cl.
  • R4 is C3-C7 cycloalkyl optionally substituted with one or more F.
  • R4 is C3-C7 cycloalkyl optionally substituted with one or more Cl.
  • R4 is C3-C7 cycloalkyl optionally substituted with one or more - CN.
  • R4 is C3-C7 cycloalkyl optionally substituted with one or more - OH.
  • R4 is C3-C7 cycloalkyl optionally substituted with one or more - NH 2.
  • R4 is C3-C7 cycloalkyl optionally substituted with one or more oxo.
  • R4 is C3-C7 cycloalkyl optionally substituted with one or more - NH(Ci-Ce alkyl), or -N(Ci-Ce alkyl) 2.
  • R4 is C3-C7 cycloalkyl optionally substituted with one or more - NH(Ci-Ce alkyl).
  • R4 is C3-C7 cycloalkyl optionally substituted with one or more - N(Ci-Ce alkyl) 2.
  • Ri is Ci 2 -Ci 6 tricyclic partially unsaturated cycloalkyl optionally substituted with one or more Ris and R 2 is 5- to 10-membered heteroaryl or 4- to 8-membered heterocycloalkyl; wherein the 5- to 10-membered heteroaryl or 4- to 8-membered
  • heterocycloalkyl is optionally substituted with one or more C1-C6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, -CN, -OH, -NH2, -NH(CI-C 6 alkyl), -N(CI-C 6 alkyl)2, or oxo.
  • Ri is C12-C16 tricyclic partially unsaturated cycloalkyl and R2 is 5- to 10-membered heteroaryl or 4- to 8-membered heterocycloalkyl; wherein the 5- to 10- membered heteroaryl or 4- to 8-membered heterocycloalkyl is optionally substituted with one or more C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, -CN, -OH, -NH2, -NH(CI-C 6 alkyl), -N(CI-C 6 alkyl)2, or oxo.
  • Ri is hexahydroindacenyl optionally substituted with one or more Ris and R2 is 5- to 10-membered heteroaryl or 4- to 8-membered heterocycloalkyl; wherein the 5- to 10-membered heteroaryl or 4- to 8-membered heterocycloalkyl is optionally substituted with one or more C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, Ci- Ce haloalkoxy, halo, -CN, -OH, -NH2, -NH(Ci-C 6 alkyl), -N(CI-C 6 alkyl)2, or oxo.
  • Ri is hexahydroindacenyl and R2 is 5- to 10-membered heteroaryl or 4- to 8-membered heterocycloalkyl; wherein the 5- to 10-membered heteroaryl or 4- to 8-membered heterocycloalkyl is optionally substituted with one or more C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, -CN, -OH, -NH2, -NH(CI-C 6 alkyl), -N(CI-C 6 alkyl)2, or oxo.
  • membered heteroaryl or 4- to 8-membered heterocycloalkyl wherein the 5- to 10-membered heteroaryl or 4- to 8-membered heterocycloalkyl is optionally substituted with one or more C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, -CN, -OH, -NH2, -NH(CI-C 6 alkyl), -N(CI-C 6 alkyl)2, or oxo.
  • Ri is C12-C16 tricyclic partially unsaturated cycloalkyl optionally substituted with one or more Ris and R2 is 5- to 10-membered heteroaryl or 4- to 8-membered heterocycloalkyl.
  • Ri is C12-C16 tricyclic partially unsaturated cycloalkyl and R2 is 5- to 10-membered heteroaryl or 4- to 8-membered heterocycloalkyl.
  • Ri is hexahydroindacenyl optionally substituted with one or more Ris and R2 is 5- to 10-membered heteroaryl or 4- to 8-membered heterocycloalkyl.
  • Ri is hexahydroindacenyl and R2 is 5- to 10-membered heteroaryl or 4- to 8-membered heterocycloalkyl.
  • membered heteroaryl or 4- to 8-membered heterocycloalkyl are membersed heteroaryl or 4- to 8-membered heterocycloalkyl.
  • Ri is C12-C16 tricyclic partially unsaturated cycloalkyl optionally substituted with one or more Ris and R2 is 5- to 10-membered heteroaryl.
  • Ri is C12-C16 tricyclic partially unsaturated cycloalkyl and R2 is 5- to 10-membered heteroaryl.
  • Ri is hexahydroindacenyl optionally substituted with one or more Ris and R2 is 5- to 10-membered heteroaryl.
  • Ri is hexahydroindacenyl and R2 is 5- to 10-membered heteroaryl.
  • membered heteroaryl In some embodiments, membered heteroaryl.
  • Ri is C12-C16 tricyclic partially unsaturated cycloalkyl optionally substituted with one or more Ris and R2 is 5- to 10-membered heteroaryl optionally substituted with one or more C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, Ci- Ce haloalkoxy, halo, -CN, -OH, -NH2, -NH(CI-C 6 alkyl), -N(CI-C 6 alkyl)2, or oxo.
  • Ri is C12-C16 tricyclic partially unsaturated cycloalkyl and R2 is 5- to 10-membered heteroaryl optionally substituted with one or more C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, -CN, -OH, -NH2, -NH(CI-C6 alkyl), -N(CI-C6 alkyl)2, or oxo.
  • Ri is hexahydroindacenyl optionally substituted with one or more Ris and R2 is 5- to 10-membered heteroaryl optionally substituted with one or more C1-C6 alkyl, C2-C 6 alkenyl, Ci-Ce alkynyl, C1-C 6 haloalkyl, C1-C 6 alkoxy, C1-C 6 haloalkoxy, halo, -CN, -OH, -NH2, -NH(CI-C 6 alkyl), -N(CI-C 6 alkyl)2, or oxo.
  • Ri is hexahydroindacenyl and R 2 is 5- to 10-membered heteroaryl optionally substituted with one or more C1-C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, Ci- Ce haloalkyl, C1-C 6 alkoxy, C1-C 6 haloalkoxy, halo, -CN, -OH, -NH2, -NH(Ci-C 6 alkyl), -N(Ci- Ce alkyl)2, or oxo.
  • membered heteroaryl optionally substituted with one or more C1-C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, C1-C 6 haloalkyl, C1-C 6 alkoxy, C1-C 6 haloalkoxy, halo, -CN, -OH, -NH2, -NH(CI-C 6 alkyl), -N(CI-C 6 alkyl)2, or oxo.
  • Ri is C12-C1 6 tricyclic partially unsaturated cycloalkyl optionally substituted with one or more Ris and R 2 is 5- to 10-membered heteroaryl optionally substituted with one or more C1-C 6 alkyl.
  • Ri is C12-C1 6 tricyclic partially unsaturated cycloalkyl and R 2 is 5- to 10-membered heteroaryl optionally substituted with one or more C1-C 6 alkyl.
  • Ri is hexahydroindacenyl optionally substituted with one or more Ris and R 2 is 5- to 10-membered heteroaryl optionally substituted with one or more C1-C 6 alkyl.
  • Ri is hexahydroindacenyl and R 2 is 5- to 10-membered heteroaryl optionally substituted with one or more C1-C 6 alkyl.
  • membered heteroaryl optionally substituted with one or more C1-C 6 alkyl.
  • Ri is C12-C1 6 tricyclic partially unsaturated cycloalkyl optionally substituted with one or more Ris and R 2 is 5-membered heteroaryl.
  • Ri is C12-C1 6 tricyclic partially unsaturated cycloalkyl and R 2 is 5-membered heteroaryl.
  • Ri is hexahydroindacenyl optionally substituted with one or more Ris and R 2 is 5-membered heteroaryl.
  • Ri is hexahydroindacenyl and R 2 is 5-membered heteroaryl.
  • Ri is C12-C1 6 tricyclic partially unsaturated cycloalkyl optionally substituted with one or more Ris and R 2 is 5-membered heteroaryl optionally substituted with one or more C1-C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, C1-C 6 haloalkyl, C1-C 6 alkoxy, C1-C 6 haloalkoxy, halo, -CN, -OH, -NH2, -NH(CI-C 6 alkyl), -N(CI-C 6 alkyl)2, or oxo.
  • Ri is C12-C1 6 tricyclic partially unsaturated cycloalkyl and R 2 is 5-membered heteroaryl optionally substituted with one or more C1-C 6 alkyl, C2-C 6 alkenyl, C2- Ce alkynyl, C1-C 6 haloalkyl, C1-C 6 alkoxy, C1-C 6 haloalkoxy, halo, -CN, -OH, -NH2, -NH(CI-C 6 alkyl), -N(CI-C 6 alkyl)2, or oxo.
  • Ri is hexahydroindacenyl optionally substituted with one or more Ris and R 2 is 5-membered heteroaryl optionally substituted with one or more C1-C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, C1-C 6 haloalkyl, C1-C 6 alkoxy, C1-C 6 haloalkoxy, halo, -CN, -OH, -NH2, -NH(CI-C6 alkyl), -N(CI-C6 alkyl)2, or oxo.
  • Ri is hexahydroindacenyl and R 2 is 5-membered heteroaryl optionally substituted with one or more C1-C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, C1-C 6 haloalkyl, C1-C 6 alkoxy, C1-C 6 haloalkoxy, halo, -CN, -OH, -NH2, -NH(Ci-C6 alkyl), -N(CI-C6 alkyl)2, or oxo.
  • -membered heteroaryl optionally substituted with one or more C1-C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, C1-C 6 haloalkyl, C1-C 6 alkoxy, C1-C 6 haloalkoxy, halo, -CN, -OH, -NH2, -NH(Ci-C6 alkyl), -N(CI-C6 alkyl)2, or oxo.
  • Ri is C12-C1 6 tricyclic partially unsaturated cycloalkyl optionally substituted with one or more Ris and R 2 is 5-membered heteroaryl optionally substituted with one or more C1-C 6 alkyl.
  • Ri is C12-C1 6 tricyclic partially unsaturated cycloalkyl and R 2 is 5-membered heteroaryl optionally substituted with one or more C1-C 6 alkyl.
  • Ri is hexahydroindacenyl optionally substituted with one or more Ris and R 2 is 5-membered heteroaryl optionally substituted with one or more C1-C 6 alkyl.
  • Ri is hexahydroindacenyl and R 2 is 5-membered heteroaryl optionally substituted with one or more C1-C 6 alkyl.
  • -membered heteroaryl optionally substituted with one or more C1-C 6 alkyl.
  • Ri is C12-C1 6 tricyclic partially unsaturated cycloalkyl optionally substituted with one or more Ris and R 2 is 6-membered heteroaryl.
  • Ri is C12-C1 6 tricyclic partially unsaturated cycloalkyl and R 2 is 6-membered heteroaryl.
  • Ri is hexahydroindacenyl optionally substituted with one or more Ris and R 2 is 6-membered heteroaryl.
  • Ri is hexahydroindacenyl and R 2 is 6-membered heteroaryl.
  • Ri is C12-C1 6 tricyclic partially unsaturated cycloalkyl optionally substituted with one or more Ris and R 2 is 6-membered heteroaryl optionally substituted with one or more C1-C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, C1-C 6 haloalkyl, C1-C 6 alkoxy, C1-C 6 haloalkoxy, halo, -CN, -OH, -NH2, -NH(CI-C 6 alkyl), -N(CI-C 6 alkyl)2, or oxo.
  • Ri is C12-C1 6 tricyclic partially unsaturated cycloalkyl and R 2 is 6-membered heteroaryl optionally substituted with one or more C1-C 6 alkyl, C2-C 6 alkenyl, C2- Ce alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, -CN, -OH, -NH2, -NH(CI-C6 alkyl), -N(CI-C6 alkyl)2, or oxo.
  • Ri is hexahydroindacenyl optionally substituted with one or more Ris and R 2 is 6-membered heteroaryl optionally substituted with one or more C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, -CN, -OH, -NH2, -NH(CI-C6 alkyl), -N(CI-C6 alkyl)2, or oxo.
  • Ri is hexahydroindacenyl and R 2 is 6-membered heteroaryl optionally substituted with one or more C1-C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, C1-C 6 haloalkyl, C1-C 6 alkoxy, C1-C 6 haloalkoxy, halo, -CN, -OH, -NH2, -NH(Ci-C6 alkyl), -N(CI-C6 alkyl)2, or oxo.
  • -membered heteroaryl optionally substituted with one or more C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, -CN, -OH, -NH2, -NH(CI-C6 alkyl), -N(CI-C6 alkyl)2, or oxo.
  • Ri is C12-C16 tricyclic partially unsaturated cycloalkyl optionally substituted with one or more Ris and R 2 is 6-membered heteroaryl optionally substituted with one or more C1-C6 alkyl.
  • Ri is C12-C16 tricyclic partially unsaturated cycloalkyl and R 2 is 6-membered heteroaryl optionally substituted with one or more C1-C6 alkyl.
  • Ri is hexahydroindacenyl optionally substituted with one or more Ris and R 2 is 6-membered heteroaryl optionally substituted with one or more C1-C6 alkyl.
  • Ri is hexahydroindacenyl and R 2 is 6-membered heteroaryl optionally substituted with one or more C1-C6 alkyl.
  • Ri is C12-C1 6 tricyclic partially unsaturated cycloalkyl optionally substituted with one or more Ris and R 2 is 7-membered heteroaryl.
  • Ri is C12-C1 6 tricyclic partially unsaturated cycloalkyl and R 2 is
  • Ri is hexahydroindacenyl optionally substituted with one or more Ris and R 2 is 7-membered heteroaryl.
  • Ri is hexahydroindacenyl and R 2 is 7-membered heteroaryl.
  • Ri is C12-C1 6 tricyclic partially unsaturated cycloalkyl optionally substituted with one or more Ris and R 2 is 8-membered heteroaryl.
  • Ri is C12-C1 6 tricyclic partially unsaturated cycloalkyl and R 2 is
  • Ri is hexahydroindacenyl optionally substituted with one or more Ris and R 2 is 8-membered heteroaryl.
  • Ri is hexahydroindacenyl and R 2 is 8-membered heteroaryl.
  • Ri is C12-C1 6 tricyclic partially unsaturated cycloalkyl optionally substituted with one or more Ris and R 2 is 8-membered heteroaryl optionally substituted with one or more C1-C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, C1-C 6 haloalkyl, C1-C 6 alkoxy, C1-C 6 haloalkoxy, halo, -CN, -OH, -NH2, -NH(CI-C 6 alkyl), -N(CI-C 6 alkyl)2, or oxo.
  • Ri is C12-C1 6 tricyclic partially unsaturated cycloalkyl and R 2 is 8-membered heteroaryl optionally substituted with one or more C1-C 6 alkyl, C2-C 6 alkenyl, C2- Ce alkynyl, C1-C 6 haloalkyl, C1-C 6 alkoxy, C1-C 6 haloalkoxy, halo, -CN, -OH, -NH2, -NH(CI-C 6 alkyl), -N(CI-C 6 alkyl)2, or oxo.
  • Ri is hexahydroindacenyl optionally substituted with one or more Ris and R 2 is 8-membered heteroaryl optionally substituted with one or more C1-C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, C1-C 6 haloalkyl, C1-C 6 alkoxy, C1-C 6 haloalkoxy, halo, -CN, -OH, -NH2, -NH(CI-C6 alkyl), -N(CI-C6 alkyl)2, or oxo.
  • Ri is hexahydroindacenyl and R 2 is 8-membered heteroaryl optionally substituted with one or more C1-C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, C1-C 6 haloalkyl, C1-C 6 alkoxy, C1-C 6 haloalkoxy, halo, -CN, -OH, -NH2, -NH(CI-C 6 alkyl), -N(CI-C 6 alkyl)2, or oxo.
  • -membered heteroaryl optionally substituted with one or more C1-C 6 alkyl, Ci-Ce alkenyl, Ci-Ce alkynyl, C1-C 6 haloalkyl, C1-C 6 alkoxy, C1-C 6 haloalkoxy, halo, -CN, -OH, -NH2, -NH(CI-C 6 alkyl), -N(CI-C 6 alkyl)2, or oxo.
  • Ri is C12-C1 6 tricyclic partially unsaturated cycloalkyl optionally substituted with one or more Ris and R 2 is 8-membered heteroaryl optionally substituted with one or more C1-C 6 alkyl.
  • Ri is C12-C1 6 tricyclic partially unsaturated cycloalkyl and R 2 is 8-membered heteroaryl optionally substituted with one or more C1-C 6 alkyl.
  • Ri is hexahydroindacenyl optionally substituted with one or more Ris and R 2 is 8-membered heteroaryl optionally substituted with one or more C1-C 6 alkyl.
  • Ri is hexahydroindacenyl and R 2 is 8-membered heteroaryl optionally substituted with one or more C1-C 6 alkyl.
  • -membered heteroaryl optionally substituted with one or more C1-C 6 alkyl.
  • Ri is C12-C1 6 tricyclic partially unsaturated cycloalkyl optionally substituted with one or more Ris and R 2 is 9-membered heteroaryl.
  • Ri is C12-C1 6 tricyclic partially unsaturated cycloalkyl and R 2 is 9-membered heteroaryl.
  • Ri is hexahydroindacenyl optionally substituted with one or more Ris and R 2 is 9-membered heteroaryl.
  • Ri is hexahydroindacenyl and R 2 is 9-membered heteroaryl.
  • R 2 is 9-membered heteroaryl.
  • Ri is C12-C1 6 tricyclic partially unsaturated cycloalkyl optionally substituted with one or more Ris and R 2 is 9-membered heteroaryl optionally substituted with one or more C1-C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, C1-C 6 haloalkyl, C1-C 6 alkoxy, C1-C 6 haloalkoxy, halo, -CN, -OH, -NH2, -NH(CI-C 6 alkyl), -N(CI-C 6 alkyl)2, or oxo.
  • Ri is C12-C1 6 tricyclic partially unsaturated cycloalkyl and R 2 is 9-membered heteroaryl optionally substituted with one or more C1-C 6 alkyl, C2-C 6 alkenyl, C2- Ce alkynyl, C1-C 6 haloalkyl, C1-C 6 alkoxy, C1-C 6 haloalkoxy, halo, -CN, -OH, -NH2, -NH(CI-C6 alkyl), -N(CI-C6 alkyl)2, or oxo.
  • Ri is hexahydroindacenyl optionally substituted with one or more Ris and R 2 is 9-membered heteroaryl optionally substituted with one or more C1-C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, C1-C 6 haloalkyl, C1-C 6 alkoxy, C1-C 6 haloalkoxy, halo, -CN, -OH, -NH2, -NH(CI-C6 alkyl), -N(CI-C6 alkyl)2, or oxo.
  • Ri is hexahydroindacenyl and R 2 is 9-membered heteroaryl optionally substituted with one or more C1-C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, C1-C 6 haloalkyl, C1-C 6 alkoxy, C1-C 6 haloalkoxy, halo, -CN, -OH, -NH2, -NH(Ci-C6 alkyl), -N(CI-C6 alkyl)2, or oxo.
  • -membered heteroaryl optionally substituted with one or more C1-C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, C1-C 6 haloalkyl, C1-C 6 alkoxy, C1-C 6 haloalkoxy, halo, -CN, -OH, -NH2, -NH(Ci-C6 alkyl), -N(CI-C6 alkyl)2, or oxo.
  • Ri is C12-C1 6 tricyclic partially unsaturated cycloalkyl optionally substituted with one or more Ris and R 2 is 9-membered heteroaryl optionally substituted with one or more C1-C 6 alkyl.
  • Ri is C12-C1 6 tricyclic partially unsaturated cycloalkyl and R 2 is 9-membered heteroaryl optionally substituted with one or more C1-C 6 alkyl.
  • Ri is hexahydroindacenyl optionally substituted with one or more Ris and R2 is 9-membered heteroaryl optionally substituted with one or more C1-C6 alkyl.
  • Ri is hexahydroindacenyl and R2 is 9-membered heteroaryl optionally substituted with one or more C1-C6 alkyl.
  • -membered heteroaryl optionally substituted with one or more C1-C6 alkyl.
  • Ri is C12-C16 tricyclic partially unsaturated cycloalkyl optionally substituted with one or more Ris and R2 is 4- to 8-membered heterocycloalkyl.
  • Ri is C12-C16 tricyclic partially unsaturated cycloalkyl and R2 is 4- to 8-membered heterocycloalkyl.
  • Ri is hexahydroindacenyl optionally substituted with one or more Ris and R2 is 4- to 8-membered heterocycloalkyl.
  • Ri is hexahydroindacenyl and R2 is 4- to 8-membered
  • -membered heterocycloalkyl In some embodiments, -membered heterocycloalkyl.
  • Ri is C12-C16 tricyclic partially unsaturated cycloalkyl optionally substituted with one or more Ris and R2 is 4- to 8-membered heterocycloalkyl optionally substituted with one or more C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, -CN, -OH, -NH2, -NH(CI-C 6 alkyl), -N(CI-C 6 alkyl)2, or oxo.
  • Ri is C12-C16 tricyclic partially unsaturated cycloalkyl and R2 is 4- to 8-membered heterocycloalkyl optionally substituted with one or more C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, -CN, -OH, -NH2, -NH(CI-C 6 alkyl), -N(CI-C 6 alkyl)2, or oxo.
  • Ri is hexahydroindacenyl optionally substituted with one or more Ris and R2 is 4- to 8-membered heterocycloalkyl optionally substituted with one or more C1-C6 alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, C1-C 6 haloalkyl, C1-C 6 alkoxy, C1-C 6 haloalkoxy, halo, -CN, -OH, -NH 2 , -NH(CI-C 6 alkyl), -N(Ci-Ce alkyl) 2 , or oxo.
  • Ri is hexahydroindacenyl and R 2 is 4- to 8-membered
  • heterocycloalkyl optionally substituted with one or more C1-C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, C1-C 6 haloalkyl, C1-C 6 alkoxy, C1-C 6 haloalkoxy, halo, -CN, -OH, -NH2, -NH(Ci-C 6 alkyl), -N(CI-C 6 alkyl)2, or oxo.
  • -membered heterocycloalkyl optionally substituted with one or more C1-C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, C1-C 6 haloalkyl, C1-C 6 alkoxy, C1-C 6 haloalkoxy, halo, -CN, -OH, -NH2, -NH(CI-C 6 alkyl), -N(CI-C 6 alkyl)2, or oxo.
  • Ri is C12-C1 6 tricyclic partially unsaturated cycloalkyl optionally substituted with one or more Ris and R 2 is 4- to 8-membered heterocycloalkyl optionally substituted with one or more C1-C 6 alkyl.
  • Ri is C12-C1 6 tricyclic partially unsaturated cycloalkyl and R 2 is 4- to 8-membered heterocycloalkyl optionally substituted with one or more C1-C 6 alkyl.
  • Ri is hexahydroindacenyl optionally substituted with one or more Ris and R 2 is 4- to 8-membered heterocycloalkyl optionally substituted with one or more C1-C 6 alkyl.
  • Ri is hexahydroindacenyl and R 2 is 4- to 8-membered
  • heterocycloalkyl optionally substituted with one or more C1-C 6 alkyl.
  • -membered heterocycloalkyl optionally substituted with one or more C1-C 6 alkyl.
  • Ri is C12-C1 6 tricyclic partially unsaturated cycloalkyl optionally substituted with one or more Ris and R 2 is 4-membered heterocycloalkyl.
  • Ri is C12-C1 6 tricyclic partially unsaturated cycloalkyl and R 2 is 4-membered heterocycloalkyl.
  • Ri is hexahydroindacenyl optionally substituted with one or more Ris and R 2 is 4-membered heterocycloalkyl.
  • Ri is hexahydroindacenyl and R 2 is 4-membered
  • Ri is C12-C1 6 tricyclic partially unsaturated cycloalkyl optionally substituted with one or more Ris and R 2 is 4-membered heterocycloalkyl optionally substituted with one or more C1-C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, C1-C 6 haloalkyl, C1-C 6 alkoxy, Ci- Ce haloalkoxy, halo, -CN, -OH, -NH2, -NH(CI-C 6 alkyl), -N(CI-C 6 alkyl)2, or oxo.
  • Ri is C12-C1 6 tricyclic partially unsaturated cycloalkyl and R 2 is 4-membered heterocycloalkyl optionally substituted with one or more C1-C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, C1-C 6 haloalkyl, C1-C 6 alkoxy, C1-C 6 haloalkoxy, halo, -CN, -OH, -NH2, -NH(CI-C6 alkyl), -N(CI-C6 alkyl)2, or oxo.
  • Ri is hexahydroindacenyl optionally substituted with one or more Ris and R 2 is 4-membered heterocycloalkyl optionally substituted with one or more C1-C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, C1-C 6 haloalkyl, C1-C 6 alkoxy, C1-C 6 haloalkoxy, halo, -CN, -OH, -NH2, -NH(CI-C 6 alkyl), -N(CI-C 6 alkyl)2, or oxo.
  • Ri is hexahydroindacenyl and R 2 is 4-membered
  • heterocycloalkyl optionally substituted with one or more C1-C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, C1-C 6 haloalkyl, C1-C 6 alkoxy, C1-C 6 haloalkoxy, halo, -CN, -OH, -NH2, -NH(Ci-C6 alkyl), -N(CI-C6 alkyl)2, or oxo.
  • -membered heterocycloalkyl optionally substituted with one or more C1-C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, C1-C 6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, -CN, -OH, -NH2, -NH(CI-C 6 alkyl), -N(CI-C 6 alkyl)2, or oxo.
  • Ri is C12-C16 tricyclic partially unsaturated cycloalkyl optionally substituted with one or more Ris and R2 is 4-membered heterocycloalkyl optionally substituted with one or more C1-C6 alkyl.
  • Ri is C12-C16 tricyclic partially unsaturated cycloalkyl and R2 is 4-membered heterocycloalkyl optionally substituted with one or more C1-C6 alkyl.
  • Ri is hexahydroindacenyl optionally substituted with one or more Ris and R2 is 4-membered heterocycloalkyl optionally substituted with one or more C1-C6 alkyl.
  • Ri is hexahydroindacenyl and R2 is 4-membered
  • heterocycloalkyl optionally substituted with one or more C1-C6 alkyl.
  • -membered heterocycloalkyl optionally substituted with one or more C1-C6 alkyl.
  • Ri is C12-C16 tricyclic partially unsaturated cycloalkyl optionally substituted with one or more Ris and R2 is 5-membered heterocycloalkyl.
  • Ri is C12-C16 tricyclic partially unsaturated cycloalkyl and R2 is 5-membered heterocycloalkyl.
  • Ri is hexahydroindacenyl optionally substituted with one or more Ris and R2 is 5-membered heterocycloalkyl.
  • Ri is hexahydroindacenyl and R2 is 5-membered
  • Ri is C12-C16 tricyclic partially unsaturated cycloalkyl optionally substituted with one or more Ris and R2 is 5-membered heterocycloalkyl optionally substituted with one or more C1-C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, C1-C 6 haloalkyl, C1-C 6 alkoxy, Ci- Ce haloalkoxy, halo, -CN, -OH, -NH2, -NH(CI-C 6 alkyl), -N(CI-C 6 alkyl)2, or oxo.
  • Ri is C12-C1 6 tricyclic partially unsaturated cycloalkyl and R 2 is 5-membered heterocycloalkyl optionally substituted with one or more C1-C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, C1-C 6 haloalkyl, C1-C 6 alkoxy, C1-C 6 haloalkoxy, halo, -CN, -OH, -NH2, -NH(CI-C6 alkyl), -N(CI-C6 alkyl)2, or oxo.
  • Ri is hexahydroindacenyl optionally substituted with one or more Ris and R 2 is 5-membered heterocycloalkyl optionally substituted with one or more C1-C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, C1-C 6 haloalkyl, C1-C 6 alkoxy, C1-C 6 haloalkoxy, halo, -CN, -OH, -NH2, -NH(CI-C 6 alkyl), -N(CI-C 6 alkyl)2, or oxo.
  • Ri is hexahydroindacenyl and R 2 is 5-membered
  • heterocycloalkyl optionally substituted with one or more C1-C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, C1-C 6 haloalkyl, C1-C 6 alkoxy, C1-C 6 haloalkoxy, halo, -CN, -OH, -NH2, -NH(Ci-C 6 alkyl), -N(CI-C 6 alkyl)2, or oxo.
  • -membered heterocycloalkyl optionally substituted with one or more C1-C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, C1-C 6 haloalkyl, C1-C 6 alkoxy, C1-C 6 haloalkoxy, halo, -CN, -OH, -NH2, -NH(CI-C6 alkyl), -N(CI-C6 alkyl)2, or oxo.
  • Ri is C12-C1 6 tricyclic partially unsaturated cycloalkyl optionally substituted with one or more Ris and R 2 is 5-membered heterocycloalkyl optionally substituted with one or more C1-C 6 alkyl.
  • Ri is C12-C1 6 tricyclic partially unsaturated cycloalkyl and R 2 is 5-membered heterocycloalkyl optionally substituted with one or more C1-C 6 alkyl.
  • Ri is hexahydroindacenyl optionally substituted with one or more Ris and R 2 is 5-membered heterocycloalkyl optionally substituted with one or more C1-C 6 alkyl.
  • Ri is hexahydroindacenyl and R 2 is 5-membered
  • heterocycloalkyl optionally substituted with one or more C1-C 6 alkyl.
  • -membered heterocycloalkyl optionally substituted with one or more C1-C 6 alkyl.
  • Ri is C12-C1 6 tricyclic partially unsaturated cycloalkyl optionally substituted with one or more Ris and R 2 is 6-membered heterocycloalkyl.
  • Ri is C12-C1 6 tricyclic partially unsaturated cycloalkyl and R 2 is 6-membered heterocycloalkyl.
  • Ri is hexahydroindacenyl optionally substituted with one or more Ris and R 2 is 6-membered heterocycloalkyl.
  • Ri is hexahydroindacenyl and R 2 is 6-membered
  • Ri is C12-C1 6 tricyclic partially unsaturated cycloalkyl optionally substituted with one or more Ris and R 2 is 6-membered heterocycloalkyl optionally substituted with one or more C1-C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, C1-C 6 haloalkyl, C1-C 6 alkoxy, Ci- Ce haloalkoxy, halo, -CN, -OH, -NH2, -NH(CI-C 6 alkyl), -N(CI-C 6 alkyl)2, or oxo.
  • Ri is C12-C1 6 tricyclic partially unsaturated cycloalkyl and R 2 is 6-membered heterocycloalkyl optionally substituted with one or more C1-C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, C1-C 6 haloalkyl, C1-C 6 alkoxy, C1-C 6 haloalkoxy, halo, -CN, -OH, -NH2, -NH(CI-C6 alkyl), -N(CI-C6 alkyl)2, or oxo.
  • Ri is hexahydroindacenyl optionally substituted with one or more Ris and R 2 is 6-membered heterocycloalkyl optionally substituted with one or more C1-C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, C1-C 6 haloalkyl, C1-C 6 alkoxy, C1-C 6 haloalkoxy, halo, -CN, -OH, -NH2, -NH(CI-C 6 alkyl), -N(CI-C 6 alkyl)2, or oxo.
  • Ri is hexahydroindacenyl and R 2 is 6-membered
  • heterocycloalkyl optionally substituted with one or more C1-C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, C1-C 6 haloalkyl, C1-C 6 alkoxy, C1-C 6 haloalkoxy, halo, -CN, -OH, -NH2, -NH(CI-C 6 alkyl), -N(CI-C 6 alkyl)2, or oxo.
  • -membered heterocycloalkyl optionally substituted with one or more C1-C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, C1-C 6 haloalkyl, C1-C 6 alkoxy, C1-C 6 haloalkoxy, halo, -CN, -OH, -NH2, -NH(CI-C 6 alkyl), -N(CI-C 6 alkyl)2, or oxo.
  • Ri is C12-C1 6 tricyclic partially unsaturated cycloalkyl optionally substituted with one or more Ris and R 2 is 6-membered heterocycloalkyl optionally substituted with one or more C1-C 6 alkyl.
  • Ri is C12-C1 6 tricyclic partially unsaturated cycloalkyl and R 2 is 6-membered heterocycloalkyl optionally substituted with one or more C1-C 6 alkyl.
  • Ri is hexahydroindacenyl optionally substituted with one or more Ris and R 2 is 6-membered heterocycloalkyl optionally substituted with one or more C1-C 6 alkyl.
  • Ri is hexahydroindacenyl and R 2 is 6-membered
  • heterocycloalkyl optionally substituted with one or more C1-C 6 alkyl.
  • -membered heterocycloalkyl optionally substituted with one or more C1-C 6 alkyl.
  • Ri is C12-C1 6 tricyclic partially unsaturated cycloalkyl optionally substituted with one or more Ris and R 2 is 7-membered heterocycloalkyl.
  • Ri is C12-C1 6 tricyclic partially unsaturated cycloalkyl and R 2 is 7-membered heterocycloalkyl.
  • Ri is hexahydroindacenyl optionally substituted with one or more Ris and R 2 is 7-membered heterocycloalkyl.
  • Ri is hexahydroindacenyl and R 2 is 7-membered
  • heterocycloalkyl [0813] In some embodiments, -membered heterocycloalkyl.
  • Ri is C12-C1 6 tricyclic partially unsaturated cycloalkyl optionally substituted with one or more Ris and R 2 is 7-membered heterocycloalkyl optionally substituted with one or more C1-C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, C1-C 6 haloalkyl, C1-C 6 alkoxy, Ci- Ce haloalkoxy, halo, -CN, -OH, -NH2, -NH(CI-C6 alkyl), -N(CI-C6 alkyl)2, or oxo.
  • Ri is C12-C1 6 tricyclic partially unsaturated cycloalkyl and R 2 is 7-membered heterocycloalkyl optionally substituted with one or more C1-C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, C1-C 6 haloalkyl, C1-C 6 alkoxy, C1-C 6 haloalkoxy, halo, -CN, -OH, -NH2, -NH(CI-C6 alkyl), -N(CI-C6 alkyl)2, or oxo.
  • Ri is hexahydroindacenyl optionally substituted with one or more Ris and R 2 is 7-membered heterocycloalkyl optionally substituted with one or more C1-C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, C1-C 6 haloalkyl, C1-C 6 alkoxy, C1-C 6 haloalkoxy, halo, -CN, -OH, -NH2, -NH(CI-C6 alkyl), -N(CI-C6 alkyl)2, or oxo.
  • Ri is hexahydroindacenyl and R 2 is 7-membered
  • heterocycloalkyl optionally substituted with one or more C1-C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, C1-C 6 haloalkyl, C1-C 6 alkoxy, C1-C 6 haloalkoxy, halo, -CN, -OH, -NH2, -NH(Ci-C6 alkyl), -N(CI-C6 alkyl)2, or oxo.
  • -membered heterocycloalkyl optionally substituted with one or more C1-C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, C1-C 6 haloalkyl, C1-C 6 alkoxy, C1-C 6 haloalkoxy, halo, -CN, -OH, -NH2, -NH(Ci-C6 alkyl), -N(CI-C 6 alkyl)2, or oxo.
  • Ri is C12-C1 6 tricyclic partially unsaturated cycloalkyl optionally substituted with one or more Ris and R2 is 7-membered heterocycloalkyl optionally substituted with one or more C1-C 6 alkyl.
  • Ri is C12-C1 6 tricyclic partially unsaturated cycloalkyl and R 2 is 7-membered heterocycloalkyl optionally substituted with one or more C1-C 6 alkyl.
  • Ri is hexahydroindacenyl optionally substituted with one or more Ris and R 2 is 7-membered heterocycloalkyl optionally substituted with one or more C1-C 6 alkyl.
  • Ri is hexahydroindacenyl and R 2 is 7-membered
  • heterocycloalkyl optionally substituted with one or more C1-C 6 alkyl.
  • -membered heterocycloalkyl optionally substituted with one or more C1-C 6 alkyl.
  • Ri is C12-C1 6 tricyclic partially unsaturated cycloalkyl optionally substituted with one or more Ris and R 2 is 8-membered heterocycloalkyl.
  • Ri is C12-C1 6 tricyclic partially unsaturated cycloalkyl and R 2 is 8-membered heterocycloalkyl.
  • Ri is hexahydroindacenyl optionally substituted with one or more Ris and R 2 is 8-membered heterocycloalkyl.
  • Ri is hexahydroindacenyl and R 2 is 8-membered
  • Ri is C12-C1 6 tricyclic partially unsaturated cycloalkyl optionally substituted with one or more Ris and R 2 is 8-membered heterocycloalkyl optionally substituted with one or more C1-C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, C1-C 6 haloalkyl, C1-C 6 alkoxy, Ci- Ce haloalkoxy, halo, -CN, -OH, -NH2, -NH(CI-C 6 alkyl), -N(CI-C 6 alkyl)2, or oxo.
  • Ri is C12-C1 6 tricyclic partially unsaturated cycloalkyl and R 2 is 8-membered heterocycloalkyl optionally substituted with one or more C1-C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, C1-C 6 haloalkyl, C1-C 6 alkoxy, C1-C 6 haloalkoxy, halo, -CN, -OH, -NH2, -NH(CI-C6 alkyl), -N(CI-C6 alkyl)2, or oxo.
  • Ri is hexahydroindacenyl optionally substituted with one or more Ris and R 2 is 8-membered heterocycloalkyl optionally substituted with one or more C1-C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, C1-C 6 haloalkyl, C1-C 6 alkoxy, C1-C 6 haloalkoxy, halo, -CN, -OH, -NH2, -NH(CI-C6 alkyl), -N(CI-C6 alkyl)2, or oxo.
  • Ri is hexahydroindacenyl and R 2 is 8-membered
  • heterocycloalkyl optionally substituted with one or more C1-C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, C1-C 6 haloalkyl, C1-C 6 alkoxy, C1-C 6 haloalkoxy, halo, -CN, -OH, -NH2, -NH(Ci-C6 alkyl), -N(CI-C6 alkyl)2, or oxo.
  • -membered heterocycloalkyl optionally substituted with one or more C1-C6 alkyl, C2-O, alkenyl, C2-O, alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, -CN, -OH, -NH2, -NH(CI-C 6 alkyl), -N(CI-C 6 alkyl)2, or oxo.
  • Ri is C12-C1 6 tricyclic partially unsaturated cycloalkyl optionally substituted with one or more Ris and R2 is 8-membered heterocycloalkyl optionally substituted with one or more C1-C 6 alkyl.
  • Ri is C12-C16 tricyclic partially unsaturated cycloalkyl and R2 is 8-membered heterocycloalkyl optionally substituted with one or more C1-C6 alkyl.
  • Ri is hexahydroindacenyl optionally substituted with one or more Ris and R2 is 8-membered heterocycloalkyl optionally substituted with one or more C1-C 6 alkyl.
  • Ri is hexahydroindacenyl and R2 is 8-membered
  • heterocycloalkyl optionally substituted with one or more C1-C 6 alkyl.
  • -membered heterocycloalkyl optionally substituted with one or more C1-C6 alkyl.
  • Ri is C12-C16 tricyclic partially unsaturated cycloalkyl optionally substituted with one or more Ris and R2 is furanyl. [0840] In some embodiments, Ri is C12-C16 tricyclic partially unsaturated cycloalkyl and R 2 is furanyl.
  • Ri is hexahydroindacenyl optionally substituted with one or more Ris and R 2 is furanyl.
  • Ri is hexahydroindacenyl and R 2 is furanyl.
  • furanyl In some embodiments, furanyl.
  • Ri is C12-C16 tricyclic partially unsaturated cycloalkyl optionally substituted with one or more Ris and R 2 is furanyl optionally substituted with one or more C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, -CN, -OH, -NH2, -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl) 2 , or oxo.
  • Ri is C12-C16 tricyclic partially unsaturated cycloalkyl and R 2 is furanyl optionally substituted with one or more C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, -CN, -OH, -NH2, -NH(CI-C6 alkyl), -N(CI-C6 alkyl)2, or oxo.
  • Ri is hexahydroindacenyl optionally substituted with one or more Ris and R 2 is furanyl optionally substituted with one or more C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, -CN, -OH, -NH2, -NH(Ci-C6 alkyl), -N(CI-C6 alkyl)2, or oxo.
  • Ri is hexahydroindacenyl and R 2 is furanyl optionally substituted with one or more C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, Ci- Ce haloalkoxy, halo, -CN, -OH, -NH2, -NH(Ci-C6 alkyl), -N(CI-C6 alkyl)2, or oxo.
  • Ri is C12-C16 tricyclic partially unsaturated cycloalkyl optionally substituted with one or more Ris and R 2 is furanyl optionally substituted with one or more C1-C6 alkyl.
  • Ri is C12-C16 tricyclic partially unsaturated cycloalkyl and R 2 is furanyl optionally substituted with one or more C1-C6 alkyl.
  • Ri is hexahydroindacenyl optionally substituted with one or more Ris and R 2 is furanyl optionally substituted with one or more C1-C6 alkyl.
  • Ri is hexahydroindacenyl and R 2 is furanyl optionally substituted with one or more C1-C6 alkyl.
  • furanyl optionally substituted with one or more C1-C6 alkyl.
  • Ri is C12-C16 tricyclic partially unsaturated cycloalkyl optionally
  • Ri is C12-C16 tricyclic partially unsaturated cycloalkyl and R 2 is
  • Ri is hexahydroindacenyl optionally substituted with one or more wherein * denotes an attachment of R2 to the adjacent nitrogen atom, and ** denotes an attachment of R2 to the adjacent carbon atom.
  • Ri is hexahydroindacenyl and R 2 is .AV* -" , wherein * denotes an attachment of R 2 to the adjacent nitrogen atom, and ** denotes an attachment of R 2 to the adjacent carbon atom.
  • * denotes an attachment of R 2 to the adjacent nitrogen atom
  • ** denotes an attachment of R 2 to the adjacent carbon atom.
  • Ri is C12-C16 tricyclic partially unsaturated cycloalkyl optionally substituted with one or more Ris and R 2 is oxazolyl.
  • Ri is C12-C16 tricyclic partially unsaturated cycloalkyl and R 2 is oxazolyl.
  • Ri is hexahydroindacenyl optionally substituted with one or more Ris and R2 is oxazolyl.
  • Ri is hexahydroindacenyl and R 2 is oxazolyl.
  • Ri is C12-C16 tricyclic partially unsaturated cycloalkyl optionally substituted with one or more Ris and R 2 is oxazolyl optionally substituted with one or more Ci- Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, - CN, -OH, -NH2, -NH(CI-C 6 alkyl), -N(Ci-Ce alkyl) 2 , or oxo.
  • Ri is C12-C16 tricyclic partially unsaturated cycloalkyl and R 2 is oxazolyl optionally substituted with one or more C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci- Ce haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, -CN, -OH, -NH2, -NH(CI-C6 alkyl), -N(Ci- Ce alkyl)2, or oxo.
  • Ri is hexahydroindacenyl optionally substituted with one or more Ris and R 2 is oxazolyl optionally substituted with one or more C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, -CN, -OH, -NH2, -NH(Ci-C 6 alkyl), -N(CI-C6 alkyl)2, or oxo.
  • Ri is hexahydroindacenyl and R 2 is oxazolyl optionally substituted with one or more C1-C 6 alkyl, Ci-Ce alkenyl, Ci-Ce alkynyl, C1-C 6 haloalkyl, C1-C 6 alkoxy, C1-C 6 haloalkoxy, halo, -CN, -OH, -NH2, -NH(CI-C6 alkyl), -N(CI-C6 alkyl)2, or oxo.
  • oxazolyl optionally substituted with one or more C1-C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, C1-C 6 haloalkyl, C1-C 6 alkoxy, C1-C 6 haloalkoxy, halo, -CN, -OH, -NH2, -NH(CI-C 6 alkyl), -N(CI-C 6 alkyl)2, or oxo.
  • Ri is C12-C1 6 tricyclic partially unsaturated cycloalkyl optionally substituted with one or more Ris and R 2 is oxazolyl optionally substituted with one or more Ci- Ce alkyl.
  • Ri is C12-C1 6 tricyclic partially unsaturated cycloalkyl and R 2 is oxazolyl optionally substituted with one or more C1-C 6 alkyl.
  • Ri is hexahydroindacenyl optionally substituted with one or more Ris and R 2 is oxazolyl optionally substituted with one or more C1-C 6 alkyl.
  • Ri is hexahydroindacenyl and R 2 is oxazolyl optionally substituted with one or more C1-C 6 alkyl.
  • oxazolyl optionally substituted with one or more C1-C 6 alkyl.

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Abstract

La présente invention concerne des composés de formule (I) : et leurs sels pharmaceutiquement acceptables, des compositions pharmaceutiques, des procédés d'utilisation et des procédés pour leur préparation. Les composés de l'invention sont utiles pour inhiber la maturation de cytokines de la famille IL-1 en inhibant des inflammasomes et peuvent être utilisés dans le traitement de troubles dans lesquels l'activité des inflammasomes est impliquée, telles que les maladies inflammatoires, auto-inflammatoires, et auto-immunes et les cancers.
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Publication number Priority date Publication date Assignee Title
WO2021043966A1 (fr) 2019-09-06 2021-03-11 Inflazome Limited Inhibiteurs de nlrp3
WO2021255279A1 (fr) * 2020-06-19 2021-12-23 Ac Immune Sa Dérivés de dihydrooxazole et de thiourée modulant la voie inflammatoire nlrp3
WO2022268935A3 (fr) * 2021-06-23 2023-02-02 F. Hoffmann-La Roche Ag Nouveau procédé
WO2023118521A1 (fr) * 2021-12-22 2023-06-29 Ac Immune Sa Composés dérivés de dihydro-oxazol

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021043966A1 (fr) 2019-09-06 2021-03-11 Inflazome Limited Inhibiteurs de nlrp3
WO2021255279A1 (fr) * 2020-06-19 2021-12-23 Ac Immune Sa Dérivés de dihydrooxazole et de thiourée modulant la voie inflammatoire nlrp3
US12624010B2 (en) 2020-06-19 2026-05-12 Ac Immune Sa Dihydrooxazole and thiourea derivatives modulating the NLRP3 inflammasome pathway
WO2022268935A3 (fr) * 2021-06-23 2023-02-02 F. Hoffmann-La Roche Ag Nouveau procédé
JP2024524215A (ja) * 2021-06-23 2024-07-05 エフ． ホフマン－ラ ロシュ アーゲー Ｎｌｒｐ３阻害剤を調製するための方法
WO2023118521A1 (fr) * 2021-12-22 2023-06-29 Ac Immune Sa Composés dérivés de dihydro-oxazol

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