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WO2025235362A1 - INDOLINONE COMPOUNDS AS KCa3.1 POTASSIUM CHANNEL BLOCKERS - Google Patents

INDOLINONE COMPOUNDS AS KCa3.1 POTASSIUM CHANNEL BLOCKERS

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Publication number
WO2025235362A1
WO2025235362A1 PCT/US2025/027715 US2025027715W WO2025235362A1 WO 2025235362 A1 WO2025235362 A1 WO 2025235362A1 US 2025027715 W US2025027715 W US 2025027715W WO 2025235362 A1 WO2025235362 A1 WO 2025235362A1
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Prior art keywords
alkyl
compound
cycloalkyl
halogen
halogenated
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PCT/US2025/027715
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French (fr)
Inventor
Fabrizio Giordanetto
Morten Østergaard JENSEN
Vishwanath JOGINI
Roger John Snow
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DE Shaw Research LLC
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DE Shaw Research LLC
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Publication of WO2025235362A1 publication Critical patent/WO2025235362A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/32—Oxygen atoms
    • C07D209/34—Oxygen atoms in position 2
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders

Definitions

  • the invention relates generally to the field of pharmaceutical science. More particularly, the invention relates to compounds and compositions useful as pharmaceuticals as potassium channel blockers.
  • BACKGROUND [0005] Calcium-activated potassium (K Ca ) channels are found on the plasma membrane of animal cells and control the permeability of potassium through the cell membrane. They have a key role in regulating calcium-signaling and membrane potential. There are eight KCa channels found in the human genome of which two were later found to be activated by sodium or chloride (Wulff, H. et al., 2010, Expert. Rev. Clin. Pharmacol.3, 3, 385-396).
  • K Ca channels include large-conductance potassium channels and small- and intermediate- conductance potassium channels (Kaczmarek, L.K. et al., 2017, Pharmacol. Rev.69:1-11).
  • K Ca 3.1 is an intermediate-conductance and voltage-insensitive K Ca channel (Wulff, H. et al., 2010, Expert Rev. Clin. Pharmacol.3, 3, 385-396).
  • KCa3.1 (SK4, IK4, Gardos) is encoded by the KCNN4 gene that belongs to the KCNN family of calcium-activated potassium-selective ion (K + ) channels located primarily on the plasma membrane of mammalian cells that functionally depend on a calcium-sensing calmodulin domain required for activation (Joiner, W.J. et al., 1997, Proc. Natl. Acad. Sci. U.S.A.94, 20, 11013-11018).
  • K + calcium-activated potassium-selective ion
  • K Ca 3.1 is an ‘intermediate’ conductance (IK) channel, genetically related to KCNN1-3 that encode the SK1-SK3 K + channels of either ‘big’ (SK1) or ‘small’ (SK2, SK3) conductance.
  • K Ca 3.1 is highly expressed on the plasma membrane of several human primary cells where it functions to regulate calcium homeostasis and signaling by providing a driving force for cellular calcium entry.
  • KCa3.1 expression is prevalent in immune cells, including T and B-lymphocytes (Khanna, R. et al., 1999, J. Biol. Chem.274, 21, P14838-14849; Fanger, C.M. et al., 2001, J. Biol.
  • K Ca 3.1 is structurally characterized by the presence of four identical transmembrane domains that together form a functional, homo-tetrameric protein with a central K + conducting pore (Lee, C.-H. et al., 2018, Science, 360, 6388, 508-513).
  • Each subunit has six transmembrane helices, two pore-contributing surrounded by four peripheral helices comprising a voltage-sensor-like domain.
  • the transmembrane protein is coupled intracellularly to four calmodulin (Cam) protein domains, one per KCa3.1 subunit.
  • KCa3.1 is activated at elevated intracellular calcium concentration where all four Cam domains become calcium-bound, leading to a tight KCa3.1-Cam coupling and a protein conformational change that results in complete opening of the ion conducting pore (Lee, C.-H. et al., 2018, Science, 360, 6388, 508-513).
  • the regulatory role of K Ca 3.1 in many immune cells has implicated the channel in autoimmune and inflammatory disorders.
  • Mouse K Ca 3.1 knock-out (KO) models have shown that KCa3.1 deletion reduced synovial inflammation and histopathological destruction and it also lowered inflammatory mediators in the murine cartilage, reducing its deterioration and bone erosion in arthritic mice (Kang, H. et al., 2014, Cell Rep.8, 4, P1210-1224).
  • common gastrointestinal inflammatory disorders i.e., inflammatory bowel diseases
  • Crohn’s disease and ulcerative colitis multiple studies in preclinical species have demonstrated that selective K Ca 3.1 inhibition improved clinical symptoms in these indications (Di, L. et al., 2009, Proc. Natl. Acad. Sci. U.S.A.107, 4, 1541-1546; Str ⁇ b ⁇ k, D.
  • K Ca 3.1 knock-out (KO) and induced (transgenic) K Ca 3.1 overexpression mouse models have suggested K Ca 3.1 as target in eczematous dermatitis with multiple clinical symptoms such as epidermal hyperplasia, hyperkeratosis, epidermal edema, and itch being improved upon treatment with a K Ca 3.1 selective inhibitor (Lozano-Gerona, J. et al., 2020, PLoS One 15, 3, e0222619).
  • KCa3.1 is implicated in sickle cell anemia (SCD) and clinical studies with a KCa3.1 inhibitor suggested improvements in hematological parameters (Gárdos, G., 1958, Biochim. Biophys. Acta 30, 3, 653-654; Jensen, B.S. et al., 2001, Curr. Drug Targets 2, 4, 401-422; Ataga, K.I. et al., 2008, Blood 111, 8, 3991-3997; Rapetti-Mauss, R. et al., 2016, Haematologica 101, 11, e431-e435; Ataga, K.I. et al., 2011, Br. J. Haematol.153, 1, 92-104).
  • K Ca 3.1 channelopathy due to gain of function mutations in the K Ca 3.1 pore that increase channel activity (Andolfo, I. et al., 2015, Am. J. Hematol.90, 10, 921-926; Fermo, E. et al., 2017, Sci. Rep.7, 1744; Rivera, A. et al., 2019, Am. J. Physio. Cell Physio.317, 2, C287- C302; Rapetti-Mauss, R.
  • K Ca 3.1 inhibition reduced restenosis in a swine model of postangioplasty restenosis (Tharp, D.L.
  • KCa3.1 has been implicated in numerous fibrotic diseases in organs such as kidney (renal fibrosis and diabetic nephropathy) (Grgic, I. et al., 2009, Proc. Natl. Acad. Sci. U.S.A. 106,34, 14518-14523; Huang, C. et al., 2013, Diabetes, 62, 8, 2923-2934; Huang, C. et al., 2018, PLoS One 13, 2, e0192800), lung (IPF) (Perera, U.E. et al., 2021, Can. Respir. J.2021, 6683195; Organ, L.
  • K Ca 3.1 drives proliferation in many cancers (Todesca, L.M. et al., 2021, Cell Physiol. Biochem.55, S3, 131-144). Increased K Ca 3.1 expression has been found in brain (Younes, S. et al., 2023, Membranes 13, 4, 434), lung (Todesca, L.M.
  • K Ca 3.1 inhibitors have proven efficacious in xenograft models of these indications. Selective inhibition of KCa3.1 in glioblastoma in patients that develop resistance to radiation therapy may help overcome such resistance, which could potentially help reduce tumor growth (Stransky, N. et al., 2023, Sci.
  • KCa3.1-mediated activation of microglia and astrocytes infiltrating peripheral or central nerve compartments has been implicated in development of neuroinflammation in acute ischemic stroke (Chen, J.-Y. et al., 2016, J. Cereb. Blood Flow Metab.36, 12, 2146- 2161; Yi, M. et al., 2017, J. Neuroinflamm.14, 1, 203), in traumatic brain injury, in spinal cord and peripheral nerve injuries, and in preclinical models of these conditions.
  • K Ca 3.1inhibition offers protective effects against nerve damage.
  • K Ca 3.1 inhibition and KO models of Alzheimer’s, Parkinson’s, and amyotrophic lateral sclerosis (ALS) suggest targeting KCa3.1 generally may reduce micro- and astrogliosis-induced neuronal impairments.
  • ALS amyotrophic lateral sclerosis
  • compositions and methods of using these compositions described herein are useful for treating conditions in vitro and in vivo.
  • Such compounds, pharmaceutical compositions, and methods of treatment have a number of clinical applications, including as pharmaceutically active agents and methods for cancer, sickle cell anemia, a cardiovascular disease, a respiratory disease, a fibrotic disease, an autoimmune disease, a central nervous system (CNS) disorder, a neurodegenerative disease, an inflammatory disorder, or a combination thereof.
  • CNS central nervous system
  • a compound of Formula I or a pharmaceutically acceptable salt thereof, or a tautomer thereof is described, wherein R1 is alkyl, cycloalkyl, halogenated alkyl, halogenated cycloalkyl, bicycloalkyl, halogenated bicycloalkyl, saturated heterocycle, partially saturated heterocycle, aryl, heteroaryl, -C 1-4 alkyl-cycloalkyl, -C 1-4 alkyl-saturated heterocycle, -C 1-4 alkyl-partially saturated heterocycle, or cycloalkenyl, each of which optionally substituted by 1-5 substituents each independently selected from the group consisting of D, halogen, alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, alkenyl, and alkynyl where valence permits; R2 is halogen, alkyl, alkynyl, halogenated
  • R 1 is phenyl that is optionally substituted by 1-5 substituents each independently selected from the group consisting of D, halogen, alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, alkenyl, and alkynyl.
  • R 1 is phenyl that is optionally substituted by 1-5 substituents each independently selected from the group consisting of D, alkyl, halogen, and halogenated alkyl.
  • R 1 is phenyl that is optionally substituted by 1-5 substituents each independently selected from the group consisting of D, CH3, CH2CH3, F, Cl, Br, CH2F, and CF3.
  • R1 is cycloalkyl, bicycloalkyl, or - C 1-4 alkyl-cycloalkyl, each of which optionally substituted by 1-5 substituents each independently selected from the group consisting of D, alkyl, halogen, and halogenated alkyl where valence permits.
  • R1 is cycloalkyl, bicycloalkyl, or -C1- 4 alkyl-cycloalkyl, each of which optionally substituted by 1-5 substituents each independently selected from the group consisting of D, CH 3 , CH 2 CH 3 , F, Cl, Br, CH 2 F, and CF3 where valence permits.
  • R1 is saturated heterocycle that is optionally substituted by 1-5 substituents each independently selected from the group consisting of D, alkyl, halogen, and halogenated alkyl where valence permits.
  • R1 is saturated heterocycle that is optionally substituted by 1-5 substituents each independently selected from the group consisting of D, CH 3 , CH 2 CH 3 , F, Cl, Br, CH 2 F, and CF 3 where valence permits.
  • R1 is alkyl that is optionally substituted by 1-5 substituents each independently selected from the group consisting of D and halogen where valence permits.
  • R1 is halogenated alkyl, halogenated cycloalkyl, halogenated bicycloalkyl, partially saturated heterocycle, heteroaryl or cycloalkenyl, each of which optionally substituted by 1-5 substituents each independently selected from the group consisting of D, halogen, alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, alkenyl, and alkynyl where valence permits.
  • R 1 is -C 1-4 alkyl-saturated heterocycle, or C1-4alkyl-partially saturated heterocycle, each of which optionally substituted by 1-5 substituents each independently selected from the group consisting of D, halogen, alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, alkenyl, and alkynyl where valence permits.
  • R1 is selected from the group consisting [0030]
  • the compound has the structure of Formula IIa: wherein R 11 is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogenated cycloalkyl, or halogenated alkyl; R12 is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogenated cycloalkyl, or halogenated alkyl; R 13 is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogenated cycloalkyl, or halogenated alkyl; R14 is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogenated cycloalkyl, or
  • R 11 is H, D, F, Cl, Br, I, alkyl, or halogenated alkyl
  • R12 is H, D, F, Cl, Br, I, alkyl, or halogenated alkyl
  • R13 is H, D, F, Cl, Br, I, alkyl, or halogenated alkyl
  • R14 is H, D, F, Cl, Br, I, alkyl, or halogenated alkyl
  • R15 is H, D, F, Cl, Br, I, alkyl, or halogenated alkyl.
  • 1-5 substituents each independently selected from the group consisting of D, alkyl, halogen, and halogenated alkyl where valence permits.
  • any one of the embodiments described herein is pyridine, pyrimidine, furan, or thiophene, each of which optionally substituted with halogen or alkyl.
  • thiane or pyrane each of which optionally substituted with halogen or alkyl.
  • R 2 is CN, OH, halogen, halogenated alkyl, alkyl optionally substituted with alkoxy or OH, or alkoxy optionally substituted with halogen, alkyl, alkoxy, or OH.
  • R 2 is selected from the group consisting of CN, F, Cl, Br, I, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , CF 3 , CH 2 F, CHF 2 , CH2Cl, CH2CF3, CHFCH3, CHFCH2F, CF2CH3, CHClCH3, CCl2CH3, CHBrCH3, CH2CH2CF3, and CHClCHClCH3.
  • R 2 is CN, OR a , SR a , -O-C 1-4 alkyl- ORa, -O-C1-4alkyl-SRa, -O-C1-4alkyl-NRaRb, -S-C1-4alkyl-ORa, -S-C1-4alkyl-SRa, or -S-C1- 4alkyl-NRaRb.
  • R 2 is CN, OR a , SR a , or -O-C 1-4 alkyl- OR a .
  • R2 is -C1-4alkyl-ORa or -C1-4alkyl- SR a .
  • R 2 is selected from the group .
  • the compound has the structure of Formula III: wherein X is O or S; and R 16 is C 1-4 alkyl that is optionally substituted with halogen, OR a , SR a , or NR a R b .
  • m is 2.
  • m is 1.
  • each occurrence of R 8 is independently H, D, OH, or alkyl.
  • each occurrence of R8 is independently H, D, OH, CH3, or CH2CH3.
  • each occurrence of R 8 is independently H, D, or OH.
  • each occurrence of R9 is independently H, D, OH, or alkyl.
  • each occurrence of R 9 is independently H, D, OH, CH 3 , or CH 2 CH 3 .
  • each occurrence of R9 is H, D, or OH.
  • the structural moiety –(CR 8 R 9 ) m – is –CH2–, –CH2CH2–, –CHOH–, or –CH2CHOH–.
  • R10 is alkyl, -COORa, -CORa, - CONR a R b , -OR a , -SOR a , or -SO 2 R a .
  • R10 is -CONRaRb.
  • R10 is saturated heterocycle, or heteroaryl, wherein R 10 is optionally substituted with halogen or OH.
  • R 10 is oxetane, pyrazole, or oxadiazole, each optionally substituted by halogen or alkyl.
  • R 10 is H, D, CN, or aryl.
  • the compound has a structure of Formula IV: .
  • the compound has the structure of Formula V: wherein X is O or S; and R16 is C1-4alkyl that is optionally substituted with halogen, ORa, SRa, or NRaRb.
  • R 1 is phenyl that is optionally substituted by 1-5 substituents each independently selected from the group consisting of D, halogen, alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, alkenyl, and alkynyl.
  • R1 is optionally substituted by 1-5 substituents each independently selected from the group consisting of D, F, Cl, Br, I, alkyl, and halogenated alkyl where valence permits.
  • R1 is alkyl, cycloalkyl, -CH2- cycloalkyl, cycloalkenyl, bicycloalkyl, heteroaryl, or saturated heterocycle, each of which optionally substituted by 1-5 substituents each independently selected from the group consisting of D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogenated cycloalkyl, and halogenated alkyl.
  • R 1 is optionally substituted by 1-5 substituents each independently selected from the group consisting of D, alkyl, halogen, and halogenated alkyl where valence permits.
  • R 1 is pyridine, pyrimidine, furan, or thiophene, each of which optionally substituted with halogen or alkyl.
  • R1 is thiane or pyrane, each of which optionally substituted with halogen or alkyl.
  • at least one of R4, R5, R6, and R7 is not H or D.
  • R 4 , R 5 , R 6 , and R 7 are not H or D.
  • R4 is H, D, halogen, CN, alkyl, halogenated alkyl, OR a , or SR a .
  • R 4 is H, D, halogen, CN, alkyl, or ORa.
  • R4 is H, D, F, Cl, Br, I, CN, OH, CH 3 , CH 2 CH 3 , OCH 3 , or CF 3 .
  • R 4 is cycloalkyl, halogenated cycloalkyl, -C 1-4 alkyl-OR a , or -C 1-4 alkyl-SR a .
  • R5 is H, D, halogen, CN, alkyl, halogenated alkyl, OR a , or SR a .
  • R 5 is H, D, halogen, CN, alkyl, or ORa.
  • R5 is H, D, F, Cl, Br, I, CN, OH, CH 3 , CH 2 CH 3 , OCH 3 , or CF 3 .
  • R5 is cycloalkyl, halogenated cycloalkyl, -C1-4alkyl-ORa, or -C1-4alkyl-SRa.
  • R 6 is H, D, halogen, CN, alkyl, halogenated alkyl, OR a , or SR a .
  • R6 is H, D, halogen, CN, alkyl, or OR a .
  • R 6 is H, D, F, Cl, Br, I, CN, OH, CH3, CH2CH3, OCH3, or CF3.
  • R 6 is cycloalkyl, halogenated cycloalkyl, -C 1-4 alkyl-OR a , or -C 1-4 alkyl-SR a .
  • R 7 is cycloalkyl, halogenated cycloalkyl, -C1-4alkyl-ORa, or -C1-4alkyl-SRa.
  • R 1 is alkyl, cycloalkyl, -C 1-4 alkyl- cycloalkyl, bicycloalkyl, saturated heterocycle, aryl, heteroaryl, or cycloalkenyl; wherein R 1 is optionally substituted by 1-5 substituents each independently selected from the group consisting of D, halogen, alkyl, and halogenated alkyl where valence permits;
  • R 2 is CN, alkyl, OR a , SR a , -C 1-4 alkyl-OR a , or -O-C 1-4 alkyl-OR a ;
  • R 3 is –(CH 2 ) m CONR a R b , –
  • R1 is cycloalkyl or phenyl; wherein the cycloalkyl or phenyl in R1 is optionally substituted by 1-5 substituents each of which is independently D or halogen where valence permits;
  • X is O;
  • R16 is C1-4alkyl that is optionally substituted with halogen, ORa, SRa, or NRaRb;
  • R 4 is H, D, or halogen;
  • R 5 is H, D, halogen, or OR a ;
  • R6 is H, D, or halogen;
  • R 7 is H, D, or halogen; and
  • R a and R b are each independently H or Me.
  • At least one occurrence of Ra or Rb is independently H, D, alkyl, cycloalkyl, saturated heterocycle, aryl, or heteroaryl.
  • each occurrence of R a or R b is independently H, D, alkyl, or halogenated alkyl.
  • At least one occurrence of Ra or Rb is H, Me, phenyl
  • R a and R b together with the nitrogen atom that they are connected to, form an optionally substituted heterocycle comprising the nitrogen atom and 0-3 additional heteroatoms each selected from the group consisting of N, O, and S.
  • each occurrence of R x is independently H, alkyl, or heterocycle optionally substituted by alkyl, halogen, or OH.
  • each occurrence of Rx is independently H or alkyl.
  • each occurrence of R x is independently H or Me.
  • the compound is selected from the group consisting of compounds 1-74 in Table 2. [0095] In any one of the embodiments described herein, the compound i
  • the compound is not in a salt form or a tautomer form.
  • a pharmaceutical composition comprising at least one compound according to any one of the embodiments described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.
  • a method of treating a condition in a mammalian species in need thereof comprising administering to the mammalian species a therapeutically effective amount of at least one compound according to any one of embodiments described herein, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, wherein the condition is selected from the group consisting of cancer, sickle cell anemia, a cardiovascular disease, a respiratory disease, a fibrotic disease, an autoimmune disease, a central nervous system (CNS) disorder, a neurodegenerative disease, and an inflammatory disorder.
  • the respiratory disease is an inflammatory airway disease, airway hyperresponsiveness, an idiopathic lung disease, chronic obstructive pulmonary disease, asthma, allergy chronic asthma, tracheobronchial or diaphragmatic dysfunction, cough, or chronic cough.
  • the autoimmune disease is rheumatoid arthritis or multiple sclerosis (MS).
  • MS multiple sclerosis
  • the CNS disorder is acute ischemic stroke, traumatic brain injury, peripheral nerve injury, glioblastoma multiforme, or spinal cord injury.
  • the fibrotic disease is liver fibrosis, kidney fibrosis, cardiac fibrosis, eye injury-related corneal fibrosis, or lung fibrosis.
  • the neurodegenerative disease is Alzheimer’s disease, Parkinson’s disease, or amyotrophic lateral sclerosis (ALS).
  • the mammalian species is human.
  • a method of inhibiting calcium-activated potassium channel KCa3.1 in a mammalian species in need thereof comprising administering to the mammalian species a therapeutically effective amount of at least one compound according to any one of embodiments described herein, or a pharmaceutically acceptable salt thereof.
  • Any one of the embodiments disclosed herein may be properly combined with any other embodiment disclosed herein.
  • the combination of any one of the embodiments disclosed herein with any other embodiments disclosed herein is expressly contemplated.
  • the selection of one or more embodiments for one substituent group can be properly combined with the selection of one or more particular embodiments for any other substituent group.
  • alkyl and alk refer to a straight or branched chain alkane (hydrocarbon) radical containing from 1 to 12 carbon atoms, preferably 1 to 6 carbon atoms.
  • exemplary “alkyl” groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, and the like.
  • (C 1 -C x )alkyl or “C 1-x alkyl” refers to a straight or branched chain alkane (hydrocarbon) radical containing from 1 to x carbon atoms.
  • (C1-C4)alkyl or “C1-4alkyl” refers to a straight or branched chain alkane (hydrocarbon) radical containing from 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, and isobutyl.
  • Substituted alkyl refers to an alkyl group substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment.
  • heteroalkyl refers to an alkyl substituent as defined above wherein at least one carbon atom has been replaced by a heteroatom such as O, S, or N.
  • a heteroalkyl can be an alkyl group where one or more of its -CH 2 - groups are replaced by -O-, -S-, or -NRz-; and/or can be an alkyl group where one or more of its -CH- groups are replaced by -N-; wherein each occurrence of Rz is hydrogen, alkyl, cycloalkyl, heterocycle, or aryl.
  • heteroalkyl can be optionally substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment.
  • groups such as alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkenyl, heterocycle, and aryl can themselves be optionally substituted.
  • alkenyl refers to a straight or branched chain hydrocarbon radical containing from 2 to 12 carbon atoms and at least one carbon-carbon double bond. Exemplary such groups include ethenyl or allyl.
  • C2-Cx alkenyl” or “C2-xalkenyl” refers to a straight or branched chain hydrocarbon radical containing from 2 to x carbon atoms and at least one carbon-carbon double bond.
  • C 2 -C 6 alkenyl or “C2-6alkenyl” refers to a straight or branched chain hydrocarbon radical containing from 2 to 6 carbon atoms and at least one carbon-carbon double bond, such as ethylenyl, propenyl, 2- propenyl, (E)-but-2-enyl, (Z)-but-2-enyl, 2-methy(E)-but-2-enyl, 2-methy(Z)-but-2-enyl, 2,3-dimethy-but-2-enyl, (Z)-pent-2-enyl, (E)-pent-1-enyl, (Z)-hex-1-enyl, (E)-pent-2-enyl, (Z)-hex-2-enyl, (E)-hex-2-enyl, (Z)-hex-1-enyl, (E)-hex-1-enyl, (Z)-hex-3-en
  • Substituted alkenyl refers to an alkenyl group substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment.
  • alkynyl refers to a straight or branched chain hydrocarbon radical containing from 2 to 12 carbon atoms and at least one carbon to carbon triple bond.
  • exemplary groups include ethynyl.
  • C2-Cxalkynyl or “C2-x alkynyl” refers to a straight or branched chain hydrocarbon radical containing from 2 to x carbon atoms and at least one carbon-carbon triple bond.
  • C 2 -C 6 alkynyl or “C 2-6 alknyl” refers to a straight or branched chain hydrocarbon radical containing from 2 to 6 carbon atoms and at least one carbon-carbon triple bond, such as ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, pent-1-ynyl, pent-2-ynyl, hex-1-ynyl, hex-2-ynyl, or hex-3-ynyl.
  • Substituted alkynyl refers to an alkynyl group substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment.
  • cycloalkyl refers to a fully saturated cyclic hydrocarbon group containing from 1 to 4 rings and 3 to 8 carbons per ring.
  • C3-C7 cycloalkyl or “C3-7cycloalkyl” refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.
  • Substituted cycloalkyl refers to a cycloalkyl group substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment.
  • exemplary substituents can themselves be optionally substituted.
  • exemplary substituents also include spiro-attached or fused cyclic substituents, especially spiro-attached cycloalkyl, spiro- attached cycloalkenyl, spiro-attached heterocycle (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, where the aforementioned cycloalkyl, cycloalkenyl, heterocycle and aryl substituents can themselves be optionally substituted.
  • cycloalkenyl refers to a partially unsaturated cyclic hydrocarbon group containing 1 to 4 rings and 3 to 8 carbons per ring. Exemplary such groups include cyclobutenyl, cyclopentenyl, cyclohexenyl, etc. “Substituted cycloalkenyl” refers to a cycloalkenyl group substituted with one more substituents, preferably 1 to 4 substituents, at any available point of attachment.
  • exemplary substituents can themselves be optionally substituted.
  • exemplary substituents also include spiro-attached or fused cyclic substituents, especially spiro-attached cycloalkyl, spiro-attached cycloalkenyl, spiro-attached heterocycle (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, where the aforementioned cycloalkyl, cycloalkenyl, heterocycle and aryl substituents can themselves be optionally substituted.
  • aryl refers to cyclic, aromatic hydrocarbon groups that have 1 to 5 aromatic rings, especially monocyclic or bicyclic groups such as phenyl, biphenyl or naphthyl. Where containing two or more aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group may be joined at a single point (e.g., biphenyl), or fused (e.g., naphthyl, phenanthrenyl and the like).
  • fused aromatic ring refers to a molecular structure having two or more aromatic rings wherein two adjacent aromatic rings have two carbon atoms in common.
  • “Substituted aryl” refers to an aryl group substituted by one or more substituents, preferably 1 to 3 substituents, at any available point of attachment.
  • exemplary substituents can themselves be optionally substituted.
  • exemplary substituents also include fused cyclic groups, especially fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, where the aforementioned cycloalkyl, cycloalkenyl, heterocycle, and aryl substituents can themselves be optionally substituted.
  • fused cyclic groups especially fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, where the aforementioned cycloalkyl, cycloalkenyl, heterocycle, and aryl substituents can themselves be optionally substituted.
  • biasing refers to two aryl groups linked by a single bond.
  • biheteroaryl refers to two heteroaryl groups linked by a single bond.
  • heteroaryl-aryl refers to a heteroaryl group and an aryl group linked by a single bond
  • aryl-heteroaryl refers to an aryl group and a heteroaryl group linked by a single bond.
  • the numbers of the ring atoms in the heteroaryl and/or aryl rings are used to specify the sizes of the aryl or heteroaryl ring in the substituents.
  • 5,6-heteroaryl-aryl refers to a substituent in which a 5-membered heteroaryl is linked to a 6-membered aryl group.
  • Other combinations and ring sizes can be similarly specified.
  • carrier or “carbon cycle” refers to a fully saturated or partially saturated cyclic hydrocarbon group containing from 1 to 4 rings and 3 to 8 carbons per ring, or cyclic, aromatic hydrocarbon groups that have 1 to 5 aromatic rings, especially monocyclic or bicyclic groups such as phenyl, biphenyl, or naphthyl.
  • the term “carbocycle” encompasses cycloalkyl, cycloalkenyl, cycloalkynyl, and aryl as defined hereinabove.
  • substituted carbocycle refers to carbocycle or carbocyclic groups substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment.
  • substituents include, but are not limited to, those described above for substituted cycloalkyl, substituted cycloalkenyl, substituted cycloalkynyl, and substituted aryl.
  • substituents also include spiro-attached or fused cyclic substituents at any available point or points of attachment, especially spiro-attached cycloalkyl, spiro-attached cycloalkenyl, spiro-attached heterocycle (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, where the aforementioned cycloalkyl, cycloalkenyl, heterocycle, and aryl substituents can themselves be optionally substituted.
  • heterocycle and “heterocyclic” refer to fully saturated, or partially or fully unsaturated, including aromatic (i.e., “heteroaryl”) cyclic groups (for example, 3 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 8 to 16 membered tricyclic ring systems) which have at least one heteroatom in at least one carbon atom-containing ring.
  • aromatic i.e., “heteroaryl”
  • heteroaryl for example, 3 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 8 to 16 membered tricyclic ring systems
  • Each ring of the heterocyclic group may independently be saturated, or partially or fully unsaturated.
  • Each ring of the heterocyclic group containing a heteroatom may have 1, 2, 3, or 4 heteroatoms selected from the group consisting of nitrogen atoms, oxygen atoms and sulfur atoms, where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized.
  • heteroarylium refers to a heteroaryl group bearing a quaternary nitrogen atom and thus a positive charge.
  • the heterocyclic group may be attached to the remainder of the molecule at any heteroatom or carbon atom of the ring or ring system.
  • Exemplary monocyclic heterocyclic groups include azetidinyl, pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2- oxoazepinyl, azepinyl, hexahydrodiazepinyl, 4-piperidonyl, pyrid
  • bicyclic heterocyclic groups include indolyl, indolinyl, isoindolyl, benzothiazolyl, benzoxazolyl, benzoxadiazolyl, benzothienyl, benzo[d][1,3]dioxolyl, dihydro-2H-benzo[b][1,4]oxazine, 2,3-dihydrobenzo[b][1,4]dioxinyl, quinuclidinyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, benzofurazanyl, dihydrobenzo[d]oxazole, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyr
  • Exemplary tricyclic heterocyclic groups include carbazolyl, benzidolyl, phenanthrolinyl, acridinyl, phenanthridinyl, xanthenyl, and the like.
  • “Substituted heterocycle” and “substituted heterocyclic” refer to heterocycle or heterocyclic groups substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment.
  • exemplary substituents can themselves be optionally substituted.
  • exemplary substituents also include spiro-attached or fused cyclic substituents at any available point or points of attachment, especially spiro-attached cycloalkyl, spiro-attached cycloalkenyl, spiro-attached heterocycle (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, where the aforementioned cycloalkyl, cycloalkenyl, heterocycle and aryl substituents can themselves be optionally substituted.
  • oxo refers to substituent group, which may be attached to a carbon ring atom on a carboncycle or heterocycle.
  • an oxo substituent group is attached to a carbon ring atom on an aromatic group, e.g., aryl or heteroaryl, the bonds on the aromatic ring may be rearranged to satisfy the valence requirement.
  • a pyridine with a 2- oxo substituent group may have the structure which also includes its tautomeric form .
  • alkylamino refers to a group having the structure -NHR’, wherein R’ is hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, as defined herein.
  • alkylamino groups include, but are not limited to, methylamino, ethylamino, n-propylamino, iso-propylamino, cyclopropylamino, n-butylamino, tert-butylamino, neopentylamino, n-pentylamino, hexylamino, cyclohexylamino, and the like.
  • dialkylamino refers to a group having the structure -NRR’, wherein R and R’ are each independently alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cyclolalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined herein. R and R’ may be the same or different in a dialkyamino moiety.
  • dialkylamino groups include, but are not limited to, dimethylamino, methyl ethylamino, diethylamino, methylpropylamino, di(n-propyl)amino, di(iso- propyl)amino, di(cyclopropyl)amino, di(n-butyl)amino, di(tert-butyl)amino, di(neopentyl)amino, di(n-pentyl)amino, di(hexyl)amino, di(cyclohexyl)amino, and the like.
  • R and R’ are linked to form a cyclic structure.
  • the resulting cyclic structure may be aromatic or non-aromatic.
  • Examples of the resulting cyclic structure include, but are not limited to, aziridinyl, pyrrolidinyl, piperidinyl, morpholinyl, pyrrolyl, imidazolyl, 1,2,4-triazolyl, and tetrazolyl.
  • halogen or “halo” refer to chlorine, bromine, fluorine, or iodine.
  • substituted refers to the embodiments in which a molecule, molecular moiety, or substituent group (e.g., alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl group or any other group disclosed herein) is substituted with one or more substituents, where valence permits, preferably 1 to 6 substituents, at any available point of attachment.
  • substituent group e.g., alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl group or any other group disclosed herein
  • groups such as alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkenyl, heterocycle, and aryl can themselves be optionally substituted.
  • optionally substituted refers to the embodiments in which a molecule, molecular moiety or substituent group (e.g., alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl group or any other group disclosed herein) may or may not be substituted with aforementioned one or more substituents.
  • any heteroatom with unsatisfied valences is assumed to have hydrogen atoms sufficient to satisfy the valences.
  • the compounds of the present invention may form salts which are also within the scope of this invention. Reference to a compound of the present invention is understood to include reference to salts thereof, unless otherwise indicated.
  • the term “salt(s)”, as employed herein, denotes acidic and/or basic salts formed with inorganic and/or organic acids and bases.
  • zwitterions when a compound of the present invention contains both a basic moiety, such as but not limited to a pyridine or imidazole, and an acidic moiety such as but not limited to a phenol or carboxylic acid, zwitterions (“inner salts”) may be formed and are included within the term “salt(s)” as used herein.
  • Pharmaceutically acceptable (i.e., non- toxic, physiologically acceptable) salts are preferred, although other salts are also useful, e.g., in isolation or purification steps which may be employed during preparation.
  • Salts of the compounds of the present invention may be formed, for example, by reacting a compound described herein with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates, or in an aqueous medium followed by lyophilization.
  • the compounds of the present invention which contain a basic moiety, such as but not limited to an amine or a pyridine or imidazole ring, may form salts with a variety of organic and inorganic acids.
  • Exemplary acid addition salts include acetates (such as those formed with acetic acid or trihaloacetic acid; for example, trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides, hydroiodides, hydroxyethanesulfonates (e.g., 2- hydroxyethanesulfonates), lactates, maleates, methanesulfonates, naphthalenesulfonates (
  • the compounds of the present invention which contain an acidic moiety may form salts with a variety of organic and inorganic bases.
  • Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as benzathines, dicyclohexylamines, hydrabamines (formed with N,N-bis(dehydroabietyl) ethylenediamine), N-methyl-D-glucamines, N-methyl-D-glycamides, t-butyl amines, and salts with amino acids such as arginine, lysine, and the like.
  • Basic nitrogen-containing groups may be quaternized with agents such as lower alkyl halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g., decyl, lauryl, myristyl and stearyl chlorides, bromides, and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides), and others.
  • lower alkyl halides e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides
  • dialkyl sulfates e.g., dimethyl, diethyl, dibutyl, and diamyl s
  • Prodrugs and solvates of the compounds of the invention are also contemplated herein.
  • the term “prodrug” as employed herein denotes a compound that, upon administration to a subject, undergoes chemical conversion by metabolic or chemical processes to yield a compound of the present invention, or a salt and/or solvate thereof.
  • Solvates of the compounds of the present invention include, for example, hydrates.
  • Compounds of the present invention, and salts or solvates thereof may exist in their tautomeric form (for example, as an amide or imino ether). All such tautomeric forms are contemplated herein as part of the present invention. As used herein, any depicted structure of the compound includes the tautomeric forms thereof.
  • All stereoisomers of the present compounds are contemplated within the scope of this invention.
  • Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers (e.g., as a pure or substantially pure optical isomer having a specified activity), or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers.
  • the chiral centers of the present invention may have the S or R configuration as defined by the International Union of Pure and Applied Chemistry (IUPAC) 1974 Recommendations.
  • racemic forms can be resolved by physical methods, such as, for example, fractional crystallization, separation or crystallization of diastereomeric derivatives, or separation by chiral column chromatography.
  • the individual optical isomers can be obtained from the racemates by any suitable method, including without limitation, conventional methods, such as, for example, salt formation with an optically active acid followed by crystallization.
  • Compounds of the present invention are, subsequent to their preparation, preferably isolated and purified to obtain a composition containing an amount by weight equal to or greater than 90%, for example, equal to or greater than 95%, equal to or greater than 99% of the compounds (“substantially pure” compounds), which is then used or formulated as described herein.
  • the present invention contemplates all such compounds, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention. [0136] Isomeric mixtures containing any of a variety of isomer ratios may be utilized in accordance with the present invention.
  • the present invention also includes isotopically labeled compounds, which are identical to the compounds disclosed herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • Compounds of the present invention, or an enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention.
  • isotopically labeled compounds of the present invention for example, those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays.
  • Tritiated, i.e., 3 H (T), and carbon- 14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability.
  • substitution with heavier isotopes such as deuterium, i.e., 2 H (D), can afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
  • Isotopically labeled compounds can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples below, by substituting a readily available isotopically labeled reagent for a non-isotopically-labeled reagent.
  • a particular enantiomer of a compound of the present invention is desired, it may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers.
  • the substituent may be either the same or different at every position.
  • substituted is contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds.
  • heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms.
  • this invention is not intended to be limited in any manner by the permissible substituents of organic compounds. Combinations of substituents and variables envisioned by this invention are preferably those that result in the formation of stable compounds useful in the treatment, for example, of proliferative disorders.
  • stable preferably refers to compounds which possess stability sufficient to allow manufacture and which maintain the integrity of the compound for a sufficient period of time to be detected and preferably for a sufficient period of time to be useful for the purposes detailed herein.
  • cancer and, equivalently, “tumor” refer to a condition in which abnormally replicating cells of host origin are present in a detectable amount in a subject.
  • the cancer can be a malignant or non-malignant cancer.
  • Cancers or tumors include, but are not limited to, biliary tract cancer; brain cancer; breast cancer; cervical cancer; choriocarcinoma; colon cancer; endometrial cancer; esophageal cancer; gastric (stomach) cancer; intraepithelial neoplasms; leukemias; lymphomas; liver cancer; lung cancer (e.g., small cell and non-small cell); melanoma; neuroblastomas; oral cancer; ovarian cancer; pancreatic cancer; prostate cancer; rectal cancer; renal (kidney) cancer; sarcomas; skin cancer; testicular cancer; thyroid cancer; as well as other carcinomas and sarcomas.
  • Cancers can be primary or metastatic. Diseases other than cancers may be associated with mutational alternation of component of Ras signaling pathways and the compound disclosed herein may be used to treat these non-cancer diseases.
  • non-cancer diseases may include: neurofibromatosis; Leopard syndrome; Noonan syndrome; Legius syndrome; Costello syndrome; cardio-facio-cutaneous syndrome; hereditary gingival fibromatosis type 1; autoimmune lymphoproliferative syndrome; and capillary malformation-arterovenous malformation.
  • “effective amount” refers to any amount that is necessary or sufficient for achieving or promoting a desired outcome. In some instances, an effective amount is a therapeutically effective amount.
  • a therapeutically effective amount is any amount that is necessary or sufficient for promoting or achieving a desired biological response in a subject.
  • the effective amount for any particular application can vary depending on such factors as the disease or condition being treated, the particular agent being administered, the size of the subject, or the severity of the disease or condition.
  • One of ordinary skill in the art can empirically determine the effective amount of a particular agent without necessitating undue experimentation.
  • the term “subject” refers to a vertebrate animal. In one embodiment, the subject is a mammal or a mammalian species. In one embodiment, the subject is a human.
  • the subject is a non-human vertebrate animal, including, without limitation, non-human primates, laboratory animals, livestock, racehorses, domesticated animals, and non-domesticated animals.
  • Compounds [0143] Novel compounds as K Ca 3.1 inhibitors are described. It has been surprisingly discovered that the compounds disclosed herein exhibit KCa3.1-inhibiting properties. Additionally, it has been surprisingly discovered that the compounds disclosed herein selectively block K Ca 3.1 and do not block the hERG channel and thus have desirable cardiovascular safety profiles. [0144] In one aspect, a compound having a structure of Formula I is described ( ), where the various substituents are defined herein.
  • the compounds of Formula I described herein can block or inhibit KCa3.1 and be used in the treatment of a variety of conditions. Methods for synthesizing these compounds are also described herein. Pharmaceutical compositions and methods of using these compositions described herein are useful for treating conditions in vitro and in vivo. Such compounds, pharmaceutical compositions, and methods of treatment have a number of clinical applications, including as pharmaceutically active agents and methods for cancer, sickle cell anemia, a cardiovascular disease, a respiratory disease, a fibrotic disease, an autoimmune disease, a central nervous system (CNS) disorder, an inflammatory disorder, a neurodegenerative disease, or a combination thereof.
  • CNS central nervous system
  • a compound of Formula I or a pharmaceutically acceptable salt thereof, or a tautomer thereof is described, wherein R1 is alkyl, cycloalkyl, halogenated alkyl, halogenated cycloalkyl, bicycloalkyl, halogenated bicycloalkyl, saturated heterocycle, partially saturated heterocycle, aryl, heteroaryl, -C 1-4 alkyl-cycloalkyl, -C 1-4 alkyl-saturated heterocycle, -C 1-4 alkyl-partially saturated heterocycle, or cycloalkenyl, each of which optionally substituted by 1-5 substituents each independently selected from the group consisting of D, halogen, alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, alkenyl, and alkynyl where valence permits; R2 is halogen, alkyl, alkynyl, halogenated
  • the compound of Formula I is not in a salt form or a tautomer form.
  • R1 is optionally substituted aryl.
  • aryl include phenyl, biphenyl, naphthyl, anthracenyl, and the like.
  • R 1 is phenyl that is optionally substituted by 1-5 substituents each independently selected from the group consisting of D, halogen, alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, alkenyl, and alkynyl.
  • R 1 is phenyl which is optionally substituted by 1-5 substituents each independently selected from the group consisting of D, halogen, alkyl, and halogenated alkyl.
  • R1 is phenyl that is optionally substituted by 1-5 substituents each independently selected from the group consisting of D, alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec- butyl, pentyl, hexyl, heptyl, and octyl), halogen (e.g., F, Cl, Br, and I), and halogenated alkyl (e.g., CF3, CH2F, CHF2, CH2Cl, CH2CF3, CHFCH3, CHFCH2F, CF2CH3, CHClCH3, CCl 2 CH 3 , CHBrCH 3 , CH 2 CH 2 CF 3 ,
  • R 1 is phenyl which is substituted with at least one substituent selected from the group consisting of D, alkyl (e.g., CH3 and CH2CH3), halogen (e.g., F, Cl, Br, and I), halogenated alkyl (e.g., CF3), alkynyl (e.g., C ⁇ CH), and cycloalkyl (e.g., ).
  • R1 is phenyl that is optionally substituted by 1-5 substituents each independently selected from the group consisting of D, CH 3 , CH 2 CH 3 , F, Cl, Br, CH 2 F, and CF 3 .
  • R 1 is phenyl which is substituted with at least one halogen. In some embodiments, R 1 is phenyl which is substituted with at least one alkyl or halogenated alkyl. [0149] In some embodiments, R 1 is cycloalkyl, bicycloalkyl, or -C 1-4 alkyl-cycloalkyl, each of which optionally substituted by 1-5 substituents each independently selected from the group consisting of D, halogen, alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, alkenyl, and alkynyl where valence permits.
  • R 1 is cycloalkyl, bicycloalkyl, or -C 1-4 alkyl-cycloalkyl, each of which optionally substituted by 1-5 substituents each independently selected from the group consisting of D, alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, pentyl, hexyl, heptyl, and octyl), halogen (e.g., F, Cl, Br, and I), and halogenated alkyl (e.g., CF 3 , CH 2 F, CHF 2 , CH 2 Cl, CH2CF3, CHFCH3, CHFCH2F, CF2CH3, CHClCH3, CCl2CH3, CHBrCH3, CH2CH2CF3, and CHClCHClCH3) where valence permits.
  • alkyl e.g., methyl, ethy
  • R1 is cycloalkyl, bicycloalkyl, or -C 1-4 alkyl-cycloalkyl, each of which optionally substituted by 1-5 substituents each independently selected from the group consisting of D, CH3, CH2CH3, F, Cl, Br, CH2F, and CF3 where valence permits.
  • R1 is cycloalkyl that is optionally substituted by 1-5 substituents each independently selected from the group consisting of D, CH 3 , CH 2 CH 3 , F, Cl, Br, CH 2 F, and CF 3 where valence permits.
  • R1 is -C1-4alkyl-cycloalkyl that is optionally substituted by 1-5 substituents each independently selected from the group consisting of D, CH 3 , CH 2 CH 3 , F, Cl, Br, CH 2 F, and CF 3 where valence permits.
  • substituents each independently selected from the group consisting of D, CH 3 , CH 2 CH 3 , F, Cl, Br, CH 2 F, and CF 3 where valence permits.
  • Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • R1 is bicycloalkyl that is optionally substituted by 1-5 substituents each independently selected from the group consisting of D, CH 3 , CH 2 CH 3 , F, Cl, Br, CH 2 F, and CF 3 where valence permits.
  • bicycloalkyl examples include bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.1.1]hexyl, octahydropentalenyl, bicyclo[3.2.1]octyl, bicyclo[3.3.3]undecanyl, decahydronaphthalenyl, bicyclo[3.2.0]heptyl, octahydro-1H-indenyl, bicyclo[4.2.1]nonanyl, spiro[4.4]nonyl, spiro[3.3]heptyl, spiro[5.5]undecyl, spiro[3.5]nonyl, and spiro[4.5]decyl.
  • R1 is selected which optionally substituted by 1-5 substituents each independently selected from the group consisting of D, CH3, CH2CH3, F, Cl, Br, CH2F, and CF3.
  • R 1 is 4-, 5-, 6- or 7-membered saturated heterocycle, partially saturated heterocycle, or heteroaryl, each containing 1-3 heteroatoms each selected from the group consisting of N, O, and S, each optionally substituted by 1-5 substituents each independently selected from the group consisting of D, halogen, alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, alkenyl, and alkynyl where valence permits.
  • R1 is selected from the group consisting of , ; wherein each is optionally substituted by 1-5 substituents each independently selected from the group consisting of D, alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, pentyl, hexyl, heptyl, and octyl), halogen (e.g., F, Cl, Br, and I), and halogenated alkyl (e.g., CF 3 , CH 2 F, CHF 2 , CH 2 Cl, CH 2 CF 3 , CHFCH 3 , CHFCH 2 F, CF 2 CH 3 , CHClCH 3 , CCl 2 CH 3 , CHBrCH 3 , CH 2 CH 2 CF 3 , and CHClCHClCH 3 ) where valence permits.
  • alkyl e.g., methyl, ethy
  • R1 is a N-containing heterocycle, partially saturated heterocycle, or heteroaryl, wherein each is optionally substituted by alkyl.
  • R 1 is a saturated heterocycle that is optionally substituted by 1-5 substituents each independently selected from the group consisting of D, alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, pentyl, hexyl, heptyl, and octyl), halogen (e.g., F, Cl, Br, and I), and halogenated alkyl (e.g., CF 3 , CH 2 F, CHF 2 , CH 2 Cl, CH 2 CF 3 , CHFCH 3 , CHFCH 2 F, CF 2 CH 3 , CHClCH3, CCl2CH3, CHBrCH3, CH2CH2CF3, and CHClCHClCH3)
  • alkyl e
  • R1 is alkyl that is optionally substituted by 1-5 substituents each independently selected from the group consisting of D, halogen, alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, alkenyl, and alkynyl where valence permits.
  • R 1 is alkyl that is optionally substituted by D or halogen (e.g., F, Cl, Br, and I).
  • Non-limiting examples of alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso- butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, and octyl.
  • R 1 is halogenated alkyl, halogenated cycloalkyl, halogenated bicycloalkyl, partially saturated heterocycle, heteroaryl or cycloalkenyl, each of which optionally substituted by 1-5 substituents each independently selected from the group consisting of D, halogen, alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, alkenyl, and alkynyl where valence permits.
  • R1 is optionally substituted halogenated alkyl.
  • Non-limiting examples of halogenated alkyl include CF3, CH 2 F, CHF 2 , CH 2 Cl, CH 2 CF 3 , CHFCH 3 , CHFCH 2 F, CF 2 CH 3 , CHClCH 3 , CCl 2 CH 3 , CHBrCH 3 , CH 2 CH 2 CF 3 , and CHClCHClCH 3 .
  • R 1 is optionally substituted halogenated cycloalkyl.
  • Non-limiting examples of halogenated cycloalkyl include cycloalkenyl.
  • Non-limiting examples of cycloalkenyl include cyclobutenyl, cyclopentenyl, and cyclohexenyl.
  • R 1 is optionally substituted heteroaryl.
  • R 1 is a 5- or 6-membered heteroaryl which is optionally substituted by 1-5 substituents each independently selected from the group consisting of D, halogen, alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, alkenyl, and alkynyl where valence permits.
  • R 1 is a 5- or 6-membered heteroaryl containing 1-3 heteroatoms each independently selected from N, O, and S.
  • R1 is pyridine, thiophene, or furan.
  • R1 is a 5-membered heteroaryl, wherein the heteroaryl is optionally substituted by alkyl, halogen, or OH.
  • R 1 is a 7- to 11-membered bicyclic, or 8- to 16-membered tricyclic aryl or heteroaryl which are each optionally substituted by 1-5 substituents each independently selected from the group consisting of H, D, halogen, alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, alkenyl, and alkynyl.
  • Non-limiting examples of bicyclic or tricyclic rings include biphenyl, naphthyl, phenanthrenyl, indolyl, isoindolyl, benzothiazolyl, benzoxazolyl, benzoxadiazolyl, benzothienyl, quinolinyl, isoquinolinyl, benzimidazolyl, chromonyl, coumarinyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (such as furo[2,3-c]pyridinyl, furo[3,2-b]pyridinyl] or furo[2,3-b]pyridinyl), carbazolyl, phenanthrolinyl, acridinyl, and phenanthridinyl.
  • R1 is -C1-4alkyl-saturated heterocycle, or C1-4alkyl-partially saturated heterocycle, each of which optionally substituted by 1-5 substituents each independently selected from the group consisting of D, halogen, alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, alkenyl, and alkynyl where valence permits.
  • R 1 is selected from the group consisting of .
  • R2 is halogen, alkyl, alkynyl, halogenated alkyl, or halogenated alkynyl.
  • R2 is halogen.
  • halogen include F, Cl, Br, and I.
  • R 2 is alkyl or halogenated alkyl.
  • alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, and octyl.
  • Non-limiting examples of halogenated alkyl include CF 3 , CH 2 F, CHF 2 , CH 2 Cl, CH 2 CF 3 , CHFCH 3 , CHFCH 2 F, CF 2 CH 3 , CHClCH 3 , CCl2CH3, CHBrCH3, CH2CH2CF3, and CHClCHClCH3.
  • R2 is alkynyl or halogenated alkynyl.
  • Non-limiting examples of alkynyl include ethynyl, prop-1- ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, pent-1-ynyl, pent-2-ynyl, hex-1-ynyl, hex-2-ynyl, and hex-3-ynyl.
  • Non-limiting examples of halogenated alkynyl include CHClC ⁇ CH, CHFC ⁇ CH, CH2C ⁇ CCF3, C ⁇ CCH2F, and C ⁇ CCF3.
  • R 2 is alkyl optionally substituted with alkoxy or OH, or alkoxy optionally substituted with halogen, alkyl, alkoxy, or OH.
  • alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, and octyl.
  • Non-limiting examples of alkoxy include OCH3, OCH2CH3, OCH 2 CH 2 CH 3 , OCH 2 CH 2 CH 2 CH 3 , OCH 2 CH 2 CH 2 CH 3 , and OCH(CH 3 ) 2 .
  • R2 is CN.
  • R2 is ORa, SRa, -O-C1-4alkyl-ORa, -O-C1-4alkyl-SRa, -O-C1- 4 alkyl-NR a R b , -S-C 1-4 alkyl-OR a , -S-C 1-4 alkyl-SR a , or -S-C 1-4 alkyl-NR a R b .
  • R 2 is OR a , or SR a .
  • R 2 is -O-C 1-4 alkyl-OR a , -O-C 1- 4alkyl-SRa, or -O-C1-4alkyl-NRaRb.
  • R2 is -S-C1-4alkyl-ORa, -S-C1- 4 alkyl-SR a , or -S-C 1-4 alkyl-NR a R b .
  • R 2 is -C 1-4 alkyl-OR a , or -C 1-4 alkyl- SR a .
  • R 2 is CN, OR a , SR a , or -O-C 1-4 alkyl-OR a .
  • R2 is OH, CH2OH, or CH2CH2OH.
  • R2 is OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, OCH2CH2OH, or OCH 2 CH 2 OCH 3 .
  • R 2 is selected from the group consisting of CN, CH 3 , CH 2 CH 3 , [0162]
  • m is 1 or 2. In some embodiments, m is 1. In some embodiments, m is 2.
  • each occurrence of R8 is independently H, D, alkyl, or ORa. In some embodiments, each occurrence of R 8 is independently H, D, or OR a (e.g., OH, OMe, or OEt). [0164] In some embodiments, at least one occurrence of R8 is H or D. In some embodiments, at least one occurrence of R 8 is OR a , e.g., OH, OMe, or OEt. In some embodiments, at least one occurrence of R 8 is alkyl.
  • alkyl examples include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, and octyl.
  • each occurrence of R 8 is independently H, D, CH 3 , CH 2 CH 3 , or OH.
  • each occurrence of R 8 is independently H, D, or OH.
  • each occurrence of R9 is independently H, D, alkyl, or ORa.
  • each occurrence of R9 is independently H, D, or ORa (e.g., OH, OMe, or OEt). [0167] In some embodiments, at least one occurrence of R9 is H or D. In some embodiments, at least one occurrence of R9 is ORa, e.g., OH, OMe, or OEt. In some embodiments, at least one occurrence of R 9 is alkyl.
  • alkyl examples include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, and octyl.
  • each occurrence of R9 is independently H, D, CH3, CH2CH3, or OH.
  • each occurrence of R 9 is independently H, D, or OH.
  • the structural moiety –(CR 8 R 9 ) m – is selected from the group consisting of –CH2–, –CH2–CH2–, –CH(CH3)–CH2–, –CH2–C(CH3)2–, –CH2–CH(OH)–, moiety –(CR 8 R 9 ) m – is selected from the group consisting of –CH 2 –, –CH 2 –CH 2 –, –CH(CH 3 )– embodiments, the structural moiety –(CR 8 R 9 ) m – is –CH 2 –, –CH 2 –CH 2 –, , or In some embodiments, the structural moiety –(CR8R9)m— is –CH2–, or –CH2– CH 2 –.
  • the structural moiety –(CR 8 R 9 ) m – is –CH 2 –.
  • R 10 is H, D, CN, aryl, or heteroaryl.
  • R10 is H, D, or CN.
  • R10 is H or D.
  • R10 is alkyl. Non-limiting examples of alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, and octyl.
  • R10 is optionally substituted aryl.
  • aryl include phenyl, biphenyl, naphthyl, anthracenyl, and the like.
  • R10 is phenyl that is optionally substituted by 1-5 substituents each independently selected from the group consisting of D, halogen, alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, alkenyl, alkynyl, CN, ORa, SRa, NRaRb, -C1-4alkyl-SRa, and -C1-4alkyl-ORa.
  • R 10 is phenyl which is optionally substituted by 1-5 substituents each independently selected from the group consisting of D, halogen, alkyl, halogenated alkyl, CN, ORa, SRa, or NRaRb.
  • R10 is phenyl that is optionally substituted by 1-5 substituents each independently selected from the group consisting of D, alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, pentyl, hexyl, heptyl, and octyl), halogen (e.g., F, Cl, Br, and I), ORa (e.g., OH, OCH3, and OEt), and halogenated alkyl (e.g., CF3, CH2F, CHF2, CH2Cl, CH2CF3, CHFCH3, CHFCH2F, CF2CH3, CHClCH3, CCl 2 CH 3 , CHBrCH 3 , CH 2 CH 2 CF 3 , and CHClCHClCH 3 ).
  • alkyl e.g., methyl, ethyl, propyl, iso
  • R 10 is phenyl that is optionally substituted by 1-5 substituents each independently selected from the group consisting of D, CH3, CH2CH3, OH, OCH3, F, Cl, Br, CH2F, CF3, and OCF3.
  • R 10 is phenyl which is substituted with at least one halogen.
  • R 10 is phenyl which is substituted with at least one OH, halogen, alkyl or halogenated alkyl.
  • R 10 is 4-, 5-, 6- or 7-membered saturated heterocycle, partially saturated heterocycle, or heteroaryl, each containing 1-3 heteroatoms each selected from the group consisting of N, O, and S, each optionally substituted by 1-5 substituents each independently selected from the group consisting of D, halogen, alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, alkenyl, alkynyl, CN, OR a , SR a , NR a R b , -C 1- 4alkyl-SRa, and -C1-4alkyl-ORa where valence permits.
  • R10 is selected from the group consisting of , , , , , , , substituted by 1-5 substituents each independently selected from the group consisting of D, alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, pentyl, hexyl, heptyl, and octyl), halogen (e.g., F, Cl, Br, and I), ORa (e.g., OH, OCH3, and OEt), and halogenated alkyl (e.g., CF 3 , CH 2 F, CHF 2 , CH 2 Cl, CH 2 CF 3 , CHFCH 3 , CHFCH 2 F, CF 2 CH 3 , CHClCH 3 , CCl 2 CH 3 , CHBrCH 3 , CH 2 CH 2 CF 3 , and CHClCHClCH
  • R10 is a N-containing heterocycle, partially saturated heterocycle, or heteroaryl, wherein each is optionally substituted by alkyl, OH, NH 2 , or oxo where valence permits.
  • R 10 is a saturated heterocycle that is optionally substituted by 1-5 substituents each independently selected from the group consisting of D, alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, pentyl, hexyl, heptyl, and octyl), halogen (e.g., F, Cl, Br, and I), OR a (e.g., OH, OCH 3 , and OEt), and halogenated alkyl (e.g., CF 3 , CH 2 F, CHF 2 , CH 2 Cl, CH 2 CF 3 , CHFCH 3 , CHFCH
  • R 10 is optionally substituted heteroaryl.
  • R10 is a 5- or 6-membered heteroaryl which is optionally substituted by 1-5 substituents each independently selected from the group consisting of D, halogen, alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, alkenyl, alkynyl, CN, OR a , SR a , NR a R b , -C 1- 4alkyl-SRa, and -C1-4alkyl-ORa.
  • R10 is a 5- or 6-membered heteroaryl containing 1-3 heteroatoms each independently selected from the group consisting of N, O, and S.
  • R 10 is pyridine, thiophene, or furan.
  • R10 is a 5-membered heteroaryl, wherein the heteroaryl is optionally substituted by alkyl, halogen, or OH.
  • Non-limiting examples of 5-membered heteroaryl include , [0175]
  • R 10 is oxetane, pyrazole, or oxadiazole, each optionally substituted by halogen (e.g., F, Cl, Br, and I) or alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, pentyl, hexyl, heptyl, and octyl).
  • halogen e.g., F, Cl, Br, and I
  • alkyl e.g., methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, pentyl, hexyl, heptyl, and octyl.
  • R 10 is -COOR a , -COR a , -CONR a R b , -OR a , -SOR a , or -SO 2 R a .
  • R 10 is -COOR a (e.g., -COOH, -COOMe, -COOEt, -COOPr, and - COOiPr).
  • R10 is -CORa (e.g., -COMe, -COEt, -COPr, and -COiPr).
  • R10 is -CONRaRb (e.g., -CONH2, -CONHMe, -CONMe2, -CONHEt, - CONEt 2 , -CONHPr, and -CONHiPr).
  • R 10 is OR a (e.g., OH, OMe, and OEt).
  • R10 is -SORa (e.g., -SOMe, -SOEt, -SOPr, and -SOiPr) or - SO2Ra (e.g., -SO2Me, -SO2Et, -SO2Pr, and -SO2iPr).
  • R 10 is selected from the group consisting of H, D, CH 3 , .
  • R10 is selected from the group consisting of H, D, CH3,
  • R3 is CH2CONH2 or (CH2)2CONH2.
  • R3 is (CH2)1-2-heterocycle, wherein the heterocycle is oxetane, pyrazole, or oxadiazole, each optionally substituted by halogen (e.g., F, Cl, Br, and I) or alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, pentyl, hexyl, heptyl, and octyl).
  • halogen e.g., F, Cl, Br, and I
  • alkyl e.g., methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, pentyl, hexyl, heptyl, and octyl.
  • R3 is (CH2)1-2-heteroaryl, wherein the heteroaryl is , optionally substituted by halogen (e.g., F, Cl, Br, and I) or alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, pentyl, hexyl, heptyl, and octyl).
  • R 3 is CH 2 CH(OH)CH 3 , CH 2 CH(OH)CH 2 CH 3 , or CH(OH)CH 2 CH 3 .
  • At least one of R 4 , R 5 , R 6 , and R 7 is not H. In some embodiments, at least two of R4, R5, R6, and R7 are not H. In some embodiments, at least one of R4, R5, R6, and R7 is not H or D. In some embodiments, at least two of R4, R5, R6, and R7 are not H or D. In some embodiments, R 4 is not H or D. In some embodiments, R 5 is not H or D. In some embodiments, R 6 is not H or D. In some embodiments, R 7 is not H or D. In some embodiments, R4 and R5 are not H or D. In some embodiments, R4 and R6 are not H or D.
  • R 4 and R 7 are not H or D. In some embodiments, R 4 , R 5 , and R 7 are not H or D. In some embodiments, at least one of R 4 , R 5 , R 6 , and R 7 is not H. In some embodiments, at least two of R 4 , R 5 , R 6 , and R 7 are not H. In some embodiments, R 4 is not H. In some embodiments, R 5 is not H. In some embodiments, R 6 is not H. In some embodiments, R7 is not H. In some embodiments, R4 and R5 are not H. In some embodiments, R 4 and R 6 are not H. In some embodiments, R 4 and R 7 are not H.
  • R 4 , R 5 , and R 7 are not H.
  • R4 is H, D, halogen, CN, alkyl, halogenated alkyl, cycloalkyl, halogenated cycloalkyl, ORa, SRa, -C1-4alkyl-ORa, or -C1-4alkyl-SRa.
  • R 4 is H, D, halogen, CN, CF 3 , CH 2 F, CHF 2 , OR a , SR a , -C 1-4 alkyl-OR a , or -C 1-4 alkyl-SR a .
  • R4 is H, D, or alkyl.
  • R4 is H, D, or alkyl, wherein the alkyl is optionally substituted by halogen, OH, oxo, or NH 2 where valence permits.
  • alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, and octyl.
  • R4 is cycloalkyl.
  • Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • R 4 is halogen.
  • Non-limiting examples of halogen include F, Cl, Br, and I.
  • R4 is halogenated alkyl.
  • Non-limiting examples of halogenated alkyl include CF3, CH2F, CHF2, CH 2 Cl, CH 2 CF 3 , CHFCH 3 , CHFCH 2 F, CF 2 CH 3 , CHClCH 3 , CCl 2 CH 3 , CHBrCH 3 , CH 2 CH 2 CF 3 , and CHClCHClCH 3 .
  • R 4 is halogenated cycloalkyl.
  • halogenated cycloalkyl include , , , .
  • R4 is ORa, SRa, -C1-4alkyl-ORa, or -C1-4alkyl-SRa.
  • R4 is ORa or SRa.
  • R4 is -C1-4alkyl-ORa or -C1-4alkyl- SR a .
  • R4 is OH, CH2OH, or CH2CH2OH.
  • R4 is selected from the group consisting of H, D, CH3, from the group consisting of H, D, CH3, CH2CH3, CF2H, CH2F, CF3, CN, Cl, Br, F, OCH3, , and .
  • R4 is selected from the group consisting of H, D, Cl, Br, F, I, some embodiments, R4 is H, D, CH3, CH2CH3, OH, F, Cl, Br, or fluorinated alkyl.
  • R4 is H, D, Cl, Br, or F.
  • R4 is OH.
  • R 4 is H, D, halogen, CN, alkyl, halogenated alkyl, OR a , or SRa.
  • R4 is H, D, halogen, CN, alkyl, or ORa.
  • R4 is H, D, F, Cl, Br, I, CN, OH, CH3, CH2CH3, OCH3, or CF3.
  • R4 is H, CN, F, or Cl.
  • R 4 is Cl.
  • R 4 is F.
  • R 4 is CN.
  • R5 is H, D, halogen, CN, alkyl, halogenated alkyl, cycloalkyl, halogenated cycloalkyl, OR a , SR a , -C 1-4 alkyl-OR a , or -C 1-4 alkyl-SR a .
  • R 5 is H, D, halogen, CN, CF 3 , CH 2 F, CHF 2 , OR a , SR a , -C 1-4 alkyl-OR a , or -C 1-4 alkyl-SR a .
  • R5 is H, D, or alkyl.
  • R5 is H, D, or alkyl, wherein the alkyl is optionally substituted by halogen, OH, oxo, or NH2 where valence permits.
  • alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, tert-butyl, sec-butyl, pentyl, hexyl, heptyl, and octyl.
  • R 5 is cycloalkyl.
  • Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • R 5 is halogen.
  • Non-limiting examples of halogen include F, Cl, Br, and I.
  • R 5 is halogenated alkyl.
  • Non-limiting examples of halogenated alkyl include CF3, CH2F, CHF2, CH 2 Cl, CH 2 CF 3 , CHFCH 3 , CHFCH 2 F, CF 2 CH 3 , CHClCH 3 , CCl 2 CH 3 , CHBrCH 3 , CH 2 CH 2 CF 3 , and CHClCHClCH 3 .
  • R 5 is halogenated cycloalkyl.
  • halogenated cycloalkyl include , , , .
  • R 5 is OR a , SR a , -C 1-4 alkyl-OR a , or -C 1-4 alkyl-SR a .
  • R5 is ORa or SRa.
  • R5 is -C1-4alkyl-ORa or -C1-4alkyl- SR a .
  • R 5 is OH, CH 2 OH, or CH 2 CH 2 OH.
  • R 5 is selected from the group consisting of H, D, CH 3 , , , , . In some embodiments, R5 is selected from the group consisting of H, D, CH3, CH2CH3, CF2H, CH2F, CF3, CN, Cl, Br, F, OCH3, [0192] In some embodiments, R5 is selected from the group consisting of H, D, Cl, Br, F, I, some embodiments, R5 is H, D, CH3, CH2CH3, OH, F, Cl, Br, or fluorinated alkyl. In some embodiments, R 5 is H, D, Cl, Br, or F. In some embodiments, R 5 is OH.
  • R 5 is H, D, halogen, CN, alkyl, halogenated alkyl, OR a , or SRa.
  • R5 is H, D, halogen, CN, alkyl, or ORa.
  • R 5 is H, D, F, Cl, Br, I, CN, OH, CH 3 , CH 2 CH 3 , OCH 3 , or CF 3 .
  • R 5 is H, F, Cl, Me, or OMe.
  • R 5 is Cl.
  • R 5 is F.
  • R5 is Me or OMe.
  • R4 and R5 are both F.
  • R4 and R5 are both Cl. In some embodiments, R4 and R5 are F and Me, respectively. In some embodiments, R 4 and R 5 are F and OMe, respectively. In some embodiments, R4 and R5 are CN and H, respectively. In some embodiments, R4 and R5 are CN and F, respectively. In some embodiments, R4 and R5 are F and H, respectively. In some embodiments, R 4 and R 5 are Cl and H, respectively. In some embodiments, R 4 and R 5 are H and F, respectively. In some embodiments, R 4 and R 5 are H and Cl, respectively. In some embodiments, R4 and R5 are F and Cl, respectively. In some embodiments, R4 and R5 are Cl and F, respectively. In some embodiments, R4 and R5 are Cl and F, respectively.
  • R 4 and R 5 are both H.
  • R 6 is H, D, halogen, CN, alkyl, halogenated alkyl, cycloalkyl, halogenated cycloalkyl, ORa, SRa, -C1-4alkyl-ORa, or -C1-4alkyl-SRa.
  • R 6 is H, D, halogen, CN, CF 3 , CH 2 F, CHF 2 , OR a , SR a , -C 1-4 alkyl-OR a , or -C 1-4 alkyl-SR a .
  • R6 is H, D, or alkyl, wherein the alkyl is optionally substituted by halogen, OH, oxo, or NH 2 where valence permits.
  • alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, and octyl.
  • R6 is cycloalkyl.
  • Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • R 6 is halogen.
  • Non-limiting examples of halogen include F, Cl, Br, and I.
  • R6 is halogenated alkyl.
  • Non-limiting examples of halogenated alkyl include CF 3 , CH 2 F, CHF 2 , CH 2 Cl, CH 2 CF 3 , CHFCH 3 , CHFCH 2 F, CF 2 CH 3 , CHClCH 3 , CCl 2 CH 3 , CHBrCH 3 , CH2CH2CF3, and CHClCHClCH3.
  • R6 is halogenated cycloalkyl.
  • Non-limiting examples of halogenated cycloalkyl include , , , .
  • R6 is ORa, SRa, -C1-4alkyl-ORa, or -C1-4alkyl-SRa.
  • R 6 is OR a or SR a .
  • R 6 is -C 1-4 alkyl-OR a or -C 1-4 alkyl- SR a .
  • R6 is OH, CH2OH, or CH2CH2OH.
  • R 6 is selected from the group consisting of H, D, CH 3 , , , , . In some embodiments, R6 is selected from the group consisting of H, D, CH3, CH2CH3, CF2H, CH2F, CF3, CN, Cl, Br, F, OCH3, [0199] In some embodiments, R 6 is selected from the group consisting of H, D, Cl, Br, F, I, some embodiments, R 6 is H, D, CH 3 , CH 2 CH 3 , OH, F, Cl, Br, or fluorinated alkyl. In some embodiments, R 6 is H, D, Cl, Br, or F. In some embodiments, R 6 is OH.
  • R6 is H, D, halogen, CN, alkyl, halogenated alkyl, ORa, or SRa. In some embodiments, R6 is H, D, halogen, CN, alkyl, or ORa. In some embodiments, R 6 is H, D, F, Cl, Br, I, CN, OH, CH 3 , CH 2 CH 3 , OCH 3 , or CF 3 . In some embodiments, R 6 is F. In some embodiments, R6 is H. In some embodiments, R4 and R6 are both F.
  • R7 is H, D, halogen, CN, alkyl, halogenated alkyl, cycloalkyl, halogenated cycloalkyl, OR a , SR a , -C 1-4 alkyl-OR a , or -C 1-4 alkyl-SR a .
  • R7 is H, D, halogen, CN, CF3, CH2F, CHF2, ORa, SRa, -C1-4alkyl-ORa, or -C1-4alkyl-SRa.
  • R7 is H, D, or alkyl.
  • R7 is H, D, or alkyl, wherein the alkyl is optionally substituted by halogen, OH, oxo, or NH 2 where valence permits.
  • alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, and octyl.
  • R7 is cycloalkyl.
  • Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • R 7 is halogen.
  • Non-limiting examples of halogen include F, Cl, Br, and I.
  • R 7 is halogenated alkyl.
  • Non-limiting examples of halogenated alkyl include CF 3 , CH 2 F, CHF 2 , CH2Cl, CH2CF3, CHFCH3, CHFCH2F, CF2CH3, CHClCH3, CCl2CH3, CHBrCH3, CH 2 CH 2 CF 3 , and CHClCHClCH 3 .
  • R 7 is halogenated cycloalkyl.
  • R 7 is OR a , SR a , -C 1-4 alkyl-OR a , or -C 1-4 alkyl-SR a .
  • R7 is ORa or SRa.
  • R7 is -C1-4alkyl-ORa or -C1-4alkyl- SRa.
  • R 7 is OH, CH 2 OH, or CH 2 CH 2 OH.
  • R 7 is selected from the group consisting of H, D, CH 3 , from the group consisting of H, D, CH 3 , CH 2 CH 3 , CF 2 H, CH 2 F, CF 3 , CN, Cl, Br, F, OCH 3 , [0206] In some embodiments, R 7 is selected from the group consisting of H, D, Cl, Br, F, I, CN, CH3, CH2CH3, CF3, CH2CH2CH3, CH(CH3)2, In some embodiments, R 7 is H, D, CH 3 , CH 2 CH 3 , OH, F, Cl, Br, or fluorinated alkyl. In some embodiments, R 7 is H, D, Cl, Br, or F.
  • R 7 is OH. [0207] In some embodiments, R 7 is H, D, halogen, CN, alkyl, halogenated alkyl, OR a , or SR a . In some embodiments, R 7 is H, D, halogen, CN, alkyl, or OR a . In some embodiments, R7 is H, D, F, Cl, Br, I, CN, OH, CH3, CH2CH3, OCH3, or CF3. In some embodiments, R7 is F. In some embodiments, R 7 is H. In some embodiments, R 4 and R 7 are both F. In some embodiments, R 4 , R 5 , and R 7 are F.
  • R1 is alkyl, cycloalkyl, -C1-4alkyl-cycloalkyl, bicycloalkyl, saturated heterocycle, aryl, heteroaryl, or cycloalkenyl; wherein R 1 is optionally substituted by 1-5 substituents each independently selected from the group consisting of D, halogen, alkyl, and halogenated alkyl where valence permits;
  • R2 is CN, alkyl, ORa, SRa, -C1-4alkyl- ORa, or -O-C1-4alkyl-ORa;
  • R11 is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogenated cycloalkyl, or halogenated alkyl
  • R 12 is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogenated cycloalkyl, or halogenated alkyl
  • R13 is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogenated cycloalkyl, or halogenated alkyl
  • R 14 is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogenated cycloalkyl, or halogenated alkyl
  • R 15 is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogenated
  • R2, R3, R4, R5, R6, and R7 in Formula IIa are as defined above for the compound of Formula I in one or more embodiments described above. Other substituents are defined herein.
  • at least one of R11, R12, R13, R14, and R15 is not H. In some embodiments, at least two of R11, R12, R13, R14, and R15 are not H. In some embodiments, at least one of R 11 , R 12 , R 13 , R 14 , and R 15 is H, D, alkyl, halogenated alkyl, or halogen.
  • At least one of R 11 , R 12 , R 13 , R 14 , and R 15 is H, D, halogen, fluorinated alkyl, alkyl, alkenyl, or alkynyl. In some embodiments, at least one of R11, R12, R13, R14, and R15 is CH3, CH2CH3, F, Cl, Br, CF3, C ⁇ CH, or . In some embodiments, at least one of R11, R12, R13, R14, and R15 is H, Me, Et, i-Pr, n-Bu, CF2H, CF2Cl, or CF3.
  • At least one of R 11 , R 12 , R 13 , R 14 , and R 15 is Cl, F, Br, or I. In some embodiments, at least one of R 11 , R 12 , R 13 , R 14 , and R 15 is Cl. In some embodiments, at least one of R 11 , R 12 , R 13 , R 14 , and R15 is CF3, CH2F, CH2Cl, CH2CF3, CHFCH3, CHFCH2F, CF2CH3, CHClCH3, CCl2CH3, CHBrCH 3 , CH 2 CH 2 CF 3 , or CHClCHClCH 3 .
  • At least one of R 11 , R 12 , R 13 , R 14 , and R 15 some embodiments, at least one of R11, R12, R13, R14, and R15 is ethylenyl, propenyl, 2-propenyl, (E)-but-2-enyl, (Z)-but- 2-enyl, 2-methyl(E)-but-2-enyl, 2-methyl(Z)-but-2-enyl, 2,3-dimethyl-but-2-enyl, (Z)-pent-2- enyl, or (E)-pent-1-enyl.
  • At least one of R 11 , R 12 , R 13 , R 14 , and R 15 25 is ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, pent-1-ynyl, pent-2-ynyl, hex-1- ynyl, hex-2-ynyl, or hex-3-ynyl.
  • R11, R12, R13, R14, and R 15 are independently selected from the group consisting of CH 3 , CH 2 CH 3 , F, Cl, Br, CF 3 , [0213]
  • R 11 is H, D, F, Cl, Br, I, alkyl, or halogenated alkyl
  • R 12 is H, D, F, Cl, Br, I, alkyl, or halogenated alkyl
  • R13 is H, D, F, Cl, Br, I, alkyl, or halogenated alkyl
  • R14 is H, D, F, Cl, Br, I, alkyl, or halogenated alkyl
  • R15 is H, D, F, Cl, Br, I, alkyl, or halogenated alkyl.
  • R11, R12, R14, and R15 are H; and R13 is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogenated cycloalkyl, or halogenated alkyl.
  • R 11 , R 12 , R 14 , and R 15 are H; and R 13 is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, or CF 3 .
  • R 11 , R 12 , R 14 , and R 15 are H; and R 13 is H or D.
  • R11, R12, R14, and R15 are H; and R13 is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, or CF 3 .
  • R 11 , R 12 , R 14 , and R 15 are H; and R 13 is H, D, halogen, or alkyl.
  • R 11 , R 12 , R 14 , and R 15 are H; and R 13 is halogen.
  • Non-limiting examples of alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, and octyl.
  • alkenyl include ethylenyl, propenyl, 2-propenyl, (E)-but-2-enyl, (Z)-but-2-enyl, 2-methyl(E)- but-2-enyl, 2-methyl(Z)-but-2-enyl, 2,3-dimethyl-but-2-enyl, (Z)-pent-2-enyl, (E)-pent-1- enyl, (Z)-hex-1-enyl, (E)-pent-2-enyl, (Z)-hex-2-enyl, (E)-hex-2-enyl, (Z)-hex-1-enyl, (E)-hex-1-enyl, (Z)-hex-3-enyl, (E)-hex-3-enyl, and (E)-hex-1,3-dienyl.
  • Non-limiting examples of alkynyl include ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, pent-1-ynyl, pent-2-ynyl, hex-1-ynyl, hex-2-ynyl, or hex-3-ynyl.
  • Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • Non-limiting examples of halogen include F, Cl, Br, and I.
  • R 13 is alkyl (e.g., CH 3 or CH 2 CH 3 ,), halogen (e.g., F, Cl, or Br), halogenated alkyl (e.g., CF3), CN, alkynyl (e.g., C ⁇ CH), or cycloalkyl (e.g., ).
  • R13 is CH3, CH2CH3, F, Cl, Br, CF3, C ⁇ CH, or .
  • R13 is halogen (e.g., F, Cl, or Br).
  • R13 is Cl.
  • R 13 is Br.
  • R 13 is F.
  • R 13 is CF 3 .
  • R11, R12, R14, and R15 are H; and R13 is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, or CF3.
  • R11, R12, R14, and R15 are H; and some embodiments, R11, R12, R14, and R15 are H; and R13 is halogen.
  • R11, R12, R14, and R15 are H; and R 13 is Cl.
  • R 11 , R 12 , R 14 , and R 15 are H; and R 13 is F.
  • R 11 , R 12 , R 14 , and R 15 are H; and R 13 is Br. In some embodiments, R 11 , R 12 , R14, and R15 are H; and R13 is CF3. [0217] In some embodiments, R 11 , R 12 , R 13 , and R 15 are H; and R 14 is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, or CF 3 . In some embodiments, R 11 , R 12 , R 13 , and R 15 are H; and some embodiments, R 11 , R 12 , R 13 , and R 15 are H; and R 14 is halogen.
  • R 11 , R 12 , R 13 , and R 15 are H; and R14 is Cl. In some embodiments, R11, R12, R13, and R15 are H; and R14 is F. In some embodiments, R 11 , R 12 , R 13 , and R 15 are H; and R 14 is Br. In some embodiments, R 11 , R 12 , R 13 , and R 15 are H; and R 14 is CF 3 .
  • the compound of Formula I has the structure of Formula IIb: wherein is alkyl, cycloalkyl, cycloalkenyl, bicycloalkyl, heteroaryl, or saturated heterocycle, each of which optionally substituted by 1-5 substituents each independently selected from the group consisting of D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogenated cycloalkyl, and halogenated alkyl where valence permits.
  • R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 in Formula IIb are as defined above for the compound of Formula I in one or more embodiments described herein.
  • substituents are defined herein.
  • alkyl that is optionally substituted by 1-5 substituents each independently selected from the group consisting of D, halogen, alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, alkenyl, and alkynyl, where valence permits.
  • alkyl that is optionally substituted by D or halogen (e.g., F, Cl, Br, and I).
  • Non-limiting examples of alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, and octyl.
  • cycloalkyl is cycloalkyl, -CH 2 -cycloalkyl, cycloalkenyl, or bicycloalkyl, each of which optionally substituted by 1-5 substituents each independently selected from the group consisting of D, halogen, alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, alkenyl, and alkynyl where valence permits.
  • alkyl e.g., methyl, ethyl, propyl,
  • cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • bicycloalkyl that is optionally substituted by 1-5 substituents each independently selected from the group consisting of D, CH 3 , CH 2 CH 3 , F, Cl, Br, CH 2 F, and CF 3 .
  • bicycloalkyl examples include bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.1.1]hexyl, octahydropentalenyl, bicyclo[3.2.1]octyl, bicyclo[3.3.3]undecanyl, decahydronaphthalenyl, bicyclo[3.2.0]heptyl, octahydro-1H- indenyl, bicyclo[4.2.1]nonanyl, spiro[4.4]nonyl, spiro[3.3]heptyl, spiro[5.5]undecyl, spiro[3.5]nonyl, and spiro[4.5]decyl.
  • cycloalkenyl that is optionally substituted by 1-5 substituents each independently selected from the group consisting of D, CH3, CH2CH3, F, Cl, Br, CH2F, and CF3, where valence permits.
  • Non- limiting examples of cycloalkenyl include cyclobutenyl, cyclopentenyl, and cyclohexenyl.
  • each is optionally substituted by 1-5 substituents each independently selected from the group consisting of D, alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec- butyl, pentyl, hexyl, heptyl, and octyl), halogen (e.g., F, Cl, Br, and I), and halogenated alkyl (e.g., CF3, CH2F, CHF2, CH2Cl, CH2CF3, CHFCH3, CHFCH2F, CF2CH3, CHClCH3, CCl 2 CH 3 , CHBrCH 3 , CH 2 CH 2 CF 3 , and CHClCHClCH 3 ) where valence permits.
  • alkyl e.g., methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-
  • the compound of Formula I has the structure of Formula III: wherein X is O or S; and R 16 is C 1-4 alkyl that is optionally substituted with halogen, OR a , SR a , or NR a R b .
  • R1, R3, R4, R5, R6, and R7 in Formula III are as defined above for the compound of Formula I in one or more embodiments described above. Other substituents are defined herein.
  • X is O.
  • X is S.
  • R16 is methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, or sec-butyl, each of which optionally substituted with halogen, OR a , SR a , or NR a R b .
  • R 16 is methyl, ethyl, propyl, or isopropyl, each of which optionally substituted with OH or OCH3.
  • R16 is CH3, CH2CH3, CH2CH2CH3, CH(CH 3 ) 2 , CH 2 CH 2 OH, CH 2 CH 2 CH 2 OH, CH 2 CH 2 OCH 3 , CH 2 CH 2 CH 2 OCH 3 , CH(CH 3 )CH 2 OH, or CH(CH 3 )CH 2 OCH 3 .
  • R1 is phenyl that is optionally substituted by 1-5 substituents each independently selected from the group consisting of D, halogen, alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, alkenyl, and alkynyl
  • R 1 is phenyl that is optionally substituted by 1-5 substituents each independently selected from the group consisting of D, F, Cl, Br, I, alkyl, and halogenated alkyl.
  • R 1 is alkyl, cycloalkyl, -CH 2 -cycloalkyl, cycloalkenyl, bicycloalkyl, heteroaryl, or saturated heterocycle, each of which optionally substituted by 1-5 substituents each independently selected from the group consisting of D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogenated cycloalkyl, and halogenated alkyl where valence permits.
  • R 1 is alkyl, cycloalkyl, -CH 2 -cycloalkyl, cycloalkenyl, bicycloalkyl, heteroaryl, or saturated heterocycle, each of which optionally substituted by 1-5 substituents each independently selected from the group consisting of D, alkyl, halogen, and halogenated alkyl where valence permits.
  • R 1 is pyridine, pyrimidine, furan, or thiophene, each of which optionally substituted with halogen or alkyl.
  • R1 is thiane or pyrane, each of which optionally substituted with halogen or alkyl.
  • R 1 is selected from the , [0231] In some embodiments, the compound of Formula I has the structure of Formula IV: . [0232] In some embodiments, R 1 , R 2 , R 4 , R 5 , R 6 , and R 7 in Formula IV are as defined above for the compound of Formula I in one or more embodiments described above. Other substituents are defined herein. [0233] In some embodiments, R 1 is phenyl that is optionally substituted by 1-5 substituents each independently selected from the group consisting of D, halogen, alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, alkenyl, and alkynyl.
  • R1 is phenyl that is optionally substituted by 1-5 substituents each independently selected from the group consisting of D, F, Cl, Br, I, alkyl, and halogenated alkyl.
  • R1 is alkyl, cycloalkyl, -CH2-cycloalkyl, cycloalkenyl, bicycloalkyl, heteroaryl, or saturated heterocycle, each of which optionally substituted by 1-5 substituents each independently selected from the group consisting of D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogenated cycloalkyl, and halogenated alkyl where valence permits.
  • R1 is alkyl, cycloalkyl, -CH2-cycloalkyl, cycloalkenyl, bicycloalkyl, heteroaryl, or saturated heterocycle, each of which optionally substituted by 1-5 substituents each independently selected from the group consisting of D, alkyl, halogen, and halogenated alkyl where valence permits.
  • R1 is pyridine, pyrimidine, furan, or thiophene, each of which optionally substituted with halogen or alkyl.
  • R 1 is thiane or pyrane, each of which optionally substituted with halogen or alkyl.
  • R1 is selected from the [0235]
  • the compound of Formula I has the structure of Formula V: wherein X is O or S; and R16 is C1-4alkyl that is optionally substituted with halogen, ORa, SRa, or NRaRb.
  • R 1 , R 4 , R 5 , R 6 , and R 7 in Formula V are as defined above for the compound of Formula I in one or more embodiments described above.
  • X and R16 in Formula V are as defined above for the compound of Formula III in one or more embodiments described above. Other substituents are defined herein.
  • R 1 is phenyl that is optionally substituted by 1-5 substituents each independently selected from the group consisting of D, halogen, alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, alkenyl, and alkynyl.
  • R1 is phenyl that is optionally substituted by 1-5 substituents each independently selected from the group consisting of D, F, Cl, Br, I, alkyl, and halogenated alkyl.
  • R1 is alkyl, cycloalkyl, -CH2-cycloalkyl, cycloalkenyl, bicycloalkyl, heteroaryl, or saturated heterocycle, each of which optionally substituted by 1-5 substituents each independently selected from the group consisting of D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogenated cycloalkyl, and halogenated alkyl where valence permits.
  • R 1 is alkyl, cycloalkyl, -CH 2 -cycloalkyl, cycloalkenyl, bicycloalkyl, heteroaryl, or saturated heterocycle, each of which optionally substituted by 1-5 substituents each independently selected from the group consisting of D, alkyl, halogen, and halogenated alkyl where valence permits.
  • R 1 is pyridine, pyrimidine, furan, or thiophene, each of which optionally substituted with halogen or alkyl.
  • R1 is thiane or pyrane, each of which optionally substituted with halogen or alkyl.
  • R1 is selected from the [0239]
  • the compound is a compound of Formula V, R1 is cycloalkyl or phenyl; wherein the cycloalkyl or phenyl in R 1 is optionally substituted by 1-5 substituents each of which is independently D or halogen where valence permits; X is O; R 16 is C 1-4 alkyl that is optionally substituted with halogen, ORa, SRa, or NRaRb where valence permits; R4 is H, D, or halogen; R 5 is H, D, halogen, or OR a ; R 6 is H, D, or halogen; R 7 is H, D, or halogen, and R a and R b are each independently H or Me.
  • R a or R b for the compounds of Formulae I, IIa, IIb, III, IV, and V [0240]
  • the following description of R a or R b is applicable for any one or more of the compounds of Formulae I, IIa, IIb, III, IV, and V.
  • at least one occurrence of Ra or Rb is independently H, D, alkyl, cycloalkyl, saturated heterocycle, aryl, or heteroaryl.
  • at least one occurrence of Ra or Rb is independently H, D, alkyl, or cycloalkyl.
  • at least one occurrence of R a or R b is independently saturated heterocycle, aryl, or heteroaryl.
  • Ra and Rb together with the nitrogen atom that they are connected to, form an optionally substituted heterocycle comprising the nitrogen atom and 0- 3 additional heteroatoms each selected from the group consisting of N, O, and S.
  • Non- R x for the compounds of Formulae I, IIa, IIb, III, IV, and V [0243] The following description of Rx is applicable for any one or more of the compounds of Formulae I, IIa, IIb, III, IV, and V.
  • each occurrence of Rx is independently H, alkyl, or heterocycle optionally substituted by alkyl, halogen, or OH where valence permits.
  • each occurrence of R x is independently H or alkyl.
  • alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, and octyl.
  • At least one occurrence of R x is optionally substituted heterocycle or optionally substituted heteroaryl.
  • each occurrence of R x is independently H or Me.
  • the compound of Formula I, IIa, IIb, III, IV, or V is selected from the group consisting of compounds 1-74 in Table 2.
  • the compound of Formula I, IIa, IIb, III, IV, or V is selected from the group consisting of compounds 2, 4, 5, 6, 9, 12, 14, 17, 18, 19, 20, 22, 23, 25, 26, 28, 29, 30, 31, 32, 33, 34, 35, 37, 38, 41, 42, 43, 44, 45, 46, 48, 49, 50, 51, 52, 53, 54, 56, 57, 60, 61, 62, 64, 65, 66, 71, 73, and 74 in Table 2.
  • the compound i is selected from the group consisting of compounds 2, 4, 5, 6, 9, 12, 14, 17, 18, 19, 20, 22, 23, 25, 26, 28, 29, 30, 31, 32, 33, 34, 35, 37, 38, 41, 42, 43, 44, 45, 46, 48, 49, 50, 51, 52, 53, 54, 56, 57, 60, 61, 62, 64, 65, 66, 71, 73, and 74 in Table 2.
  • the compound i is selected from the group consisting of compounds 2, 4, 5, 6, 9, 12, 14, 17, 18, 19, 20, 22, 23, 25, 26, 28, 29, 30, 31,
  • Formula I, IIa, IIb, III, IV, or V is not in a salt form or a tautomer form.
  • the compound is any one of the compounds described herein, or pharmaceutically acceptable salts thereof or an enantiomer thereof.
  • the enumerated compounds in Tables 2 and Examples 1-20 are representative and non-limiting compounds of the embodiments disclosed herein.
  • the compound is any one of the compounds described herein, or pharmaceutically acceptable salts thereof or an enantiomer thereof.
  • Schemes 1-6 below describe synthetic routes which may be used for the synthesis of compounds of the present invention, e.g., compounds having a structure of Formula I, IIa, IIb, III, IV, or V, or a precursor thereof. Various modifications to these methods may be envisioned by those skilled in the art to achieve similar results to that of the embodiments given below. In the embodiments below, the synthetic route is described using compounds having the structure of Formula I, IIa, IIb, III, IV, or V, or a precursor thereof as examples.
  • the general synthetic routes described in Schemes 1-6 and examples described in the Example section below illustrate methods used for the preparation of the compounds described herein.
  • Removal of the hydroxy group in I-4 may be carried out by treatment with a silane reducing agent such as triethylsilane and an acid such as TFA, optionally with a cosolvent such as DCM, to give indolinone I-5.
  • a silane reducing agent such as triethylsilane and an acid such as TFA
  • a cosolvent such as DCM
  • the OH may also be removed by converting to chlorine with thionyl chloride and reduction with zinc.
  • a more direct way to obtain I-5 when R1 is aryl is through reaction of indolinone I-3 with an aryl halide R1Br using a palladium catalyst such as the Xphos 3rd generation catalyst, Xphos ligand, and a base such as potassium carbonate in a solvent such as dioxane.
  • the R1 group can be introduced by condensation of indolinone I-3 with a suitable ketone or aldehyde precursor to give vinyl indolinone I-6.
  • the condensation can be carried out with a base such as triethylamine or piperidine, or with a Lewis acid such as titanium tetraisopropoxide.
  • a suitable catalyst such as palladium on carbon provides I-5.
  • a reducing agent such as sodium borohydride in ethanol can be used to convert I- 6 to I-5.
  • R 2 group can be introduced as shown in Scheme 2 by alkylation of I-5 with R2X, where X is Br or I, in the presence of a base such as potassium carbonate, cesium carbonate, or sodium hydride in a solvent such as DMF to form I-7.
  • a base such as potassium carbonate, cesium carbonate, or sodium hydride in a solvent such as DMF to form I-7.
  • a suitable protecting group such as Boc can be added by treating I-5 with di-t- butyl decarbonate, dimethylaminopyridine, and a base such as triethylamine in a solvent such as DCM to give I-8.
  • Reaction of I-5 with phenyltrimethylammonium tribromide in DCM gives I-11 where X is Br.
  • reaction of I-4 with thionyl chloride gives I-11 where X is Cl.
  • treatment of I-5 with an alcohol R16OH and a base such as NaOR16 converts I-5 to I-10.
  • Compounds where R2 is SR16 can be obtained by heating I-4 with a thiol R16SH and an acid such as p-toluene sulfonic acid in a solvent such as toluene to form I-12.
  • indolinone I-5 where R 1 is aryl is shown in Scheme 5, along with a way to obtain enantiomerically enriched 3-alkoxy-indolinones.
  • a suitably substituted 2-fluoronitrobenezene I-16 undergoes SNAr reaction with an arylacetic ester in the presence of a base such as potassium t-butoxide in a solvent such as THF at low temperature, for example, -78 oC to give I-17.
  • Reduction of the nitro group by hydrogenation over a catalyst such as palladium on carbon in a solvent such as THF followed by cyclization with aqueous acid in the same solvent provides indolinone I-5.
  • the anion of I-5 is formed using a base such as potassium hexamethyldisilazide in a solvent such as THF at low temperature and reacted with the (S)-Davis chiral oxaziridine I-18 to give the 3-hydroxyindolinone I-4S enriched in the S-enantiomer.
  • a base such as potassium hexamethyldisilazide
  • THF a solvent
  • R 3 X I or Br
  • the R3 group can be added in the last step by alkylation of I-7 with R3Br or R3I and a base such as potassium carbonate as shown in Scheme 6.
  • This invention also provides a pharmaceutical composition comprising at least one of the compounds as described herein or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier or diluent.
  • the present invention provides a pharmaceutical composition comprising at least one compound selected from the group consisting of compounds of Formula I, IIa, IIb, III, IV, or V, as described herein and a pharmaceutically acceptable carrier or diluent.
  • the compound in the composition is in the form of a hydrate, solvate, or pharmaceutically acceptable salt.
  • the composition can be administered to the subject by any suitable route of administration, including, without limitation, oral and parenteral.
  • pharmaceutically acceptable carrier means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, involved in carrying or transporting the subject pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • materials which can serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose, and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols, such as butylene glycol; polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline;
  • carrier denotes an organic or inorganic ingredient, natural or synthetic, with which the active ingredient is combined to facilitate the application.
  • the components of the pharmaceutical compositions also are capable of being comingled with the compounds of the present invention, and with each other, in a manner such that there is no interaction which would substantially impair the desired pharmaceutical efficiency.
  • pharmaceutically acceptable salt refers to the relatively non-toxic, inorganic and organic acid salts of compounds of the present invention.
  • salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or by separately reacting a purified compound of the invention in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed.
  • Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts, and the like.
  • the pharmaceutically acceptable salts of the subject compounds include the conventional nontoxic salts or quaternary ammonium salts of the compounds, e.g., from non- toxic organic or inorganic acids.
  • such conventional nontoxic salts include those derived from inorganic acids such as hydrochloride, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like; and the salts prepared from organic acids such as acetic, butionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, palmitic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicyclic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isothionic, and the like.
  • inorganic acids such as hydrochloride, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like
  • organic acids such as acetic, butionic, succinic, glycolic, stearic,
  • the compounds of the present invention may contain one or more acidic functional groups and, thus, are capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases.
  • pharmaceutically acceptable salts refers to the relatively non-toxic, inorganic and organic base addition salts of compounds of the present invention. These salts can likewise be prepared in situ during the final isolation and purification of the compounds, or by separately reacting the purified compound in its free acid form with a suitable base, such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, or tertiary amine.
  • Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts, and the like.
  • Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. See, e.g., Berge et al. (supra).
  • compositions can also be present in the compositions.
  • wetting agents, emulsifiers, and lubricants such as sodium lauryl sulfate, magnesium stearate, and polyethylene oxide-polybutylene oxide copolymer, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives, and antioxidants can also be present in the compositions.
  • Formulations of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal, and/or parenteral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated and the particular mode of administration.
  • the amount of active ingredient, which can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of 100%, this amount will range from about 1% to about 99% of active ingredient, preferably from about 5% to about 70%, most preferably from about 10% to about 30%.
  • Methods of preparing these formulations or compositions include the step of bringing into association a compound of the present invention with the carrier and, optionally, one or more accessory ingredients.
  • Formulations of the invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia), and/or as mouthwashes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient.
  • a compound of the present invention may also be administered as a bolus, electuary or paste.
  • the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and/or acacia; humectants, such as glycerol; disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, sodium carbonate, and sodium starch glycolate; solution retarding agents, such as paraffin; absorption accelerators, such as paraffin; absorption accelerators
  • the pharmaceutical compositions may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxybutylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets, and other solid dosage forms of the pharmaceutical compositions of the present invention such as dragees, capsules, pills, and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxybutylmethyl cellulose in varying proportions, to provide the desired release profile, other polymer matrices, liposomes, and/or microspheres.
  • compositions may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions, which can be dissolved in sterile water or some other sterile injectable medium immediately before use.
  • These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner.
  • embedding compositions which can be used include polymeric substances and waxes.
  • the active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.
  • Liquid dosage forms for oral administration of the compounds of the invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isobutyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, butylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents
  • cyclodextrins e.g., hydroxybutyl- ⁇ -cyclodextrin
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming, and preservative agents.
  • Suspensions in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar, and tragacanth, and mixtures thereof.
  • Dosage forms for the topical or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants.
  • the active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required.
  • the ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays can contain, in addition to a compound of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body. Such dosage forms can be made by dissolving or dispersing the pharmaceutical agents in the proper medium. Absorption enhancers can also be used to increase the flux of the pharmaceutical agents of the invention across the skin. The rate of such flux can be controlled, by either providing a rate-controlling membrane or dispersing the compound in a polymer matrix or gel. [0279] Ophthalmic formulations, eye ointments, powders, solutions, and the like, are also contemplated as being within the scope of this invention.
  • compositions of this invention suitable for parenteral administration comprise one or more compounds of the invention in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions, or emulsions; or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, or solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
  • sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions, or emulsions or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, or solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
  • Injectable depot forms are made by forming microencapsule matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide.
  • the rate of drug release can be controlled.
  • biodegradable polymers include poly(orthoesters) and poly(anhydrides).
  • Depot-injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions, which are compatible with body tissue.
  • the compounds and pharmaceutical compositions of the present invention can be employed in combination therapies, that is, the compounds and pharmaceutical compositions can be administered concurrently with, prior to, or subsequent to, one or more other desired therapeutics or medical procedures.
  • the particular combination of therapies (therapeutics or procedures) to employ in a combination regimen will take into account compatibility of the desired therapeutics and/or procedures and the desired therapeutic effect to be achieved. It will also be appreciated that the therapies employed may achieve a desired effect for the same disorder (for example, the compound of the present invention may be administered concurrently with another anticancer agents).
  • the compounds of the invention may be administered intravenously, intramuscularly, intraperitoneally, subcutaneously, topically, orally, or by other acceptable means.
  • the compounds may be used to treat arthritic conditions in mammals (e.g., humans, livestock, and domestic animals), racehorses, birds, lizards, and any other organism which can tolerate the compounds.
  • the invention also provides a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention.
  • Optionally associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use, or sale for human administration.
  • the present invention provides a method for treating a condition in a mammalian species in need thereof, the method comprising administering to the mammalian species a therapeutically effective amount of at least one compound selected from the group consisting of compounds of Formula I, IIa, IIb, III, IV, or V, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof, wherein the condition is selected from the group consisting of cancer, sickle cell anemia, a cardiovascular disease, a respiratory disease, a fibrotic disease, an autoimmune disease, a central nervous system (CNS) disorder, a neurodegenerative disease, and an inflammatory disorder.
  • a therapeutically effective amount of at least one compound selected from the group consisting of compounds of Formula I, IIa, IIb, III, IV, or V, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof wherein the condition is selected from the group consisting of cancer, sickle cell anemia, a cardiovascular disease, a respiratory disease, a fibrotic disease, an autoimmune disease, a central nervous system (
  • the respiratory disease is an inflammatory airway disease, airway hyperresponsiveness, an idiopathic lung disease, chronic obstructive pulmonary disease, asthma, chronic asthma, allergy, tracheobronchial or diaphragmatic dysfunction, or cough or chronic cough.
  • the autoimmune disease is rheumatoid arthritis or multiple sclerosis.
  • the central nervous system disorder is acute ischemic stroke, traumatic brain injury, peripheral nerve injury, glioblastoma multiforme, or spinal cord injury.
  • the fibrotic disease is liver fibrosis, kidney fibrosis, cardiac fibrosis, eye injury-related corneal fibrosis, or lung fibrosis.
  • the neurodegenerative disease is Alzheimer’s disease, Parkinson’s disease, or amyotrophic lateral sclerosis (ALS).
  • the mammalian species is human.
  • a method of inhibiting calcium-activated potassium channel KCa3.1 in a mammalian species in need thereof including administering to the mammalian species a therapeutically effective amount of at least one compound of Formula I, IIa, IIb, III, IV, or V, or a pharmaceutically acceptable salt or pharmaceutical composition thereof.
  • the compounds described herein are selective in inhibiting K Ca 3.1 with minimal or no off-target inhibition activities against potassium channels, or against calcium or sodium channels.
  • the compounds described herein do not block the hERG channels and therefore have desirable cardiovascular safety profiles.
  • Some aspects of the invention involve administering an effective amount of a composition to a subject to achieve a specific outcome.
  • the small molecule compositions useful according to the methods of the present invention thus can be formulated in any manner suitable for pharmaceutical use.
  • the formulations of the invention are administered in pharmaceutically acceptable solutions, which may routinely contain pharmaceutically acceptable concentrations of salt, buffering agents, preservatives, compatible carriers, adjuvants, and optionally other therapeutic ingredients.
  • an effective amount of the compound can be administered to a subject by any mode allowing the compound to be taken up by the appropriate target cells.
  • administering can be accomplished by any means known to the skilled artisan.
  • Specific routes of administration include, but are not limited to, oral, transdermal (e.g., via a patch), parenteral injection (subcutaneous, intradermal, intramuscular, intravenous, intraperitoneal, intrathecal, etc.), or mucosal (intranasal, intratracheal, inhalation, intrarectal, intravaginal, etc.).
  • An injection can be in a bolus or a continuous infusion.
  • the pharmaceutical compositions according to the invention are often administered by intravenous, intramuscular, or other parenteral means.
  • liquid or solid pharmaceutical preparation forms are, for example, aqueous or saline solutions for injection or inhalation, microencapsulated, encochleated, coated onto microscopic gold particles, contained in liposomes, nebulized, aerosols, pellets for implantation into the skin, or dried onto a sharp object to be scratched into the skin.
  • the pharmaceutical compositions also include granules, powders, tablets, coated tablets, (micro)capsules, suppositories, syrups, emulsions, suspensions, creams, drops, or preparations with protracted release of active compounds in whose preparation excipients and additives and/or auxiliaries such as disintegrants, binders, coating agents, swelling agents, lubricants, flavorings, sweeteners, or solubilizers are customarily used as described above.
  • the pharmaceutical compositions are suitable for use in a variety of drug delivery systems. For a brief review of present methods for drug delivery, see Langer, R. (1990) Science 249:1527-33, which is incorporated herein by reference in its entirety.
  • compositions used in the methods of the invention can range from about 1 nM to about 100 ⁇ M. Effective doses are believed to range from about 10 picomole/kg to about 100 micromole/kg.
  • the pharmaceutical compositions are preferably prepared and administered in dose units. Liquid dose units are vials or ampoules for injection or other parenteral administration. Solid dose units are tablets, capsules, powders, and suppositories. For treatment of a patient, different doses may be necessary depending on activity of the compound, manner of administration, purpose of the administration (i.e., prophylactic or therapeutic), nature and severity of the disorder, age and body weight of the patient.
  • compositions can be administered per se (neat) or in the form of a pharmaceutically acceptable salt.
  • salts should be pharmaceutically acceptable, but non-pharmaceutically acceptable salts can conveniently be used to prepare pharmaceutically acceptable salts thereof.
  • Such salts include, but are not limited to, those discussed above and those prepared from the following acids: hydrochloric, hydrobromic, sulphuric, nitric, phosphoric, maleic, acetic, salicylic, p-toluene sulphonic, tartaric, citric, methane sulphonic, formic, malonic, succinic, naphthalene-2-sulphonic, and benzene sulphonic.
  • such salts can be prepared as alkaline metal or alkaline earth salts, such as sodium, potassium, or calcium salts of the carboxylic acid group.
  • Suitable buffering agents include, but are not limited to: acetic acid and a salt (1-2% w/v); citric acid and a salt (1-3% w/v); boric acid and a salt (0.5-2.5% w/v); and phosphoric acid and a salt (0.8-2% w/v).
  • Suitable preservatives include benzalkonium chloride (0.003- 0.03% w/v); chlorobutanol (0.3-0.9% w/v); parabens (0.01-0.25% w/v); and thimerosal (0.004-0.02% w/v).
  • compositions suitable for parenteral administration conveniently include sterile aqueous preparations, which can be isotonic with the blood of the recipient.
  • acceptable vehicles and solvents are water, Ringer’s solution, phosphate buffered saline, and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed mineral or non-mineral oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • administrations can be found in Remington’s Pharmaceutical Sciences, Mack Publishing Company, Easton, PA; incorporated herein by reference in its entirety.
  • the compounds useful in the invention can be delivered in mixtures of more than two such compounds.
  • a mixture can further include one or more adjuvants in addition to the combination of compounds.
  • a variety of administration routes is available. The particular mode selected will depend upon the particular compound selected, the age and general health status of the subject, the particular condition being treated, and the dosage required for therapeutic efficacy.
  • the methods of this invention generally speaking, can be practiced using any mode of administration that is medically acceptable, meaning any mode that produces effective levels of response without causing clinically unacceptable adverse effects. Preferred modes of administration are discussed above.
  • compositions can conveniently be presented in unit dosage form and can be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the compounds into association with a carrier which constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing the compounds into association with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product.
  • Other delivery systems can include time-release, delayed release, or sustained-release delivery systems. Such systems can avoid repeated administrations of the compounds, increasing convenience to the subject and the physician. Many types of release delivery systems are available and known to those of ordinary skill in the art.
  • polymer base systems such as poly(lactide-glycolide), copolyoxalates, polycaprolactones, polyesteramides, polyorthoesters, polyhydroxybutyric acid, and polyanhydrides.
  • Microcapsules of the foregoing polymers containing drugs are described in, for example, U.S. Pat. No.5,075,109.
  • Delivery systems also include non-polymer systems that are: lipids including sterols such as cholesterol, cholesterol esters and fatty acids, or neutral fats such as mono-di-and tri-glycerides; hydrogel release systems; silastic systems; peptide-based systems; wax coatings; compressed tablets using conventional binders and excipients; partially fused implants; and the like.
  • the compounds as described herein were tested for their K Ca 3.1 channel electrophysiology. In some embodiments, the compounds as described herein were tested for their hERG electrophysiology.
  • Equivalents [0307] The representative examples which follow are intended to help illustrate the invention, and are not intended to, nor should they be construed to, limit the scope of the invention. Indeed, various modifications of the invention and many further embodiments thereof, in addition to those shown and described herein, will become apparent to those skilled in the art from the full contents of this document, including the examples which follow and the references to the scientific and patent literature cited herein. It should further be appreciated that the contents of those cited references are incorporated herein by reference to help illustrate the state of the art.
  • Examples 1-16 describe various intermediates used in the syntheses of representative compounds of Formula I, IIa, IIb, III, IV, or V disclosed herein. Example 1.
  • Step a [0310] A stirred solution of 4,7-difluoro-1H-indole-2,3-dione (8.00 g, 43.7 mmol) in EtOH (160 mL) containing NH 2 NH 2 ⁇ H 2 O (4.37 g, 87.4 mmol) was heated at 80 °C for 1 h under nitrogen. The mixture was cooled to room temperature, KOH (7.35 g, 131 mmol) was added and heated at 80 °C for an additional 6 h.
  • Step b [0312] (2E)-2-(N-hydroxyimino)-N-(2,4,5-trifluorophenyl)acetamide (7.00 g, 32.1 mmol) was added in portions to conc. H2SO4 (55 mL) at 70 o C over 1 h. The reaction was stirred at 100 °C for an additional 16 h. After cooling to room temperature, the cooled mixture was poured slowly into ice water (300 mL) and extracted with EA (5 x 80 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure.
  • Step b [0315] To a stirred solution of 3,3,5-tribromo-4-fluoro-1H-indol-2-one (2.10 g, 5.42 mmol) in ACN (20 mL) and AcOH (10 mL) was added Zn (1.06 g, 16.3 mmol) in portions at room temperature. After 2 h, the mixture was filtered, the filter cake washed with ACN (3 x 30 mL) and the filtrate concentrated under reduced pressure. The residue was diluted with water (100 mL) and EA (80 mL). The aqueous solution was extracted with EA (3 x 40 mL).
  • the reaction was degassed under reduced pressure, purged with nitrogen three times, and stirred at 80 °C for 16 h.
  • the resulting mixture was diluted with water (100 mL) and extracted with EA (3 x 200 mL). The combined organic layers were washed with brine (5 x 50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure.
  • Step b [0318] To a stirred solution of 5-bromo-4-fluoro-1H-indole-2,3-dione (1.00 g, 4.09 mmol) in THF (20 mL) was added (4-fluorophenyl)magnesium bromide (6.15 mL, 6.15 mmol, 1 M in THF) dropwise at 0 °C under nitrogen. The reaction was stirred at room temperature for 2 h, quenched with saturated aq. NH 4 Cl (50 mL) at 0 °C and extracted with EA (3 x 50 mL).
  • Step c [0319] To a stirred solution of 5-bromo-4-fluoro-3-(4-fluorophenyl)-3-hydroxy-1H-indol-2- one (0.700 g, 2.06 mmol) in TFA (10 mL) was added Et 3 SiH (0.720 g, 6.17 mmol) dropwise at 0 °C under nitrogen. The reaction was heated at 80 °C for 2 h and concentrated under reduced pressure.
  • reaction was stirred at -78 °C for 30 min then at room temperature for 2 h, quenched with water (30 mL) and extracted with EA (3 x 50 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure.
  • Step b [0321] To a stirred solution of 4,6-difluoro-3-(4-fluorophenyl)-3-hydroxy-1H-indol-2-one (1.65 g, 5.90 mmol) in TFA (15 mL) was added Et3SiH (2.06 g, 17.7 mmol) at room temperature under nitrogen.
  • Example 10 (4,5-difluoro-3-(4-fluorophenyl)-3-methoxyindolin-2-one) [0323] To a stirred solution of 4,5-difluoro-3-(4-fluorophenyl)-1,3-dihydroindol-2-one (11.0 g, 41.8 mmol) in MeOH (200 mL) was added (NH 4 ) 2 Ce(NO 3 ) 6 (46.0 g, 83.6 mmol) in two portions. The reaction was stirred at room temperature for 2 h, diluted with water (200 mL) and extracted with EA (3 x 500 mL).
  • Step b [0327] To a stirred mixture of 3-bromo-5-chloro-4-fluoro-1H-indole (1.30 g, 5.23 mmol) in dioxane (8 mL) and H 2 O (2 mL) were added Na 2 CO 3 (1.10 g, 10.5 mmol), 4- fluorophenylboronic acid (1.10 g, 7.85 mmol) and Pd(dppf)Cl 2 ⁇ CH 2 Cl 2 (0.426 g, 0.523 mmol) at room temperature. The reaction was degassed under vacuum, purged with nitrogen three times and heated at 80 °C for 1 h.
  • Step c [0328] To a stirred solution of 5-chloro-4-fluoro-3-(4-fluorophenyl)-1H-indole (0.530 g, 2.01 mmol) in DCM (5 mL) was added t-butyl hypochlorite (0.436 g, 4.02 mmol). The reaction was stirred at room temperature for 1 h and concentrated under reduced pressure. The residue was dissolved in dioxane (4 mL) and conc. H2SO4 (2 mL), stirred at room temperature for 1 h then diluted with water (30 mL) and extracted with EA (3 x 30 mL).
  • Step d [0329] To a stirred mixture of 3,5-dichloro-4-fluoro-3-(4-fluorophenyl)indolin-2-one (0.150 g, 0.478 mmol) in MeOH (2 mL) was added NaOMe (51.6 mg, 0.956 mmol). The reaction was stirred at room temperature for 2 h, diluted with water (20 mL) and extracted with EA (3 x 30 mL). The combined organic layers were washed with brine (3 x 30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure.
  • Step b [0332] To a stirred solution of Na (0.260 g, 11.3 mmol) in MeOH (3 mL) was added a solution of 5-bromo-4-fluoro-3-(4-fluorophenyl)-3-methoxy-1H-indol-2-one (0.200 g, 0.560 mmol) in DMF (3 mL). The reaction was stirred at 100 °C for 16 h, cooled, diluted with water (50 mL) and extracted with EA (3 x 50 mL). The combined organic layers were washed with brine (3 x 30 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure.
  • the reaction was degassed under vacuum, purged with nitrogen three times and heated at 110 °C for 16 h.
  • the cooled reaction was diluted with water (20 mL) and extracted with EA (5 x 20 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure.
  • Examples 17-20 describe the exemplified syntheses of representative compounds of Formula I, IIa, IIb, III, IV, or V disclosed herein.
  • Example 17. Compound 1 (2-[(3S)-4,5-difluoro-3-(4-fluorophenyl)-3-methyl-2-oxoindol- 1-yl]acetamide); Compound 2 (2-[(3R)-4,5-difluoro-3-(4-fluorophenyl)-3-methyl-2- oxoindol-1-yl]acetamide) [0335] To a stirred mixture of 4,5-difluoro-3-(4-fluorophenyl)-3-methyl-1H-indol-2-one (0.100 g, 0.360 mmol) and bromoacetamide (74.4 mg, 0.540 mmol) in DMF (1 mL) was added K 2 CO 3 (0.150 g, 1.08 mmol).
  • Step b [0336] The 2-[4,5-difluoro-3-(4-fluorophenyl)-3-methyl-2-oxoindol-1-yl]acetamide (60.0 mg, 0.179 mmol) was separated by Prep Chiral HPLC with the following conditions: Column: (R, R)-WHELK-O1-Kromasil, 2.11 x 25 cm, 5 ⁇ m; Mobile Phase A: Hex (0.5% 2 M NH3-MeOH), Mobile Phase B: EtOH; Flow rate: 20 mL/min; Gradient: 50% B to 50% B in 11 min; Wavelength: 220/254 nm; Retention Time 1: 6.26 min; Retention Time 2: 8.45 min.
  • Example 18 Compound 3 ((R)-2-(4,5-difluoro-3-(4-fluorophenyl)-3-methoxy-2- oxoindolin-1-yl)acetamide); Compound 4 ((S)-2-(4,5-difluoro-3-(4-fluorophenyl)-3- methoxy-2-oxoindolin-1-yl)acetamide) Step a: [0337] To a stirred solution of 4,5-difluoro-3-(4-fluorophenyl)-3-methoxyindolin-2-one (50.0 mg, 0.171 mmol) and bromoacetamide (28.2 mg, 0.205 mmol) in DMF (1 mL) was added K 2 CO 3 (47.1 mg, 0.342 mmol).
  • Step b [0338] 2-(4,5-difluoro-3-(4-fluorophenyl)-3-methoxy-2-oxoindolin-1-yl)acetamide (37.0 mg, 0.106 mmol) was separated by Prep Chiral HPLC with the following conditions: Column: (R, R)-WHELK-O1-Kromasil, 2.12 x 25 cm, 5 ⁇ m; Mobile Phase A: Hex (0.5% 2 M NH3- MeOH), Mobile Phase B: EtOH; Flow rate: 20 mL/min; Gradient: 15% B to 15% B in 21 min; Wavelength: 220/254 nm; Retention Time 1: 14.77 min; Retention Time 2: 18.39 min.
  • Example 19 Compound 5 (2-[(3S)-3-[3,3-difluorocyclohexyl]-4,5-difluoro-3-methoxy-2- oxoindol-1-yl]acetamide isomer 1); Compound 6 (2-[(3S)-3-[3,3-difluorocyclohexyl]-4,5- difluoro-3-methoxy-2-oxoindol-1-yl]acetamide isomer 2); Compound 7 (2-[(3R)-3-[3,3- difluorocyclohexyl]-4,5-difluoro-3-methoxy-2-oxoindol-1-yl]acetamide isomer 3); Compound 8 (2-[(3R)-3-[3,3-difluorocyclohexyl]-4,5-difluoro-3-methoxy-2-oxoindol-1- Step a: [0339] To a stir
  • Step b [0340] To a stirred solution of 3-(1,4-dioxaspiro[4.5]decan-7-ylidene)-4,5-difluoro-1H-indol- 2-one (2.00 g, 6.51 mmol) in MeOH (5 mL) and THF (5 mL) was added Pd/C (0.350 g, 3.25 mmol). The solution was degassed under reduced pressure, purged with hydrogen three times and stirred at room temperature for 16 h under hydrogen (1.5 atm). The resulting mixture was filtered, and the filter cake washed with MeOH (3 x 20 mL). The filtrate was concentrated under reduced pressure.
  • Step c [0341] To a stirred solution of 4,5-difluoro-3-(1,4-dioxaspiro[4.5]decan-7-yl)indolin-2-one (1.50 g, 4.84 mmol) in MeOH (10 mL) was added bis(trifluoroacetoxy)iodobenzene (5.20 g, 12.1 mmol). The reaction was stirred at 60 °C for 16 h and concentrated under reduced pressure.
  • Step d [0342] To a stirred mixture of 4,5-difluoro-3-methoxy-3-(1,4-dioxaspiro[4.5]decan-7- yl)indolin-2-one (0.700 g, 2.06 mmol) and bromoacetamide (0.420 g, 3.09 mmol) in DMF (7 mL) were added K2CO3 (1.42 g, 10.3 mmol) and NaI (30.9 mg, 0.210 mmol). The reaction was stirred at 30 °C for 2 h, diluted with water (30 mL) and extracted with EA (4 x 50 mL).
  • Step e [0343] To a stirred solution of 2-(4,5-difluoro-3-methoxy-2-oxo-3-(1,4-dioxaspiro[4.5]decan- 7-yl)indolin-1-yl)acetamide (0.400 g, 1.01 mmol) in dioxane (3 mL) was added aq. HCl (1 mL, 3 M) dropwise.
  • Step f [0344] To a stirred solution of 2-[4,5-difluoro-3-methoxy-2-oxo-3-(3-oxocyclohexyl)indolin- 1-yl]acetamide (0.150 g, 0.430 mmol) in DCM (2 mL) was added DAST (0.210 g, 1.28 mmol) at room temperature under nitrogen.
  • Example 20 Compound 9 (2-((R)-4,5-difluoro-3-methoxy-2-oxo-3-(tetrahydro-2H- thiopyran-3-yl)indolin-1-yl)acetamide isomer 1); Compound 10 (2-((R)-4,5-difluoro-3- methoxy-2-oxo-3-(tetrahydro-2H-thiopyran-3-yl)indolin-1-yl)acetamide isomer 2); Compound 11 (2-((S)-4,5-difluoro-3-methoxy-2-oxo-3-(tetrahydro-2H-thiopyran-3-
  • the reaction was stirred at 60 °C for 2 h.
  • the cooled mixture was quenched with water (30 mL) filtered, and the filter cake washed with EA (2 x 5 mL).
  • the filtrate was extracted with EA (3 x 50 mL).
  • the combined organic layers were washed with brine (3 x 50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure.
  • Step b [0347] A mixture of 3-(3,4-dihydro-2H-thiopyran-5-yl)-4,5-difluoroindolin-2-one (0.600 g, 2.24 mmol) and NaBH 4 (0.170 g, 4.50 mmol) in THF (10 mL) was stirred at 70 °C for 2 h and concentrated under reduced pressure.
  • Step c [0348] A mixture of 4,5-difluoro-3-(tetrahydro-2H-thiopyran-3-yl)indolin-2-one (0.500 g, 1.86 mmol) and phenyl trimethylammonium tribromide (0.838 g, 2.23 mmol) in DCM (10 mL) was stirred at room temperature for 1 h, quenched with saturated aq. Na 2 SO 3 (aq.) (5 mL) and extracted with CH2Cl2 (2 x 30 mL). The combined organic layers were washed with brine (2 x 30 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure.
  • Step d [0349] A solution of 3-bromo-4,5-difluoro-3-(tetrahydro-2H-thiopyran-3-yl)indolin-2-one (0.400 g, 1.15 mmol) and NaOMe (0.310 g, 1.72 mmol, 30%) in MeOH (5 mL) was stirred at room temperature for 1 h, diluted with water (30 mL) and extracted with EA (3 x 30 mL). The combined organic layers were washed with brine (2 x 30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure.
  • Step e [0350] To a stirred solution of 4,5-difluoro-3-methoxy-3-(tetrahydro-2H-thiopyran-3- yl)indolin-2-one (40.0 mg, 0.134 mmol) and bromoacetamide (22.1 mg, 0.161 mmol) in DMF (1 mL) was added K 2 CO 3 (36.9 mg, 0.268 mmol). The mixture was stirred for 2 h at room temperature, diluted with water (20 mL) and extracted with EA (2 x 20 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure.
  • Example 21 Evaluation of K Ca 3.1 inhibitor activities
  • This assay was used to evaluate the disclosed compounds’ inhibition activities against the human KCa3.1 channel.
  • Cell culture [0357] CHO-K1 cells constitutively expressing human K Ca 3.1 were grown in DMEM containing 10% heat-inactivated FBS, 1 mM Sodium Pyruvate, 2 mM L-Glutamine, 1% Penicillin-Streptomycin and Zeocin (100 ⁇ g/mL). Cells used for electrophysiology were plated in plastic culture flasks and grown at 37°C in a 5% CO 2 -humidified tissue culture incubator per ChanPharm SOP. Stocks were maintained in cryogenic storage.
  • the cells were bathed in an extracellular solution containing 140 mM NaCl, 4 mM KCl, 2 mM CaCl2, 1 mM MgCl2, 5 mM Glucose, 10 mM HEPES; pH adjusted to 7.4 with NaOH; 295-305 mOsm.
  • Two intracellular solutions were used during current recordings.
  • the intracellular solution #1 contained 30 mM K-Gluconate, 80 mM KF, 20 mM KCl, 10 mM NaCl, 10 mM HEDTA, 10 mM HEPES; pH adjusted to 7.2 with KOH; 285-290 mOsm.
  • the intracellular solution #2 contained 30 mM K-Gluconate, 80 mM KF, 10 mM KCl, 2 mM CaCl 2 (to achieve 1 ⁇ M free Ca 2+ as calculated with the CABUF program), 10 mM NaCl, 2 mM NaATP, 10 mM HEDTA, 10 mM HEPES; pH adjusted to 7.2 with KOH; 285-290 mOsm.
  • Test compounds were dissolved in DMSO at 30 mM.
  • Compound stock solutions were freshly diluted with extracellular solution to concentrations of 0.3 nM, 1 nM, 3 nM, 10 nM, 30 nM, 100 nM, 300 nM, and 1 ⁇ M.
  • K Ca 3.1 was activated by exchanging the intracellular solution to a solution containing free Ca 2+ (intracellular solution #2, see above), and the K Ca 3.1 currents were elicited by a voltage protocol that held at -80 mV for 20 ms, stepped to -120 mV for 20 ms, ramped from -120 to +40 mV in 208 ms, and then stepped back to -120 mV for 20 ms. This pulse protocol was applied every 10 s. Leak currents were not subtracted during recordings. In the end of each recording session, Senicapoc (5 ⁇ M) was applied to achieve full block of K Ca 3.1 current.
  • Data analysis was performed using DataControl384 (Nanion's proprietary software). To determine IC50 values, AUC (measured during ramp between -120 and +40 mV) and peak values (measured at +40 mV), obtained in the presence of a given compound concentration, were normalized to control values in absence of compound as follows: where AUC/peak (full block) are values obtained in the presence of 5 ⁇ M Senicapoc. The concentration-response curves were generated by plotting the calculated responses vs the concentrations on a logarithmic scale.
  • CHO-K1 cells stably expressing hERG were grown in Ham’s F-12 Medium with Glutamine containing 10% heat-inactivated FBS, 1% Penicillin/Streptomycin, Hygromycin (100 ⁇ g/ml), and G418 (100 ⁇ g/ml).
  • Cells used for electrophysiology were plated in plastic culture flasks and grown at 37°C in a 5% CO 2 -humidified incubator per ChanPharm SOP. Stocks were maintained in cryogenic storage.
  • the cells were bathed in an extracellular solution containing 140 mM NaCl, 4 mM KCl, 2 mM CaCl2, 1 mM MgCl2, 5 mM Glucose, and 10 mM HEPES; pH adjusted to 7.4 with NaOH; 295-305 mOsm.
  • the internal solution contained 10 mM KCl, 110 mM KF, 10 mM NaCl, 10 mM EGTA, 10 mM HEPES; pH adjusted to 7.2 with KOH; 280-285 mOsm. All compounds were dissolved in DMSO at 30 mM. Compound stock solutions were freshly diluted with external solution to concentrations of 50 ⁇ M and 100 ⁇ M.
  • hERG currents were elicited by a voltage pulse pattern with fixed amplitudes (depolarization: +40mV amplitude, 300 ms duration; repolarization: -50mV, 300 ms duration) repeated at 3 s intervals from a holding potential of - 80 mV.
  • Data analysis [0365] Data acquisition and analysis were performed using DataControl384 (Nanion's proprietary software). To determine the (percentage) inhibition, the last single pulse in the pulse train (i.e., the repolarization step to -50 mV; tail current) at a given compound concentration was used.
  • Table 2 provides a summary of the inhibition activities (IC 50 ( ⁇ M) values) of certain exemplified compounds against K Ca 3.1 channel and hERG channel.

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Abstract

A compound of Formula I or a pharmaceutically acceptable salt thereof, is described, wherein the substituents are as defined herein. Pharmaceutical compositions comprising the same and method of using the same are also described.

Description

INDOLINONE COMPOUNDS AS KCa3.1 POTASSIUM CHANNEL BLOCKERS [0001] This patent disclosure contains material that is subject to copyright protection. The copyright owner has no objection to the facsimile reproduction of the patent document or the patent disclosure as it appears in the U.S. Patent and Trademark Office patent file or records, but otherwise reserves any and all copyright rights. CROSS-REFERENCE TO RELATED APPLICATIONS [0002] This application claims the benefit and priority of U.S. Provisional Application No. 63/643,075, filed May 6, 2024, the content of which is incorporated herein by reference in its entirety. INCORPORATION BY REFERENCE [0003] All documents cited herein are incorporated herein by reference in their entirety. FIELD OF THE INVENTION [0004] The invention relates generally to the field of pharmaceutical science. More particularly, the invention relates to compounds and compositions useful as pharmaceuticals as potassium channel blockers. BACKGROUND [0005] Calcium-activated potassium (KCa) channels are found on the plasma membrane of animal cells and control the permeability of potassium through the cell membrane. They have a key role in regulating calcium-signaling and membrane potential. There are eight KCa channels found in the human genome of which two were later found to be activated by sodium or chloride (Wulff, H. et al., 2010, Expert. Rev. Clin. Pharmacol.3, 3, 385-396). KCa channels include large-conductance potassium channels and small- and intermediate- conductance potassium channels (Kaczmarek, L.K. et al., 2017, Pharmacol. Rev.69:1-11). KCa3.1 is an intermediate-conductance and voltage-insensitive KCa channel (Wulff, H. et al., 2010, Expert Rev. Clin. Pharmacol.3, 3, 385-396). [0006] KCa3.1 (SK4, IK4, Gardos) is encoded by the KCNN4 gene that belongs to the KCNN family of calcium-activated potassium-selective ion (K+) channels located primarily on the plasma membrane of mammalian cells that functionally depend on a calcium-sensing calmodulin domain required for activation (Joiner, W.J. et al., 1997, Proc. Natl. Acad. Sci. U.S.A.94, 20, 11013-11018). There are in total 78 human genes encoding structurally related K+ channels that can subdivided into four groups: calcium-activated, voltage-gated, inwardly rectifying, and tandem pore domain channels. KCa3.1 is an ‘intermediate’ conductance (IK) channel, genetically related to KCNN1-3 that encode the SK1-SK3 K+ channels of either ‘big’ (SK1) or ‘small’ (SK2, SK3) conductance. [0007] KCa3.1 is highly expressed on the plasma membrane of several human primary cells where it functions to regulate calcium homeostasis and signaling by providing a driving force for cellular calcium entry. KCa3.1 expression is prevalent in immune cells, including T and B-lymphocytes (Khanna, R. et al., 1999, J. Biol. Chem.274, 21, P14838-14849; Fanger, C.M. et al., 2001, J. Biol. Chem.276, 15, P12249-12256; Zhang, S. et al., 2016, Int. Immunopharmacol.31, 266-271), macrophages (Zhu, Y.-R. et al., 2019, J. Mol. Med.97, 1219-1229), microglia, and mast cells (Duffy, S.M. et al., 2004, J. Allergy Clin. Immunol. 114, 1, 66-72; Duffy, S.M. et al., 2015, Cell Commun. Signal.13, 32), in red blood cells and platelets, in myofibroblasts and epithelial skin cells, in endothelial cells lining lung, kidney, small intestine, colon, pancreas, and bladder, and in skeletal and smooth muscle cells (Jensen, B.S. et al., 2001, Curr. Drug Targets 2, 4, 401-422). [0008] KCa3.1 is structurally characterized by the presence of four identical transmembrane domains that together form a functional, homo-tetrameric protein with a central K+ conducting pore (Lee, C.-H. et al., 2018, Science, 360, 6388, 508-513). Each subunit has six transmembrane helices, two pore-contributing surrounded by four peripheral helices comprising a voltage-sensor-like domain. The transmembrane protein is coupled intracellularly to four calmodulin (Cam) protein domains, one per KCa3.1 subunit. KCa3.1 is activated at elevated intracellular calcium concentration where all four Cam domains become calcium-bound, leading to a tight KCa3.1-Cam coupling and a protein conformational change that results in complete opening of the ion conducting pore (Lee, C.-H. et al., 2018, Science, 360, 6388, 508-513). [0009] The regulatory role of KCa3.1 in many immune cells has implicated the channel in autoimmune and inflammatory disorders. Mouse model studies of multiple sclerosis (MS) using the experimental autoimmune encephalomyelitis (EAE) model, suggest that KCa3.1 is a viable MS target (Reich, E.-P. et al., 2005, Eur. J. Immunol.35, 4, 1027-1036), reflecting the general potential of targeting KCa3.1 in T cell-mediated diseases (Lam, J. et al., 2011, Drug Dev. Res.72, 7, 573-584; Jenzen, B.S. et al., 2005, Expert Opin. Ther. Targets 6, 6, 623-636; Vianna-Jorge, R. et al., 2012, BioDrugs 18, 329-341; Mei, Y. et al., 2019, Inflamm. Bowel Dis.25, 10, e115-e116; Di, L. et al., 2009, Proc. Natl. Acad. Sci. U.S.A.107, 4, 1541-1546; Ohya, S. et al., 2021, J. Pharmacol. Exp. Ther.377, 1, 75-85). Abnormal activation of KCa3.1 has been observed in peripheral blood and fibroblasts in the synovium of rheumatoid arthritis (RA) patients (Lin, Y. et al.2022, Front. Immunol.13, 997621; Friebel, K. et al., 2014, J. Cell Physiol.230, 7, 1677-1688). Mouse KCa3.1 knock-out (KO) models have shown that KCa3.1 deletion reduced synovial inflammation and histopathological destruction and it also lowered inflammatory mediators in the murine cartilage, reducing its deterioration and bone erosion in arthritic mice (Kang, H. et al., 2014, Cell Rep.8, 4, P1210-1224). In common gastrointestinal inflammatory disorders (i.e., inflammatory bowel diseases) including Crohn’s disease and ulcerative colitis, multiple studies in preclinical species have demonstrated that selective KCa3.1 inhibition improved clinical symptoms in these indications (Di, L. et al., 2009, Proc. Natl. Acad. Sci. U.S.A.107, 4, 1541-1546; Strøbæk, D. et al., 2012, Br. J. Pharmacol.168, 2, 432-444; Reich, E.-P. et al., 2005, Eur. J. Immunol.35, 4, 1027- 1036). KCa3.1 knock-out (KO) and induced (transgenic) KCa3.1 overexpression mouse models have suggested KCa3.1 as target in eczematous dermatitis with multiple clinical symptoms such as epidermal hyperplasia, hyperkeratosis, epidermal edema, and itch being improved upon treatment with a KCa3.1 selective inhibitor (Lozano-Gerona, J. et al., 2020, PLoS One 15, 3, e0222619). [0010] KCa3.1 is implicated in sickle cell anemia (SCD) and clinical studies with a KCa3.1 inhibitor suggested improvements in hematological parameters (Gárdos, G., 1958, Biochim. Biophys. Acta 30, 3, 653-654; Jensen, B.S. et al., 2001, Curr. Drug Targets 2, 4, 401-422; Ataga, K.I. et al., 2008, Blood 111, 8, 3991-3997; Rapetti-Mauss, R. et al., 2016, Haematologica 101, 11, e431-e435; Ataga, K.I. et al., 2011, Br. J. Haematol.153, 1, 92-104). KCa3.1 channelopathy, due to gain of function mutations in the KCa3.1 pore that increase channel activity (Andolfo, I. et al., 2015, Am. J. Hematol.90, 10, 921-926; Fermo, E. et al., 2017, Sci. Rep.7, 1744; Rivera, A. et al., 2019, Am. J. Physio. Cell Physio.317, 2, C287- C302; Rapetti-Mauss, R. et al., 2015, Blood 126, 11, 1273-1280), causes a KCa3.1-specific form of autosomal dominant congenital hemolytic anemia known as hereditary xerocytosis (or stomatocytosis) that potentially could be treated by KCa3.1-specific inhibition. [0011] KCa3.1 is implicated in coronary artery disease and elevated expression levels of KCa3.1 have been observed in patients with atherosclerosis, and KCa3.1 KO mouse models showed reduced clinical symptoms (Toyama, K. et al., 2008, J. Clin. Invest.118, 9, 3025- 3037). KCa3.1 inhibition reduced restenosis in a swine model of postangioplasty restenosis (Tharp, D.L. et al., 2008, Arterioscler. Thromb. Vasc. Biol.28, 1084-1089), and selective inhibition of KCa3.1 has also been proposed to prevent allograft vasculopathy (Chen, Y.-J. et al., 2013, PLoS One 8, 11, e81006), a common complication upon solid organ transplantation. [0012] Preclinical studies have shown that KCa3.1 expression on airway smooth muscle cells and myofibroblasts is increased by allergic and inflammatory mediators and that KCa3.1 also plays a role in allergen-induced mast cell degranulation. KCa3.1 inhibition relaxes pulmonary arteries and bronchi and prevents or reduces airway inflammation. In a clinical allergen challenge study with asthmatic patients, treatment with a KCa3.1 inhibitor was found to reduce airway hyperresponsiveness, bronchoconstriction, and airway inflammation (Wulff, H. et al., 2014, Expert Rev. Clin. Pharmacol.3, 3, 385-396; Van Der Velden, J. et al.2013, PLoS One 8, 6, e66886; Girodet, P.-O. et al., 2012, Am. J. Respir. Cell Mol. Biol.48, 2, 212- 219; Yu, Z.-H. et al., 2012, Am. J. Respir. Cell Mol. Biol.48, 6, 685-693; Orfali, R. et al., 2023, Biomedicines, 11, 7, 1780) [0013] KCa3.1 has been implicated in numerous fibrotic diseases in organs such as kidney (renal fibrosis and diabetic nephropathy) (Grgic, I. et al., 2009, Proc. Natl. Acad. Sci. U.S.A. 106,34, 14518-14523; Huang, C. et al., 2013, Diabetes, 62, 8, 2923-2934; Huang, C. et al., 2018, PLoS One 13, 2, e0192800), lung (IPF) (Perera, U.E. et al., 2021, Can. Respir. J.2021, 6683195; Organ, L. et al., 2016, Am. J. Respir. Cell. Mol. Biol.56, 4, 539-550; Roach, K.M. et al., 2013, PLoS One 8, 12, e85244), heart (cardiac fibrosis), and eye injury-related corneal fibrosis (e.g., KCa3.1 KO mice had reduced corneal fibrosis and lowered expression of pro- fibrotic marker genes, and KCa3.1 inhibition also attenuated corneal fibrosis in vitro) (Anumanthan, G. et al., 2018, PLOS One 13, 3, e0192145). In a rat in vivo model of liver fibrosis, treatment with a KCa3.1 inhibitor mitigated steatosis and fibrosis (Paka, L. et al., 2017, World J. Gastroenterol.23, 23, 4181-4190). [0014] Due to its regulation of cell proliferation, KCa3.1 drives proliferation in many cancers (Todesca, L.M. et al., 2021, Cell Physiol. Biochem.55, S3, 131-144). Increased KCa3.1 expression has been found in brain (Younes, S. et al., 2023, Membranes 13, 4, 434), lung (Todesca, L.M. et al., 2024, Cell Death Discov.10, 2), bile duct (Song, P. et al., 2017, J. Cancer 8, 9, 1568-1578), colon (Lai, W. et al., 2011, Oncol. Rep.26, 4, 909-917), and endometrial cancer (Zhang, Y. et al., 2019, Onco Targets Ther.12, 10287-10297). KCa3.1 inhibitors have proven efficacious in xenograft models of these indications. Selective inhibition of KCa3.1 in glioblastoma in patients that develop resistance to radiation therapy may help overcome such resistance, which could potentially help reduce tumor growth (Stransky, N. et al., 2023, Sci. Rep.13, 20604). [0015] KCa3.1-mediated activation of microglia and astrocytes infiltrating peripheral or central nerve compartments has been implicated in development of neuroinflammation in acute ischemic stroke (Chen, J.-Y. et al., 2016, J. Cereb. Blood Flow Metab.36, 12, 2146- 2161; Yi, M. et al., 2017, J. Neuroinflamm.14, 1, 203), in traumatic brain injury, in spinal cord and peripheral nerve injuries, and in preclinical models of these conditions. KCa3.1inhibition offers protective effects against nerve damage. KCa3.1 inhibition and KO models of Alzheimer’s, Parkinson’s, and amyotrophic lateral sclerosis (ALS) suggest targeting KCa3.1 generally may reduce micro- and astrogliosis-induced neuronal impairments. [0016] Thus, there remains a need for development of novel KCa3.1 inhibitors as pharmaceutical agents for the treatment of a number of conditions, disorders, and diseases. SUMMARY OF THE INVENTION [0017] In one aspect, a compound useful as a KCa3.1 inhibitor having a structure of Formula I ( ) is described, where the various substituents are defined herein. The compounds of Formula I described herein can block or inhibit KCa3.1 and be used in the treatment of a variety of conditions. Methods for synthesizing these compounds are also described herein. Pharmaceutical compositions and methods of using these compositions described herein are useful for treating conditions in vitro and in vivo. Such compounds, pharmaceutical compositions, and methods of treatment have a number of clinical applications, including as pharmaceutically active agents and methods for cancer, sickle cell anemia, a cardiovascular disease, a respiratory disease, a fibrotic disease, an autoimmune disease, a central nervous system (CNS) disorder, a neurodegenerative disease, an inflammatory disorder, or a combination thereof. [0018] In one aspect, a compound of Formula I or a pharmaceutically acceptable salt thereof, or a tautomer thereof is described, wherein R1 is alkyl, cycloalkyl, halogenated alkyl, halogenated cycloalkyl, bicycloalkyl, halogenated bicycloalkyl, saturated heterocycle, partially saturated heterocycle, aryl, heteroaryl, -C1-4alkyl-cycloalkyl, -C1-4alkyl-saturated heterocycle, -C1-4alkyl-partially saturated heterocycle, or cycloalkenyl, each of which optionally substituted by 1-5 substituents each independently selected from the group consisting of D, halogen, alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, alkenyl, and alkynyl where valence permits; R2 is halogen, alkyl, alkynyl, halogenated alkyl, halogenated alkynyl, CN, ORa, SRa, - C1-4alkyl-ORa, -C1-4alkyl-SRa, -O-C1-4alkyl-ORa, -O-C1-4alkyl-SRa, -O-C1-4alkyl-NRaRb, -S- C1-4alkyl-ORa, -S-C1-4alkyl-SRa, or -S-C1-4alkyl-NRaRb; R3 is –(CR8R9)mR10; R4 is H, D, halogen, CN, alkyl, halogenated alkyl, cycloalkyl, halogenated cycloalkyl, ORa, SRa, -C1-4alkyl-ORa, or -C1-4alkyl-SRa; R5 is H, D, halogen, CN, alkyl, halogenated alkyl, cycloalkyl, halogenated cycloalkyl, ORa, SRa, -C1-4alkyl-ORa, or -C1-4alkyl-SRa; R6 is H, D, halogen, CN, alkyl, halogenated alkyl, cycloalkyl, halogenated cycloalkyl, ORa, SRa, -C1-4alkyl-ORa, or -C1-4alkyl-SRa; R7 is H, D, halogen, CN, alkyl, halogenated alkyl, cycloalkyl, halogenated cycloalkyl, ORa, SRa, -C1-4alkyl-ORa, or -C1-4alkyl-SRa; m is 1 or 2; each occurrence of R8 is independently H, D, OH, ORa, or alkyl; each occurrence of R9 is independently H, D, OH, ORa, or alkyl; R10 is H, D, CN, alkyl, saturated heterocycle, aryl, heteroaryl, -CORa, -COORa, - CONRaRb, -ORa, -SORa, or -SO2Ra; each occurrence of Ra and Rb is independently selected from the group consisting of H, D, alkyl, cycloalkyl, halogenated alkyl, heteroalkyl, halogenated heteroalkyl, halogenated cycloalkyl, saturated heterocycle comprising 1-3 heteroatoms each selected from the group consisting of N, O, and S, aryl, and heteroaryl; or alternatively, Ra and Rb, together with the carbon or nitrogen atom that they are connected to, form a cycloalkyl or saturated heterocycle comprising the nitrogen atom and 0-3 additional heteroatoms each selected from the group consisting of N, O, and S; the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, saturated heterocycle, partially saturated heterocycle, aryl, and heteroaryl in R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, Ra, or Rb, where applicable, are each optionally substituted by 1-4 substituents each independently selected from the group consisting of alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, halogen, CN, ORx, -(CH2)1-2ORx, N(Rx)2, -(CH2)1-2N(Rx)2, (C=O)Rx, (C=O)N(Rx)2, NRx(C=O)Rx, and oxo where valence permits; and each occurrence of Rx is independently H, D, alkyl, halogenated alkyl, or heterocycle optionally substituted by alkyl, halogen, or OH; or alternatively, the two Rx groups together with the nitrogen atom that they are connected to, form a heterocycle optionally substituted by alkyl and comprising the nitrogen atom and 0-3 additional heteroatoms each selected from the group consisting of N, O, and S. [0019] In any one of the embodiments described herein, R1 is phenyl that is optionally substituted by 1-5 substituents each independently selected from the group consisting of D, halogen, alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, alkenyl, and alkynyl. [0020] In any one of the embodiments described herein, R1 is phenyl that is optionally substituted by 1-5 substituents each independently selected from the group consisting of D, alkyl, halogen, and halogenated alkyl. [0021] In any one of the embodiments described herein, R1 is phenyl that is optionally substituted by 1-5 substituents each independently selected from the group consisting of D, CH3, CH2CH3, F, Cl, Br, CH2F, and CF3. [0022] In any one of the embodiments described herein, R1 is cycloalkyl, bicycloalkyl, or - C1-4alkyl-cycloalkyl, each of which optionally substituted by 1-5 substituents each independently selected from the group consisting of D, alkyl, halogen, and halogenated alkyl where valence permits. [0023] In any one of the embodiments described herein, R1 is cycloalkyl, bicycloalkyl, or -C1- 4alkyl-cycloalkyl, each of which optionally substituted by 1-5 substituents each independently selected from the group consisting of D, CH3, CH2CH3, F, Cl, Br, CH2F, and CF3 where valence permits. [0024] In any one of the embodiments described herein, R1 is saturated heterocycle that is optionally substituted by 1-5 substituents each independently selected from the group consisting of D, alkyl, halogen, and halogenated alkyl where valence permits. [0025] In any one of the embodiments described herein, R1 is saturated heterocycle that is optionally substituted by 1-5 substituents each independently selected from the group consisting of D, CH3, CH2CH3, F, Cl, Br, CH2F, and CF3 where valence permits. [0026] In any one of the embodiments described herein, R1 is alkyl that is optionally substituted by 1-5 substituents each independently selected from the group consisting of D and halogen where valence permits. [0027] In any one of the embodiments described herein, R1 is halogenated alkyl, halogenated cycloalkyl, halogenated bicycloalkyl, partially saturated heterocycle, heteroaryl or cycloalkenyl, each of which optionally substituted by 1-5 substituents each independently selected from the group consisting of D, halogen, alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, alkenyl, and alkynyl where valence permits. [0028] In any one of the embodiments described herein, R1 is -C1-4alkyl-saturated heterocycle, or C1-4alkyl-partially saturated heterocycle, each of which optionally substituted by 1-5 substituents each independently selected from the group consisting of D, halogen, alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, alkenyl, and alkynyl where valence permits. [0029] In any one of the embodiments described herein, R1 is selected from the group consisting [0030] In any one of the embodiments described herein, the compound has the structure of Formula IIa: wherein R11 is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogenated cycloalkyl, or halogenated alkyl; R12 is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogenated cycloalkyl, or halogenated alkyl; R13 is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogenated cycloalkyl, or halogenated alkyl; R14 is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogenated cycloalkyl, or halogenated alkyl; and R15 is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogenated cycloalkyl, or halogenated alkyl. [0031] In any one of the embodiments described herein, R11 is H, D, F, Cl, Br, I, alkyl, or halogenated alkyl; R12 is H, D, F, Cl, Br, I, alkyl, or halogenated alkyl; R13 is H, D, F, Cl, Br, I, alkyl, or halogenated alkyl; R14 is H, D, F, Cl, Br, I, alkyl, or halogenated alkyl; and R15 is H, D, F, Cl, Br, I, alkyl, or halogenated alkyl. [0032] In any one of the embodiments described herein, the compound has the structure of Formula IIb:
wherein is alkyl, cycloalkyl, -CH2-cycloalkyl, cycloalkenyl, bicycloalkyl, heteroaryl, or saturated heterocycle, each of which optionally substituted by 1-5 substituents each independently selected from the group consisting of D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogenated cycloalkyl, and halogenated alkyl where valence permits. [0033] In any one of the embodiments described herein, is optionally substituted by 1-5 substituents each independently selected from the group consisting of D, alkyl, halogen, and halogenated alkyl where valence permits. [0034] In any one of the embodiments described herein, is pyridine, pyrimidine, furan, or thiophene, each of which optionally substituted with halogen or alkyl. [0035] In any one of the embodiments described herein, is thiane or pyrane, each of which optionally substituted with halogen or alkyl. [0036] In any one of the embodiments described herein, R2 is CN, OH, halogen, halogenated alkyl, alkyl optionally substituted with alkoxy or OH, or alkoxy optionally substituted with halogen, alkyl, alkoxy, or OH. [0037] In any one of the embodiments described herein, R2 is selected from the group consisting of CN, F, Cl, Br, I, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CF3, CH2F, CHF2, CH2Cl, CH2CF3, CHFCH3, CHFCH2F, CF2CH3, CHClCH3, CCl2CH3, CHBrCH3, CH2CH2CF3, and CHClCHClCH3. [0038] In any one of the embodiments described herein, R2 is CN, ORa, SRa, -O-C1-4alkyl- ORa, -O-C1-4alkyl-SRa, -O-C1-4alkyl-NRaRb, -S-C1-4alkyl-ORa, -S-C1-4alkyl-SRa, or -S-C1- 4alkyl-NRaRb. [0039] In any one of the embodiments described herein, R2 is CN, ORa, SRa, or -O-C1-4alkyl- ORa. [0040] In any one of the embodiments described herein, R2 is -C1-4alkyl-ORa or -C1-4alkyl- SRa. [0041] In any one of the embodiments described herein, R2 is selected from the group . [0042] In any one of the embodiments described herein, the compound has the structure of Formula III: wherein X is O or S; and R16 is C1-4alkyl that is optionally substituted with halogen, ORa, SRa, or NRaRb. [0043] In any one of the embodiments described herein, m is 2. [0044] In any one of the embodiments described herein, m is 1. [0045] In any one of the embodiments described herein, each occurrence of R8 is independently H, D, OH, or alkyl. [0046] In any one of the embodiments described herein, each occurrence of R8 is independently H, D, OH, CH3, or CH2CH3. [0047] In any one of the embodiments described herein, each occurrence of R8 is independently H, D, or OH. [0048] In any one of the embodiments described herein, each occurrence of R9 is independently H, D, OH, or alkyl. [0049] In any one of the embodiments described herein, each occurrence of R9 is independently H, D, OH, CH3, or CH2CH3. [0050] In any one of the embodiments described herein, each occurrence of R9 is H, D, or OH. [0051] In any one of the embodiments described herein, the structural moiety –(CR8R9)m– is –CH2–, –CH2CH2–, –CHOH–, or –CH2CHOH–. [0052] In any one of the embodiments described herein, R10 is alkyl, -COORa, -CORa, - CONRaRb, -ORa, -SORa, or -SO2Ra. [0053] In any one of the embodiments described herein, R10 is -CONRaRb. [0054] In any one of the embodiments described herein, R10 is saturated heterocycle, or heteroaryl, wherein R10 is optionally substituted with halogen or OH. [0055] In any one of the embodiments described herein, R10 is oxetane, pyrazole, or oxadiazole, each optionally substituted by halogen or alkyl. [0056] In any one of the embodiments described herein, R10 is H, D, CN, or aryl. [0057] In any one of the embodiments described herein, R3 is (CH2)1-2CONRaRb, CH2C(=O)Ra, CH2CH(OH)Ra, CH2CH(OH)CH2OH, CH2SORa, CH2SO2Ra, (CH2)1-2- heterocycle, or (CH2)1-2-heteroaryl. [0058] In any one of the embodiments described herein, the compound has a structure of Formula IV: . [0059] In any one of the embodiments described herein, the compound has the structure of Formula V: wherein X is O or S; and R16 is C1-4alkyl that is optionally substituted with halogen, ORa, SRa, or NRaRb. [0060] In any one of the embodiments described herein, R1 is phenyl that is optionally substituted by 1-5 substituents each independently selected from the group consisting of D, halogen, alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, alkenyl, and alkynyl. [0061] In any one of the embodiments described herein, R1 is optionally substituted by 1-5 substituents each independently selected from the group consisting of D, F, Cl, Br, I, alkyl, and halogenated alkyl where valence permits. [0062] In any one of the embodiments described herein, R1 is alkyl, cycloalkyl, -CH2- cycloalkyl, cycloalkenyl, bicycloalkyl, heteroaryl, or saturated heterocycle, each of which optionally substituted by 1-5 substituents each independently selected from the group consisting of D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogenated cycloalkyl, and halogenated alkyl. [0063] In any one of the embodiments described herein, R1 is optionally substituted by 1-5 substituents each independently selected from the group consisting of D, alkyl, halogen, and halogenated alkyl where valence permits. [0064] In any one of the embodiments described herein, R1 is pyridine, pyrimidine, furan, or thiophene, each of which optionally substituted with halogen or alkyl. [0065] In any one of the embodiments described herein, R1 is thiane or pyrane, each of which optionally substituted with halogen or alkyl. [0066] In any one of the embodiments described herein, at least one of R4, R5, R6, and R7 is not H or D. [0067] In any one of the embodiments described herein, at least two of R4, R5, R6, and R7 are not H or D. [0068] In any one of the embodiments described herein, R4 is H, D, halogen, CN, alkyl, halogenated alkyl, ORa, or SRa. [0069] In any one of the embodiments described herein, R4 is H, D, halogen, CN, alkyl, or ORa. [0070] In any one of the embodiments described herein, R4 is H, D, F, Cl, Br, I, CN, OH, CH3, CH2CH3, OCH3, or CF3. [0071] In any one of the embodiments described herein, R4 is cycloalkyl, halogenated cycloalkyl, -C1-4alkyl-ORa, or -C1-4alkyl-SRa. [0072] In any one of the embodiments described herein, R5 is H, D, halogen, CN, alkyl, halogenated alkyl, ORa, or SRa. [0073] In any one of the embodiments described herein, R5 is H, D, halogen, CN, alkyl, or ORa. [0074] In any one of the embodiments described herein, R5 is H, D, F, Cl, Br, I, CN, OH, CH3, CH2CH3, OCH3, or CF3. [0075] In any one of the embodiments described herein, R5 is cycloalkyl, halogenated cycloalkyl, -C1-4alkyl-ORa, or -C1-4alkyl-SRa. [0076] In any one of the embodiments described herein, R6 is H, D, halogen, CN, alkyl, halogenated alkyl, ORa, or SRa. [0077] In any one of the embodiments described herein, R6 is H, D, halogen, CN, alkyl, or ORa. [0078] In any one of the embodiments described herein, R6 is H, D, F, Cl, Br, I, CN, OH, CH3, CH2CH3, OCH3, or CF3. [0079] In any one of the embodiments described herein, R6 is cycloalkyl, halogenated cycloalkyl, -C1-4alkyl-ORa, or -C1-4alkyl-SRa. [0080] In any one of the embodiments described herein, R7 is H, D, halogen, CN, alkyl, halogenated alkyl, ORa, or SRa. [0081] In any one of the embodiments described herein, R7 is H, D, halogen, CN, alkyl, or ORa. [0082] In any one of the embodiments described herein, R7 is H, D, F, Cl, Br, I, CN, OH, CH3, CH2CH3, OCH3, or CF3. [0083] In any one of the embodiments described herein, R7 is cycloalkyl, halogenated cycloalkyl, -C1-4alkyl-ORa, or -C1-4alkyl-SRa. [0084] In any one of the embodiments described herein, R1 is alkyl, cycloalkyl, -C1-4alkyl- cycloalkyl, bicycloalkyl, saturated heterocycle, aryl, heteroaryl, or cycloalkenyl; wherein R1 is optionally substituted by 1-5 substituents each independently selected from the group consisting of D, halogen, alkyl, and halogenated alkyl where valence permits; R2 is CN, alkyl, ORa, SRa, -C1-4alkyl-ORa, or -O-C1-4alkyl-ORa; R3 is –(CH2)mCONRaRb, –(CH2)mC(=O)Ra, –CH2CH(OH)R10, –CH2CH(OH)CH2OH, –CH2SORa, –CH2SO2Ra, –(CH2)m-heterocycle, or –(CH2)m-heteroaryl; R4 is H, D, halogen, CN, or alkyl; R5 is H, D, halogen, alkyl, or ORa; R6 is H, D, or halogen; R7 is H, D, or halogen; m is 1 or 2; and R10 is H, D, or alkyl. [0085] In any one of the embodiments described herein, R1 is cycloalkyl or phenyl; wherein the cycloalkyl or phenyl in R1 is optionally substituted by 1-5 substituents each of which is independently D or halogen where valence permits; X is O; R16 is C1-4alkyl that is optionally substituted with halogen, ORa, SRa, or NRaRb; R4 is H, D, or halogen; R5 is H, D, halogen, or ORa; R6 is H, D, or halogen; R7 is H, D, or halogen; and Ra and Rb are each independently H or Me. [0086] In any one of the embodiments described herein, at least one occurrence of Ra or Rb is independently H, D, alkyl, cycloalkyl, saturated heterocycle, aryl, or heteroaryl. [0087] In any one of the embodiments described herein, each occurrence of Ra or Rb is independently H, D, alkyl, or halogenated alkyl. [0088] In any one of the embodiments described herein, at least one occurrence of Ra or Rb is independently H, D, Me, Et, Pr, CH2CH2OH, phenyl, or a heterocycle selected from the heterocycle is optionally substituted by alkyl, OH, oxo, or (C=O)C1-4alkyl where valence permits. [0089] In any one of the embodiments described herein, at least one occurrence of Ra or Rb is H, Me, phenyl, [0090] In any one of the embodiments described herein, Ra and Rb, together with the nitrogen atom that they are connected to, form an optionally substituted heterocycle comprising the nitrogen atom and 0-3 additional heteroatoms each selected from the group consisting of N, O, and S. [0091] In any one of the embodiments described herein, each occurrence of Rx is independently H, alkyl, or heterocycle optionally substituted by alkyl, halogen, or OH. [0092] In any one of the embodiments described herein, each occurrence of Rx is independently H or alkyl. [0093] In any one of the embodiments described herein, each occurrence of Rx is independently H or Me. [0094] In any one of the embodiments described herein, the compound is selected from the group consisting of compounds 1-74 in Table 2. [0095] In any one of the embodiments described herein, the compound i
[0096] In any one of the embodiments described herein, the compound is not in a salt form or a tautomer form. [0097] In another aspect, a pharmaceutical composition is described, comprising at least one compound according to any one of the embodiments described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent. [0098] In yet another aspect, a method of treating a condition in a mammalian species in need thereof is described, comprising administering to the mammalian species a therapeutically effective amount of at least one compound according to any one of embodiments described herein, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, wherein the condition is selected from the group consisting of cancer, sickle cell anemia, a cardiovascular disease, a respiratory disease, a fibrotic disease, an autoimmune disease, a central nervous system (CNS) disorder, a neurodegenerative disease, and an inflammatory disorder. [0099] In any one of the embodiments described herein, the respiratory disease is an inflammatory airway disease, airway hyperresponsiveness, an idiopathic lung disease, chronic obstructive pulmonary disease, asthma, allergy chronic asthma, tracheobronchial or diaphragmatic dysfunction, cough, or chronic cough. [0100] In any one of the embodiments described herein, the autoimmune disease is rheumatoid arthritis or multiple sclerosis (MS). [0101] In any one of the embodiments described herein, the CNS disorder is acute ischemic stroke, traumatic brain injury, peripheral nerve injury, glioblastoma multiforme, or spinal cord injury. [0102] In any one of the embodiments described herein, the fibrotic disease is liver fibrosis, kidney fibrosis, cardiac fibrosis, eye injury-related corneal fibrosis, or lung fibrosis. [0103] In any one of the embodiments described herein, the neurodegenerative disease is Alzheimer’s disease, Parkinson’s disease, or amyotrophic lateral sclerosis (ALS). [0104] In any one of the embodiments described herein, the mammalian species is human. [0105] In yet another aspect, a method of inhibiting calcium-activated potassium channel KCa3.1 in a mammalian species in need thereof is described, comprising administering to the mammalian species a therapeutically effective amount of at least one compound according to any one of embodiments described herein, or a pharmaceutically acceptable salt thereof. [0106] Any one of the embodiments disclosed herein may be properly combined with any other embodiment disclosed herein. The combination of any one of the embodiments disclosed herein with any other embodiments disclosed herein is expressly contemplated. Specifically, the selection of one or more embodiments for one substituent group can be properly combined with the selection of one or more particular embodiments for any other substituent group. Such combination can be made in any one or more embodiments of the application described herein or any formula described herein. DETAILED DESCRIPTION OF THE INVENTION Definitions [0107] The following are definitions of terms used in the present specification. The initial definition provided for a group or term herein applies to that group or term throughout the present specification individually or as part of another group, unless otherwise indicated. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. It is to be understood that the terminology used herein is for the purpose of describing certain embodiments only and is not intended to be limiting. [0108] The terms “alkyl” and “alk” refer to a straight or branched chain alkane (hydrocarbon) radical containing from 1 to 12 carbon atoms, preferably 1 to 6 carbon atoms. Exemplary “alkyl” groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, and the like. The term “(C1-Cx)alkyl” or “C1-xalkyl” refers to a straight or branched chain alkane (hydrocarbon) radical containing from 1 to x carbon atoms. For example, the term “(C1-C4)alkyl” or “C1-4alkyl” refers to a straight or branched chain alkane (hydrocarbon) radical containing from 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, and isobutyl. “Substituted alkyl” refers to an alkyl group substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halo substituents forming, in the latter case, groups such as CF3 or an alkyl group bearing CCl3), cyano, nitro, oxo (i.e., =O), CF3, OCF3, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, ORa, SRa, S(=O)Re, S(=O)2Re, P(=O)2Re, S(=O)2ORe, P(=O)2ORe, NRbRc, NRbS(=O)2Re, NRbP(=O)2Re, S(=O)2NRbRc, P(=O)2NRbRc, C(=O)ORd, C(=O)Ra, C(=O)NRbRc, OC(=O)Ra, OC(=O)NRbRc, NRbC(=O)ORe, NRdC(=O)NRbRc, NRdS(=O)2NRbRc, NRdP(=O)2NRbRc, NRbC(=O)Ra, or NRbP(=O)2Re, wherein each occurrence of Ra is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; each occurrence of Rb, Rc and Rd is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or said Rb and Rc together with the N to which they are bonded optionally form a heterocycle, and each occurrence of Re is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. In some embodiments, groups such as alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkenyl, heterocycle, and aryl can themselves be optionally substituted. [0109] The term “heteroalkyl” refers to an alkyl substituent as defined above wherein at least one carbon atom has been replaced by a heteroatom such as O, S, or N. For example, a heteroalkyl can be an alkyl group where one or more of its -CH2- groups are replaced by -O-, -S-, or -NRz-; and/or can be an alkyl group where one or more of its -CH- groups are replaced by -N-; wherein each occurrence of Rz is hydrogen, alkyl, cycloalkyl, heterocycle, or aryl. In some embodiments, heteroalkyl can be optionally substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halo substituents forming, in the latter case, groups such as CF3 or an alkyl group bearing CCl3), cyano, nitro, oxo (i.e., =O), CF3, OCF3, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, ORa, SRa, S(=O)Re, S(=O)2Re, P(=O)2Re, S(=O)2ORe, P(=O)2ORe, NRbRc, NRbS(=O)2Re, NRbP(=O)2Re, S(=O)2NRbRc, P(=O)2NRbRc, C(=O)ORd, C(=O)Ra, C(=O)NRbRc, OC(=O)Ra, OC(=O)NRbRc, NRbC(=O)ORe, NRdC(=O)NRbRc, NRdS(=O)2NRbRc, NRdP(=O)2NRbRc, NRbC(=O)Ra, or NRbP(=O)2Re, wherein each occurrence of Ra is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; each occurrence of Rb, Rc, and Rd is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or said Rb and Rc together with the N to which they are bonded optionally form a heterocycle, and each occurrence of Re is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. In some embodiments, groups such as alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkenyl, heterocycle, and aryl can themselves be optionally substituted. [0110] The term “alkenyl” refers to a straight or branched chain hydrocarbon radical containing from 2 to 12 carbon atoms and at least one carbon-carbon double bond. Exemplary such groups include ethenyl or allyl. The term “C2-Cx alkenyl” or “C2-xalkenyl” refers to a straight or branched chain hydrocarbon radical containing from 2 to x carbon atoms and at least one carbon-carbon double bond. For example, the term “C2-C6alkenyl” or “C2-6alkenyl” refers to a straight or branched chain hydrocarbon radical containing from 2 to 6 carbon atoms and at least one carbon-carbon double bond, such as ethylenyl, propenyl, 2- propenyl, (E)-but-2-enyl, (Z)-but-2-enyl, 2-methy(E)-but-2-enyl, 2-methy(Z)-but-2-enyl, 2,3-dimethy-but-2-enyl, (Z)-pent-2-enyl, (E)-pent-1-enyl, (Z)-hex-1-enyl, (E)-pent-2-enyl, (Z)-hex-2-enyl, (E)-hex-2-enyl, (Z)-hex-1-enyl, (E)-hex-1-enyl, (Z)-hex-3-enyl, (E)-hex-3- enyl, and (E)-hex-1,3-dienyl. “Substituted alkenyl” refers to an alkenyl group substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen, alkyl, halogenated alkyl (i.e., an alkyl group bearing a single halogen substituent or multiple halogen substituents such as CF3 or CCl3), cyano, nitro, oxo (i.e., =O), CF3, OCF3, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, ORa, SRa, S(=O)Re, S(=O)2Re, P(=O)2Re, S(=O)2ORe, P(=O)2ORe, NRbRc, NRbS(=O)2Re, NRbP(=O)2Re, S(=O)2NRbRc, P(=O)2NRbRc, C(=O)ORd, C(=O)Ra, C(=O)NRbRc, OC(=O)Ra, OC(=O)NRbRc, NRbC(=O)ORe, NRdC(=O)NRbRc, NRdS(=O)2NRbRc, NRdP(=O)2NRbRc, NRbC(=O)Ra, or NRbP(=O)2Re, wherein each occurrence of Ra is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; each occurrence of Rb, Rc and Rd is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or said Rb and Rc together with the N to which they are bonded optionally form a heterocycle; and each occurrence of Re is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. The exemplary substituents can themselves be optionally substituted. [0111] The term “alkynyl” refers to a straight or branched chain hydrocarbon radical containing from 2 to 12 carbon atoms and at least one carbon to carbon triple bond. Exemplary groups include ethynyl. The term “C2-Cxalkynyl” or “C2-x alkynyl” refers to a straight or branched chain hydrocarbon radical containing from 2 to x carbon atoms and at least one carbon-carbon triple bond. For example, the term “C2-C6 alkynyl” or “C2-6alknyl” refers to a straight or branched chain hydrocarbon radical containing from 2 to 6 carbon atoms and at least one carbon-carbon triple bond, such as ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, pent-1-ynyl, pent-2-ynyl, hex-1-ynyl, hex-2-ynyl, or hex-3-ynyl. “Substituted alkynyl” refers to an alkynyl group substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halo substituents forming, in the latter case, groups such as CF3 or an alkyl group bearing CCl3), cyano, nitro, oxo (i.e., =O), CF3, OCF3, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, ORa, SRa, S(=O)Re, S(=O)2Re, P(=O)2Re, S(=O)2ORe, P(=O)2ORe, NRbRc, NRbS(=O)2Re, NRbP(=O)2Re, S(=O)2NRbRc, P(=O)2NRbRc, C(=O)ORd, C(=O)Ra, C(=O)NRbRc, OC(=O)Ra, OC(=O)NRbRc, NRbC(=O)ORe, NRdC(=O)NRbRc, NRdS(=O)2NRbRc, NRdP(=O)2NRbRc, NRbC(=O)Ra, or NRbP(=O)2Re, wherein each occurrence of Ra is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; each occurrence of Rb, Rc and Rd is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or said Rb and Rc together with the N to which they are bonded optionally to form a heterocycle; and each occurrence of Re is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. The exemplary substituents can themselves be optionally substituted. [0112] The term “cycloalkyl” refers to a fully saturated cyclic hydrocarbon group containing from 1 to 4 rings and 3 to 8 carbons per ring. “C3-C7 cycloalkyl” or “C3-7cycloalkyl” refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. “Substituted cycloalkyl” refers to a cycloalkyl group substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halo substituents forming, in the latter case, groups such as CF3 or an alkyl group bearing CCl3), cyano, nitro, oxo (i.e., =O), CF3, OCF3, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, ORa, SRa, S(=O)Re, S(=O)2Re, P(=O)2Re, S(=O)2ORe, P(=O)2ORe, NRbRc, NRbS(=O)2Re, NRbP(=O)2Re, S(=O)2NRbRc, P(=O)2NRbRc, C(=O)ORd, C(=O)Ra, C(=O)NRbRc, OC(=O)Ra, OC(=O)NRbRc, NRbC(=O)ORe, NRdC(=O)NRbRc, NRdS(=O)2NRbRc, NRdP(=O)2NRbRc, NRbC(=O)Ra, or NRbP(=O)2Re, wherein each occurrence of Ra is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; each occurrence of Rb, Rc and Rd is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or said Rb and Rc together with the N to which they are bonded optionally to form a heterocycle; and each occurrence of Re is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. The exemplary substituents can themselves be optionally substituted. Exemplary substituents also include spiro-attached or fused cyclic substituents, especially spiro-attached cycloalkyl, spiro- attached cycloalkenyl, spiro-attached heterocycle (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, where the aforementioned cycloalkyl, cycloalkenyl, heterocycle and aryl substituents can themselves be optionally substituted. [0113] The term “cycloalkenyl” refers to a partially unsaturated cyclic hydrocarbon group containing 1 to 4 rings and 3 to 8 carbons per ring. Exemplary such groups include cyclobutenyl, cyclopentenyl, cyclohexenyl, etc. “Substituted cycloalkenyl” refers to a cycloalkenyl group substituted with one more substituents, preferably 1 to 4 substituents, at any available point of attachment. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halo substituents forming, in the latter case, groups such as CF3 or an alkyl group bearing CCl3), cyano, nitro, oxo (i.e., =O), CF3, OCF3, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, ORa, SRa, S(=O)Re, S(=O)2Re, P(=O)2Re, S(=O)2ORe, P(=O)2ORe, NRbRc, NRbS(=O)2Re, NRbP(=O)2Re, S(=O)2NRbRc, P(=O)2NRbRc, C(=O)ORd, C(=O)Ra, C(=O)NRbRc, OC(=O)Ra, OC(=O)NRbRc, NRbC(=O)ORe, NRdC(=O)NRbRc, NRdS(=O)2NRbRc, NRdP(=O)2NRbRc, NRbC(=O)Ra, or NRbP(=O)2Re, wherein each occurrence of Ra is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; each occurrence of Rb, Rc, and Rd is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or said Rb and Rc together with the N to which they are bonded optionally form a heterocycle; and each occurrence of Re is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. The exemplary substituents can themselves be optionally substituted. Exemplary substituents also include spiro-attached or fused cyclic substituents, especially spiro-attached cycloalkyl, spiro-attached cycloalkenyl, spiro-attached heterocycle (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, where the aforementioned cycloalkyl, cycloalkenyl, heterocycle and aryl substituents can themselves be optionally substituted. [0114] The term “aryl” refers to cyclic, aromatic hydrocarbon groups that have 1 to 5 aromatic rings, especially monocyclic or bicyclic groups such as phenyl, biphenyl or naphthyl. Where containing two or more aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group may be joined at a single point (e.g., biphenyl), or fused (e.g., naphthyl, phenanthrenyl and the like). The term “fused aromatic ring” refers to a molecular structure having two or more aromatic rings wherein two adjacent aromatic rings have two carbon atoms in common. “Substituted aryl” refers to an aryl group substituted by one or more substituents, preferably 1 to 3 substituents, at any available point of attachment. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halo substituents forming, in the latter case, groups such as CF3 or an alkyl group bearing CCl3), cyano, nitro, oxo (i.e., =O), CF3, OCF3, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, ORa, SRa, S(=O)Re, S(=O)2Re, P(=O)2Re, S(=O)2ORe, P(=O)2ORe, NRbRc, NRbS(=O)2Re, NRbP(=O)2Re, S(=O)2NRbRc, P(=O)2NRbRc, C(=O)ORd, C(=O)Ra, C(=O)NRbRc, OC(=O)Ra, OC(=O)NRbRc, NRbC(=O)ORe, NRdC(=O)NRbRc, NRdS(=O)2NRbRc, NRdP(=O)2NRbRc, NRbC(=O)Ra, or NRbP(=O)2Re, wherein each occurrence of Ra is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; each occurrence of Rb, Rc and Rd is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or said Rb and Rc together with the N to which they are bonded optionally form a heterocycle; and each occurrence of Re is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. The exemplary substituents can themselves be optionally substituted. Exemplary substituents also include fused cyclic groups, especially fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, where the aforementioned cycloalkyl, cycloalkenyl, heterocycle, and aryl substituents can themselves be optionally substituted. [0115] The term “biaryl” refers to two aryl groups linked by a single bond. The term “biheteroaryl” refers to two heteroaryl groups linked by a single bond. Similarly, the term “heteroaryl-aryl” refers to a heteroaryl group and an aryl group linked by a single bond and the term “aryl-heteroaryl” refers to an aryl group and a heteroaryl group linked by a single bond. In certain embodiments, the numbers of the ring atoms in the heteroaryl and/or aryl rings are used to specify the sizes of the aryl or heteroaryl ring in the substituents. For example, 5,6-heteroaryl-aryl refers to a substituent in which a 5-membered heteroaryl is linked to a 6-membered aryl group. Other combinations and ring sizes can be similarly specified. [0116] The term “carbocycle” or “carbon cycle” refers to a fully saturated or partially saturated cyclic hydrocarbon group containing from 1 to 4 rings and 3 to 8 carbons per ring, or cyclic, aromatic hydrocarbon groups that have 1 to 5 aromatic rings, especially monocyclic or bicyclic groups such as phenyl, biphenyl, or naphthyl. The term “carbocycle” encompasses cycloalkyl, cycloalkenyl, cycloalkynyl, and aryl as defined hereinabove. The term “substituted carbocycle” refers to carbocycle or carbocyclic groups substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment. Exemplary substituents include, but are not limited to, those described above for substituted cycloalkyl, substituted cycloalkenyl, substituted cycloalkynyl, and substituted aryl. Exemplary substituents also include spiro-attached or fused cyclic substituents at any available point or points of attachment, especially spiro-attached cycloalkyl, spiro-attached cycloalkenyl, spiro-attached heterocycle (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, where the aforementioned cycloalkyl, cycloalkenyl, heterocycle, and aryl substituents can themselves be optionally substituted. [0117] The terms “heterocycle” and “heterocyclic” refer to fully saturated, or partially or fully unsaturated, including aromatic (i.e., “heteroaryl”) cyclic groups (for example, 3 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 8 to 16 membered tricyclic ring systems) which have at least one heteroatom in at least one carbon atom-containing ring. Each ring of the heterocyclic group may independently be saturated, or partially or fully unsaturated. Each ring of the heterocyclic group containing a heteroatom may have 1, 2, 3, or 4 heteroatoms selected from the group consisting of nitrogen atoms, oxygen atoms and sulfur atoms, where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized. (The term “heteroarylium” refers to a heteroaryl group bearing a quaternary nitrogen atom and thus a positive charge.) The heterocyclic group may be attached to the remainder of the molecule at any heteroatom or carbon atom of the ring or ring system. Exemplary monocyclic heterocyclic groups include azetidinyl, pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2- oxoazepinyl, azepinyl, hexahydrodiazepinyl, 4-piperidonyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl, tetrazolyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane and tetrahydro-1,1- dioxothienyl, and the like. Exemplary bicyclic heterocyclic groups include indolyl, indolinyl, isoindolyl, benzothiazolyl, benzoxazolyl, benzoxadiazolyl, benzothienyl, benzo[d][1,3]dioxolyl, dihydro-2H-benzo[b][1,4]oxazine, 2,3-dihydrobenzo[b][1,4]dioxinyl, quinuclidinyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, benzofurazanyl, dihydrobenzo[d]oxazole, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (such as furo[2,3-c]pyridinyl, furo[3,2-b]pyridinyl] or furo[2,3-b]pyridinyl), dihydroisoindolyl, dihydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolinyl), triazinylazepinyl, tetrahydroquinolinyl, and the like. Exemplary tricyclic heterocyclic groups include carbazolyl, benzidolyl, phenanthrolinyl, acridinyl, phenanthridinyl, xanthenyl, and the like. [0118] “Substituted heterocycle” and “substituted heterocyclic” (such as “substituted heteroaryl”) refer to heterocycle or heterocyclic groups substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halo substituents forming, in the latter case, groups such as CF3 or an alkyl group bearing CCl3), cyano, nitro, oxo (i.e., =O), CF3, OCF3, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, ORa, SRa, S(=O)Re, S(=O)2Re, P(=O)2Re, S(=O)2ORe, P(=O)2ORe, NRbRc, NRbS(=O)2Re, NRbP(=O)2Re, S(=O)2NRbRc, P(=O)2NRbRc, C(=O)ORd, C(=O)Ra, C(=O)NRbRc, OC(=O)Ra, OC(=O)NRbRc, NRbC(=O)ORe, NRdC(=O)NRbRc, NRdS(=O)2NRbRc, NRdP(=O)2NRbRc, NRbC(=O)Ra, or NRbP(=O)2Re, wherein each occurrence of Ra is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; each occurrence of Rb, Rc and Rd is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or said Rb and Rc together with the N to which they are bonded optionally form a heterocycle; and each occurrence of Re is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. The exemplary substituents can themselves be optionally substituted. Exemplary substituents also include spiro-attached or fused cyclic substituents at any available point or points of attachment, especially spiro-attached cycloalkyl, spiro-attached cycloalkenyl, spiro-attached heterocycle (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, where the aforementioned cycloalkyl, cycloalkenyl, heterocycle and aryl substituents can themselves be optionally substituted. [0119] The term “oxo” refers to substituent group, which may be attached to a carbon ring atom on a carboncycle or heterocycle. When an oxo substituent group is attached to a carbon ring atom on an aromatic group, e.g., aryl or heteroaryl, the bonds on the aromatic ring may be rearranged to satisfy the valence requirement. For instance, a pyridine with a 2- oxo substituent group may have the structure which also includes its tautomeric form . [0120] The term “alkylamino” refers to a group having the structure -NHR’, wherein R’ is hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, as defined herein. Examples of alkylamino groups include, but are not limited to, methylamino, ethylamino, n-propylamino, iso-propylamino, cyclopropylamino, n-butylamino, tert-butylamino, neopentylamino, n-pentylamino, hexylamino, cyclohexylamino, and the like. [0121] The term “dialkylamino” refers to a group having the structure -NRR’, wherein R and R’ are each independently alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cyclolalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined herein. R and R’ may be the same or different in a dialkyamino moiety. Examples of dialkylamino groups include, but are not limited to, dimethylamino, methyl ethylamino, diethylamino, methylpropylamino, di(n-propyl)amino, di(iso- propyl)amino, di(cyclopropyl)amino, di(n-butyl)amino, di(tert-butyl)amino, di(neopentyl)amino, di(n-pentyl)amino, di(hexyl)amino, di(cyclohexyl)amino, and the like. In certain embodiments, R and R’ are linked to form a cyclic structure. The resulting cyclic structure may be aromatic or non-aromatic. Examples of the resulting cyclic structure include, but are not limited to, aziridinyl, pyrrolidinyl, piperidinyl, morpholinyl, pyrrolyl, imidazolyl, 1,2,4-triazolyl, and tetrazolyl. [0122] The terms “halogen” or “halo” refer to chlorine, bromine, fluorine, or iodine. [0123] The term “substituted” refers to the embodiments in which a molecule, molecular moiety, or substituent group (e.g., alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl group or any other group disclosed herein) is substituted with one or more substituents, where valence permits, preferably 1 to 6 substituents, at any available point of attachment. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halo substituents forming, in the latter case, groups such as CF3 or an alkyl group bearing CCl3), cyano, nitro, oxo (i.e., =O), CF3, OCF3, alkyl, halogen-substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, ORa, SRa, S(=O)Re, S(=O)2Re, P(=O)2Re, S(=O)2ORe, P(=O)2ORe, NRbRc, NRbS(=O)2Re, NRbP(=O)2Re, S(=O)2NRbRc, P(=O)2NRbRc, C(=O)ORd, C(=O)Ra, C(=O)NRbRc, OC(=O)Ra, OC(=O)NRbRc, NRbC(=O)ORe, NRdC(=O)NRbRc, NRdS(=O)2NRbRc, NRdP(=O)2NRbRc, NRbC(=O)Ra, or NRbP(=O)2Re, wherein each occurrence of Ra is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; each occurrence of Rb, Rc and Rd is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or said Rb and Rc together with the N to which they are bonded optionally form a heterocycle; and each occurrence of Re is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. In the aforementioned exemplary substituents, groups such as alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkenyl, heterocycle, and aryl can themselves be optionally substituted. The term “optionally substituted” refers to the embodiments in which a molecule, molecular moiety or substituent group (e.g., alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl group or any other group disclosed herein) may or may not be substituted with aforementioned one or more substituents. [0124] Unless otherwise indicated, any heteroatom with unsatisfied valences is assumed to have hydrogen atoms sufficient to satisfy the valences. [0125] The compounds of the present invention may form salts which are also within the scope of this invention. Reference to a compound of the present invention is understood to include reference to salts thereof, unless otherwise indicated. The term “salt(s)”, as employed herein, denotes acidic and/or basic salts formed with inorganic and/or organic acids and bases. In addition, when a compound of the present invention contains both a basic moiety, such as but not limited to a pyridine or imidazole, and an acidic moiety such as but not limited to a phenol or carboxylic acid, zwitterions (“inner salts”) may be formed and are included within the term “salt(s)” as used herein. Pharmaceutically acceptable (i.e., non- toxic, physiologically acceptable) salts are preferred, although other salts are also useful, e.g., in isolation or purification steps which may be employed during preparation. Salts of the compounds of the present invention may be formed, for example, by reacting a compound described herein with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates, or in an aqueous medium followed by lyophilization. [0126] The compounds of the present invention which contain a basic moiety, such as but not limited to an amine or a pyridine or imidazole ring, may form salts with a variety of organic and inorganic acids. Exemplary acid addition salts include acetates (such as those formed with acetic acid or trihaloacetic acid; for example, trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides, hydroiodides, hydroxyethanesulfonates (e.g., 2- hydroxyethanesulfonates), lactates, maleates, methanesulfonates, naphthalenesulfonates (e.g., 2-naphthalenesulfonates), nicotinates, nitrates, oxalates, pectinates, persulfates, phenylpropionates (e.g., 3-phenylpropionates), phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates (such as those formed with sulfuric acid), sulfonates, tartrates, thiocyanates, toluenesulfonates such as tosylates, undecanoates, and the like. [0127] The compounds of the present invention which contain an acidic moiety, such as but not limited to a phenol or carboxylic acid, may form salts with a variety of organic and inorganic bases. Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as benzathines, dicyclohexylamines, hydrabamines (formed with N,N-bis(dehydroabietyl) ethylenediamine), N-methyl-D-glucamines, N-methyl-D-glycamides, t-butyl amines, and salts with amino acids such as arginine, lysine, and the like. Basic nitrogen-containing groups may be quaternized with agents such as lower alkyl halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g., decyl, lauryl, myristyl and stearyl chlorides, bromides, and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides), and others. [0128] Prodrugs and solvates of the compounds of the invention are also contemplated herein. The term “prodrug” as employed herein denotes a compound that, upon administration to a subject, undergoes chemical conversion by metabolic or chemical processes to yield a compound of the present invention, or a salt and/or solvate thereof. Solvates of the compounds of the present invention include, for example, hydrates. [0129] Compounds of the present invention, and salts or solvates thereof, may exist in their tautomeric form (for example, as an amide or imino ether). All such tautomeric forms are contemplated herein as part of the present invention. As used herein, any depicted structure of the compound includes the tautomeric forms thereof. [0130] All stereoisomers of the present compounds (for example, those which may exist due to asymmetric carbons on various substituents), including enantiomeric forms and diastereomeric forms, are contemplated within the scope of this invention. Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers (e.g., as a pure or substantially pure optical isomer having a specified activity), or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. The chiral centers of the present invention may have the S or R configuration as defined by the International Union of Pure and Applied Chemistry (IUPAC) 1974 Recommendations. The racemic forms can be resolved by physical methods, such as, for example, fractional crystallization, separation or crystallization of diastereomeric derivatives, or separation by chiral column chromatography. The individual optical isomers can be obtained from the racemates by any suitable method, including without limitation, conventional methods, such as, for example, salt formation with an optically active acid followed by crystallization. [0131] Compounds of the present invention are, subsequent to their preparation, preferably isolated and purified to obtain a composition containing an amount by weight equal to or greater than 90%, for example, equal to or greater than 95%, equal to or greater than 99% of the compounds (“substantially pure” compounds), which is then used or formulated as described herein. Such “substantially pure” compounds of the present invention are also contemplated herein as part of the present invention. [0132] All configurational isomers of the compounds of the present invention are contemplated, either in admixture or in pure or substantially pure form. The definition of compounds of the present invention embraces both cis (Z) and trans (E) alkene isomers, as well as cis and trans isomers of cyclic hydrocarbon or heterocyclic rings. [0133] Throughout the specification, groups and substituents thereof may be chosen to provide stable moieties and compounds. [0134] Definitions of specific functional groups and chemical terms are described in more detail herein. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito (1999), the entire contents of which are incorporated herein by reference. [0135] Certain compounds of the present invention may exist in particular geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention. [0136] Isomeric mixtures containing any of a variety of isomer ratios may be utilized in accordance with the present invention. For example, where only two isomers are combined, mixtures containing 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0 isomer ratios (by moles or weights) are all contemplated by the present invention. Those of ordinary skill in the art will readily appreciate that analogous ratios are contemplated for more complex isomer mixtures. [0137] The present invention also includes isotopically labeled compounds, which are identical to the compounds disclosed herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chlorine, such as 2H (D), 3H (T), 13C, 11C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F, and 36Cl, respectively. Compounds of the present invention, or an enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically labeled compounds of the present invention, for example, those into which radioactive isotopes such as 3H and 14C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3H (T), and carbon- 14, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e., 2H (D), can afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances. Isotopically labeled compounds can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples below, by substituting a readily available isotopically labeled reagent for a non-isotopically-labeled reagent. [0138] If, for instance, a particular enantiomer of a compound of the present invention is desired, it may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers. Alternatively, where the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers. [0139] It will be appreciated that the compounds, as described herein, may be substituted with any number of substituents or functional moieties. In general, the term “substituted” whether preceded by the term “optionally” or not, and substituents contained in formulas of this invention, refer to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent. When more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. For purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. Furthermore, this invention is not intended to be limited in any manner by the permissible substituents of organic compounds. Combinations of substituents and variables envisioned by this invention are preferably those that result in the formation of stable compounds useful in the treatment, for example, of proliferative disorders. The term “stable,” as used herein, preferably refers to compounds which possess stability sufficient to allow manufacture and which maintain the integrity of the compound for a sufficient period of time to be detected and preferably for a sufficient period of time to be useful for the purposes detailed herein. [0140] As used herein, the terms “cancer” and, equivalently, “tumor” refer to a condition in which abnormally replicating cells of host origin are present in a detectable amount in a subject. The cancer can be a malignant or non-malignant cancer. Cancers or tumors include, but are not limited to, biliary tract cancer; brain cancer; breast cancer; cervical cancer; choriocarcinoma; colon cancer; endometrial cancer; esophageal cancer; gastric (stomach) cancer; intraepithelial neoplasms; leukemias; lymphomas; liver cancer; lung cancer (e.g., small cell and non-small cell); melanoma; neuroblastomas; oral cancer; ovarian cancer; pancreatic cancer; prostate cancer; rectal cancer; renal (kidney) cancer; sarcomas; skin cancer; testicular cancer; thyroid cancer; as well as other carcinomas and sarcomas. Cancers can be primary or metastatic. Diseases other than cancers may be associated with mutational alternation of component of Ras signaling pathways and the compound disclosed herein may be used to treat these non-cancer diseases. Such non-cancer diseases may include: neurofibromatosis; Leopard syndrome; Noonan syndrome; Legius syndrome; Costello syndrome; cardio-facio-cutaneous syndrome; hereditary gingival fibromatosis type 1; autoimmune lymphoproliferative syndrome; and capillary malformation-arterovenous malformation. [0141] As used herein, “effective amount” refers to any amount that is necessary or sufficient for achieving or promoting a desired outcome. In some instances, an effective amount is a therapeutically effective amount. A therapeutically effective amount is any amount that is necessary or sufficient for promoting or achieving a desired biological response in a subject. The effective amount for any particular application can vary depending on such factors as the disease or condition being treated, the particular agent being administered, the size of the subject, or the severity of the disease or condition. One of ordinary skill in the art can empirically determine the effective amount of a particular agent without necessitating undue experimentation. [0142] As used herein, the term “subject” refers to a vertebrate animal. In one embodiment, the subject is a mammal or a mammalian species. In one embodiment, the subject is a human. In other embodiments, the subject is a non-human vertebrate animal, including, without limitation, non-human primates, laboratory animals, livestock, racehorses, domesticated animals, and non-domesticated animals. Compounds [0143] Novel compounds as KCa3.1 inhibitors are described. It has been surprisingly discovered that the compounds disclosed herein exhibit KCa3.1-inhibiting properties. Additionally, it has been surprisingly discovered that the compounds disclosed herein selectively block KCa3.1 and do not block the hERG channel and thus have desirable cardiovascular safety profiles. [0144] In one aspect, a compound having a structure of Formula I is described ( ), where the various substituents are defined herein. The compounds of Formula I described herein can block or inhibit KCa3.1 and be used in the treatment of a variety of conditions. Methods for synthesizing these compounds are also described herein. Pharmaceutical compositions and methods of using these compositions described herein are useful for treating conditions in vitro and in vivo. Such compounds, pharmaceutical compositions, and methods of treatment have a number of clinical applications, including as pharmaceutically active agents and methods for cancer, sickle cell anemia, a cardiovascular disease, a respiratory disease, a fibrotic disease, an autoimmune disease, a central nervous system (CNS) disorder, an inflammatory disorder, a neurodegenerative disease, or a combination thereof. [0145] In one aspect, a compound of Formula I or a pharmaceutically acceptable salt thereof, or a tautomer thereof is described, wherein R1 is alkyl, cycloalkyl, halogenated alkyl, halogenated cycloalkyl, bicycloalkyl, halogenated bicycloalkyl, saturated heterocycle, partially saturated heterocycle, aryl, heteroaryl, -C1-4alkyl-cycloalkyl, -C1-4alkyl-saturated heterocycle, -C1-4alkyl-partially saturated heterocycle, or cycloalkenyl, each of which optionally substituted by 1-5 substituents each independently selected from the group consisting of D, halogen, alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, alkenyl, and alkynyl where valence permits; R2 is halogen, alkyl, alkynyl, halogenated alkyl, halogenated alkynyl, CN, ORa, SRa, - C1-4alkyl-ORa, -C1-4alkyl-SRa, -O-C1-4alkyl-ORa, -O-C1-4alkyl-SRa, -O-C1-4alkyl-NRaRb, -S- C1-4alkyl-ORa, -S-C1-4alkyl-SRa, or -S-C1-4alkyl-NRaRb; R3 is –(CR8R9)mR10; R4 is H, D, halogen, CN, alkyl, halogenated alkyl, cycloalkyl, halogenated cycloalkyl, ORa, SRa, -C1-4alkyl-ORa, or -C1-4alkyl-SRa; R5 is H, D, halogen, CN, alkyl, halogenated alkyl, cycloalkyl, halogenated cycloalkyl, ORa, SRa, -C1-4alkyl-ORa, or -C1-4alkyl-SRa; R6 is H, D, halogen, CN, alkyl, halogenated alkyl, cycloalkyl, halogenated cycloalkyl, ORa, SRa, -C1-4alkyl-ORa, or -C1-4alkyl-SRa; R7 is H, D, halogen, CN, alkyl, halogenated alkyl, cycloalkyl, halogenated cycloalkyl, ORa, SRa, -C1-4alkyl-ORa, or -C1-4alkyl-SRa; m is 1 or 2; each occurrence of R8 is independently H, D, OH, ORa, or alkyl; each occurrence of R9 is independently H, D, OH, ORa, or alkyl; R10 is H, D, CN, alkyl, saturated heterocycle, aryl, heteroaryl, -CORa, -COORa, - CONRaRb, -ORa, -SORa, or -SO2Ra; each occurrence of Ra and Rb is independently selected from the group consisting of H, D, alkyl, cycloalkyl, halogenated alkyl, heteroalkyl, halogenated heteroalkyl, halogenated cycloalkyl, saturated heterocycle comprising 1-3 heteroatoms each selected from the group consisting of N, O, and S, aryl, and heteroaryl; or alternatively, Ra and Rb, together with the carbon or nitrogen atom that they are connected to, form a cycloalkyl or saturated heterocycle comprising the nitrogen atom and 0-3 additional heteroatoms each selected from the group consisting of N, O, and S; the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, saturated heterocycle, partially saturated heterocycle, aryl, and heteroaryl in R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, Ra, or Rb, where applicable, are each optionally substituted by 1-4 substituents each independently selected from the group consisting of alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, halogen, CN, ORx, -(CH2)1-2ORx, N(Rx)2, -(CH2)1-2N(Rx)2, (C=O)Rx, (C=O)N(Rx)2, NRx(C=O)Rx, and oxo where valence permits; and each occurrence of Rx is independently H, D, alkyl, halogenated alkyl, or heterocycle optionally substituted by alkyl, halogen, or OH; or alternatively, the two Rx groups together with the nitrogen atom that they are connected to, form a heterocycle optionally substituted by alkyl and comprising the nitrogen atom and 0-3 additional heteroatoms each selected from the group consisting of N, O, and S. [0146] In some embodiments, the compound of Formula I is not in a salt form or a tautomer form. [0147] In some embodiments, R1 is optionally substituted aryl. Non-limiting examples of aryl include phenyl, biphenyl, naphthyl, anthracenyl, and the like. [0148] In some embodiments, R1 is phenyl that is optionally substituted by 1-5 substituents each independently selected from the group consisting of D, halogen, alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, alkenyl, and alkynyl. In certain embodiments, R1 is phenyl which is optionally substituted by 1-5 substituents each independently selected from the group consisting of D, halogen, alkyl, and halogenated alkyl. In some embodiments, R1 is phenyl that is optionally substituted by 1-5 substituents each independently selected from the group consisting of D, alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec- butyl, pentyl, hexyl, heptyl, and octyl), halogen (e.g., F, Cl, Br, and I), and halogenated alkyl (e.g., CF3, CH2F, CHF2, CH2Cl, CH2CF3, CHFCH3, CHFCH2F, CF2CH3, CHClCH3, CCl2CH3, CHBrCH3, CH2CH2CF3, and CHClCHClCH3). In some embodiments, R1 is phenyl which is substituted with at least one substituent selected from the group consisting of D, alkyl (e.g., CH3 and CH2CH3), halogen (e.g., F, Cl, Br, and I), halogenated alkyl (e.g., CF3), alkynyl (e.g., C≡CH), and cycloalkyl (e.g., ). In some embodiments, R1 is phenyl that is optionally substituted by 1-5 substituents each independently selected from the group consisting of D, CH3, CH2CH3, F, Cl, Br, CH2F, and CF3. In some embodiments, R1 is phenyl which is substituted with at least one halogen. In some embodiments, R1 is phenyl which is substituted with at least one alkyl or halogenated alkyl. [0149] In some embodiments, R1 is cycloalkyl, bicycloalkyl, or -C1-4alkyl-cycloalkyl, each of which optionally substituted by 1-5 substituents each independently selected from the group consisting of D, halogen, alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, alkenyl, and alkynyl where valence permits. In some embodiments, R1 is cycloalkyl, bicycloalkyl, or -C1-4alkyl-cycloalkyl, each of which optionally substituted by 1-5 substituents each independently selected from the group consisting of D, alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, pentyl, hexyl, heptyl, and octyl), halogen (e.g., F, Cl, Br, and I), and halogenated alkyl (e.g., CF3, CH2F, CHF2, CH2Cl, CH2CF3, CHFCH3, CHFCH2F, CF2CH3, CHClCH3, CCl2CH3, CHBrCH3, CH2CH2CF3, and CHClCHClCH3) where valence permits. In some embodiments, R1 is cycloalkyl, bicycloalkyl, or -C1-4alkyl-cycloalkyl, each of which optionally substituted by 1-5 substituents each independently selected from the group consisting of D, CH3, CH2CH3, F, Cl, Br, CH2F, and CF3 where valence permits. In some embodiments, R1 is cycloalkyl that is optionally substituted by 1-5 substituents each independently selected from the group consisting of D, CH3, CH2CH3, F, Cl, Br, CH2F, and CF3 where valence permits. In some embodiments, R1 is -C1-4alkyl-cycloalkyl that is optionally substituted by 1-5 substituents each independently selected from the group consisting of D, CH3, CH2CH3, F, Cl, Br, CH2F, and CF3 where valence permits. Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. In some embodiments, R1 is bicycloalkyl that is optionally substituted by 1-5 substituents each independently selected from the group consisting of D, CH3, CH2CH3, F, Cl, Br, CH2F, and CF3 where valence permits. Non-limiting examples of bicycloalkyl include bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.1.1]hexyl, octahydropentalenyl, bicyclo[3.2.1]octyl, bicyclo[3.3.3]undecanyl, decahydronaphthalenyl, bicyclo[3.2.0]heptyl, octahydro-1H-indenyl, bicyclo[4.2.1]nonanyl, spiro[4.4]nonyl, spiro[3.3]heptyl, spiro[5.5]undecyl, spiro[3.5]nonyl, and spiro[4.5]decyl. In some embodiments, R1 is selected which optionally substituted by 1-5 substituents each independently selected from the group consisting of D, CH3, CH2CH3, F, Cl, Br, CH2F, and CF3. [0150] In some embodiments, R1 is 4-, 5-, 6- or 7-membered saturated heterocycle, partially saturated heterocycle, or heteroaryl, each containing 1-3 heteroatoms each selected from the group consisting of N, O, and S, each optionally substituted by 1-5 substituents each independently selected from the group consisting of D, halogen, alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, alkenyl, and alkynyl where valence permits. In further embodiments, R1 is selected from the group consisting of , ; wherein each is optionally substituted by 1-5 substituents each independently selected from the group consisting of D, alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, pentyl, hexyl, heptyl, and octyl), halogen (e.g., F, Cl, Br, and I), and halogenated alkyl (e.g., CF3, CH2F, CHF2, CH2Cl, CH2CF3, CHFCH3, CHFCH2F, CF2CH3, CHClCH3, CCl2CH3, CHBrCH3, CH2CH2CF3, and CHClCHClCH3) where valence permits. In some embodiments, R1 is a N-containing heterocycle, partially saturated heterocycle, or heteroaryl, wherein each is optionally substituted by alkyl. In some embodiments, R1 is a saturated heterocycle that is optionally substituted by 1-5 substituents each independently selected from the group consisting of D, alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, pentyl, hexyl, heptyl, and octyl), halogen (e.g., F, Cl, Br, and I), and halogenated alkyl (e.g., CF3, CH2F, CHF2, CH2Cl, CH2CF3, CHFCH3, CHFCH2F, CF2CH3, CHClCH3, CCl2CH3, CHBrCH3, CH2CH2CF3, and CHClCHClCH3) where valence permits. In some embodiments, R1 is selected from the group consisting of , ,
1-5 substituents each independently selected from the group consisting of D, CH3, CH2CH3, F, Cl, Br, CH2F, and CF3 where valence permits. [0151] In some embodiments, R1 is alkyl that is optionally substituted by 1-5 substituents each independently selected from the group consisting of D, halogen, alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, alkenyl, and alkynyl where valence permits. In some embodiments, R1 is alkyl that is optionally substituted by D or halogen (e.g., F, Cl, Br, and I). Non-limiting examples of alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso- butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, and octyl. [0152] In some embodiments, R1 is halogenated alkyl, halogenated cycloalkyl, halogenated bicycloalkyl, partially saturated heterocycle, heteroaryl or cycloalkenyl, each of which optionally substituted by 1-5 substituents each independently selected from the group consisting of D, halogen, alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, alkenyl, and alkynyl where valence permits. In some embodiments, R1 is optionally substituted halogenated alkyl. Non-limiting examples of halogenated alkyl include CF3, CH2F, CHF2, CH2Cl, CH2CF3, CHFCH3, CHFCH2F, CF2CH3, CHClCH3, CCl2CH3, CHBrCH3, CH2CH2CF3, and CHClCHClCH3. In some embodiments, R1 is optionally substituted halogenated cycloalkyl. Non-limiting examples of halogenated cycloalkyl include cycloalkenyl. Non-limiting examples of cycloalkenyl include cyclobutenyl, cyclopentenyl, and cyclohexenyl. [0153] In some embodiments, R1 is optionally substituted heteroaryl. In some embodiments, R1 is a 5- or 6-membered heteroaryl which is optionally substituted by 1-5 substituents each independently selected from the group consisting of D, halogen, alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, alkenyl, and alkynyl where valence permits. In some embodiments, R1 is a 5- or 6-membered heteroaryl containing 1-3 heteroatoms each independently selected from N, O, and S. In further embodiments, R1 is pyridine, thiophene, or furan. In some embodiments, R1 is a 5-membered heteroaryl, wherein the heteroaryl is optionally substituted by alkyl, halogen, or OH. Non-limiting examples of 5-membered [0154] In some embodiments, R1 is a 7- to 11-membered bicyclic, or 8- to 16-membered tricyclic aryl or heteroaryl which are each optionally substituted by 1-5 substituents each independently selected from the group consisting of H, D, halogen, alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, alkenyl, and alkynyl. Non-limiting examples of bicyclic or tricyclic rings include biphenyl, naphthyl, phenanthrenyl, indolyl, isoindolyl, benzothiazolyl, benzoxazolyl, benzoxadiazolyl, benzothienyl, quinolinyl, isoquinolinyl, benzimidazolyl, chromonyl, coumarinyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (such as furo[2,3-c]pyridinyl, furo[3,2-b]pyridinyl] or furo[2,3-b]pyridinyl), carbazolyl, phenanthrolinyl, acridinyl, and phenanthridinyl. [0155] In some embodiments, R1 is -C1-4alkyl-saturated heterocycle, or C1-4alkyl-partially saturated heterocycle, each of which optionally substituted by 1-5 substituents each independently selected from the group consisting of D, halogen, alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, alkenyl, and alkynyl where valence permits. [0156] In some embodiments, R1 is selected from the group consisting of , [0157] In some embodiments, R2 is halogen, alkyl, alkynyl, halogenated alkyl, or halogenated alkynyl. In some embodiments, R2 is halogen. Non-limiting examples of halogen include F, Cl, Br, and I. In some embodiments, R2 is alkyl or halogenated alkyl. Non-limiting examples of alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, and octyl. Non-limiting examples of halogenated alkyl include CF3, CH2F, CHF2, CH2Cl, CH2CF3, CHFCH3, CHFCH2F, CF2CH3, CHClCH3, CCl2CH3, CHBrCH3, CH2CH2CF3, and CHClCHClCH3. In some embodiments, R2 is alkynyl or halogenated alkynyl. Non-limiting examples of alkynyl include ethynyl, prop-1- ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, pent-1-ynyl, pent-2-ynyl, hex-1-ynyl, hex-2-ynyl, and hex-3-ynyl. Non-limiting examples of halogenated alkynyl include CHClC≡CH, CHFC≡CH, CH2C≡CCF3, C≡CCH2F, and C≡CCF3. [0158] In some specific embodiments, R2 is alkyl optionally substituted with alkoxy or OH, or alkoxy optionally substituted with halogen, alkyl, alkoxy, or OH. Non-limiting examples of alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, and octyl. Non-limiting examples of alkoxy include OCH3, OCH2CH3, OCH2CH2CH3, OCH2CH2CH2CH3, OCH2CH2CH2CH2CH3, and OCH(CH3)2. In some embodiments, R2 is CN. [0159] In some embodiments, R2 is ORa, SRa, -O-C1-4alkyl-ORa, -O-C1-4alkyl-SRa, -O-C1- 4alkyl-NRaRb, -S-C1-4alkyl-ORa, -S-C1-4alkyl-SRa, or -S-C1-4alkyl-NRaRb. In some embodiments, R2 is ORa, or SRa. In some embodiments, R2 is -O-C1-4alkyl-ORa, -O-C1- 4alkyl-SRa, or -O-C1-4alkyl-NRaRb. In some embodiments, R2 is -S-C1-4alkyl-ORa, -S-C1- 4alkyl-SRa, or -S-C1-4alkyl-NRaRb. In some embodiments, R2 is -C1-4alkyl-ORa, or -C1-4alkyl- SRa. In some embodiments, R2 is CN, ORa, SRa, or -O-C1-4alkyl-ORa. [0160] In other specific embodiments, R2 is OH, CH2OH, or CH2CH2OH. In other specific embodiments, R2 is OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, OCH2CH2OH, or OCH2CH2OCH3. [0161] In some embodiments, R2 is selected from the group consisting of CN, CH3, CH2CH3, [0162] In some embodiments, m is 1 or 2. In some embodiments, m is 1. In some embodiments, m is 2. [0163] In some embodiments, each occurrence of R8 is independently H, D, alkyl, or ORa. In some embodiments, each occurrence of R8 is independently H, D, or ORa (e.g., OH, OMe, or OEt). [0164] In some embodiments, at least one occurrence of R8 is H or D. In some embodiments, at least one occurrence of R8 is ORa, e.g., OH, OMe, or OEt. In some embodiments, at least one occurrence of R8 is alkyl. Non-limiting examples of alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, and octyl. [0165] In some embodiments, each occurrence of R8 is independently H, D, CH3, CH2CH3, or OH. In certain embodiments, each occurrence of R8 is independently H, D, or OH. [0166] In some embodiments, each occurrence of R9 is independently H, D, alkyl, or ORa. In some embodiments, each occurrence of R9 is independently H, D, or ORa (e.g., OH, OMe, or OEt). [0167] In some embodiments, at least one occurrence of R9 is H or D. In some embodiments, at least one occurrence of R9 is ORa, e.g., OH, OMe, or OEt. In some embodiments, at least one occurrence of R9 is alkyl. Non-limiting examples of alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, and octyl. [0168] In some embodiments, each occurrence of R9 is independently H, D, CH3, CH2CH3, or OH. In further embodiments, each occurrence of R9 is independently H, D, or OH. [0169] In some embodiments, the structural moiety –(CR8R9)m– is selected from the group consisting of –CH2–, –CH2–CH2–, –CH(CH3)–CH2–, –CH2–C(CH3)2–, –CH2–CH(OH)–, moiety –(CR8R9)m– is selected from the group consisting of –CH2–, –CH2–CH2–, –CH(CH3)– embodiments, the structural moiety –(CR8R9)m– is –CH2–, –CH2–CH2–, , or In some embodiments, the structural moiety –(CR8R9)m– is –CH2–, or –CH2– CH2–. In some embodiments, the structural moiety –(CR8R9)m– is –CH2–. [0171] In some embodiments, R10 is H, D, CN, aryl, or heteroaryl. In some embodiments, R10 is H, D, or CN. In some embodiments, R10 is H or D. In some embodiments, R10 is alkyl. Non-limiting examples of alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, and octyl. [0172] In some embodiments, R10 is optionally substituted aryl. Non-limiting examples of aryl include phenyl, biphenyl, naphthyl, anthracenyl, and the like. In some embodiments, R10 is phenyl that is optionally substituted by 1-5 substituents each independently selected from the group consisting of D, halogen, alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, alkenyl, alkynyl, CN, ORa, SRa, NRaRb, -C1-4alkyl-SRa, and -C1-4alkyl-ORa. In certain embodiments, R10 is phenyl which is optionally substituted by 1-5 substituents each independently selected from the group consisting of D, halogen, alkyl, halogenated alkyl, CN, ORa, SRa, or NRaRb. In some embodiments, R10 is phenyl that is optionally substituted by 1-5 substituents each independently selected from the group consisting of D, alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, pentyl, hexyl, heptyl, and octyl), halogen (e.g., F, Cl, Br, and I), ORa (e.g., OH, OCH3, and OEt), and halogenated alkyl (e.g., CF3, CH2F, CHF2, CH2Cl, CH2CF3, CHFCH3, CHFCH2F, CF2CH3, CHClCH3, CCl2CH3, CHBrCH3, CH2CH2CF3, and CHClCHClCH3). In some embodiments, R10 is phenyl that is optionally substituted by 1-5 substituents each independently selected from the group consisting of D, CH3, CH2CH3, OH, OCH3, F, Cl, Br, CH2F, CF3, and OCF3. In some embodiments, R10 is phenyl which is substituted with at least one halogen. In some embodiments, R10 is phenyl which is substituted with at least one OH, halogen, alkyl or halogenated alkyl. [0173] In some embodiments, R10 is 4-, 5-, 6- or 7-membered saturated heterocycle, partially saturated heterocycle, or heteroaryl, each containing 1-3 heteroatoms each selected from the group consisting of N, O, and S, each optionally substituted by 1-5 substituents each independently selected from the group consisting of D, halogen, alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, alkenyl, alkynyl, CN, ORa, SRa, NRaRb, -C1- 4alkyl-SRa, and -C1-4alkyl-ORa where valence permits. In further embodiments, R10 is selected from the group consisting of , , , , , , , substituted by 1-5 substituents each independently selected from the group consisting of D, alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, pentyl, hexyl, heptyl, and octyl), halogen (e.g., F, Cl, Br, and I), ORa (e.g., OH, OCH3, and OEt), and halogenated alkyl (e.g., CF3, CH2F, CHF2, CH2Cl, CH2CF3, CHFCH3, CHFCH2F, CF2CH3, CHClCH3, CCl2CH3, CHBrCH3, CH2CH2CF3, and CHClCHClCH3) where valence permits. In some embodiments, R10 is a N-containing heterocycle, partially saturated heterocycle, or heteroaryl, wherein each is optionally substituted by alkyl, OH, NH2, or oxo where valence permits. In some embodiments, R10 is a saturated heterocycle that is optionally substituted by 1-5 substituents each independently selected from the group consisting of D, alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, pentyl, hexyl, heptyl, and octyl), halogen (e.g., F, Cl, Br, and I), ORa (e.g., OH, OCH3, and OEt), and halogenated alkyl (e.g., CF3, CH2F, CHF2, CH2Cl, CH2CF3, CHFCH3, CHFCH2F, CF2CH3, CHClCH3, CCl2CH3, CHBrCH3, CH2CH2CF3, and CHClCHClCH3) where valence permits. In some 1-5 substituents each independently selected from the group consisting of D, CH3, CH2CH3, OH, OCH3, F, Cl, Br, CH2F, CF3, and OCF3 where valence permits. [0174] In some embodiments, R10 is optionally substituted heteroaryl. In some embodiments, R10 is a 5- or 6-membered heteroaryl which is optionally substituted by 1-5 substituents each independently selected from the group consisting of D, halogen, alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, alkenyl, alkynyl, CN, ORa, SRa, NRaRb, -C1- 4alkyl-SRa, and -C1-4alkyl-ORa. In some embodiments, R10 is a 5- or 6-membered heteroaryl containing 1-3 heteroatoms each independently selected from the group consisting of N, O, and S. In further embodiments, R10 is pyridine, thiophene, or furan. In some embodiments, R10 is a 5-membered heteroaryl, wherein the heteroaryl is optionally substituted by alkyl, halogen, or OH. Non-limiting examples of 5-membered heteroaryl include , [0175] In some embodiments, R10 is oxetane, pyrazole, or oxadiazole, each optionally substituted by halogen (e.g., F, Cl, Br, and I) or alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, pentyl, hexyl, heptyl, and octyl). [0176] In some embodiments, R10 is -COORa, -CORa, -CONRaRb, -ORa, -SORa, or -SO2Ra. In some embodiments, R10 is -COORa (e.g., -COOH, -COOMe, -COOEt, -COOPr, and - COOiPr). In some embodiments, R10 is -CORa (e.g., -COMe, -COEt, -COPr, and -COiPr). In some embodiments, R10 is -CONRaRb (e.g., -CONH2, -CONHMe, -CONMe2, -CONHEt, - CONEt2, -CONHPr, and -CONHiPr). In some embodiments, R10 is ORa (e.g., OH, OMe, and OEt). In some embodiments, R10 is -SORa (e.g., -SOMe, -SOEt, -SOPr, and -SOiPr) or - SO2Ra (e.g., -SO2Me, -SO2Et, -SO2Pr, and -SO2iPr). [0177] In some embodiments, R10 is selected from the group consisting of H, D, CH3, . In some embodiments, R10 is selected from the group consisting of H, D, CH3, [0178] In some embodiments, R3 is (CH2)1-2CONRaRb, CH2C(=O)Ra, CH2CH(OH)Ra, CH2CH(OH)CH2OH, CH2SORa, CH2SO2Ra, (CH2)1-2-heterocycle, or (CH2)1-2-heteroaryl. In some embodiments, R3 is CH2CONH2 or (CH2)2CONH2. In some embodiments, R3 is CH2CONH2. In some embodiments, R3 is CH2C(=O)Ra, CH2CH(OH)Ra, CH2CH(OH)CH2OH, CH2SORa, or CH2SO2Ra. In some embodiments, R3 is CH2C(=O)CH3. In some embodiments, R3 is (CH2)1-2-heterocycle, wherein the heterocycle is oxetane, pyrazole, or oxadiazole, each optionally substituted by halogen (e.g., F, Cl, Br, and I) or alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, pentyl, hexyl, heptyl, and octyl). In some embodiments, R3 is (CH2)1-2-heteroaryl, wherein the heteroaryl is , optionally substituted by halogen (e.g., F, Cl, Br, and I) or alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, pentyl, hexyl, heptyl, and octyl). In some embodiments, R3 is CH2CH(OH)CH3, CH2CH(OH)CH2CH3, or CH(OH)CH2CH3. In some [0179] In some embodiments, at least one of R4, R5, R6, and R7 is not H. In some embodiments, at least two of R4, R5, R6, and R7 are not H. In some embodiments, at least one of R4, R5, R6, and R7 is not H or D. In some embodiments, at least two of R4, R5, R6, and R7 are not H or D. In some embodiments, R4 is not H or D. In some embodiments, R5 is not H or D. In some embodiments, R6 is not H or D. In some embodiments, R7 is not H or D. In some embodiments, R4 and R5 are not H or D. In some embodiments, R4 and R6 are not H or D. In some embodiments, R4 and R7 are not H or D. In some embodiments, R4, R5, and R7 are not H or D. In some embodiments, at least one of R4, R5, R6, and R7 is not H. In some embodiments, at least two of R4, R5, R6, and R7 are not H. In some embodiments, R4 is not H. In some embodiments, R5 is not H. In some embodiments, R6 is not H. In some embodiments, R7 is not H. In some embodiments, R4 and R5 are not H. In some embodiments, R4 and R6 are not H. In some embodiments, R4 and R7 are not H. In some embodiments, R4, R5, and R7 are not H. [0180] In some embodiments, R4 is H, D, halogen, CN, alkyl, halogenated alkyl, cycloalkyl, halogenated cycloalkyl, ORa, SRa, -C1-4alkyl-ORa, or -C1-4alkyl-SRa. In some embodiments, R4 is H, D, halogen, CN, CF3, CH2F, CHF2, ORa, SRa, -C1-4alkyl-ORa, or -C1-4alkyl-SRa. In some embodiments, R4 is alkyl or halogenated alkyl, each optionally substituted with 1-3 substituents selected from the group consisting of halogen, CN, ORx, -(CH2)1-2ORx, N(Rx)2, - (CH2)1-2N(Rx)2, (C=O)Rx, (C=O)N(Rx)2, NRx(C=O)Rx, and oxo where valence permits. In some embodiments, R4 is cycloalkyl or halogenated cycloalkyl, each optionally substituted with 1-3 substituents selected from the group consisting of halogen, CN, ORx, -(CH2)1-2ORx, N(Rx)2, -(CH2)1-2N(Rx)2, (C=O)Rx, (C=O)N(Rx)2, NRx(C=O)Rx, and oxo where valence permits. [0181] In some embodiments, R4 is H, D, or alkyl. In some embodiments, R4 is H, D, or alkyl, wherein the alkyl is optionally substituted by halogen, OH, oxo, or NH2 where valence permits. Non-limiting examples of alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, and octyl. In some embodiments, R4 is cycloalkyl. Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. In some embodiments, R4 is halogen. Non- limiting examples of halogen include F, Cl, Br, and I. In some embodiments, R4 is halogenated alkyl. Non-limiting examples of halogenated alkyl include CF3, CH2F, CHF2, CH2Cl, CH2CF3, CHFCH3, CHFCH2F, CF2CH3, CHClCH3, CCl2CH3, CHBrCH3, CH2CH2CF3, and CHClCHClCH3. In some embodiments, R4 is halogenated cycloalkyl. Non-limiting examples of halogenated cycloalkyl include , , , . [0182] In some embodiments, R4 is ORa, SRa, -C1-4alkyl-ORa, or -C1-4alkyl-SRa. In some embodiments, R4 is ORa or SRa. In some embodiments, R4 is -C1-4alkyl-ORa or -C1-4alkyl- SRa. [0183] In some specific embodiments, R4 is OH, CH2OH, or CH2CH2OH. [0184] In some embodiments, R4 is selected from the group consisting of H, D, CH3, from the group consisting of H, D, CH3, CH2CH3, CF2H, CH2F, CF3, CN, Cl, Br, F, OCH3, , and . [0185] In some embodiments, R4 is selected from the group consisting of H, D, Cl, Br, F, I, some embodiments, R4 is H, D, CH3, CH2CH3, OH, F, Cl, Br, or fluorinated alkyl. In some embodiments, R4 is H, D, Cl, Br, or F. In some embodiments, R4 is OH. [0186] In some embodiments, R4 is H, D, halogen, CN, alkyl, halogenated alkyl, ORa, or SRa. In some embodiments, R4 is H, D, halogen, CN, alkyl, or ORa. In some embodiments, R4 is H, D, F, Cl, Br, I, CN, OH, CH3, CH2CH3, OCH3, or CF3. In some embodiments, R4 is H, CN, F, or Cl. In some embodiments, R4 is Cl. In some embodiments, R4 is F. In some embodiments, R4 is CN. [0187] In some embodiments, R5 is H, D, halogen, CN, alkyl, halogenated alkyl, cycloalkyl, halogenated cycloalkyl, ORa, SRa, -C1-4alkyl-ORa, or -C1-4alkyl-SRa. In some embodiments, R5 is H, D, halogen, CN, CF3, CH2F, CHF2, ORa, SRa, -C1-4alkyl-ORa, or -C1-4alkyl-SRa. In some embodiments, R5 is alkyl or halogenated alkyl, each optionally substituted with 1-3 substituents selected from the group consisting of halogen, CN, ORx, -(CH2)1-2ORx, N(Rx)2, - (CH2)1-2N(Rx)2, (C=O)Rx, (C=O)N(Rx)2, NRx(C=O)Rx, and oxo where valence permits. In some embodiments, R5 is cycloalkyl or halogenated cycloalkyl, each optionally substituted with 1-3 substituents selected from the group consisting of halogen, CN, ORx, -(CH2)1-2ORx, N(Rx)2, -(CH2)1-2N(Rx)2, (C=O)Rx, (C=O)N(Rx)2, NRx(C=O)Rx, and oxo where valence permits. [0188] In some embodiments, R5 is H, D, or alkyl. In some embodiments, R5 is H, D, or alkyl, wherein the alkyl is optionally substituted by halogen, OH, oxo, or NH2 where valence permits. Non-limiting examples of alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, tert-butyl, sec-butyl, pentyl, hexyl, heptyl, and octyl. In some embodiments, R5 is cycloalkyl. Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. In some embodiments, R5 is halogen. Non- limiting examples of halogen include F, Cl, Br, and I. In some embodiments, R5 is halogenated alkyl. Non-limiting examples of halogenated alkyl include CF3, CH2F, CHF2, CH2Cl, CH2CF3, CHFCH3, CHFCH2F, CF2CH3, CHClCH3, CCl2CH3, CHBrCH3, CH2CH2CF3, and CHClCHClCH3. In some embodiments, R5 is halogenated cycloalkyl. Non-limiting examples of halogenated cycloalkyl include , , , . [0189] In some embodiments, R5 is ORa, SRa, -C1-4alkyl-ORa, or -C1-4alkyl-SRa. In some embodiments, R5 is ORa or SRa. In some embodiments, R5 is -C1-4alkyl-ORa or -C1-4alkyl- SRa. [0190] In some specific embodiments, R5 is OH, CH2OH, or CH2CH2OH. [0191] In some embodiments, R5 is selected from the group consisting of H, D, CH3, , , , . In some embodiments, R5 is selected from the group consisting of H, D, CH3, CH2CH3, CF2H, CH2F, CF3, CN, Cl, Br, F, OCH3, [0192] In some embodiments, R5 is selected from the group consisting of H, D, Cl, Br, F, I, some embodiments, R5 is H, D, CH3, CH2CH3, OH, F, Cl, Br, or fluorinated alkyl. In some embodiments, R5 is H, D, Cl, Br, or F. In some embodiments, R5 is OH. [0193] In some embodiments, R5 is H, D, halogen, CN, alkyl, halogenated alkyl, ORa, or SRa. In some embodiments, R5 is H, D, halogen, CN, alkyl, or ORa. In some embodiments, R5 is H, D, F, Cl, Br, I, CN, OH, CH3, CH2CH3, OCH3, or CF3. In some embodiments, R5 is H, F, Cl, Me, or OMe. In some embodiments, R5 is Cl. In some embodiments, R5 is F. In some embodiments, R5 is Me or OMe. In some embodiments, R4 and R5 are both F. In some embodiments, R4 and R5 are both Cl. In some embodiments, R4 and R5 are F and Me, respectively. In some embodiments, R4 and R5 are F and OMe, respectively. In some embodiments, R4 and R5 are CN and H, respectively. In some embodiments, R4 and R5 are CN and F, respectively. In some embodiments, R4 and R5 are F and H, respectively. In some embodiments, R4 and R5 are Cl and H, respectively. In some embodiments, R4 and R5 are H and F, respectively. In some embodiments, R4 and R5 are H and Cl, respectively. In some embodiments, R4 and R5 are F and Cl, respectively. In some embodiments, R4 and R5 are Cl and F, respectively. In some embodiments, R4 and R5 are both H. [0194] In some embodiments, R6 is H, D, halogen, CN, alkyl, halogenated alkyl, cycloalkyl, halogenated cycloalkyl, ORa, SRa, -C1-4alkyl-ORa, or -C1-4alkyl-SRa. In some embodiments, R6 is H, D, halogen, CN, CF3, CH2F, CHF2, ORa, SRa, -C1-4alkyl-ORa, or -C1-4alkyl-SRa. In some embodiments, R6 is alkyl or halogenated alkyl, each optionally substituted with 1-3 substituents selected from the group consisting of halogen, CN, ORx, -(CH2)1-2ORx, N(Rx)2, - (CH2)1-2N(Rx)2, (C=O)Rx, (C=O)N(Rx)2, NRx(C=O)Rx, and oxo where valence permits. In some embodiments, R6 is cycloalkyl or halogenated cycloalkyl, each optionally substituted with 1-3 substituents selected from the group consisting of halogen, CN, ORx, -(CH2)1-2ORx, N(Rx)2, -(CH2)1-2N(Rx)2, (C=O)Rx, (C=O)N(Rx)2, NRx(C=O)Rx, and oxo where valence permits. [0195] In some embodiments, R6 is H, D, or alkyl. In some embodiments, R6 is H, D, or alkyl, wherein the alkyl is optionally substituted by halogen, OH, oxo, or NH2 where valence permits. Non-limiting examples of alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, and octyl. In some embodiments, R6 is cycloalkyl. Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. In some embodiments, R6 is halogen. Non- limiting examples of halogen include F, Cl, Br, and I. In some embodiments, R6 is halogenated alkyl. Non-limiting examples of halogenated alkyl include CF3, CH2F, CHF2, CH2Cl, CH2CF3, CHFCH3, CHFCH2F, CF2CH3, CHClCH3, CCl2CH3, CHBrCH3, CH2CH2CF3, and CHClCHClCH3. In some embodiments, R6 is halogenated cycloalkyl. Non-limiting examples of halogenated cycloalkyl include , , , . [0196] In some embodiments, R6 is ORa, SRa, -C1-4alkyl-ORa, or -C1-4alkyl-SRa. In some embodiments, R6 is ORa or SRa. In some embodiments, R6 is -C1-4alkyl-ORa or -C1-4alkyl- SRa. [0197] In some specific embodiments, R6 is OH, CH2OH, or CH2CH2OH. [0198] In some embodiments, R6 is selected from the group consisting of H, D, CH3, , , , . In some embodiments, R6 is selected from the group consisting of H, D, CH3, CH2CH3, CF2H, CH2F, CF3, CN, Cl, Br, F, OCH3, [0199] In some embodiments, R6 is selected from the group consisting of H, D, Cl, Br, F, I, some embodiments, R6 is H, D, CH3, CH2CH3, OH, F, Cl, Br, or fluorinated alkyl. In some embodiments, R6 is H, D, Cl, Br, or F. In some embodiments, R6 is OH. [0200] In some embodiments, R6 is H, D, halogen, CN, alkyl, halogenated alkyl, ORa, or SRa. In some embodiments, R6 is H, D, halogen, CN, alkyl, or ORa. In some embodiments, R6 is H, D, F, Cl, Br, I, CN, OH, CH3, CH2CH3, OCH3, or CF3. In some embodiments, R6 is F. In some embodiments, R6 is H. In some embodiments, R4 and R6 are both F. [0201] In some embodiments, R7 is H, D, halogen, CN, alkyl, halogenated alkyl, cycloalkyl, halogenated cycloalkyl, ORa, SRa, -C1-4alkyl-ORa, or -C1-4alkyl-SRa. In some embodiments, R7 is H, D, halogen, CN, CF3, CH2F, CHF2, ORa, SRa, -C1-4alkyl-ORa, or -C1-4alkyl-SRa. In some embodiments, R7 is alkyl or halogenated alkyl, each optionally substituted with 1-3 substituents selected from the group consisting of halogen, CN, ORx, -(CH2)1-2ORx, N(Rx)2, - (CH2)1-2N(Rx)2, (C=O)Rx, (C=O)N(Rx)2, NRx(C=O)Rx, and oxo where valence permits. In some embodiments, R7 is cycloalkyl or halogenated cycloalkyl, each optionally substituted with 1-3 substituents selected from the group consisting of halogen, CN, ORx, -(CH2)1-2ORx, N(Rx)2, -(CH2)1-2N(Rx)2, (C=O)Rx, (C=O)N(Rx)2, NRx(C=O)Rx, and oxo where valence permits. [0202] In some embodiments, R7 is H, D, or alkyl. In some embodiments, R7 is H, D, or alkyl, wherein the alkyl is optionally substituted by halogen, OH, oxo, or NH2 where valence permits. Non-limiting examples of alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, and octyl. In some embodiments, R7 is cycloalkyl. Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. In some embodiments, R7 is halogen. Non- limiting examples of halogen include F, Cl, Br, and I. In some embodiments, R7 is halogenated alkyl. Non-limiting examples of halogenated alkyl include CF3, CH2F, CHF2, CH2Cl, CH2CF3, CHFCH3, CHFCH2F, CF2CH3, CHClCH3, CCl2CH3, CHBrCH3, CH2CH2CF3, and CHClCHClCH3. In some embodiments, R7 is halogenated cycloalkyl. [0203] In some embodiments, R7 is ORa, SRa, -C1-4alkyl-ORa, or -C1-4alkyl-SRa. In some embodiments, R7 is ORa or SRa. In some embodiments, R7 is -C1-4alkyl-ORa or -C1-4alkyl- SRa. [0204] In some specific embodiments, R7 is OH, CH2OH, or CH2CH2OH. [0205] In some embodiments, R7 is selected from the group consisting of H, D, CH3, from the group consisting of H, D, CH3, CH2CH3, CF2H, CH2F, CF3, CN, Cl, Br, F, OCH3, [0206] In some embodiments, R7 is selected from the group consisting of H, D, Cl, Br, F, I, CN, CH3, CH2CH3, CF3, CH2CH2CH3, CH(CH3)2, In some embodiments, R7 is H, D, CH3, CH2CH3, OH, F, Cl, Br, or fluorinated alkyl. In some embodiments, R7 is H, D, Cl, Br, or F. In some embodiments, R7 is OH. [0207] In some embodiments, R7 is H, D, halogen, CN, alkyl, halogenated alkyl, ORa, or SRa. In some embodiments, R7 is H, D, halogen, CN, alkyl, or ORa. In some embodiments, R7 is H, D, F, Cl, Br, I, CN, OH, CH3, CH2CH3, OCH3, or CF3. In some embodiments, R7 is F. In some embodiments, R7 is H. In some embodiments, R4 and R7 are both F. In some embodiments, R4, R5, and R7 are F. [0208] In some embodiments, the structural moiety selected from the group [0209] In some embodiments, R1 is alkyl, cycloalkyl, -C1-4alkyl-cycloalkyl, bicycloalkyl, saturated heterocycle, aryl, heteroaryl, or cycloalkenyl; wherein R1 is optionally substituted by 1-5 substituents each independently selected from the group consisting of D, halogen, alkyl, and halogenated alkyl where valence permits; R2 is CN, alkyl, ORa, SRa, -C1-4alkyl- ORa, or -O-C1-4alkyl-ORa; R3 is –(CH2)mCONRaRb, –(CH2)mC(=O)Ra, –CH2CH(OH)R10, – CH2CH(OH)CH2OH, –CH2SORa, –CH2SO2Ra, –(CH2)m-heterocycle, or –(CH2)m-heteroaryl; R4 is H, D, halogen, CN, or alkyl; R5 is H, D, halogen, alkyl, or ORa; R6 is H, D, or halogen; R7 is H, D, or halogen; m is 1 or 2; and R10 is H, D, or alkyl. [0210] In some embodiments, the compound of Formula I has the structure of Formula IIa:
wherein R11 is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogenated cycloalkyl, or halogenated alkyl; R12 is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogenated cycloalkyl, or halogenated alkyl; R13 is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogenated cycloalkyl, or halogenated alkyl; R14 is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogenated cycloalkyl, or halogenated alkyl; and R15 is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogenated cycloalkyl, or halogenated alkyl. [0211] In some embodiments, R2, R3, R4, R5, R6, and R7 in Formula IIa are as defined above for the compound of Formula I in one or more embodiments described above. Other substituents are defined herein. [0212] In some embodiments, at least one of R11, R12, R13, R14, and R15 is not H. In some embodiments, at least two of R11, R12, R13, R14, and R15 are not H. In some embodiments, at least one of R11, R12, R13, R14, and R15 is H, D, alkyl, halogenated alkyl, or halogen. In some embodiments, at least one of R11, R12, R13, R14, and R15 is H, D, halogen, fluorinated alkyl, alkyl, alkenyl, or alkynyl. In some embodiments, at least one of R11, R12, R13, R14, and R15 is CH3, CH2CH3, F, Cl, Br, CF3, C≡CH, or . In some embodiments, at least one of R11, R12, R13, R14, and R15 is H, Me, Et, i-Pr, n-Bu, CF2H, CF2Cl, or CF3. In some embodiments, at least one of R11, R12, R13, R14, and R15 is Cl, F, Br, or I. In some embodiments, at least one of R11, R12, R13, R14, and R15 is Cl. In some embodiments, at least one of R11, R12, R13, R14, and R15 is CF3, CH2F, CH2Cl, CH2CF3, CHFCH3, CHFCH2F, CF2CH3, CHClCH3, CCl2CH3, CHBrCH3, CH2CH2CF3, or CHClCHClCH3. In some embodiments, at least one of R11, R12, R13, R14, and R15 some embodiments, at least one of R11, R12, R13, R14, and R15 is ethylenyl, propenyl, 2-propenyl, (E)-but-2-enyl, (Z)-but- 2-enyl, 2-methyl(E)-but-2-enyl, 2-methyl(Z)-but-2-enyl, 2,3-dimethyl-but-2-enyl, (Z)-pent-2- enyl, or (E)-pent-1-enyl. In some embodiments, at least one of R11, R12, R13, R14, and R15 25 is ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, pent-1-ynyl, pent-2-ynyl, hex-1- ynyl, hex-2-ynyl, or hex-3-ynyl. In some embodiments, at least two of R11, R12, R13, R14, and R15 are independently selected from the group consisting of CH3, CH2CH3, F, Cl, Br, CF3, [0213] In some embodiments, R11 is H, D, F, Cl, Br, I, alkyl, or halogenated alkyl; R12 is H, D, F, Cl, Br, I, alkyl, or halogenated alkyl; R13 is H, D, F, Cl, Br, I, alkyl, or halogenated alkyl; R14 is H, D, F, Cl, Br, I, alkyl, or halogenated alkyl; and R15 is H, D, F, Cl, Br, I, alkyl, or halogenated alkyl. [0214] In some embodiments, R11, R12, R14, and R15 are H; and R13 is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogenated cycloalkyl, or halogenated alkyl. In some embodiments, R11, R12, R14, and R15 are H; and R13 is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, or CF3. In certain embodiments, R11, R12, R14, and R15 are H; and R13 is H or D. In certain embodiments, R11, R12, R14, and R15 are H; and R13 is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, or CF3. In certain embodiments, R11, R12, R14, and R15 are H; and R13 is H, D, halogen, or alkyl. In certain embodiments, R11, R12, R14, and R15 are H; and R13 is halogen. Non-limiting examples of alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, and octyl. Non-limiting examples of alkenyl include ethylenyl, propenyl, 2-propenyl, (E)-but-2-enyl, (Z)-but-2-enyl, 2-methyl(E)- but-2-enyl, 2-methyl(Z)-but-2-enyl, 2,3-dimethyl-but-2-enyl, (Z)-pent-2-enyl, (E)-pent-1- enyl, (Z)-hex-1-enyl, (E)-pent-2-enyl, (Z)-hex-2-enyl, (E)-hex-2-enyl, (Z)-hex-1-enyl, (E)- hex-1-enyl, (Z)-hex-3-enyl, (E)-hex-3-enyl, and (E)-hex-1,3-dienyl. Non-limiting examples of alkynyl include ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, pent-1-ynyl, pent-2-ynyl, hex-1-ynyl, hex-2-ynyl, or hex-3-ynyl. Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Non-limiting examples of halogen include F, Cl, Br, and I. [0215] In some embodiments, R13 is alkyl (e.g., CH3 or CH2CH3,), halogen (e.g., F, Cl, or Br), halogenated alkyl (e.g., CF3), CN, alkynyl (e.g., C≡CH), or cycloalkyl (e.g., ). In some embodiments, R13 is CH3, CH2CH3, F, Cl, Br, CF3, C≡CH, or . In certain embodiments, R13 is halogen (e.g., F, Cl, or Br). In some embodiments, R13 is Cl. In some embodiments, R13 is Br. In some embodiments, R13 is F. In some embodiments, R13 is CF3. [0216] In some embodiments, R11, R12, R14, and R15 are H; and R13 is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, or CF3. In some embodiments, R11, R12, R14, and R15 are H; and some embodiments, R11, R12, R14, and R15 are H; and R13 is halogen. In some embodiments, R11, R12, R14, and R15 are H; and R13 is Cl. In some embodiments, R11, R12, R14, and R15 are H; and R13 is F. In some embodiments, R11, R12, R14, and R15 are H; and R13 is Br. In some embodiments, R11, R12, R14, and R15 are H; and R13 is CF3. [0217] In some embodiments, R11, R12, R13, and R15 are H; and R14 is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, or CF3. In some embodiments, R11, R12, R13, and R15 are H; and some embodiments, R11, R12, R13, and R15 are H; and R14 is halogen. In some embodiments, R11, R12, R13, and R15 are H; and R14 is Cl. In some embodiments, R11, R12, R13, and R15 are H; and R14 is F. In some embodiments, R11, R12, R13, and R15 are H; and R14 is Br. In some embodiments, R11, R12, R13, and R15 are H; and R14 is CF3. [0218] In some embodiments, the compound of Formula I has the structure of Formula IIb: wherein is alkyl, cycloalkyl, cycloalkenyl, bicycloalkyl, heteroaryl, or saturated heterocycle, each of which optionally substituted by 1-5 substituents each independently selected from the group consisting of D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogenated cycloalkyl, and halogenated alkyl where valence permits. [0219] In some embodiments, R2, R3, R4, R5, R6, and R7 in Formula IIb are as defined above for the compound of Formula I in one or more embodiments described herein. Other substituents are defined herein. [0220] In some embodiments, is alkyl, cycloalkyl, -CH2-cycloalkyl, cycloalkenyl, bicycloalkyl, heteroaryl, or saturated heterocycle, each of which optionally substituted by 1-5 substituents each independently selected from the group consisting of D, alkyl, halogen, and halogenated alkyl where valence permits. [0221] In some embodiments, is alkyl that is optionally substituted by 1-5 substituents each independently selected from the group consisting of D, halogen, alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, alkenyl, and alkynyl, where valence permits. In some embodiments, is alkyl that is optionally substituted by D or halogen (e.g., F, Cl, Br, and I). Non-limiting examples of alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, and octyl. [0222] In some embodiments, is cycloalkyl, -CH2-cycloalkyl, cycloalkenyl, or bicycloalkyl, each of which optionally substituted by 1-5 substituents each independently selected from the group consisting of D, halogen, alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, alkenyl, and alkynyl where valence permits. In some embodiments, is cycloalkyl, bicycloalkyl, or -CH2-cycloalkyl, each of which optionally substituted by 1-5 substituents each independently selected from the group consisting of D, alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, pentyl, hexyl, heptyl, and octyl), halogen (e.g., F, Cl, Br, and I), and halogenated alkyl (e.g., CF3, CH2F, CHF2, CH2Cl, CH2CF3, CHFCH3, CHFCH2F, CF2CH3, CHClCH3, CCl2CH3, CHBrCH3, CH2CH2CF3, and CHClCHClCH3) where valence permits. In some embodiments, is cycloalkyl, bicycloalkyl, or -CH2-cycloalkyl, each of which optionally substituted by 1-5 substituents each independently selected from the group consisting of D, CH3, CH2CH3, F, Cl, Br, CH2F, and CF3 where valence permits. In some embodiments, is cycloalkyl that is optionally substituted by 1-5 substituents each independently selected from the group consisting of D, CH3, CH2CH3, F, Cl, Br, CH2F, and CF3 where valence permits. In some embodiments, is -CH2-cycloalkyl that is optionally substituted by 1-5 substituents each independently selected from the group consisting of D, CH3, CH2CH3, F, Cl, Br, CH2F, and CF3 where valence permits. Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. In some embodiments, bicycloalkyl that is optionally substituted by 1-5 substituents each independently selected from the group consisting of D, CH3, CH2CH3, F, Cl, Br, CH2F, and CF3. Non-limiting examples of bicycloalkyl include bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.1.1]hexyl, octahydropentalenyl, bicyclo[3.2.1]octyl, bicyclo[3.3.3]undecanyl, decahydronaphthalenyl, bicyclo[3.2.0]heptyl, octahydro-1H- indenyl, bicyclo[4.2.1]nonanyl, spiro[4.4]nonyl, spiro[3.3]heptyl, spiro[5.5]undecyl, spiro[3.5]nonyl, and spiro[4.5]decyl. In some embodiments, is cycloalkenyl that is optionally substituted by 1-5 substituents each independently selected from the group consisting of D, CH3, CH2CH3, F, Cl, Br, CH2F, and CF3, where valence permits. Non- limiting examples of cycloalkenyl include cyclobutenyl, cyclopentenyl, and cyclohexenyl. In some embodiments, is selected from the group consisting of , , , , , , , , , , , each of which optionally substituted by 1-5 substituents each independently selected from the group consisting of D, CH3, CH2CH3, F, Cl, Br, CH2F, and CF3. [0223] In some embodiments, is 4-, 5-, 6- or 7-membered saturated heterocycle or heteroaryl, each containing 1-3 heteroatoms each selected from the group consisting of N, O, and S, each optionally substituted by 1-5 substituents each independently selected from the group consisting of D, halogen, alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, alkenyl, and alkynyl where valence permits. In further embodiments, is selected from wherein each is optionally substituted by 1-5 substituents each independently selected from the group consisting of D, alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec- butyl, pentyl, hexyl, heptyl, and octyl), halogen (e.g., F, Cl, Br, and I), and halogenated alkyl (e.g., CF3, CH2F, CHF2, CH2Cl, CH2CF3, CHFCH3, CHFCH2F, CF2CH3, CHClCH3, CCl2CH3, CHBrCH3, CH2CH2CF3, and CHClCHClCH3) where valence permits. [0224] In some specific embodiments, is pyridine, pyrimidine, furan, or thiophene, each of which optionally substituted with halogen or alkyl. In other specific embodiments, is thiane or pyrane, each of which optionally substituted with halogen or alkyl. In some specific embodiments, is selected from the group consisting of , [0225] In some embodiments, the compound of Formula I has the structure of Formula III: wherein X is O or S; and R16 is C1-4alkyl that is optionally substituted with halogen, ORa, SRa, or NRaRb. [0226] In some embodiments, R1, R3, R4, R5, R6, and R7 in Formula III are as defined above for the compound of Formula I in one or more embodiments described above. Other substituents are defined herein. [0227] In some embodiments, X is O. In some embodiments, X is S. [0228] In some embodiments, R16 is methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, or sec-butyl, each of which optionally substituted with halogen, ORa, SRa, or NRaRb. In some embodiments, R16 is methyl, ethyl, propyl, or isopropyl, each of which optionally substituted with OH or OCH3. In some specific embodiments, R16 is CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2OH, CH2CH2CH2OH, CH2CH2OCH3, CH2CH2CH2OCH3, CH(CH3)CH2OH, or CH(CH3)CH2OCH3. [0229] In some embodiments, R1 is phenyl that is optionally substituted by 1-5 substituents each independently selected from the group consisting of D, halogen, alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, alkenyl, and alkynyl In some embodiments, R1 is phenyl that is optionally substituted by 1-5 substituents each independently selected from the group consisting of D, F, Cl, Br, I, alkyl, and halogenated alkyl. [0230] In some embodiments, R1 is alkyl, cycloalkyl, -CH2-cycloalkyl, cycloalkenyl, bicycloalkyl, heteroaryl, or saturated heterocycle, each of which optionally substituted by 1-5 substituents each independently selected from the group consisting of D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogenated cycloalkyl, and halogenated alkyl where valence permits. In some embodiments, R1 is alkyl, cycloalkyl, -CH2-cycloalkyl, cycloalkenyl, bicycloalkyl, heteroaryl, or saturated heterocycle, each of which optionally substituted by 1-5 substituents each independently selected from the group consisting of D, alkyl, halogen, and halogenated alkyl where valence permits. In some specific embodiments, R1 is pyridine, pyrimidine, furan, or thiophene, each of which optionally substituted with halogen or alkyl. In some other specific embodiments, R1 is thiane or pyrane, each of which optionally substituted with halogen or alkyl. In some specific embodiments, R1 is selected from the , [0231] In some embodiments, the compound of Formula I has the structure of Formula IV: . [0232] In some embodiments, R1, R2, R4, R5, R6, and R7 in Formula IV are as defined above for the compound of Formula I in one or more embodiments described above. Other substituents are defined herein. [0233] In some embodiments, R1 is phenyl that is optionally substituted by 1-5 substituents each independently selected from the group consisting of D, halogen, alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, alkenyl, and alkynyl. In some embodiments, R1 is phenyl that is optionally substituted by 1-5 substituents each independently selected from the group consisting of D, F, Cl, Br, I, alkyl, and halogenated alkyl. [0234] In some embodiments, R1 is alkyl, cycloalkyl, -CH2-cycloalkyl, cycloalkenyl, bicycloalkyl, heteroaryl, or saturated heterocycle, each of which optionally substituted by 1-5 substituents each independently selected from the group consisting of D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogenated cycloalkyl, and halogenated alkyl where valence permits. In some embodiments, R1 is alkyl, cycloalkyl, -CH2-cycloalkyl, cycloalkenyl, bicycloalkyl, heteroaryl, or saturated heterocycle, each of which optionally substituted by 1-5 substituents each independently selected from the group consisting of D, alkyl, halogen, and halogenated alkyl where valence permits. In some specific embodiments, R1 is pyridine, pyrimidine, furan, or thiophene, each of which optionally substituted with halogen or alkyl. In some other specific embodiments, R1 is thiane or pyrane, each of which optionally substituted with halogen or alkyl. In some specific embodiments, R1 is selected from the [0235] In some embodiments, the compound of Formula I has the structure of Formula V: wherein X is O or S; and R16 is C1-4alkyl that is optionally substituted with halogen, ORa, SRa, or NRaRb. [0236] In some embodiments, R1, R4, R5, R6, and R7 in Formula V are as defined above for the compound of Formula I in one or more embodiments described above. In some embodiments, X and R16 in Formula V are as defined above for the compound of Formula III in one or more embodiments described above. Other substituents are defined herein. [0237] In some embodiments, R1 is phenyl that is optionally substituted by 1-5 substituents each independently selected from the group consisting of D, halogen, alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, alkenyl, and alkynyl. In some embodiments, R1 is phenyl that is optionally substituted by 1-5 substituents each independently selected from the group consisting of D, F, Cl, Br, I, alkyl, and halogenated alkyl. [0238] In some embodiments, R1 is alkyl, cycloalkyl, -CH2-cycloalkyl, cycloalkenyl, bicycloalkyl, heteroaryl, or saturated heterocycle, each of which optionally substituted by 1-5 substituents each independently selected from the group consisting of D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogenated cycloalkyl, and halogenated alkyl where valence permits. In some embodiments, R1 is alkyl, cycloalkyl, -CH2-cycloalkyl, cycloalkenyl, bicycloalkyl, heteroaryl, or saturated heterocycle, each of which optionally substituted by 1-5 substituents each independently selected from the group consisting of D, alkyl, halogen, and halogenated alkyl where valence permits. In some specific embodiments, R1 is pyridine, pyrimidine, furan, or thiophene, each of which optionally substituted with halogen or alkyl. In some other specific embodiments, R1 is thiane or pyrane, each of which optionally substituted with halogen or alkyl. In some specific embodiments, R1 is selected from the [0239] In some embodiments, the compound is a compound of Formula V, R1 is cycloalkyl or phenyl; wherein the cycloalkyl or phenyl in R1 is optionally substituted by 1-5 substituents each of which is independently D or halogen where valence permits; X is O; R16 is C1-4alkyl that is optionally substituted with halogen, ORa, SRa, or NRaRb where valence permits; R4 is H, D, or halogen; R5 is H, D, halogen, or ORa; R6 is H, D, or halogen; R7 is H, D, or halogen, and Ra and Rb are each independently H or Me. Ra or Rb for the compounds of Formulae I, IIa, IIb, III, IV, and V [0240] The following description of Ra or Rb is applicable for any one or more of the compounds of Formulae I, IIa, IIb, III, IV, and V. In some embodiments, at least one occurrence of Ra or Rb is independently H, D, alkyl, cycloalkyl, saturated heterocycle, aryl, or heteroaryl. In some embodiments, at least one occurrence of Ra or Rb is independently H, D, alkyl, or cycloalkyl. In some embodiments, at least one occurrence of Ra or Rb is independently saturated heterocycle, aryl, or heteroaryl. [0241] In some embodiments, at least one occurrence of Ra or Rb is independently H, D, heterocycle or heteroaryl is optionally substituted by alkyl, OH, oxo, or (C=O)C1-4alkyl where valence permits. In some embodiments, at least one occurrence of Ra or Rb is substituted by alkyl, OH, oxo, or (C=O)C1-4alkyl where valence permits. In some embodiments described herein, at least one occurrence of Ra or Rb is H, Me, phenyl, , . In some embodiments described herein, Ra and Rb are both H. [0242] In some embodiments, Ra and Rb, together with the nitrogen atom that they are connected to, form an optionally substituted heterocycle comprising the nitrogen atom and 0- 3 additional heteroatoms each selected from the group consisting of N, O, and S. Non- Rx for the compounds of Formulae I, IIa, IIb, III, IV, and V [0243] The following description of Rx is applicable for any one or more of the compounds of Formulae I, IIa, IIb, III, IV, and V. [0244] In some embodiments, for a compound of any of Formulae I, IIa, IIb, III, IV, and V described herein, each occurrence of Rx is independently H, alkyl, or heterocycle optionally substituted by alkyl, halogen, or OH where valence permits. In some embodiments, each occurrence of Rx is independently H or alkyl. Non-limiting examples of alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, and octyl. In some embodiments, at least one occurrence of Rx is optionally substituted heterocycle or optionally substituted heteroaryl. Non-limiting examples of heterocycle or groups, together with the nitrogen atom that they are connected to, form an optionally substituted heterocycle including the nitrogen atom and 0-3 additional heteroatoms each selected from the group consisting of N, O, and S. In some embodiments, each occurrence of Rx is independently H or Me. [0245] In some embodiments, the compound of Formula I, IIa, IIb, III, IV, or V is selected from the group consisting of compounds 1-74 in Table 2. In some embodiments, the compound of Formula I, IIa, IIb, III, IV, or V is selected from the group consisting of compounds 2, 4, 5, 6, 9, 12, 14, 17, 18, 19, 20, 22, 23, 25, 26, 28, 29, 30, 31, 32, 33, 34, 35, 37, 38, 41, 42, 43, 44, 45, 46, 48, 49, 50, 51, 52, 53, 54, 56, 57, 60, 61, 62, 64, 65, 66, 71, 73, and 74 in Table 2. In some embodiments, the compound i ,
Formula I, IIa, IIb, III, IV, or V is not in a salt form or a tautomer form. In some embodiments, the compound is any one of the compounds described herein, or pharmaceutically acceptable salts thereof or an enantiomer thereof. [0246] The enumerated compounds in Tables 2 and Examples 1-20 are representative and non-limiting compounds of the embodiments disclosed herein. In some embodiments, the compound is any one of the compounds described herein, or pharmaceutically acceptable salts thereof or an enantiomer thereof.
Methods of Preparation [0247] Following are general synthetic schemes for manufacturing compounds of the present invention. These schemes are illustrative and are not meant to limit the possible techniques one skilled in the art may use to manufacture the compounds disclosed herein. Different methods will be evident to those skilled in the art. Additionally, the various steps in the synthesis may be performed in an alternate sequence or order to give the desired compound(s). All documents cited herein are incorporated herein by reference in their entirety. For example, the following reactions are illustrations, but not limitations of the preparation of some of the starting materials and compounds disclosed herein. [0248] Schemes 1-6 below describe synthetic routes which may be used for the synthesis of compounds of the present invention, e.g., compounds having a structure of Formula I, IIa, IIb, III, IV, or V, or a precursor thereof. Various modifications to these methods may be envisioned by those skilled in the art to achieve similar results to that of the embodiments given below. In the embodiments below, the synthetic route is described using compounds having the structure of Formula I, IIa, IIb, III, IV, or V, or a precursor thereof as examples. The general synthetic routes described in Schemes 1-6 and examples described in the Example section below illustrate methods used for the preparation of the compounds described herein. [0249] One route to synthesize indolinones of structure I-1 is carried out by introducing the groups R1, R2 and R3 sequentially starting from either a suitably substituted isatin I-2 or a suitably substituted indolinone I-3 (see Scheme 1). Many isatins and indolinones are known compounds that are commercial or can be prepared by known methods in the art. [0250] The group R1 can be introduced as shown in Scheme 1. Reaction of isatin I-2 with a Grignard reagent R1MgBr in an ether solvent such as THF gives the 3-hydroxyindolinone I-4. Removal of the hydroxy group in I-4 may be carried out by treatment with a silane reducing agent such as triethylsilane and an acid such as TFA, optionally with a cosolvent such as DCM, to give indolinone I-5. The OH may also be removed by converting to chlorine with thionyl chloride and reduction with zinc. A more direct way to obtain I-5 when R1 is aryl is through reaction of indolinone I-3 with an aryl halide R1Br using a palladium catalyst such as the Xphos 3rd generation catalyst, Xphos ligand, and a base such as potassium carbonate in a solvent such as dioxane. [0251] For compounds where R1 is alkyl or heterocycle, the R1 group can be introduced by condensation of indolinone I-3 with a suitable ketone or aldehyde precursor to give vinyl indolinone I-6. The condensation can be carried out with a base such as triethylamine or piperidine, or with a Lewis acid such as titanium tetraisopropoxide. Reduction of the double bond by hydrogenation over a suitable catalyst such as palladium on carbon provides I-5. In some cases, a reducing agent such as sodium borohydride in ethanol can be used to convert I- 6 to I-5.
[0252] For compounds where R1 is aryl and R2 is alkyl, the R2 group can be introduced as shown in Scheme 2 by alkylation of I-5 with R2X, where X is Br or I, in the presence of a base such as potassium carbonate, cesium carbonate, or sodium hydride in a solvent such as DMF to form I-7. When R1 is alkyl, it is often necessary to protect the indole nitrogen before alkylation. A suitable protecting group such as Boc can be added by treating I-5 with di-t- butyl decarbonate, dimethylaminopyridine, and a base such as triethylamine in a solvent such as DCM to give I-8. Alkylation of I-8 is carried out in the same manner as I-5, and the protecting group such as Boc is removed by treatment with an acid such as TFA in DCM to give I-7. When R2 is cyano group, reaction of I-5 with benziodaoxazole-1-carbonitrile in a solvent such as DMF provides I-9.
[0253] Compounds where R2 is alkoxy or alkylthio may be prepared as shown in Scheme 3. Reaction of I-5 with an alcohol R16OH, also used as solvent, and an oxidizing agent such as ceric ammonium nitrate (CAN) or bis(trifluoroacetoxy)iodobenzene gives I-10 directly. Alternatively, hydroxy indolinone I-4 can be treated with R16OH and an acid such as p- toluene sulfonic acid and heating to give I-10. Another approach is alkylation of I-4 with R16X and silver oxide in a solvent such as acetonitrile. Both I-5 and I-4 can be converted to the 3-halo indolinone I-11. Reaction of I-5 with phenyltrimethylammonium tribromide in DCM gives I-11 where X is Br. Similarly, reaction of I-4 with thionyl chloride gives I-11 where X is Cl. Treatment of I-5 with an alcohol R16OH and a base such as NaOR16 converts I-5 to I-10. Compounds where R2 is SR16 can be obtained by heating I-4 with a thiol R16SH and an acid such as p-toluene sulfonic acid in a solvent such as toluene to form I-12.
[0254] Another route to synthesize compounds where R2 is alkoxy is shown in Scheme 4. Monobromination of a suitably substituted indole I-13 gives the 3-bromo indole I-14. The R1 group is introduced by Suzuki reaction of I-14 and a suitable boronic acid in the presence of a palladium catalyst such as Pd(dppf)Cl2 and a base such as sodium carbonate in a solvent such as dioxane and water to provide I-15. Reaction of I-15 with t-butyl hypochlorite and an aqueous acid, for example, sulfuric acid, in a mixed solvent containing DCM and dioxane forms the 3-chloro indolinone I-11a. Treatment of I-11a with an alcohol R16OH and NaOR16 as above gives the 3-alkoxy indolinone I-10.
[0255] An alternative method to make indolinone I-5 where R1 is aryl is shown in Scheme 5, along with a way to obtain enantiomerically enriched 3-alkoxy-indolinones. A suitably substituted 2-fluoronitrobenezene I-16 undergoes SNAr reaction with an arylacetic ester in the presence of a base such as potassium t-butoxide in a solvent such as THF at low temperature, for example, -78 ºC to give I-17. Reduction of the nitro group by hydrogenation over a catalyst such as palladium on carbon in a solvent such as THF followed by cyclization with aqueous acid in the same solvent provides indolinone I-5. The anion of I-5 is formed using a base such as potassium hexamethyldisilazide in a solvent such as THF at low temperature and reacted with the (S)-Davis chiral oxaziridine I-18 to give the 3-hydroxyindolinone I-4S enriched in the S-enantiomer. [0256] In this sequence, it is preferable to add the R3 group first by alkylation with R3X (X = I or Br) in the presence of a base such as potassium carbonate in a solvent such as DMF to give I-19S and then alkylate the OH group using R16X under similar conditions to obtain the 3-alkoxy indolinone I-20S, predominantly as the S enantiomer.
[0257] In most cases, the R3 group can be added in the last step by alkylation of I-7 with R3Br or R3I and a base such as potassium carbonate as shown in Scheme 6. Pharmaceutical Compositions [0258] This invention also provides a pharmaceutical composition comprising at least one of the compounds as described herein or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier or diluent. [0259] In yet another aspect, the present invention provides a pharmaceutical composition comprising at least one compound selected from the group consisting of compounds of Formula I, IIa, IIb, III, IV, or V, as described herein and a pharmaceutically acceptable carrier or diluent. [0260] In certain embodiments, the compound in the composition is in the form of a hydrate, solvate, or pharmaceutically acceptable salt. The composition can be administered to the subject by any suitable route of administration, including, without limitation, oral and parenteral. [0261] The phrase “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, involved in carrying or transporting the subject pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose, and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols, such as butylene glycol; polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer’s solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances employed in pharmaceutical formulations. The term “carrier” denotes an organic or inorganic ingredient, natural or synthetic, with which the active ingredient is combined to facilitate the application. The components of the pharmaceutical compositions also are capable of being comingled with the compounds of the present invention, and with each other, in a manner such that there is no interaction which would substantially impair the desired pharmaceutical efficiency. [0262] As set out above, certain embodiments of the present pharmaceutical agents may be provided in the form of pharmaceutically acceptable salts. The term “pharmaceutically acceptable salt,” as used herein, refers to the relatively non-toxic, inorganic and organic acid salts of compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or by separately reacting a purified compound of the invention in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts, and the like. See, e.g., Berge et al., (1977) “Pharmaceutical Salts”, J. Pharm. Sci.66:1-19 (incorporated herein by reference in its entirety). [0263] The pharmaceutically acceptable salts of the subject compounds include the conventional nontoxic salts or quaternary ammonium salts of the compounds, e.g., from non- toxic organic or inorganic acids. For example, such conventional nontoxic salts include those derived from inorganic acids such as hydrochloride, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like; and the salts prepared from organic acids such as acetic, butionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, palmitic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicyclic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isothionic, and the like. [0264] In other cases, the compounds of the present invention may contain one or more acidic functional groups and, thus, are capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases. The term “pharmaceutically acceptable salts” in these instances refers to the relatively non-toxic, inorganic and organic base addition salts of compounds of the present invention. These salts can likewise be prepared in situ during the final isolation and purification of the compounds, or by separately reacting the purified compound in its free acid form with a suitable base, such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, or tertiary amine. Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts, and the like. Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. See, e.g., Berge et al. (supra). [0265] Wetting agents, emulsifiers, and lubricants, such as sodium lauryl sulfate, magnesium stearate, and polyethylene oxide-polybutylene oxide copolymer, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives, and antioxidants can also be present in the compositions. [0266] Formulations of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal, and/or parenteral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated and the particular mode of administration. The amount of active ingredient, which can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of 100%, this amount will range from about 1% to about 99% of active ingredient, preferably from about 5% to about 70%, most preferably from about 10% to about 30%. [0267] Methods of preparing these formulations or compositions include the step of bringing into association a compound of the present invention with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product. [0268] Formulations of the invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia), and/or as mouthwashes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient. A compound of the present invention may also be administered as a bolus, electuary or paste. [0269] In solid dosage forms of the invention for oral administration (capsules, tablets, pills, dragees, powders, granules, and the like), the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and/or acacia; humectants, such as glycerol; disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, sodium carbonate, and sodium starch glycolate; solution retarding agents, such as paraffin; absorption accelerators, such as quaternary ammonium compounds; wetting agents, such as, for example, cetyl alcohol, glycerol monostearate, and polyethylene oxide-polybutylene oxide copolymer; absorbents, such as kaolin and bentonite clay; lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and coloring agents. In the case of capsules, tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like. [0270] A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxybutylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. [0271] The tablets, and other solid dosage forms of the pharmaceutical compositions of the present invention, such as dragees, capsules, pills, and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxybutylmethyl cellulose in varying proportions, to provide the desired release profile, other polymer matrices, liposomes, and/or microspheres. They may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions, which can be dissolved in sterile water or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions, which can be used include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients. [0272] Liquid dosage forms for oral administration of the compounds of the invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isobutyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, butylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Additionally, cyclodextrins, e.g., hydroxybutyl-β-cyclodextrin, may be used to solubilize compounds. [0273] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming, and preservative agents. [0274] Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar, and tragacanth, and mixtures thereof. [0275] Dosage forms for the topical or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required. [0276] The ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof. [0277] Powders and sprays can contain, in addition to a compound of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and butane. [0278] Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body. Such dosage forms can be made by dissolving or dispersing the pharmaceutical agents in the proper medium. Absorption enhancers can also be used to increase the flux of the pharmaceutical agents of the invention across the skin. The rate of such flux can be controlled, by either providing a rate-controlling membrane or dispersing the compound in a polymer matrix or gel. [0279] Ophthalmic formulations, eye ointments, powders, solutions, and the like, are also contemplated as being within the scope of this invention. [0280] Pharmaceutical compositions of this invention suitable for parenteral administration comprise one or more compounds of the invention in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions, or emulsions; or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, or solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents. [0281] In some cases, in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle. One strategy for depot injections includes the use of polyethylene oxide-polypropylene oxide copolymers wherein the vehicle is fluid at room temperature and solidifies at body temperature. [0282] Injectable depot forms are made by forming microencapsule matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot-injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions, which are compatible with body tissue. [0283] When the compounds of the present invention are administered as pharmaceuticals, to humans and animals, they can be given per se or as a pharmaceutical composition containing, for example, 0.1% to 99.5% (more preferably, 0.5% to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier. [0284] The compounds and pharmaceutical compositions of the present invention can be employed in combination therapies, that is, the compounds and pharmaceutical compositions can be administered concurrently with, prior to, or subsequent to, one or more other desired therapeutics or medical procedures. The particular combination of therapies (therapeutics or procedures) to employ in a combination regimen will take into account compatibility of the desired therapeutics and/or procedures and the desired therapeutic effect to be achieved. It will also be appreciated that the therapies employed may achieve a desired effect for the same disorder (for example, the compound of the present invention may be administered concurrently with another anticancer agents). [0285] The compounds of the invention may be administered intravenously, intramuscularly, intraperitoneally, subcutaneously, topically, orally, or by other acceptable means. The compounds may be used to treat arthritic conditions in mammals (e.g., humans, livestock, and domestic animals), racehorses, birds, lizards, and any other organism which can tolerate the compounds. [0286] The invention also provides a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention. Optionally associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use, or sale for human administration. Administration to a Subject/Methods of Treating a Condition [0287] In yet another aspect, the present invention provides a method for treating a condition in a mammalian species in need thereof, the method comprising administering to the mammalian species a therapeutically effective amount of at least one compound selected from the group consisting of compounds of Formula I, IIa, IIb, III, IV, or V, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof, wherein the condition is selected from the group consisting of cancer, sickle cell anemia, a cardiovascular disease, a respiratory disease, a fibrotic disease, an autoimmune disease, a central nervous system (CNS) disorder, a neurodegenerative disease, and an inflammatory disorder. [0288] In some embodiments, the respiratory disease is an inflammatory airway disease, airway hyperresponsiveness, an idiopathic lung disease, chronic obstructive pulmonary disease, asthma, chronic asthma, allergy, tracheobronchial or diaphragmatic dysfunction, or cough or chronic cough. [0289] In some embodiments, the autoimmune disease is rheumatoid arthritis or multiple sclerosis. In some embodiments, the central nervous system disorder is acute ischemic stroke, traumatic brain injury, peripheral nerve injury, glioblastoma multiforme, or spinal cord injury. In some embodiments, the fibrotic disease is liver fibrosis, kidney fibrosis, cardiac fibrosis, eye injury-related corneal fibrosis, or lung fibrosis. In some embodiments, the neurodegenerative disease is Alzheimer’s disease, Parkinson’s disease, or amyotrophic lateral sclerosis (ALS). [0290] In some embodiments, the mammalian species is human. [0291] In yet another aspect, a method of inhibiting calcium-activated potassium channel KCa3.1 in a mammalian species in need thereof is described, including administering to the mammalian species a therapeutically effective amount of at least one compound of Formula I, IIa, IIb, III, IV, or V, or a pharmaceutically acceptable salt or pharmaceutical composition thereof. [0292] In some embodiments, the compounds described herein are selective in inhibiting KCa3.1 with minimal or no off-target inhibition activities against potassium channels, or against calcium or sodium channels. In some embodiments, the compounds described herein do not block the hERG channels and therefore have desirable cardiovascular safety profiles. [0293] Some aspects of the invention involve administering an effective amount of a composition to a subject to achieve a specific outcome. The small molecule compositions useful according to the methods of the present invention thus can be formulated in any manner suitable for pharmaceutical use. [0294] The formulations of the invention are administered in pharmaceutically acceptable solutions, which may routinely contain pharmaceutically acceptable concentrations of salt, buffering agents, preservatives, compatible carriers, adjuvants, and optionally other therapeutic ingredients. [0295] For use in therapy, an effective amount of the compound can be administered to a subject by any mode allowing the compound to be taken up by the appropriate target cells. “Administering” the pharmaceutical composition of the present invention can be accomplished by any means known to the skilled artisan. Specific routes of administration include, but are not limited to, oral, transdermal (e.g., via a patch), parenteral injection (subcutaneous, intradermal, intramuscular, intravenous, intraperitoneal, intrathecal, etc.), or mucosal (intranasal, intratracheal, inhalation, intrarectal, intravaginal, etc.). An injection can be in a bolus or a continuous infusion. [0296] For example the pharmaceutical compositions according to the invention are often administered by intravenous, intramuscular, or other parenteral means. They can also be administered by intranasal application, inhalation, topically, orally, or as implants; even rectal or vaginal use is possible. Suitable liquid or solid pharmaceutical preparation forms are, for example, aqueous or saline solutions for injection or inhalation, microencapsulated, encochleated, coated onto microscopic gold particles, contained in liposomes, nebulized, aerosols, pellets for implantation into the skin, or dried onto a sharp object to be scratched into the skin. The pharmaceutical compositions also include granules, powders, tablets, coated tablets, (micro)capsules, suppositories, syrups, emulsions, suspensions, creams, drops, or preparations with protracted release of active compounds in whose preparation excipients and additives and/or auxiliaries such as disintegrants, binders, coating agents, swelling agents, lubricants, flavorings, sweeteners, or solubilizers are customarily used as described above. The pharmaceutical compositions are suitable for use in a variety of drug delivery systems. For a brief review of present methods for drug delivery, see Langer, R. (1990) Science 249:1527-33, which is incorporated herein by reference in its entirety. [0297] The concentration of compounds included in compositions used in the methods of the invention can range from about 1 nM to about 100 μM. Effective doses are believed to range from about 10 picomole/kg to about 100 micromole/kg. [0298] The pharmaceutical compositions are preferably prepared and administered in dose units. Liquid dose units are vials or ampoules for injection or other parenteral administration. Solid dose units are tablets, capsules, powders, and suppositories. For treatment of a patient, different doses may be necessary depending on activity of the compound, manner of administration, purpose of the administration (i.e., prophylactic or therapeutic), nature and severity of the disorder, age and body weight of the patient. The administration of a given dose can be carried out both by single administration in the form of an individual dose unit or else several smaller dose units. Repeated and multiple administration of doses at specific intervals of days, weeks, or months apart are also contemplated by the invention. [0299] The compositions can be administered per se (neat) or in the form of a pharmaceutically acceptable salt. When used in medicine the salts should be pharmaceutically acceptable, but non-pharmaceutically acceptable salts can conveniently be used to prepare pharmaceutically acceptable salts thereof. Such salts include, but are not limited to, those discussed above and those prepared from the following acids: hydrochloric, hydrobromic, sulphuric, nitric, phosphoric, maleic, acetic, salicylic, p-toluene sulphonic, tartaric, citric, methane sulphonic, formic, malonic, succinic, naphthalene-2-sulphonic, and benzene sulphonic. Also, such salts can be prepared as alkaline metal or alkaline earth salts, such as sodium, potassium, or calcium salts of the carboxylic acid group. [0300] Suitable buffering agents include, but are not limited to: acetic acid and a salt (1-2% w/v); citric acid and a salt (1-3% w/v); boric acid and a salt (0.5-2.5% w/v); and phosphoric acid and a salt (0.8-2% w/v). Suitable preservatives include benzalkonium chloride (0.003- 0.03% w/v); chlorobutanol (0.3-0.9% w/v); parabens (0.01-0.25% w/v); and thimerosal (0.004-0.02% w/v). [0301] Compositions suitable for parenteral administration conveniently include sterile aqueous preparations, which can be isotonic with the blood of the recipient. Among the acceptable vehicles and solvents are water, Ringer’s solution, phosphate buffered saline, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed mineral or non-mineral oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. Carrier formulations suitable for subcutaneous, intramuscular, intraperitoneal, intravenous, etc. administrations can be found in Remington’s Pharmaceutical Sciences, Mack Publishing Company, Easton, PA; incorporated herein by reference in its entirety. [0302] The compounds useful in the invention can be delivered in mixtures of more than two such compounds. A mixture can further include one or more adjuvants in addition to the combination of compounds. [0303] A variety of administration routes is available. The particular mode selected will depend upon the particular compound selected, the age and general health status of the subject, the particular condition being treated, and the dosage required for therapeutic efficacy. The methods of this invention, generally speaking, can be practiced using any mode of administration that is medically acceptable, meaning any mode that produces effective levels of response without causing clinically unacceptable adverse effects. Preferred modes of administration are discussed above. [0304] The compositions can conveniently be presented in unit dosage form and can be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the compounds into association with a carrier which constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing the compounds into association with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product. [0305] Other delivery systems can include time-release, delayed release, or sustained-release delivery systems. Such systems can avoid repeated administrations of the compounds, increasing convenience to the subject and the physician. Many types of release delivery systems are available and known to those of ordinary skill in the art. They include polymer base systems such as poly(lactide-glycolide), copolyoxalates, polycaprolactones, polyesteramides, polyorthoesters, polyhydroxybutyric acid, and polyanhydrides. Microcapsules of the foregoing polymers containing drugs are described in, for example, U.S. Pat. No.5,075,109. Delivery systems also include non-polymer systems that are: lipids including sterols such as cholesterol, cholesterol esters and fatty acids, or neutral fats such as mono-di-and tri-glycerides; hydrogel release systems; silastic systems; peptide-based systems; wax coatings; compressed tablets using conventional binders and excipients; partially fused implants; and the like. Specific examples include, but are not limited to: (a) erosional systems in which an agent of the invention is contained in a form within a matrix such as those described in U.S. Pat. Nos.4,452,775, 4,675,189, and 5,736,152, and (b) diffusional systems in which an active component permeates at a controlled rate from a polymer such as described in U.S. Pat. Nos.3,854,480, 5,133,974, and 5,407,686. In addition, pump-based hardware delivery systems can be used, some of which are adapted for implantation. Assays for Effectiveness of KCa3.1 channel inhibitors [0306] In some embodiments, the compounds as described herein were tested for their activities against KCa3.1 channel. In some embodiments, the compounds as described herein were tested for their KCa3.1 channel electrophysiology. In some embodiments, the compounds as described herein were tested for their hERG electrophysiology. Equivalents [0307] The representative examples which follow are intended to help illustrate the invention, and are not intended to, nor should they be construed to, limit the scope of the invention. Indeed, various modifications of the invention and many further embodiments thereof, in addition to those shown and described herein, will become apparent to those skilled in the art from the full contents of this document, including the examples which follow and the references to the scientific and patent literature cited herein. It should further be appreciated that the contents of those cited references are incorporated herein by reference to help illustrate the state of the art. The following examples contain important additional information, exemplification, and guidance which can be adapted to the practice of this invention in its various embodiments and equivalents thereof. EXAMPLES [0308] Examples 1-16 describe various intermediates used in the syntheses of representative compounds of Formula I, IIa, IIb, III, IV, or V disclosed herein. Example 1. Intermediate 1 (4,5-difluoro-1H-indole-2,3-dione) Step a: [0309] To a stirred solution of 4,5-difluoro-1,3-dihydroindol-2-one (2.00 g, 11.8 mmol) in dioxane (20 mL) was added SeO2 (6.56 g, 59.1 mmol) in portions at 25 °C. The reaction was heated at 110 °C for 2 h, diluted with water (100 mL) and extracted with EA (3 x 50 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE/EA (1/1) to afford 4,5-difluoro-1H-indole-2,3- dione as an orange solid (1.70 g, 54.9%): LCMS (ESI) calc’d for C8H3F2NO2 [M - H]-: 182 found 182; 1H NMR (400 MHz, DMSO-d6) δ 11.22 (s, 1H), 7.72-7.54 (m, 1H), 6.74-6.61 (m, 1H). Example 2. Intermediate 2 (4,7-difluoro-1,3-dihydroindol-2-one) Step a: [0310] A stirred solution of 4,7-difluoro-1H-indole-2,3-dione (8.00 g, 43.7 mmol) in EtOH (160 mL) containing NH2NH2·H2O (4.37 g, 87.4 mmol) was heated at 80 °C for 1 h under nitrogen. The mixture was cooled to room temperature, KOH (7.35 g, 131 mmol) was added and heated at 80 °C for an additional 6 h. The resulting mixture was diluted with water (100 mL) at 0 °C and extracted with EA (5 x 100 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford 4,7-difluoro-1,3-dihydroindol-2-one as a yellow solid (8.50 g, crude), which was used in the next step without purification: LCMS (ESI) calc’d for C8H5F2NO [M + H]+ : 170 found 170; 1H NMR (400 MHz, DMSO-d6) δ 11.06 (s, 1H), 7.21- 7.10 (m, 1H), 6.84-6.72 (m, 1H), 3.62 (s, 2H). Example 3. Intermediate 3 (4,5,7-trifluoro-1H-indole-2,3-dione) Step a: [0311] To a stirred solution of 2,4,5-trifluoroaniline (5.00 g, 34.0 mmol) and Na2SO4 (29.0 g, 203 mmol) in H2O (100 mL) were added hydroxylamine hydrochloride (7.09 g, 102 mmol) and chloral hydrate (6.75 g, 40.8 mmol) in portions at room temperature. Conc. HCl (0.85 mL, 10.20 mmol) was added dropwise over 3 min and the resulting mixture stirred at 70 °C for 4 h. After cooling to room temperature, the precipitated solids were collected by filtration and washed with water (3 x 50 mL) to afford (2E)-2-(N-hydroxyimino)-N-(2,4,5- trifluorophenyl)acetamide as a light brown solid (6.50 g, 87.7%): LCMS (ESI) calc’d for C8H5F3N2O2 [M - H]-: 217 found 217; 1H NMR (300 MHz, DMSO-d6) δ 12.36 (s, 1H), 9.97 (s, 1H), 8.06-7.87 (m, 1H), 7.75 (s, 1H), 7.72-7.57 (m, 1H). Step b: [0312] (2E)-2-(N-hydroxyimino)-N-(2,4,5-trifluorophenyl)acetamide (7.00 g, 32.1 mmol) was added in portions to conc. H2SO4 (55 mL) at 70 oC over 1 h. The reaction was stirred at 100 °C for an additional 16 h. After cooling to room temperature, the cooled mixture was poured slowly into ice water (300 mL) and extracted with EA (5 x 80 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluting with 25% ACN in water (plus 20 mM NH4HCO3) to afford 4,5,7- trifluoro-1H-indole-2,3-dione as a reddish brown solid (0.800 g, 12.4%): LCMS (ESI) calc’d for C8H2F3NO2 [M - H]-: 200 found 200; 1H NMR (400 MHz, DMSO-d6) δ 11.76 (s, 1H), 8.04-7.87 (m, 1H). Example 4. Intermediate 4 (5-bromo-4-fluoro-1H-indole-2,3-dione) Step a: [0313] To a stirred solution of 5-bromo-4-fluoro-1H-indole (1.00 g, 4.67 mmol) and NIS (1.26 g, 5.60 mmol) in DMSO (10 mL) was added 2-iodoxybenzoic acid (3.92 g, 14.0 mmol) in portions at room temperature. After 2 h, the mixture was diluted with water (80 mL) and extracted with EA (3 x 50 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE/EA (2/1) to afford 5-bromo-4-fluoro-1H-indole-2,3-dione as an orange solid (1.00 g, 87.7%): LCMS (ESI) calc’d for C8H3BrFNO2 [M - H]-: 242, 244 (1 : 1) found 242, 244 (1 : 1); 1H NMR (400 MHz, DMSO-d6) δ 11.32 (s, 1H), 7.88 (dd, J = 8.35, 7.15 Hz, 1H), 6.71 (d, J = 8.34 Hz, 1H). Example 5. Intermediate 5 (5-bromo-4-fluoro-1,3-dihydroindol-2-one) Step a: [0314] To a stirred solution of 5-bromo-4-fluoro-1H-indole (2.00 g, 9.34 mmol) in t-BuOH (20 mL) was added NBS (6.65 g, 37.3 mmol) in portions at room temperature under nitrogen. The reaction was for 2 h, concentrated under reduced pressure and the residue purified by silica gel column chromatography, eluting with PE/EA (2/1) to afford 3,3,5-tribromo-4- fluoro-1H-indol-2-one as an orange solid (2.18 g, 60.2%): LCMS (ESI) calc’d for C8H3Br3FNO [M - H]-: 384, 386, 388 (3 : 3 : 1) found 384, 386, 388 (3 : 3 : 1); 1H NMR (400 MHz, DMSO-d6) δ 11.65 (s, 1H), 7.72 (dd, J = 8.40, 7.09 Hz, 1H), 6.78 (d, J = 8.41 Hz, 1H). Step b: [0315] To a stirred solution of 3,3,5-tribromo-4-fluoro-1H-indol-2-one (2.10 g, 5.42 mmol) in ACN (20 mL) and AcOH (10 mL) was added Zn (1.06 g, 16.3 mmol) in portions at room temperature. After 2 h, the mixture was filtered, the filter cake washed with ACN (3 x 30 mL) and the filtrate concentrated under reduced pressure. The residue was diluted with water (100 mL) and EA (80 mL). The aqueous solution was extracted with EA (3 x 40 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE/EA (1/1) to afford 5-bromo-4-fluoro-1,3- dihydroindol-2-one as a pink solid (1.19 g, 95.5%): LCMS (ESI) calc’d for C8H5BrFNO [M - H] -: 228, 230 (1 : 1) found 228, 230 (1 : 1); 1H NMR (400 MHz, DMSO-d6) δ 10.69 (s, 1H), 7.55-7.46 (m, 1H), 6.65 (d, J = 8.28 Hz, 1H), 3.63 (s, 2H). Example 6. Intermediate 6 (4,5-difluoro-3-(4-fluorophenyl)-1,3-dihydroindol-2-one) Step a: [0316] To a stirred solution of 4,5-difluoro-1,3-dihydroindol-2-one (5.00 g, 29.6 mmol) and 4-bromofluorobenzene (7.76 g, 44.3 mmol) in dioxane (60 mL) were added XPhos Pd G3 (5.00 g, 5.91 mmol), XPhos (2.82 g, 5.91 mmol) and K2CO3 (12.3 g, 88.7 mmol) at room temperature. The reaction was degassed under reduced pressure, purged with nitrogen three times, and stirred at 80 °C for 16 h. The resulting mixture was diluted with water (100 mL) and extracted with EA (3 x 200 mL). The combined organic layers were washed with brine (5 x 50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was triturated with DCM/PE (v/v, 1/1, 200 mL) to afford 4,5-difluoro-3-(4- fluorophenyl)-1,3-dihydroindol-2-one as an off-white solid (6.00 g, 54.6%): LCMS (ESI) calc’d for C14H8F3NO [M + H]+: 264 found 264; 1H NMR (300 MHz, DMSO-d6) δ 10.75 (s, 1H), 7.41-7.26 (m, 1H), 7.26-7.14 (m, 4H), 6.80-6.70 (m, 1H), 5.07 (s, 1H). Example 7. Intermediate 7 (5-bromo-4-fluoro-3-(4-fluorophenyl)-1,3-dihydroindol-2- one) Step a: [0317] To a stirred solution of 5-bromo-4-fluoro-1,3-dihydroindol-2-one (1.10 g, 4.78 mmol) in dioxane (15 mL) was added SeO2 (2.65 g, 23.9 mmol) in portions at room temperature then heated to 110 °C for 2 h. The cooled mixture was concentrated under reduced pressure and the residue purified by silica gel column chromatography, eluting with PE/EA (2/1) to afford 5-bromo-4-fluoro-1H-indole-2,3-dione as an orange solid (1.09 g, 93.4%): LCMS (ESI) calc’d for C8H3BrFNO2 [M - H]-: 242, 244 (1 : 1) found 242, 244 (1 : 1); 1H NMR (400 MHz, DMSO-d6) δ 11.32 (s, 1H), 7.88 (dd, J = 8.33, 7.18 Hz, 1H), 6.71 (d, J = 8.34 Hz, 1H). Step b: [0318] To a stirred solution of 5-bromo-4-fluoro-1H-indole-2,3-dione (1.00 g, 4.09 mmol) in THF (20 mL) was added (4-fluorophenyl)magnesium bromide (6.15 mL, 6.15 mmol, 1 M in THF) dropwise at 0 °C under nitrogen. The reaction was stirred at room temperature for 2 h, quenched with saturated aq. NH4Cl (50 mL) at 0 °C and extracted with EA (3 x 50 mL). The combined organic layers were washed with brine (2 x 80 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluting with 30% ACN in water (plus 0.05% FA) to afford 5-bromo-4- fluoro-3-(4-fluorophenyl)-3-hydroxy-1H-indol-2-one as a light yellow solid (0.830 g, 59.6%): LCMS (ESI) calc’d for C14H8BrF2NO2 [M - H]-: 338, 340 (1 : 1) found 338, 340 (1 : 1); 1H NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 7.62 (dd, J = 8.27, 7.02 Hz, 1H), 7.37- 7.30 (m, 2H), 7.22-7.13 (m, 2H), 7.02 (s, 1H), 6.76 (d, J = 8.28 Hz, 1H). Step c: [0319] To a stirred solution of 5-bromo-4-fluoro-3-(4-fluorophenyl)-3-hydroxy-1H-indol-2- one (0.700 g, 2.06 mmol) in TFA (10 mL) was added Et3SiH (0.720 g, 6.17 mmol) dropwise at 0 °C under nitrogen. The reaction was heated at 80 °C for 2 h and concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluting with 40% ACN in water (plus 10 mM NH4HCO3) to afford 5-bromo-4-fluoro-3-(4-fluorophenyl)- 1,3-dihydroindol-2-one as an off-white solid (0.560 g, 83.9%): LCMS (ESI) calc’d for C14H8BrF2NO [M + H]+: 324, 326 (1 : 1) found 324, 326 (1 : 1); 1H NMR (400 MHz, DMSO-d6) δ 10.88 (s, 1H), 7.66-7.53 (m, 1H), 7.20 (d, J = 7.17 Hz, 4H), 6.77 (d, J = 8.30 Hz, 1H), 5.07 (s, 1H). Example 8. Intermediate 8 (4,6-difluoro-3-(4-fluorophenyl)-1,3-dihydroindol-2-one) Step a: [0320] To a stirred solution of 4-bromofluorobenzene (4.30 g, 24.5 mmol) in THF (30 mL) was added n-BuLi (9.80 mL, 24.5 mmol, 2.5 M in hexane) dropwise at -78 °C under nitrogen. The reaction was stirred at -78 °C for 30 min and 4,6-difluoro-1H-indole-2,3-dione (1.50 g, 8.19 mmol) in THF (2 mL) was added dropwise. The reaction was stirred at -78 °C for 30 min then at room temperature for 2 h, quenched with water (30 mL) and extracted with EA (3 x 50 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluting with 41% ACN in water (plus 10 mM NH4HCO3) to afford 4,6-difluoro-3-(4-fluorophenyl)-3-hydroxy-1H-indol-2-one as an off- white solid (1.70 g, 74.3%): LCMS (ESI) calc’d for C14H8F3NO2 [M - H]-: 278 found 278; 1H NMR (400 MHz, DMSO-d6) δ 10.83 (s, 1H), 7.37-7.30 (m, 2H), 7.22-7.12 (m, 2H), 6.93 (s, 1H), 6.82-6.73 (m, 1H), 6.64 (dd, J = 8.73, 2.19 Hz, 1H). Step b: [0321] To a stirred solution of 4,6-difluoro-3-(4-fluorophenyl)-3-hydroxy-1H-indol-2-one (1.65 g, 5.90 mmol) in TFA (15 mL) was added Et3SiH (2.06 g, 17.7 mmol) at room temperature under nitrogen. After 2 h, the mixture was concentrated under reduced pressure and the residue purified by silica gel column chromatography, eluting with PE/EA (2/1) to afford 4,6-difluoro-3-(4-fluorophenyl)-1,3-dihydroindol-2-one as an off-white solid (1.40 g, 90.0%): LCMS (ESI) calc’d for C14H8F3NO [M - H]+: 262 found 262; 1H NMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 7.23-7.13 (m, 4H), 6.84-6.75 (m, 1H), 6.66 (dd, J = 8.73, 2.17 Hz, 1H), 4.96 (s, 1H). Example 9. Intermediate 9 (4,5-difluoro-3-(4-fluorophenyl)-3-methyl-1H-indol-2-one) Step a: [0322] To a stirred solution of 4,5-difluoro-3-(4-fluorophenyl)-1,3-dihydroindol-2-one (6.00 g, 22.8 mmol) and K2CO3 (4.73 g, 34.2 mmol) in DMF (60 mL) was added CH3I (3.24 g, 22.8 mmol). The reaction was stirred at room temperature for 2 h, diluted with water (100 mL) and extracted with EA (3 x 200 mL). The combined organic layers were washed with brine (5 x 100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE/EA (2/1) to afford 4,5-difluoro-3-(4-fluorophenyl)-3-methyl-1H-indol-2-one as a light yellow solid (4.50 g, 71.2%): LCMS (ESI) calc’d for C15H10F3NO [M + H]+: 278 found 278; 1H NMR (300 MHz, DMSO-d6) δ 10.78 (s, 1H), 7.41-7.33 (m, 1H), 7.32-7.23 (m, 2H), 7.23- 7.13 (m, 2H), 6.82-6.73 (m, 1H), 1.76 (s, 3H). Example 10. Intermediate 10 (4,5-difluoro-3-(4-fluorophenyl)-3-methoxyindolin-2-one) [0323] To a stirred solution of 4,5-difluoro-3-(4-fluorophenyl)-1,3-dihydroindol-2-one (11.0 g, 41.8 mmol) in MeOH (200 mL) was added (NH4)2Ce(NO3)6 (46.0 g, 83.6 mmol) in two portions. The reaction was stirred at room temperature for 2 h, diluted with water (200 mL) and extracted with EA (3 x 500 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE/EA (2/1) to afford 4,5-difluoro-3-(4-fluorophenyl)-3-methoxyindolin-2-one as a light yellow solid (8.00 g, 65.3%): LCMS (ESI) calc’d for C15H10F3NO2 [M - H]-: 292 found 292; 1H NMR (400 MHz, CDCl3) δ 8.89 (s, 1H), 7.48-7.38 (m, 2H), 7.26-7.15 (m, 1H), 7.10-7.01 (m, 2H), 6.74-6.64 (m, 1H), 3.39 (s, 3H). Example 11. Intermediate 11 (4,7-difluoro-3-(4-fluorophenyl)-3-methoxyindolin-2-one) Step a: [0324] To a stirred solution of 4,7-difluoro-3-(4-fluorophenyl)-3-hydroxyindolin-2-one (15.0 g, 53.7 mmol) and MeOH (3.44 g, 107 mmol) in toluene (150 mL) was added TsOH (27.7 g, 161 mmol) and heated to 110 °C for 16 h. The cooled mixture was concentrated under reduced pressure, diluted with water (100 mL) and extracted with EA (3 x 100 mL). The combined organic layers were washed with brine (3 x 60 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE/EA (2/1) to afford 4,7-difluoro-3-(4-fluorophenyl)- 3-methoxyindolin-2-one as a yellow solid (10.0 g, 63.5%): LCMS (ESI) calc’d for C15H10F3NO2 [M - H]-: 292 found 292; 1H NMR (300 MHz, CD3OD) δ 7.42-7.36 (m, 2H), 7.26-7.23 (m, 1H), 7.12-7.02 (m, 2H), 6.85-6.75 (m, 1H), 3.29 (s, 3H). Example 12. Intermediate 12 (4,7-difluoro-3-(3-fluorophenyl)-3-methoxyindolin-2-one) Step a: [0325] To a stirred mixture of 4,7-difluoro-3-(3-fluorophenyl)-3-hydroxyindolin-2-one (0.100 g, 0.358 mmol) and CH3I (0.153 g, 1.07 mmol) in ACN (1 mL) was added Ag2O (0.124 g, 0.537 mmol) at room temperature. The reaction was stirred at 40 °C for 16 h, diluted with water (20 mL) and extracted with EA (3 x 20 mL). The combined organic layers were washed with brine (3 x 20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE/EA (3/1) to afford 4,7-difluoro-3-(3-fluorophenyl)-3-methoxyindolin-2-one as a light yellow liquid (40.0 mg, 38.1%): LCMS (ESI) calc’d for C15H10F3NO2 [M - H]-: 292 found 292; 1H NMR (400 MHz, DMSO-d6) δ 11.57 (s, 1H), 7.47-7.35 (m, 2H), 7.25-7.14 (m, 2H), 7.02 (d, J = 7.84 Hz, 1H), 6.94-6.91 (m, 1H), 3.21 (s, 3H). Example 13. Intermediate 13 (5-chloro-4-fluoro-3-(4-fluorophenyl)-3-methoxyindolin-2- one) Step a: [0326] To a stirred solution of 5-chloro-4-fluoro-1H-indole (2.00 g, 11.8 mmol) in DMF (20 mL) was added NBS (2.31 g, 13.0 mmol). The reaction was stirred at room temperature for 2 h, diluted with water (20 mL) and extracted with EA (3 x 20 mL). The combined organic layers were washed with brine (3 x 50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE/EA (4/1) to afford 3-bromo-5-chloro-4-fluoro-1H-indole as a brown solid (1.30 g, 44.3%): LCMS (ESI) calc’d for C8H4BrClFN [M - H]-: 246, 248, 250 (3 : 3 : 1) found 246, 248, 250 (3 : 3 : 1); 1H NMR (400 MHz, DMSO-d6) δ 11.92 (s, 1H), 7.65 (d, J = 2.69 Hz, 1H), 7.33-7.21 (m, 2H). Step b: [0327] To a stirred mixture of 3-bromo-5-chloro-4-fluoro-1H-indole (1.30 g, 5.23 mmol) in dioxane (8 mL) and H2O (2 mL) were added Na2CO3 (1.10 g, 10.5 mmol), 4- fluorophenylboronic acid (1.10 g, 7.85 mmol) and Pd(dppf)Cl2^CH2Cl2 (0.426 g, 0.523 mmol) at room temperature. The reaction was degassed under vacuum, purged with nitrogen three times and heated at 80 °C for 1 h. The resulting mixture was diluted with water (50 mL) and extracted with EA (3 x 50 mL). The combined organic layers were washed with brine (3 x 50 mL), dried over anhydrous Na2SO4, fitered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE/EA (4/1) to afford 5-chloro-4-fluoro-3-(4-fluorophenyl)-1H-indole as a brown solid (0.630 g, 45.7%): LCMS (ESI) calc’d for C14H8ClF2N [M - H]-: 262, 264 (3 : 1) found 262, 264 (3 : 1); 1H NMR (400 MHz, DMSO-d6) δ 11.83 (s, 1H), 7.64 (d, J = 2.58 Hz, 1H), 7.62-7.55 (m, 2H), 7.31 (d, J = 8.69 Hz, 1H), 7.28-7.19 (m, 3H). Step c: [0328] To a stirred solution of 5-chloro-4-fluoro-3-(4-fluorophenyl)-1H-indole (0.530 g, 2.01 mmol) in DCM (5 mL) was added t-butyl hypochlorite (0.436 g, 4.02 mmol). The reaction was stirred at room temperature for 1 h and concentrated under reduced pressure. The residue was dissolved in dioxane (4 mL) and conc. H2SO4 (2 mL), stirred at room temperature for 1 h then diluted with water (30 mL) and extracted with EA (3 x 30 mL). The combined organic layers were washed with brine (3 x 30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE/EA (2/1) to afford 3,5-dichloro-4-fluoro-3-(4- fluorophenyl)indolin-2-one as a light yellow oil (0.150 g, 23.8%): LCMS (ESI) calc’d for C14H7Cl2F2NO [M - H]-: 312, 314 (3 : 2) found 312, 314 (3 : 2); 1H NMR (400 MHz, DMSO- d6) δ 11.41 (s, 1H), 7.68-7.65 (m, 1H), 7.56-7.48 (m, 2H), 7.34-7.26 (m, 2H), 6.92 (d, J = 8.46 Hz, 1H). Step d: [0329] To a stirred mixture of 3,5-dichloro-4-fluoro-3-(4-fluorophenyl)indolin-2-one (0.150 g, 0.478 mmol) in MeOH (2 mL) was added NaOMe (51.6 mg, 0.956 mmol). The reaction was stirred at room temperature for 2 h, diluted with water (20 mL) and extracted with EA (3 x 30 mL). The combined organic layers were washed with brine (3 x 30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE/EA (2/1) to afford 5-chloro-4- fluoro-3-(4-fluorophenyl)-3-methoxyindolin-2-one as a light yellow oil (45.0 mg, 30.4%): LCMS (ESI) calc’d for C15H10ClF2NO2 [M - H]-: 308, 310 (3 : 1) found 308, 310 (3 : 1); 1H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 7.63-7.60 (m, 1H), 7.36-7.28 (m, 2H), 7.25- 7.15 (m, 2H), 6.88 (d, J = 8.35 Hz, 1H), 3.19 (s, 3H). Example 14. Intermediate 14 (4,5-difluoro-3-(4-fluorophenyl)-2-oxo-1H-indole-3- carbonitrile) Step a: [0330] A solution of 4,5-difluoro-3-(4-fluorophenyl)-1,3-dihydroindol-2-one (0.200 g, 0.760 mmol) and 3-oxo-1,2-benziodoxole-1(3H)-carbonitrile (0.249 g, 0.912 mmol) in DMF (2 mL) was stirred at room temperature for 2 h, diluted with water (30 mL) and extracted with EA (3 x 30 mL). The combined organic layers were washed with brine (3 x 30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE/EA (5/1) to afford 4,5- difluoro-3-(4-fluorophenyl)-2-oxo-1H-indole-3-carbonitrile as a light-yellow oil (70.0 mg, 32.0%). LCMS (ESI) calc’d for C15H7F3N2O [M - H]-: 287 found 287; 1H NMR (300 MHz, DMSO-d6) δ 11.62 (s, 1H), 7.80-7.56 (m, 1H), 7.51-7.31 (m, 4H), 7.28-7.05 (m, 1H). Example 15. Intermediate 15 (4-fluoro-3-(4-fluorophenyl)-3,5-dimethoxy-1H-indol-2- one) Step a: [0331] To a stirred solution of 5-bromo-4-fluoro-3-(4-fluorophenyl)-1,3-dihydroindol-2-one (0.560 g, 1.73 mmol) in MeOH (10 mL) was added bis(trifluoroacetoxy)iodobenzene (1.49 g, 3.46 mmol) in portions at room temperature. The reaction was stirred for 2 h and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE/EA (2/1) to afford 5-bromo-4-fluoro-3-(4-fluorophenyl)-3- methoxy-1H-indol-2-one as an off-white solid (0.580 g, 94.8%): LCMS (ESI) calc’d for C15H10BrF2NO2 [M - H]-: 352, 354 (1 : 1) found 352, 354 (1 : 1); 1H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 7.73 (dd, J = 8.29, 7.06 Hz, 1H), 7.36-7.29 (m, 2H), 7.25-7.16 (m, 2H), 6.83 (d, J = 8.34 Hz, 1H), 3.19 (s, 3H). Step b: [0332] To a stirred solution of Na (0.260 g, 11.3 mmol) in MeOH (3 mL) was added a solution of 5-bromo-4-fluoro-3-(4-fluorophenyl)-3-methoxy-1H-indol-2-one (0.200 g, 0.560 mmol) in DMF (3 mL). The reaction was stirred at 100 °C for 16 h, cooled, diluted with water (50 mL) and extracted with EA (3 x 50 mL). The combined organic layers were washed with brine (3 x 30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluting with 42% ACN in water (plus 10 mM NH4HCO3) to afford 4-fluoro-3-(4-fluorophenyl)-3,5- dimethoxy-1H-indol-2-one as an off-white solid (0.140 g, 81.2%): LCMS (ESI) calc’d for C16H13F2NO3 [M - H]-: 304 found 304; 1H NMR (400 MHz, DMSO-d6) δ 10.75 (s, 1H), 7.33- 7.28 (m, 2H), 7.18 (dd, J = 9.48, 8.39 Hz, 3H), 6.74 (d, J = 8.46 Hz, 1H), 3.81 (s, 3H), 3.18 (s, 3H). Example 16. Intermediate 16 (4-fluoro-3-(4-fluorophenyl)-3-methoxy-5-methyl-1H- indol-2-one) Step a: [0333] To a stirred mixture of 5-bromo-4-fluoro-3-(4-fluorophenyl)-3-methoxy-1H-indol-2- one (0.100 g, 0.28 mmol) and trimethylboroxine (0.210 g, 1.69 mmol) in dioxane (1 mL) were added Pd(PPh3)2Cl2 (19.8 mg, 0.028 mmol) and Na2CO3 (59.8 mg, 0.564 mmol). The reaction was degassed under vacuum, purged with nitrogen three times and heated at 110 °C for 16 h. The cooled reaction was diluted with water (20 mL) and extracted with EA (5 x 20 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluting with 60% ACN in water (plus 10 mM NH4HCO3) to afford 4-fluoro-3-(4-fluorophenyl)-3-methoxy-5-methyl-1H-indol-2-one as a colorless liquid (70.0 mg, 85.7%): LCMS (ESI) calc’d for C16H13F2NO2 [M - H]-: 288 found 288; 1H NMR (400 MHz, DMSO-d6) δ 10.84 (s, 1H), 7.34-7.27 (m, 3H), 7.22-7.14 (m, 2H), 6.74 (d, J = 7.86 Hz, 1H), 3.16 (s, 3H), 2.17 (s, 3H). [0334] Examples 17-20 describe the exemplified syntheses of representative compounds of Formula I, IIa, IIb, III, IV, or V disclosed herein. Example 17. Compound 1 (2-[(3S)-4,5-difluoro-3-(4-fluorophenyl)-3-methyl-2-oxoindol- 1-yl]acetamide); Compound 2 (2-[(3R)-4,5-difluoro-3-(4-fluorophenyl)-3-methyl-2- oxoindol-1-yl]acetamide) [0335] To a stirred mixture of 4,5-difluoro-3-(4-fluorophenyl)-3-methyl-1H-indol-2-one (0.100 g, 0.360 mmol) and bromoacetamide (74.4 mg, 0.540 mmol) in DMF (1 mL) was added K2CO3 (0.150 g, 1.08 mmol). The reaction was stirred at room temperature for 2 h, filtered, and the filter cake washed with MeOH (3 x 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluting with 30% ACN in water (plus 0.05% TFA) to afford 2-[4,5-difluoro-3-(4-fluorophenyl)-3- methyl-2-oxoindol-1-yl]acetamide as an off-white solid (60.0 mg, 49.8%): LCMS (ESI) calc’d for C17H13F3N2O2 [M + H]+: 335, found 335. Step b: [0336] The 2-[4,5-difluoro-3-(4-fluorophenyl)-3-methyl-2-oxoindol-1-yl]acetamide (60.0 mg, 0.179 mmol) was separated by Prep Chiral HPLC with the following conditions: Column: (R, R)-WHELK-O1-Kromasil, 2.11 x 25 cm, 5 μm; Mobile Phase A: Hex (0.5% 2 M NH3-MeOH), Mobile Phase B: EtOH; Flow rate: 20 mL/min; Gradient: 50% B to 50% B in 11 min; Wavelength: 220/254 nm; Retention Time 1: 6.26 min; Retention Time 2: 8.45 min. The faster-eluting enantiomer at 6.26 min was obtained 2-[(3R)-4,5-difluoro-3-(4- fluorophenyl)-3-methyl-2-oxoindol-1-yl]acetamide as an off-white solid (18.1 mg, 30.2%): LCMS (ESI) calc’d for C17H13F3N2O2 [M + H]+: 335, found 335; 1H NMR (300 MHz, CD3OD) δ 7.41-7.33 (m, 2H), 7.31-7.19 (m, 1H), 7.10-7.00 (m, 2H), 6.82-6.75 (m, 1H), 4.55- 4.37 (m, 2H), 1.89 (s, 3H). The slower-eluting enantiomer at 8.45 min was obtained 2-[(3S)- 4,5-difluoro-3-(4-fluorophenyl)-3-methyl-2-oxoindol-1-yl]acetamide as an off-white solid (20.9 mg, 34.8%): LCMS (ESI) calc’d for C17H13F3N2O2 [M + H]+: 335, found 335; 1H NMR (300 MHz, CD3OD) δ 7.41-7.33 (m, 2H), 7.31-7.19 (m, 1H), 7.10-7.00 (m, 2H), 6.82-6.75 (m, 1H), 4.55-4.37 (m, 2H), 1.89 (s, 3H). Example 18. Compound 3 ((R)-2-(4,5-difluoro-3-(4-fluorophenyl)-3-methoxy-2- oxoindolin-1-yl)acetamide); Compound 4 ((S)-2-(4,5-difluoro-3-(4-fluorophenyl)-3- methoxy-2-oxoindolin-1-yl)acetamide) Step a: [0337] To a stirred solution of 4,5-difluoro-3-(4-fluorophenyl)-3-methoxyindolin-2-one (50.0 mg, 0.171 mmol) and bromoacetamide (28.2 mg, 0.205 mmol) in DMF (1 mL) was added K2CO3 (47.1 mg, 0.342 mmol). The reaction was stirred at room temperature for 2 h, diluted with water (30 mL) and extracted with EA (3 x 20 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions: Column: XBridge Shield RP18 OBD Column, 19 x 250 mm, 10 μm; Mobile Phase A: water (plus 10 mM NH4HCO3), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 45% B to 60% B in 6 min, 60% B; Wavelength: 254/210 nm; Retention Time: 6.0 min. The fractions containing the desired product were collected and concentrated under reduced pressure to afford 2-(4,5-difluoro-3-(4-fluorophenyl)-3-methoxy-2-oxoindolin-1- yl)acetamide as an off-white solid (37.2 mg, 62.3%): LCMS (ESI) calc’d for C17H13F3N2O3 [M - H]-: 349 found 349; 1H NMR (400 MHz, DMSO-d6) δ 7.74 (s, 1H), 7.62-7.50 (m, 1H), 7.42 (dd, J = 8.66, 5.42 Hz, 2H), 7.30 (s, 1H), 7.23-7.15 (m, 2H), 6.94 (dd, J = 8.69, 3.12 Hz, 1H), 4.45-4.30 (m, 2H), 3.22 (s, 3H). Step b: [0338] 2-(4,5-difluoro-3-(4-fluorophenyl)-3-methoxy-2-oxoindolin-1-yl)acetamide (37.0 mg, 0.106 mmol) was separated by Prep Chiral HPLC with the following conditions: Column: (R, R)-WHELK-O1-Kromasil, 2.12 x 25 cm, 5 μm; Mobile Phase A: Hex (0.5% 2 M NH3- MeOH), Mobile Phase B: EtOH; Flow rate: 20 mL/min; Gradient: 15% B to 15% B in 21 min; Wavelength: 220/254 nm; Retention Time 1: 14.77 min; Retention Time 2: 18.39 min. The faster-eluting enantiomer at 14.77 min was obtained (S)-2-(4,5-difluoro-3-(4- fluorophenyl)-3-methoxy-2-oxoindolin-1-yl)acetamide as an off-white solid (11.0 mg, 29.7%): LCMS (ESI) calc’d for C17H13F3N2O3 [M - H]-: 349 found 349; 1H NMR (400 MHz, DMSO-d6) δ 7.74 (s, 1H), 7.62-7.50 (m, 1H), 7.42 (dd, J = 8.66, 5.42 Hz, 2H), 7.30 (s, 1H), 7.23-7.15 (m, 2H), 6.94 (dd, J = 8.69, 3.12 Hz, 1H), 4.45-4.30 (m, 2H), 3.22 (s, 3H); [α]25 D = + 91.5o (c = 2 mg/mL, CHCl3). The slower-eluting enantiomer at 18.39 min was obtained (R)-2-(4,5-difluoro-3-(4-fluorophenyl)-3-methoxy-2-oxoindolin-1-yl)acetamide as an off- white solid (11.6 mg, 31.4%): LCMS (ESI) calc’d for C17H13F3N2O3 [M - H]-: 349 found 349; 1H NMR (400 MHz, DMSO-d6) δ 7.74 (s, 1H), 7.62-7.50 (m, 1H), 7.42 (dd, J = 8.66, 5.42 Hz, 2H), 7.30 (s, 1H), 7.23-7.15 (m, 2H), 6.94 (dd, J = 8.69, 3.12 Hz, 1H), 4.45-4.30 (m, 2H), 3.22 (s, 3H); [α]25 = - o D 67.2 (c = 2 mg/mL, CHCl3). Example 19. Compound 5 (2-[(3S)-3-[3,3-difluorocyclohexyl]-4,5-difluoro-3-methoxy-2- oxoindol-1-yl]acetamide isomer 1); Compound 6 (2-[(3S)-3-[3,3-difluorocyclohexyl]-4,5- difluoro-3-methoxy-2-oxoindol-1-yl]acetamide isomer 2); Compound 7 (2-[(3R)-3-[3,3- difluorocyclohexyl]-4,5-difluoro-3-methoxy-2-oxoindol-1-yl]acetamide isomer 3); Compound 8 (2-[(3R)-3-[3,3-difluorocyclohexyl]-4,5-difluoro-3-methoxy-2-oxoindol-1- Step a: [0339] To a stirred solution of 4,5-difluoro-1,3-dihydroindol-2-one (1.50 g, 8.87 mmol) and 1,4-dioxaspiro[4.5]decan-8-one (1.66 g, 10.6 mmol) in THF (10 mL) were added pyridine (1.40 g, 17.4 mmol) and Ti(Oi-Pr)4 (7.56 g, 26.6 mmol). The reaction was stirred at room temperature for 2 h under nitrogen then quenched with water (10 mL) and filtered. The filter cake was washed with EA (3 x 10 mL), the filtrate was diluted with water (50 mL) and extracted with EA (3 x 50 mL). The combined organic layers were washed with brine (3 x 50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE/EA (2/1) to afford 3-(1,4-dioxaspiro[4.5]decan-7-ylidene)-4,5-difluoro-1H-indol-2-one as a yellow solid (2.00 g, 73.4%): LCMS (ESI) calc’d for C16H15F2NO3 [M + H]+ : 308 found 308; 1H NMR (400 MHz, DMSO-d6) δ 10.67 (s, 1H), 7.33-7.19 (m, 1H), 6.68-6.55 (m, 1H), 3.95-3.90 (m, 2H), 3.90-3.85 (m, 2H), 3.58 (s, 2H), 2.73 (t, J = 5.79 Hz, 2H), 1.87-1.69 (m, 4H). Step b: [0340] To a stirred solution of 3-(1,4-dioxaspiro[4.5]decan-7-ylidene)-4,5-difluoro-1H-indol- 2-one (2.00 g, 6.51 mmol) in MeOH (5 mL) and THF (5 mL) was added Pd/C (0.350 g, 3.25 mmol). The solution was degassed under reduced pressure, purged with hydrogen three times and stirred at room temperature for 16 h under hydrogen (1.5 atm). The resulting mixture was filtered, and the filter cake washed with MeOH (3 x 20 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluting with 46% ACN in water (plus 10 mM NH4HCO3) to afford 4,5- difluoro-3-(1,4-dioxaspiro[4.5]decan-7-yl)indolin-2-one as a light yellow solid (1.50 g, 74.5%): LCMS (ESI) calc’d for C16H17F2NO3 [M + H]+ : 310 found 310; DMSO-d6) δ 10.57 (d, J = 10.29 Hz, 1H), 7.30-7.21 (m, 1H), 6.64-6.58 (m, 1H), 3.91-3.76 (m, 4H), 2.43-2.30 (m, 1H), 1.71-1.52 (m, 4H), 1.48-1.26 (m, 2H), 1.22-1.04 (m, 1H), 0.91- 0.78 (m, 2H). Step c: [0341] To a stirred solution of 4,5-difluoro-3-(1,4-dioxaspiro[4.5]decan-7-yl)indolin-2-one (1.50 g, 4.84 mmol) in MeOH (10 mL) was added bis(trifluoroacetoxy)iodobenzene (5.20 g, 12.1 mmol). The reaction was stirred at 60 °C for 16 h and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE/EA (2/1) to afford 4,5-difluoro-3-methoxy-3-(1,4-dioxaspiro[4.5]decan-7-yl)indolin-2-one as a yellow liquid (0.700 g, 42.5%): LCMS (ESI) calc’d for C17H19F2NO4 [M + H]+ : 340 found 340; 1H NMR (400 MHz, DMSO-d6) δ 10.78 (d, J = 14.58 Hz, 1H), 7.44-7.21 (m, 1H), 6.73- 6.58 (m, 1H), 3.93-3.77 (m, 4H), 3.00 (d, J = 3.78 Hz, 3H), 2.41-2.17 (m, 1H), 1.88-1.39 (m, 4H), 1.39-1.21 (m, 3H), 1.02-0.71 (m, 1H). Step d: [0342] To a stirred mixture of 4,5-difluoro-3-methoxy-3-(1,4-dioxaspiro[4.5]decan-7- yl)indolin-2-one (0.700 g, 2.06 mmol) and bromoacetamide (0.420 g, 3.09 mmol) in DMF (7 mL) were added K2CO3 (1.42 g, 10.3 mmol) and NaI (30.9 mg, 0.210 mmol). The reaction was stirred at 30 °C for 2 h, diluted with water (30 mL) and extracted with EA (4 x 50 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluting with 50% ACN in water (plus 10 mM NH4HCO3) to afford 2-(4,5-difluoro-3-methoxy-2-oxo-3-(1,4-dioxaspiro[4.5]decan-7-yl)indolin-1- yl)acetamide as a yellow solid (0.440 g, 43.0%): LCMS (ESI) calc’d for C19H22F2N2O5 [M + H]+ : 397 found 397; 1H NMR (400 MHz, DMSO-d6) δ 7.68 (s, 1H), 7.53-7.41 (m, 1H), 7.22 (s, 1H), 6.87-6.76 (m, 1H), 4.33-4.30 (m, 2H), 3.87-3.76 (m, 4H), 3.06-2.95 (m, 3H), 2.35- 2.21 (m, 1H), 1.86-1.76 (m, 1H), 1.68-1.51 (m, 3H), 1.36-1.22 (m, 3H), 1.03-0.72 (m, 1H). Step e: [0343] To a stirred solution of 2-(4,5-difluoro-3-methoxy-2-oxo-3-(1,4-dioxaspiro[4.5]decan- 7-yl)indolin-1-yl)acetamide (0.400 g, 1.01 mmol) in dioxane (3 mL) was added aq. HCl (1 mL, 3 M) dropwise. The reaction was stirred at room temperature for 8 h, concentrated under reduced pressure and the residue purified by reverse phase chromatography, eluting with 50% ACN in water (plus 10 mM NH4HCO3) to afford 2-[4,5-difluoro-3-methoxy-2-oxo-3-(3- oxocyclohexyl)indolin-1-yl]acetamide as a yellow solid (0.250 g, 70.3%): LCMS (ESI) calc’d for C17H18F2N2O4 [M + NH4]+: 370 found 370; 1H NMR (400 MHz, DMSO-d6) δ 7.70 (s, 1H), 7.55-7.44 (m, 1H), 7.25 (s, 1H), 6.88-6.80 (m, 1H), 4.42-4.27 (m, 2H), 3.03 (s, 3H), 2.39-2.21 (m, 4H), 2.17-2.09 (m, 1H), 1.98-1.87 (m, 1H), 1.86-1.75 (m, 1H), 1.54-1.30 (m, 2H). Step f: [0344] To a stirred solution of 2-[4,5-difluoro-3-methoxy-2-oxo-3-(3-oxocyclohexyl)indolin- 1-yl]acetamide (0.150 g, 0.430 mmol) in DCM (2 mL) was added DAST (0.210 g, 1.28 mmol) at room temperature under nitrogen. After 2h, the mixture was concentrated under reduced pressure and the residue purified by reverse phase chromatography, eluting with 50% ACN in water (plus 10 mM NH4HCO3) to afford 2-[3-(3,3-difluorocyclohexyl)-4,5-difluoro- 3-methoxy-2-oxoindolin-1-yl]acetamide as a yellow solid (95.0 mg, 59.6%): LCMS (ESI) calc’d for C17H18F4N2O3 [M + NH4]+ : 392 found 392; 1H NMR (400 MHz, DMSO-d6) δ 7.70 (s, 1H), 7.57-7.44 (m, 1H), 7.24 (s, 1H), 6.88-6.80 (m, 1H), 4.41-4.25 (m, 2H), 3.03 (d, J = 2.97 Hz, 3H), 2.37-2.11 (m, 2H), 2.04-1.88 (m, 1H), 1.81-1.52 (m, 4H), 1.39-1.27 (m, 1H), 1.15-0.87 (m, 1H). Step g: [0345] 2-[3-(3,3-difluorocyclohexyl)-4,5-difluoro-3-methoxy-2-oxoindol-1-yl]acetamide (95.0 mg, 0.250 mmol) was separated by Prep Chiral HPLC with the following conditions: Column: CHIRAL ART Cellulose-SC, 2 x 25 cm, 5 μm; Mobile Phase A: Hex (0.5% 2 M NH3-MeOH), Mobile Phase B : EtOH : DCM = 1 : 1; Flow rate: 20 mL/min; Gradient: 40% B to 40% B in 16.5 min; Wavelength: 220/254 nm; Retention Time 1: 6.25 min; Retention Time 2: 7.68 min; Retention Time 3: 10.17 min; Retention Time 4: 14.91 min. The first eluting isomer at 6.25 min was obtained 2-[(3S)-3-[3,3-difluorocyclohexyl]-4,5-difluoro-3- methoxy-2-oxoindol-1-yl]acetamide isomer 1 as an off-white solid (11.0 mg, 11.6%): LCMS (ESI) calc’d for C17H18F4N2O3 [M - H]- : 373 found 373; 1H NMR (400 MHz, DMSO-d6) δ 7.70 (s, 1H), 7.57-7.43 (m, 1H), 7.25 (s, 1H), 6.84 (dd, J = 8.63, 3.15 Hz, 1H), 4.41-4.24 (m, 2H), 3.03 (s, 3H), 2.28-2.10 (m, 2H), 2.00-1.87 (m, 1H), 1.80-1.57 (m, 4H), 1.38-1.21 (m, 1H), 1.01-0.86 (m, 1H). The second eluting isomer at 7.68 min was obtained 2-[(3S)-3-[3,3- difluorocyclohexyl]-4,5-difluoro-3-methoxy-2-oxoindol-1-yl]acetamide isomer 2 as an off- white solid (5.40 mg, 5.68%): LCMS (ESI) calc’d for C17H18F4N2O3 [M - H]- : 373 found 373; 1H NMR (400 MHz, DMSO-d6) δ 7.70 (s, 1H), 7.54-7.42 (m, 1H), 7.25 (s, 1H), 6.84 (dd, J = 8.61, 3.17 Hz, 1H), 4.46-4.21 (m, 2H), 3.03 (s, 3H), 2.39-2.26 (m, 1H), 2.26-2.12 (m, 1H), 2.03-1.88 (m, 1H), 1.81-1.49 (m, 4H), 1.41-1.26 (m, 1H), 1.17-0.96 (m, 1H). The third eluting isomer at 10.17 min was obtained 2-[(3R)-3-[3,3-difluorocyclohexyl]-4,5-difluoro-3- methoxy-2-oxoindol-1-yl]acetamide isomer 3 as an off-white solid (5.10 mg, 5.37%): LCMS (ESI) calc’d for C17H18F4N2O3 [M - H]- : 373 found 373; 1H NMR (400 MHz, DMSO-d6) δ 7.70 (s, 1H), 7.55-7.43 (m, 1H), 7.25 (s, 1H), 6.84 (dd, J = 8.72, 3.16 Hz, 1H), 4.40-4.26 (m, 2H), 3.03 (s, 3H), 2.37-2.26 (m, 1H), 2.23-2.10 (m, 1H), 2.02-1.89 (m, 1H), 1.80-1.52 (m, 4H), 1.42-1.26 (m, 1H), 1.16-1.01 (m, 1H). The final eluting isomer at 14.91 min was obtained 2-[(3R)-3-[3,3-difluorocyclohexyl]-4,5-difluoro-3-methoxy-2-oxoindol-1- yl]acetamide isomer 4 as an off-white solid (7.00 mg, 7.37%): LCMS (ESI) calc’d for C17H18F4N2O3 [M - H]- : 373 found 373; 1H NMR (400 MHz, DMSO-d6) δ 7.70 (s, 1H), 7.58-7.44 (m, 1H), 7.24 (s, 1H), 6.84 (dd, J = 8.67, 3.20 Hz, 1H), 4.43-4.23 (m, 2H), 3.03 (s, 3H), 2.28-2.10 (m, 2H), 2.08-1.86 (m, 1H), 1.81-1.50 (m, 4H), 1.37-1.21 (m, 1H), 1.01-0.85 (m, 1H). Example 20. Compound 9 (2-((R)-4,5-difluoro-3-methoxy-2-oxo-3-(tetrahydro-2H- thiopyran-3-yl)indolin-1-yl)acetamide isomer 1); Compound 10 (2-((R)-4,5-difluoro-3- methoxy-2-oxo-3-(tetrahydro-2H-thiopyran-3-yl)indolin-1-yl)acetamide isomer 2); Compound 11 (2-((S)-4,5-difluoro-3-methoxy-2-oxo-3-(tetrahydro-2H-thiopyran-3-
yl)indolin-1-yl)acetamide isomer 3); Compound 12 (2-((S)-4,5-difluoro-3-methoxy-2- oxo-3-(tetrahydro-2H-thiopyran-3-yl)indolin-1-yl)acetamide isomer 4) [0346] To a stirred solution of 4,5-difluoro-1,3-dihydroindol-2-one (0.500 g, 2.96 mmol) and tetrahydrothiopyran-3-one (0.412 g, 3.55 mmol) in THF (10 mL) were added pyridine (0.468 g, 5.91 mmol) and Ti(Oi-Pr)4 (1.68 g, 5.91 mmol). The reaction was stirred at 60 ℃ for 2 h. The cooled mixture was quenched with water (30 mL) filtered, and the filter cake washed with EA (2 x 5 mL). The filtrate was extracted with EA (3 x 50 mL). The combined organic layers were washed with brine (3 x 50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE/EA (4/1) to afford 3-(3,4-dihydro-2H-thiopyran-5-yl)-4,5- difluoroindolin-2-one as a yellow solid (0.600 g, 75.9%): LCMS (ESI) calc’d for C13H11F2NOS [M + H]+: 268 found 268; 1H NMR (300 MHz, CDCl3) δ 8.37 (s, 1H), 7.16- 7.02 (m, 1H), 6.62 (d, J = 8.57 Hz, 1H), 6.13 (s, 1H), 4.22 (s, 1H), 2.94-2.80 (m, 2H), 2.18- 1.90 (m, 4H). Step b: [0347] A mixture of 3-(3,4-dihydro-2H-thiopyran-5-yl)-4,5-difluoroindolin-2-one (0.600 g, 2.24 mmol) and NaBH4 (0.170 g, 4.50 mmol) in THF (10 mL) was stirred at 70 ℃ for 2 h and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE/EA (2/1) to afford 4,5-difluoro-3-(tetrahydro-2H-thiopyran- 3-yl)indolin-2-one as a yellow solid (0.400 g, 66.2%): LCMS (ESI) calc’d for C13H13F2NOS [M + H]+: 270 found 270; 1H NMR (300 MHz, CDCl3) δ 8.12-7.96 (m, 1H), 7.17-6.99 (m, 1H), 6.59 (d, J = 8.63 Hz, 1H), 3.63 (d, J = 8.72 Hz, 1H), 3.12-2.74 (m, 1H), 2.74-2.58 (m, 2H), 2.58-2.35 (m, 2H), 2.17-1.99 (m, 1H), 1.91-1.56 (m, 3H). Step c: [0348] A mixture of 4,5-difluoro-3-(tetrahydro-2H-thiopyran-3-yl)indolin-2-one (0.500 g, 1.86 mmol) and phenyl trimethylammonium tribromide (0.838 g, 2.23 mmol) in DCM (10 mL) was stirred at room temperature for 1 h, quenched with saturated aq. Na2SO3 (aq.) (5 mL) and extracted with CH2Cl2 (2 x 30 mL). The combined organic layers were washed with brine (2 x 30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE/EA (1/2) to afford 3-bromo-4,5-difluoro-3-(tetrahydro-2H-thiopyran-3-yl)indolin-2-one as a yellow solid (0.400 g, 61.9%): LCMS (ESI) calc’d for C13H12BrF2NOS [M + H]+: 348, 350 (1 : 1) found 348, 350 (1 : 1); 1H NMR (400 MHz, CDCl3) δ 8.64 (d, J = 12.43 Hz, 1H), 7.23- 7.09 (m, 1H), 6.75-6.61 (m, 1H), 3.00-2.64 (m, 3H), 2.62-2.53 (m, 1H), 2.53-2.45 (m, 1H), 2.16-2.04 (m, 1H), 2.03-1.88 (m, 1H), 1.88-1.70 (m, 1H), 1.35-1.18 (m, 1H). Step d: [0349] A solution of 3-bromo-4,5-difluoro-3-(tetrahydro-2H-thiopyran-3-yl)indolin-2-one (0.400 g, 1.15 mmol) and NaOMe (0.310 g, 1.72 mmol, 30%) in MeOH (5 mL) was stirred at room temperature for 1 h, diluted with water (30 mL) and extracted with EA (3 x 30 mL). The combined organic layers were washed with brine (2 x 30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE/EA (1/1) to afford 4,5-difluoro-3-methoxy-3- (tetrahydro-2H-thiopyran-3-yl)indolin-2-one as a yellow solid (0.120 g, 34.9%): LCMS (ESI) calc’d for C14H15F2NO2S [M + H]+: 300 found 300; 1H NMR (400 MHz, DMSO-d6) δ 10.86 (d, J = 17.51 Hz, 1H), 7.51-7.35 (m, 1H), 6.77-6.62 (m, 1H), 3.01 (d, J = 9.56 Hz, 3H), 2.78- 2.53 (m, 2H), 2.48-2.39 (m, 2H), 2.39-2.20 (m, 1H), 2.01-1.91 (m, 1H), 1.60-1.46 (m, 2H), 0.94-0.80 (m, 1H). Step e: [0350] To a stirred solution of 4,5-difluoro-3-methoxy-3-(tetrahydro-2H-thiopyran-3- yl)indolin-2-one (40.0 mg, 0.134 mmol) and bromoacetamide (22.1 mg, 0.161 mmol) in DMF (1 mL) was added K2CO3 (36.9 mg, 0.268 mmol). The mixture was stirred for 2 h at room temperature, diluted with water (20 mL) and extracted with EA (2 x 20 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluting with 50% ACN in water (plus 0.05% TFA) to afford 2-(4,5- difluoro-3-methoxy-2-oxo-3-(tetrahydro-2H-thiopyran-3-yl)indolin-1-yl)acetamide as an off- white solid (12.6 mg, 26.5%): LCMS (ESI) calc’d for C16H18F2N2O3S [M + H]+: 357 found 357; 1H NMR (400 MHz, DMSO-d6) δ 7.70 (s, 1H), 7.53-7.42 (m, 1H), 7.24 (s, 1H), 6.87- 6.74 (m, 1H), 4.39-4.26 (m, 2H), 3.02 (d, J = 7.15 Hz, 3H), 2.73-2.65 (m, 1H), 2.57-2.53 (m, 1H), 2.47-2.25 (m, 3H), 2.03-1.86 (m, 1H), 1.77-1.59 (m, 1H), 1.59-1.41 (m, 1H), 1.18-0.78 (m, 1H). Step f: [0351] 2-[4,5-difluoro-3-methoxy-2-oxo-3-(thian-3-yl)indol-1-yl]acetamide (0.110 g, 0.309 mmol) was separated by Prep Chiral HPLC with the following conditions: Column: CHIRAL ART Cellulose-SC, 2 x 25 cm, 5 μm; Mobile Phase A: Hex (0.5% 2 M NH3-MeOH), Mobile Phase B: EtOH : DCM = 1 : 1; Flow rate: 20 mL/min; Gradient: 50% B to 50% B in 16 min; Wavelength: 220/254 nm; Retention Time 1: 5.91 min; Retention Time 2: 9.59 min; Retention Time 3: 10.53 min; Retention Time 4: 13.76 min. The first eluting isomer at 5.91 min was obtained 2-((R)-4,5-difluoro-3-methoxy-2-oxo-3-(tetrahydro-2H-thiopyran-3- yl)indolin-1-yl)acetamide isomer 1 as an off-white solid (13.8 mg, 12.6%): LCMS (ESI) calc’d for C16H18F2N2O3S [M + H]+: 357 found 357; 1H NMR (400 MHz, DMSO-d6) δ 7.70 (s, 1H), 7.53-7.43 (m, 1H), 7.24 (s, 1H), 6.82 (dd, J = 8.79, 3.18 Hz, 1H), 4.39-4.27 (m, 2H), 3.01 (s, 3H), 2.74-2.66 (m, 1H), 2.58-2.54 (m, 1H), 2.49-2.24 (m, 3H), 1.98-1.87 (m, 1H), 1.76-1.66 (m, 1H), 1.56-1.42 (m, 1H), 0.98-0.82 (m, 1H). The second eluting isomer at 9.59 min was obtained 2-((R)-4,5-difluoro-3-methoxy-2-oxo-3-(tetrahydro-2H-thiopyran-3- yl)indolin-1-yl)acetamide isomer 2 as an off-white solid (13.1 mg, 11.9%): LCMS (ESI) calc’d for C16H18F2N2O3S [M + H]+: 357 found 357; 1H NMR (400 MHz, DMSO-d6) δ 7.70 (s, 1H), 7.54-7.44 (m, 1H), 7.24 (s, 1H), 6.82 (dd, J = 8.72, 3.14 Hz, 1H), 4.38-4.26 (m, 2H), 3.03 (s, 3H), 2.69 (d, J = 12.86 Hz, 1H), 2.53-2.52 (m, 1H), 2.49-2.31 (m, 3H), 2.04-1.93 (m, 1H), 1.71-1.60 (m, 1H), 1.58-1.43 (m, 1H), 1.18-1.03 (m, 1H). The third eluting isomer at 10.53 min was obtained 2-((S)-4,5-difluoro-3-methoxy-2-oxo-3-(tetrahydro-2H-thiopyran-3- yl)indolin-1-yl)acetamide isomer 3 as an off-white solid (6.60 mg, 6.00%): LCMS (ESI) calc’d for C16H18F2N2O3S [M + Na]+: 379 found 379; 1H NMR (400 MHz, DMSO-d6) δ 7.70 (s, 1H), 7.56-7.41 (m, 1H), 7.24 (s, 1H), 6.88-6.77 (m, 1H), 4.44-4.21 (m, 2H), 3.01 (s, 3H), 2.74-2.66 (m, 1H), 2.58-2.54 (m, 1H), 2.49-2.25 (m, 3H), 1.97-1.88 (m, 1H), 1.76-1.67 (m, 1H), 1.57-1.43 (m, 1H), 0.97-0.81 (m, 1H). The final eluting peak at 13.76 min was obtained 2-((S)-4,5-difluoro-3-methoxy-2-oxo-3-(tetrahydro-2H-thiopyran-3-yl)indolin-1-yl)acetamide as an off-white solid (11.5 mg, 10.5%): LCMS (ESI) calc’d for C16H18F2N2O3S [M + H]+: 357 found 357; 1H NMR (400 MHz, DMSO-d6) δ 7.70 (s, 1H), 7.54-7.42 (m, 1H), 7.24 (s, 1H), 6.82 (dd, J = 8.71, 3.17 Hz, 1H), 4.40-4.25 (m, 2H), 3.03 (s, 3H), 2.69 (d, J = 12.86 Hz, 1H), 2.49-2.31 (m, 4H), 2.04-1.92 (m, 1H), 1.70-1.59 (m, 1H), 1.59-1.43 (m, 1H), 1.17-1.02 (m, 1H). [0352] The following compounds in Table 1a were prepared in an analogous fashion to Example 17 using the appropriate intermediates. Table 1a
[0353] The following compounds in Table 1b were prepared in an analogous fashion to Example 18 using the appropriate intermediate. Table 1b
[0354] The following compounds in Table 1c were prepared in an analogous fashion to Example 19 or Example 20. Table 1c
[0355] The following compounds in Table 1d were prepared in an analogous fashion to Example 18 by replacing bromoacetamide with the appropriate alkylating agents to react with the nitrogen moiety on the indolinone ring. Table 1d
Example 21. Evaluation of KCa3.1 inhibitor activities [0356] This assay was used to evaluate the disclosed compounds’ inhibition activities against the human KCa3.1 channel. Cell culture [0357] CHO-K1 cells constitutively expressing human KCa3.1 were grown in DMEM containing 10% heat-inactivated FBS, 1 mM Sodium Pyruvate, 2 mM L-Glutamine, 1% Penicillin-Streptomycin and Zeocin (100 µg/mL). Cells used for electrophysiology were plated in plastic culture flasks and grown at 37°C in a 5% CO2-humidified tissue culture incubator per ChanPharm SOP. Stocks were maintained in cryogenic storage. Solutions [0358] The cells were bathed in an extracellular solution containing 140 mM NaCl, 4 mM KCl, 2 mM CaCl2, 1 mM MgCl2, 5 mM Glucose, 10 mM HEPES; pH adjusted to 7.4 with NaOH; 295-305 mOsm. Two intracellular solutions were used during current recordings. The intracellular solution #1 contained 30 mM K-Gluconate, 80 mM KF, 20 mM KCl, 10 mM NaCl, 10 mM HEDTA, 10 mM HEPES; pH adjusted to 7.2 with KOH; 285-290 mOsm. The intracellular solution #2 contained 30 mM K-Gluconate, 80 mM KF, 10 mM KCl, 2 mM CaCl2 (to achieve 1 µM free Ca2+ as calculated with the CABUF program), 10 mM NaCl, 2 mM NaATP, 10 mM HEDTA, 10 mM HEPES; pH adjusted to 7.2 with KOH; 285-290 mOsm. Test compounds were dissolved in DMSO at 30 mM. Compound stock solutions were freshly diluted with extracellular solution to concentrations of 0.3 nM, 1 nM, 3 nM, 10 nM, 30 nM, 100 nM, 300 nM, and 1 µM. The highest content of DMSO (0.003%) was present at 1 µM. Senicapoc (SML2500, Sigma-Aldrich) was dissolved in DMSO at 5 mM. Senicapoc stock was freshly diluted with extracellular solution to 5 µM. Patch clamp recordings and compound application [0359] All experiments were performed at room temperature. Each cell acted as its own control. In preparation for a current recording session, intracellular solution #1 (see above) was loaded into the intracellular compartments of the automated patch clamp platform SyncroPatch (Nanion Technologies GmbH) chip and the cell suspension was pipetted into the extracellular compartments. Cell catching, sealing, whole-cell formation and the following membrane current recordings and compound application were enabled by means of the SyncroPatch according to Nanion’s procedure. KCa3.1 was activated by exchanging the intracellular solution to a solution containing free Ca2+ (intracellular solution #2, see above), and the KCa3.1 currents were elicited by a voltage protocol that held at -80 mV for 20 ms, stepped to -120 mV for 20 ms, ramped from -120 to +40 mV in 208 ms, and then stepped back to -120 mV for 20 ms. This pulse protocol was applied every 10 s. Leak currents were not subtracted during recordings. In the end of each recording session, Senicapoc (5 µM) was applied to achieve full block of KCa3.1 current. Data analysis [0360] Data analysis was performed using DataControl384 (Nanion's proprietary software). To determine IC50 values, AUC (measured during ramp between -120 and +40 mV) and peak values (measured at +40 mV), obtained in the presence of a given compound concentration, were normalized to control values in absence of compound as follows: where AUC/peak (full block) are values obtained in the presence of 5 µM Senicapoc. The concentration-response curves were generated by plotting the calculated responses vs the concentrations on a logarithmic scale. The Hill equation was fitted to the data by non-linear least square regression analysis: The four variables that can be calculated from the fit are minimum (Min) and maximum (Max) of the curve as well as Hill coefficient (Hill) and the half maximum concentration (IC50). Min was fixed to 0 and Max was fixed to 1. The optimization algorithm was “Levenberg-Marquart.” Example 22. Evaluation of hERG activities [0361] This assay was used to evaluate the disclosed compounds’ inhibition activities against the hERG channel. Cell culture [0362] CHO-K1 cells stably expressing hERG were grown in Ham’s F-12 Medium with Glutamine containing 10% heat-inactivated FBS, 1% Penicillin/Streptomycin, Hygromycin (100 µg/ml), and G418 (100 µg/ml). Cells used for electrophysiology were plated in plastic culture flasks and grown at 37°C in a 5% CO2-humidified incubator per ChanPharm SOP. Stocks were maintained in cryogenic storage. Solutions [0363] The cells were bathed in an extracellular solution containing 140 mM NaCl, 4 mM KCl, 2 mM CaCl2, 1 mM MgCl2, 5 mM Glucose, and 10 mM HEPES; pH adjusted to 7.4 with NaOH; 295-305 mOsm. The internal solution contained 10 mM KCl, 110 mM KF, 10 mM NaCl, 10 mM EGTA, 10 mM HEPES; pH adjusted to 7.2 with KOH; 280-285 mOsm. All compounds were dissolved in DMSO at 30 mM. Compound stock solutions were freshly diluted with external solution to concentrations of 50 µM and 100 µM. The highest content of DMSO (0.17%) was present at 50 µM. Voltage protocol [0364] All experiments were performed at room temperature. Each cell acted as its own control. In preparation for a current recording session, intracellular solution (see above) was loaded into the intracellular compartments of the automated patch clamp platform SyncroPatch (Nanion Technologies GmbH) chip and the cell suspension was pipetted into the extracellular compartments. Cell catching, sealing, whole-cell formation and the following membrane current recordings and compound application were enabled by means of the SyncroPatch according to Nanion’s procedure. hERG currents were elicited by a voltage pulse pattern with fixed amplitudes (depolarization: +40mV amplitude, 300 ms duration; repolarization: -50mV, 300 ms duration) repeated at 3 s intervals from a holding potential of - 80 mV. Data analysis [0365] Data acquisition and analysis were performed using DataControl384 (Nanion's proprietary software). To determine the (percentage) inhibition, the last single pulse in the pulse train (i.e., the repolarization step to -50 mV; tail current) at a given compound concentration was used. AUC and peak values, obtained in the presence of compound, were normalized to control values in the absence of compound as follows: [0366] Table 2 provides a summary of the inhibition activities (IC50 (μM) values) of certain exemplified compounds against KCa3.1 channel and hERG channel.
* Not tested

Claims

CLAIMS 1. A compound of Formula I, or a pharmaceutically acceptable salt thereof, or a tautomer thereof: wherein R1 is alkyl, cycloalkyl, halogenated alkyl, halogenated cycloalkyl, bicycloalkyl, halogenated bicycloalkyl, saturated heterocycle, partially saturated heterocycle, aryl, heteroaryl, -C1-4alkyl-cycloalkyl, -C1-4alkyl-saturated heterocycle, -C1-4alkyl-partially saturated heterocycle, or cycloalkenyl, each of which optionally substituted by 1-5 substituents each independently selected from the group consisting of D, halogen, alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, alkenyl, and alkynyl where valence permits; R2 is halogen, alkyl, alkynyl, halogenated alkyl, halogenated alkynyl, CN, ORa, SRa, - C1-4alkyl-ORa, -C1-4alkyl-SRa, -O-C1-4alkyl-ORa, -O-C1-4alkyl-SRa, -O-C1-4alkyl-NRaRb, -S- C1-4alkyl-ORa, -S-C1-4alkyl-SRa, or -S-C1-4alkyl-NRaRb; R3 is –(CR8R9)mR10; R4 is H, D, halogen, CN, alkyl, halogenated alkyl, cycloalkyl, halogenated cycloalkyl, ORa, SRa, -C1-4alkyl-ORa, or -C1-4alkyl-SRa; R5 is H, D, halogen, CN, alkyl, halogenated alkyl, cycloalkyl, halogenated cycloalkyl, ORa, SRa, -C1-4alkyl-ORa, or -C1-4alkyl-SRa; R6 is H, D, halogen, CN, alkyl, halogenated alkyl, cycloalkyl, halogenated cycloalkyl, ORa, SRa, -C1-4alkyl-ORa, or -C1-4alkyl-SRa; R7 is H, D, halogen, CN, alkyl, halogenated alkyl, cycloalkyl, halogenated cycloalkyl, ORa, SRa, -C1-4alkyl-ORa, or -C1-4alkyl-SRa; m is 1 or 2; each occurrence of R8 is independently H, D, OH, ORa, or alkyl; each occurrence of R9 is independently H, D, OH, ORa, or alkyl; R10 is H, D, CN, alkyl, saturated heterocycle, aryl, heteroaryl, -CORa, -COORa, - CONRaRb, -ORa, -SORa, or -SO2Ra; each occurrence of Ra and Rb is independently selected from the group consisting of H, D, alkyl, cycloalkyl, halogenated alkyl, heteroalkyl, halogenated heteroalkyl, halogenated cycloalkyl, saturated heterocycle comprising 1-3 heteroatoms each selected from the group consisting of N, O, and S, aryl, and heteroaryl; or alternatively, Ra and Rb, together with the carbon or nitrogen atom that they are connected to, form a cycloalkyl or saturated heterocycle comprising the nitrogen atom and 0-3 additional heteroatoms each selected from the group consisting of N, O, and S; the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, saturated heterocycle, partially saturated heterocycle, aryl, and heteroaryl in R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, Ra, or Rb, where applicable, are each optionally substituted by 1-4 substituents each independently selected from the group consisting of alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, halogen, CN, ORx, -(CH2)1-2ORx, N(Rx)2, -(CH2)1-2N(Rx)2, (C=O)Rx, (C=O)N(Rx)2, NRx(C=O)Rx, and oxo where valence permits; and each occurrence of Rx is independently H, D, alkyl, halogenated alkyl, or heterocycle optionally substituted by alkyl, halogen, or OH; or alternatively, the two Rx groups together with the nitrogen atom that they are connected to, form a heterocycle optionally substituted by alkyl and comprising the nitrogen atom and 0-3 additional heteroatoms each selected from the group consisting of N, O, and S.
2. The compound of claim 1, wherein R1 is phenyl that is optionally substituted by 1-5 substituents each independently selected from the group consisting of D, halogen, alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, alkenyl, and alkynyl.
3. The compound of claim 2, wherein, R1 is phenyl that is optionally substituted by 1-5 substituents each independently selected from the group consisting of D, alkyl, halogen, and halogenated alkyl.
4. The compound of claim 3, wherein, R1 is phenyl that is optionally substituted by 1-5 substituents each independently selected from the group consisting of D, CH3, CH2CH3, F, Cl, Br, CH2F, and CF3.
5. The compound of claim 1, wherein R1 is cycloalkyl, bicycloalkyl, or -C1-4alkyl- cycloalkyl, each of which optionally substituted by 1-5 substituents each independently selected from the group consisting of D, alkyl, halogen, and halogenated alkyl where valence permits.
6. The compound of claim 5, wherein R1 is cycloalkyl, bicycloalkyl, or -C1-4alkyl- cycloalkyl, each of which optionally substituted by 1-5 substituents each independently selected from the group consisting of D, CH3, CH2CH3, F, Cl, Br, CH2F, and CF3 where valence permits.
7. The compound of claim 1, wherein R1 is saturated heterocycle that is optionally substituted by 1-5 substituents each independently selected from the group consisting of D, alkyl, halogen, and halogenated alkyl where valence permits.
8. The compound of claim 7, wherein R1 is saturated heterocycle that is optionally substituted by 1-5 substituents each independently selected from the group consisting of D, CH3, CH2CH3, F, Cl, Br, CH2F, and CF3 where valence permits.
9. The compound of claim 1, wherein R1 is alkyl that is optionally substituted by 1-5 substituents each independently selected from the group consisting of D and halogen where valence permits.
10. The compound of claim 1, wherein R1 is halogenated alkyl, halogenated cycloalkyl, halogenated bicycloalkyl, partially saturated heterocycle, heteroaryl, or cycloalkenyl, each of which optionally substituted by 1-5 substituents each independently selected from the group consisting of D, halogen, alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, alkenyl, and alkynyl where valence permits.
11. The compound of claim 1, wherein R1 is -C1-4alkyl-saturated heterocycle or C1-4alkyl- partially saturated heterocycle, each of which optionally substituted by 1-5 substituents each independently selected from the group consisting of D, halogen, alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, alkenyl, and alkynyl where valence permits.
12. The compound of claim 1, wherein R1 is selected from the group consisting of
13. The compound of claim 1, wherein the compound has the structure of Formula IIa: wherein R11 is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogenated cycloalkyl, or halogenated alkyl; R12 is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogenated cycloalkyl, or halogenated alkyl; R13 is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogenated cycloalkyl, or halogenated alkyl; R14 is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogenated cycloalkyl, or halogenated alkyl; and R15 is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogenated cycloalkyl, or halogenated alkyl.
14. The compound of claim 13, wherein R11 is H, D, F, Cl, Br, I, alkyl, or halogenated alkyl; R12 is H, D, F, Cl, Br, I, alkyl, or halogenated alkyl; R13 is H, D, F, Cl, Br, I, alkyl, or halogenated alkyl; R14 is H, D, F, Cl, Br, I, alkyl, or halogenated alkyl; and R15 is H, D, F, Cl, Br, I, alkyl, or halogenated alkyl.
15. The compound of claim 1, wherein the compound has the structure of Formula IIb:
wherein is alkyl, cycloalkyl, -CH2-cycloalkyl, cycloalkenyl, bicycloalkyl, heteroaryl, or saturated heterocycle, each of which optionally substituted by 1-5 substituents each independently selected from the group consisting of D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogenated cycloalkyl, and halogenated alkyl where valence permits.
16. The compound of claim 15, wherein is optionally substituted by 1-5 substituents each independently selected from the group consisting of D, alkyl, halogen, and halogenated alkyl.
17. The compound of claim 15, wherein is pyridine, pyrimidine, furan, or thiophene, each of which optionally substituted with halogen or alkyl.
18. The compound of claim 15, wherein is thiane or pyrane, each of which optionally substituted with halogen or alkyl.
19. The compound of any one of claims 1-18, wherein R2 is CN, OH, halogen, halogenated alkyl, alkyl optionally substituted with alkoxy or OH, or alkoxy optionally substituted with halogen, alkyl, alkoxy, or OH.
20. The compound of claim 19, wherein R2 is selected from the group consisting of CN, F, Cl, Br, I, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CF3, CH2F, CHF2, CH2Cl, CH2CF3, CHFCH3, CHFCH2F, CF2CH3, CHClCH3, CCl2CH3, CHBrCH3, CH2CH2CF3, and CHClCHClCH3.
21. The compound of any one of claims 1-18, wherein R2 is CN, ORa, SRa, -O-C1-4alkyl- ORa, -O-C1-4alkyl-SRa, -O-C1-4alkyl-NRaRb, -S-C1-4alkyl-ORa, -S-C1-4alkyl-SRa, or -S-C1- 4alkyl-NRaRb.
22. The compound of claim 21, wherein R2 is CN, ORa, SRa, or -O-C1-4alkyl-ORa.
23. The compound of any one of claims 1-18, wherein R2 is -C1-4alkyl-ORa or -C1-4alkyl- SRa.
24. The compound of any one of claims 1-18, wherein R2 is selected from the group .
25. The compound of claim 1, wherein the compound has the structure of Formula III: wherein X is O or S; and R16 is C1-4alkyl that is optionally substituted with halogen, ORa, SRa, or NRaRb.
26. The compound of any one of claims 1-25, wherein m is 2.
27. The compound of any one of claims 1-25, wherein m is 1.
28. The compound of any one of claims 1-27, wherein each occurrence of R8 is independently H, D, OH, or alkyl.
29. The compound of claim 28, wherein each occurrence of R8 is independently H, D, OH, CH3, or CH2CH3.
30. The compound of any one of claims 1-27, wherein each occurrence of R8 is independently H, D, or OH.
31. The compound of any one of claims 1-30, wherein each occurrence of R9 is independently H, D, OH, or alkyl.
32. The compound of claim 31, wherein each occurrence of R9 is independently H, D, OH, CH3, or CH2CH3.
33. The compound of any one of claims 1-30, wherein each occurrence of R9 is H, D, or OH.
34. The compound of any one of claims 1-25, wherein the structural moiety –(CR8R9)m– is –CH2–, –CH2CH2–, –CHOH–, or –CH2CHOH–.
35. The compound of any one of claims 1-34, wherein R10 is alkyl, -COORa, -CORa, - CONRaRb, -ORa, -SORa, or -SO2Ra.
36. The compound of claim 35, wherein R10 is -CONRaRb.
37. The compound of any one of claims 1-34, wherein R10 is saturated heterocycle or heteroaryl, wherein R10 is optionally substituted with halogen or OH.
38. The compound of claim 37, wherein R10 is oxetane, pyrazole, or oxadiazole, each optionally substituted by halogen or alkyl.
39. The compound of any one of claims 1-34, wherein R10 is H, D, CN, or aryl.
40. The compound of any one of claims 1-27, wherein R3 is (CH2)1-2CONRaRb, CH2C(=O)Ra, CH2CH(OH)Ra, CH2CH(OH)CH2OH, CH2SORa, CH2SO2Ra, (CH2)1-2- heterocycle, or (CH2)1-2-heteroaryl.
41. The compound of claim 1, wherein the compound has a structure of Formula IV: .
42. The compound of claim 1, wherein the compound has the structure of Formula V: wherein X is O or S; and R16 is C1-4alkyl that is optionally substituted with halogen, ORa, SRa, or NRaRb.
43. The compound of claim 41 or 42, wherein R1 is phenyl that is optionally substituted by 1-5 substituents each independently selected from the group consisting of D, halogen, alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, alkenyl, and alkynyl.
44. The compound of claim 43, wherein R1 is optionally substituted by 1-5 substituents each independently selected from the group consisting of D, F, Cl, Br, I, alkyl, and halogenated alkyl.
45. The compound of claim 41 or 42, wherein R1 is alkyl, cycloalkyl, -CH2-cycloalkyl, cycloalkenyl, bicycloalkyl, heteroaryl, or saturated heterocycle, each of which optionally substituted by 1-5 substituents each independently selected from the group consisting of D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogenated cycloalkyl, and halogenated alkyl where valence permits.
46. The compound of claim 45, wherein R1 is optionally substituted by 1-5 substituents each independently selected from the group consisting of D, alkyl, halogen, and halogenated alkyl where valence permits.
47. The compound of claim 41 or 42, wherein R1 is pyridine, pyrimidine, furan, or thiophene, each of which optionally substituted with halogen or alkyl.
48. The compound of claim 41 or 42, wherein R1 is thiane or pyrane, each of which optionally substituted with halogen or alkyl.
49. The compound of any one of claims 1-48, wherein at least one of R4, R5, R6, and R7 is not H or D.
50. The compound of any one of claims 1-48, wherein at least two of R4, R5, R6, and R7 are not H or D.
51. The compound of any one of claims 1-50, wherein R4 is H, D, halogen, CN, alkyl, halogenated alkyl, ORa, or SRa.
52. The compound of claim 51, wherein R4 is H, D, halogen, CN, alkyl, or ORa.
53. The compound of claim 51, wherein R4 is H, D, F, Cl, Br, I, CN, OH, CH3, CH2CH3, OCH3, or CF3.
54. The compound of any one of claims 1-50, wherein R4 is cycloalkyl, halogenated cycloalkyl, -C1-4alkyl-ORa, or -C1-4alkyl-SRa.
55. The compound of any one of claims 1-54, wherein R5 is H, D, halogen, CN, alkyl, halogenated alkyl, ORa, or SRa.
56. The compound of claim 55, wherein R5 is H, D, halogen, CN, alkyl, or ORa.
57. The compound of claim 55, wherein R5 is H, D, F, Cl, Br, I, CN, OH, CH3, CH2CH3, OCH3, or CF3.
58. The compound of any one of claims 1-54, wherein R5 is cycloalkyl, halogenated cycloalkyl, -C1-4alkyl-ORa, or -C1-4alkyl-SRa.
59. The compound of any one of claims 1-58, wherein R6 is H, D, halogen, CN, alkyl, halogenated alkyl, ORa, or SRa.
60. The compound of claim 59, wherein R6 is H, D, halogen, CN, alkyl, or ORa.
61. The compound of claim 59, wherein R6 is H, D, F, Cl, Br, I, CN, OH, CH3, CH2CH3, OCH3, or CF3.
62. The compound of any one of claims 1-58, wherein R6 is cycloalkyl, halogenated cycloalkyl, -C1-4alkyl-ORa, or -C1-4alkyl-SRa.
63. The compound of any one of claims 1-62, wherein R7 is H, D, halogen, CN, alkyl, halogenated alkyl, ORa, or SRa.
64. The compound of claim 63, wherein R7 is H, D, halogen, CN, alkyl, or ORa.
65. The compound of claim 63, wherein R7 is H, D, F, Cl, Br, I, CN, OH, CH3, CH2CH3, OCH3, or CF3.
66. The compound of any one of claims 1-62, wherein R7 is cycloalkyl, halogenated cycloalkyl, -C1-4alkyl-ORa, or -C1-4alkyl-SRa.
67. The compound of claim 1, wherein R1 is alkyl, cycloalkyl, -C1-4alkyl-cycloalkyl, bicycloalkyl, saturated heterocycle, aryl, heteroaryl, or cycloalkenyl; wherein R1 is optionally substituted by 1-5 substituents each independently selected from the group consisting of D, halogen, alkyl, halogenated and alkyl where valence permits; R2 is CN, alkyl, ORa, SRa, -C1-4alkyl-ORa, or -O-C1-4alkyl-ORa; R3 is –(CH2)mCONRaRb, –(CH2)mC(=O)Ra, –CH2CH(OH)R10, –CH2CH(OH)CH2OH, –CH2SORa, –CH2SO2Ra, –(CH2)m-heterocycle, or –(CH2)m-heteroaryl; R4 is H, D, halogen, CN, or alkyl; R5 is H, D, halogen, alkyl, or ORa; R6 is H, D, or halogen; R7 is H, D, or halogen; m is 1 or 2; and R10 is H, D, or alkyl.
68. The compound of claim 42, wherein R1 is cycloalkyl or phenyl; wherein the cycloalkyl or phenyl in R1 is optionally substituted by 1-5 substituents each of which is independently D or halogen where valence permits; X is O; R16 is C1-4alkyl that is optionally substituted with halogen, ORa, SRa, or NRaRb; R4 is H, D, or halogen; R5 is H, D, halogen, or ORa; R6 is H, D, or halogen; R7 is H, D, or halogen; and Ra and Rb are each independently H or Me.
69. The compound of any one of the claims 1-68, wherein at least one occurrence of Ra or Rb is independently H, D, alkyl, cycloalkyl, saturated heterocycle, aryl, or heteroaryl.
70. The compound of any one of the claims 1-68, wherein each occurrence of Ra or Rb is independently H, D, alkyl, or halogenated alkyl.
71. The compound of any one of claims 1-68, wherein at least one occurrence of Ra or Rb is independently H, D, Me, Et, Pr, CH2CH2OH, phenyl, or a heterocycle selected from the heterocycle is optionally substituted by alkyl, OH, oxo, or (C=O)C1-4alkyl where valence permits.
72. The compound of claim 70, wherein at least one occurrence of Ra or Rb is H, Me,
73. The compound of any one of claims 1-68, wherein Ra and Rb, together with the nitrogen atom that they are connected to, form an optionally substituted heterocycle comprising the nitrogen atom and 0-3 additional heteroatoms each selected from the group consisting of N, O, and S.
74. The compound of any one of the proceeding claims, wherein each occurrence of Rx is independently H, alkyl, or heterocycle optionally substituted by alkyl, halogen, or OH.
75. The compound of claim 74, wherein each occurrence of Rx is independently H or alkyl.
76. The compound of claim 74, wherein each occurrence of Rx is independently H or Me.
77. The compound of claim 1, wherein the compound is selected from the group consisting of compounds 1-74 in Table 2.
78. The compound of claim 1, wherein the compound i ,
79. The compound of any one of the proceeding claims, wherein the compound is not in a salt form or a tautomer form.
80. A pharmaceutical composition comprising at least one compound according to any one of claims 1-78 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent.
81. A method of treating a condition in a mammalian species in need thereof, comprising administering to the mammalian species a therapeutically effective amount of at least one compound according to any one of claims 1-79 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 80, wherein the condition is selected from the group consisting of cancer, sickle cell anemia, a cardiovascular disease, a respiratory disease, a fibrotic disease, an autoimmune disease, a central nervous system (CNS) disorder, a neurodegenerative disease, and an inflammatory disorder.
82. The method of claim 81, wherein the respiratory disease is an inflammatory airway disease, airway hyperresponsiveness, an idiopathic lung disease, chronic obstructive pulmonary disease, asthma, allergy, chronic asthma, tracheobronchial or diaphragmatic dysfunction, cough, or chronic cough.
83. The method of claim 81, wherein the autoimmune disease is rheumatoid arthritis or multiple sclerosis.
84. The method of claim 81, wherein the CNS disorder is acute ischemic stroke, traumatic brain injury, peripheral nerve injury, glioblastoma multiforme, or spinal cord injury.
85. The method of claim 81, wherein the fibrotic disease is liver fibrosis, kidney fibrosis, cardiac fibrosis, eye injury-related corneal fibrosis, or lung fibrosis.
86. The method of claim 81, wherein the neurodegenerative disease is Alzheimer’s disease, Parkinson’s disease, or amyotrophic lateral sclerosis (ALS).
87. The method of claim 81, wherein the mammalian species is human.
88. A method of inhibiting calcium-activated potassium channel KCa3.1 in a mammalian species in need thereof, comprising administering to the mammalian species a therapeutically effective amount of at least one compound according to any one of claims 1-78 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 79.
89. The method of claim 88, wherein the mammalian species is human.
PCT/US2025/027715 2024-05-06 2025-05-05 INDOLINONE COMPOUNDS AS KCa3.1 POTASSIUM CHANNEL BLOCKERS Pending WO2025235362A1 (en)

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