Spiroindolinone compounds as potassium channel blockers

Abstract

A compound having a structure of Formula I, is described, where the various substituents are defined herein. The compounds can block or inhibit Kca3.1 and be used in the treatment of a variety of conditions. Methods for synthesizing the compounds, pharmaceutical compositions comprising the compounds, and methods of using the compounds and compositions are also described.

Description

SPIROINDOLINONE COMPOUNDS AS 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 / 704,217, filed October 7, 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). KCachannels 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 KCachannel (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 be 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 encodes 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 the 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. BowelDis.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 cancers (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 therapymay 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 disease, Parkinson’s disease, and amyotrophic lateral sclerosis (ALS) suggest that 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 Idescribed, 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 A is O, S, or C(R11)2; B is C(R12)2or absent, wherein when B is absent, A and E are connected by a bond; E is O, S, or C(R13)2; X is N or CR14; Y is N or CR15; R1is H, D, halogen, –CN, alkyl, halogenated alkyl, cycloalkyl, halogenated cycloalkyl, –ORa, –SRa, –C1-4alkyl–ORa, or –C1-4alkyl–SRa; R2is H, D, or halogen; R3is –(CR8R9)mR10; R4 is H, D, halogen, or alkyl; 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; R7is H, D, halogen, or alkyl; each occurrence of R8is independently H, D, or alkyl; each occurrence of R9 is independently H, D, or alkyl; R10is –CN, saturated heterocycle, heteroaryl, –CORa, –CO2Ra, –CONRaRb, –ORa, – SORa, or –SO2Ra; each occurrence of R11 is independently H, D, or alkyl; each occurrence of R12 is independently H, D, or alkyl; each occurrence of R13is independently H, D, or alkyl; R14 is H, D, halogen, –CN, alkyl, halogenated alkyl, cycloalkyl, halogenated cycloalkyl, –ORa, –SRa, –C1-4alkyl–ORa, or –C1-4alkyl–SRa;R15 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 Ra and Rb is independently selected from the group consisting of H, alkyl, cycloalkyl, halogenated alkyl, heteroalkyl, halogenated heteroalkyl, or halogenated cycloalkyl; or alternatively, Raand Rb, together with the 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, cycloalkyl, heteroalkyl, saturated heterocycle, aryl, and / or heteroaryl in R1, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, Ra, or Rb, where applicable, are each optionally and independently substituted by 1-4 substituents each independently selected from the group consisting of alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, halogen, –ORx, –(CH2)1-2ORx, 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.

[0019] In any one of the embodiments described herein, the structural moietyhas the structure

[0020] In any one of the embodiments described herein, R1is H, halogen, –ORa, or –C1-4alkyl–ORa.

[0021] In any one of the embodiments described herein, R1 is H, F, Cl, OCH3, or OCH2CH3.

[0022] In any one of the embodiments described herein, R1is H, F, or Cl.

[0023] In any one of the embodiments described herein, R2is H or halogen.

[0024] In any one of the embodiments described herein, R2 is H, F, or Cl.

[0025] In any one of the embodiments described herein, R14 is H, halogen, –ORa, or – C1-4alkyl–ORa.

[0026] In any one of the embodiments described herein, R14 is H, F, Cl, –OCH3, –OCH2CH3, –C1-4alkyl–OCH3, or –C1-4alkyl–OCH2CH3.

[0027] In any one of the embodiments described herein, R14is H, F, Cl, or –OCH3.

[0028] In any one of the embodiments described herein, R15 is H, halogen, –ORa, or –C1- 4alkyl–ORa.

[0029] In any one of the embodiments described herein, R15is H, F, Cl, –OCH3, or – OCH2CH3.

[0030] In any one of the embodiments described herein, R15 is H, F, or Cl. ,

[0033] In any one of the embodiments described herein, m is 1.

[0034] In any one of the embodiments described herein, m is 2.

[0035] In any one of the embodiments described herein, each occurrence of R8 is independently H or alkyl.

[0036] In any one of the embodiments described herein, each occurrence of R9is independently H or alkyl.

[0037] In any one of the embodiments described herein, the structural moiety –(CR8R9)m– has the structure of –CH2–, –CH2CH2–, –CH(CH3)–, -CH(CH3)CH2–, or – CH(CH3)CH(CH3)–.

[0038] In any one of the embodiments described herein, each occurrence of R8 is H.

[0039] In any one of the embodiments described herein, each occurrence of R9is H.

[0040] In any one of the embodiments described herein, the structural moiety –(CR8R9)m– has the structure of –CH2– or –CH2CH2–.

[0041] In any one of the embodiments described herein, R10is CN, –CO2Ra, –CORa, – CONRaRb, –ORa, –SORa, or –SO2Ra.

[0042] In any one of the embodiments described herein, R10 is saturated heterocycle or heteroaryl, wherein R10is optionally substituted with halogen or OH.

[0043] In any one of the embodiments described herein, R10is –CONRaRb.

[0044] In any one of the embodiments described herein, R3 is –(CH2)1-2CONRaRb.

[0045] In any one of the embodiments described herein, R4 is H, F, or Cl.

[0046] In any one of the embodiments described herein, R4 is H.

[0047] In any one of the embodiments described herein, R5is H, F, Cl, OCH3, or OCH2CH3.

[0048] In any one of the embodiments described herein, R5 is H, F, or Cl.

[0049] In any one of the embodiments described herein, R6 is H, F, Cl, –OCH3, or – OCH2CH3.

[0050] In any one of the embodiments described herein, R6is H, F, or Cl.

[0051] In any one of the embodiments described herein, R7 is H, F, or Cl.

[0052] In any one of the embodiments described herein, the structural moiety

[0053] In any one of the embodiments described herein, the structural moietyhas the structure.

[0054] In any one of the embodiments described herein, R5 and R6 are each independently H, F, or Cl.

[0055] In any one of the embodiments described herein, the structural moiety

[0056] In any one of the embodiments described herein, each occurrence of R11 is independently H or alkyl.

[0057] In any one of the embodiments described herein, each occurrence of R12is independently H or alkyl.

[0058] In any one of the embodiments described herein, each occurrence of R13 is independently H or alkyl.

[0059] In any one of the embodiments described herein, the compound has the structure of Formula Ia:Ia.

[0060] In any one of the embodiments described herein, the structural moiety; wherein A, when present, is C(R11)2; B is C(R12)2; and E, when present, is C(R13)2.each occurrence of R11, R12, and R13is independently H, –CH3, or –CH2CH3.

[0062] In any one of the embodiments described herein, the structural moietythe structure,

[0063] In any one of the embodiments described herein, the structural moietythe structure

[0064] In any one of the embodiments described herein, the compound has the structure of Formula Ib:

[0065] In any one of the embodiments described herein, the structural moietypresent, is (R11)2; and E, when present, is C(R13)2.

[0066] In any one of the embodiments described herein, the structural moietythe structure; wherein each occurrence of R11 and R13 is independently H, –CH3, or –CH2CH3.

[0067] In any one of the embodiments described herein, the structural moiety,

[0069] In any one of the embodiments described herein, each occurrence of Raor Rbis independently H, D, alkyl, or halogenated alkyl.

[0070] In any one of the embodiments described herein, each occurrence of Ra or Rb is independently H, D, or cycloalkyl.

[0071] In any one of the embodiments described herein, each occurrence of Raor Rbis independently H or alkyl.

[0072] In any one of the embodiments described herein, each occurrence of Ra or Rb is independently H, –CH3, –CH2CH3, –CH2CH2CH3, –CH(CH3)2, or –C(CH3)3.

[0073] In any one of the embodiments described herein, each occurrence of Ra or Rb is independently H, –CH3, or –CH2CH3.

[0074] In any one of the embodiments described herein, Raand 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.

[0075] In any one of the embodiments described herein, each occurrence of Rxis independently H, alkyl, or heterocycle.

[0076] In any one of the embodiments described herein, each occurrence of Rxis independently H, –CH3, or –CH2CH3.

[0077] In any one of the embodiments described herein, the compound has the structure of Formula II:II wherein A is O, S, or C(R11)2; B is C(R12)2 or absent, wherein when B is absent, A and E are connected by a bond; E is O or C(R13)2; X is N or CR14; Y is N or CR15; R1 is H, D, or halogen; R3is –(CR8R9)mR10; R5is H, D, or halogen; R6 is H, D, or halogen; each occurrence of R8is independently H, D, or alkyl; each occurrence of R9is independently H, D, or alkyl; R10 is –CN, saturated heterocycle, heteroaryl, –CORa, –CO2Ra, –CONRaRb, –ORa, – SORa, or –SO2Ra; each occurrence of R11is independently H or alkyl; each occurrence of R12 is independently H or alkyl; each occurrence of R13 is independently H or alkyl; R14is H, D, halogen, alkyl, –ORa, or –C1-4alkyl–ORa; R15 is H, D, halogen, alkyl, –ORa, or –C1-4alkyl–ORa; m is 1 or 2; each occurrence of Raand Rbis independently selected from the group consisting of H, D, alkyl, cycloalkyl, halogenated alkyl, heteroalkyl, halogenated heteroalkyl, halogenatedcycloalkyl; or alternatively, Ra and Rb, together with the 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, cycloalkyl, heteroalkyl, saturated heterocycle, aryl, and / or heteroaryl in R8, R9, R10, R11, R12, R13, R14, R15, Ra, or Rb, where applicable, are each optionally and independently substituted by 1-4 substituents each independently selected from the group consisting of alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, halogen, –ORx, – (CH2)1-2ORx, and oxo, where valence permits; and each occurrence of Rxis independently H, D, alkyl, halogenated alkyl, or heterocycle optionally substituted by alkyl, halogen, or OH.

[0078] In any one of the embodiments described herein, A is O, S, or C(R11)2; B is C(R12)2or absent, wherein when B is absent, A and E are connected by a bond; E is O or C(R13)2; X is N or CR14; Y is N or CR15; R1is H or halogen; R3 is –(CR8R9)1-2R10; R5is H or halogen; R6is H or halogen; each occurrence of R8 is independently H or alkyl; each occurrence of R9is independently H or alkyl; R10is –CONRaRb; each occurrence of R11 is independently H or alkyl; each occurrence of R12 is independently H or alkyl; each occurrence of R13is independently H or alkyl; R14 is H, halogen, –ORa, or –C1-4alkyl–ORa; R15 is H, halogen, –ORa, or –C1-4alkyl–ORa; andeach occurrence of Ra and Rb is independently selected from the group consisting of H or alkyl.

[0079] In any one of the embodiments described herein, the compound has the structure of Formula IIa:wherein A is O, S, or CH2; E is O or CHR13; X is N or CR14; Y is N or CR15; R1 is H or halogen; R3is –(CR8R9)1-2R10; R5is H or halogen; R6 is H or halogen; each occurrence of R8 is independently H or alkyl; each occurrence of R9is independently H or alkyl; R10 is –CONRaRb; R13 is H or alkyl; R14is H, halogen, –ORa, or –C1-4alkyl–ORa; R15 is H, halogen, –ORa, or –C1-4alkyl–ORa; and each occurrence of Ra and Rb is independently selected from the group consisting of H or alkyl.

[0080] In any one of the embodiments described herein, the compound has the structure of Formula IIb:wherein A is O or CH2;E is O or CHR13; X is N or CR14; Y is N or CR15; R1 is H or halogen; R3 is –(CR8R9)1-2R10; R5is H or halogen; R6is H or halogen; each occurrence of R8 is independently H or alkyl; each occurrence of R9is independently H or alkyl; R10is –CONRaRb; each occurrence of R13 is independently H or alkyl; R14 is H, halogen, –ORa, or –C1-4alkyl–ORa; R15is H, halogen, –ORa, or –C1-4alkyl–ORa; and each occurrence of Ra and Rb is independently selected from the group consisting of H or alkyl.

[0081] In any one of the embodiments described herein, the compound is, , , ,

[0082] In any one of the embodiments described herein, the compound is selected from the group consisting of Compounds 1-40 in Table 3.

[0083] In any one of the embodiments described herein, the compound is not in a salt form or a tautomer form.

[0084] 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.

[0085] 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 the 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.

[0086] 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.

[0087] In any one of the embodiments described herein, the autoimmune disease is rheumatoid arthritis or multiple sclerosis (MS).

[0088] 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.

[0089] 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.

[0090] In any one of the embodiments described herein, the neurodegenerative disease is Alzheimer’s disease, Parkinson’s disease, or amyotrophic lateral sclerosis (ALS).

[0091] 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 the embodiments described herein or a pharmaceutically acceptable salt thereof.

[0092] In any one of the embodiments described herein, the mammalian species is human.

[0093] Any one of the embodiments disclosed herein may be properly combined with any other embodiment disclosed herein. The combination of any one of the embodimentsdisclosed 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

[0094] 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.

[0095] 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 CF3or 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)(Re)2, S(=O)2ORe, P(=O)(ORe)2, NRbRc, NRbS(=O)2Re, NRbP(=O)(Re)2, S(=O)2NRbRc, P(=O)(NRbRc)2, 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)(NRbRc)2, NRbC(=O)Ra, or NRbP(=O)(Re)2, wherein eachoccurrence 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 Rband Rctogether 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.

[0096] 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 CF3or 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)(Re)2, S(=O)2ORe, P(=O)(ORe)2, NRbRc, NRbS(=O)2Re, NRbP(=O)(Re)2, S(=O)2NRbRc, P(=O)(NRbRc)2, 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)(NRbRc)2, NRbC(=O)Ra, or NRbP(=O)(Re)2, wherein each occurrence of Ra is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; each occurrence of Rb, Rc, and Rdis 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.

[0097] 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 CF3or 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)(Re)2, S(=O)2ORe, P(=O)(ORe)2, NRbRc, NRbS(=O)2Re, NRbP(=O)(Re)2, S(=O)2NRbRc, P(=O)(NRbRc)2, 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)(NRbRc)2, NRbC(=O)Ra, or NRbP(=O)(Re)2, wherein each occurrence of Ra is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; each occurrence of Rb, Rc, and Rdis 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 Reis independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. The exemplary substituents can themselves be optionally substituted.

[0098] The term “alkynyl” refers to a straight or branched chain hydrocarbon radical containing from 2 to 12 carbon atoms and at least one carbon-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-C6alkynyl” 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 asCF3or 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)(Re)2, S(=O)2ORe, P(=O)(ORe)2, NRbRc, NRbS(=O)2Re, NRbP(=O)(Re)2, S(=O)2NRbRc, P(=O)(NRbRc)2, 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)(NRbRc)2, NRbC(=O)Ra, or NRbP(=O)(Re)2, wherein each occurrence of Rais 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 Reis independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. The exemplary substituents can themselves be optionally substituted.

[0099] The term “cycloalkyl” refers to a fully saturated cyclic hydrocarbon group containing from 1 to 4 rings and 3 to 8 carbon atoms per ring. “C3-C7cycloalkyl” 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 CF3or 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)(Re)2, S(=O)2ORe, P(=O)(ORe)2, NRbRc, NRbS(=O)2Re, NRbP(=O)(Re)2, S(=O)2NRbRc, P(=O)(NRbRc)2, 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)(NRbRc)2, NRbC(=O)Ra, or NRbP(=O)(Re)2, 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 Rband Rctogether 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 aforementionedcycloalkyl, cycloalkenyl, heterocycle and aryl substituents can themselves be optionally substituted.

[0100] 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 CF3or 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)(Re)2, S(=O)2ORe, P(=O)(ORe)2, NRbRc, NRbS(=O)2Re, NRbP(=O)(Re)2, S(=O)2NRbRc, P(=O)(NRbRc)2, 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)(NRbRc)2, NRbC(=O)Ra, or NRbP(=O)(Re)2, wherein each occurrence of Ra is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; each occurrence of Rb, Rc, and Rdis 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.

[0101] 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. Exemplarysubstituents 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 CF3or 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)(Re)2, S(=O)2ORe, P(=O)(ORe)2, NRbRc, NRbS(=O)2Re, NRbP(=O)(Re)2, S(=O)2NRbRc, P(=O)(NRbRc)2, 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)(NRbRc)2, NRbC(=O)Ra, or NRbP(=O)(Re)2, wherein each occurrence of Ra is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; each occurrence of Rb, Rc, and Rdis independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or said Rband Rctogether 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.

[0102] 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.

[0103] 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 substitutedcycloalkyl, 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.

[0104] 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.

[0105] “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 CF3or 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)(Re)2, S(=O)2ORe, P(=O)(ORe)2, NRbRc, NRbS(=O)2Re, NRbP(=O)(Re)2, S(=O)2NRbRc, P(=O)(NRbRc)2, 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)(NRbRc)2, NRbC(=O)Ra, or NRbP(=O)(Re)2, wherein each occurrence of Ra is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; each occurrence of Rb, Rc, and Rdis independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or said Rband Rctogether 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.

[0106] The term “oxo” refers to thesubstituent group, which may be attached to a carbon ring atom on a carbocycle 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 structurewhich also includes its tautomeric form of .

[0107] 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.

[0108] 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, and 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.

[0109] The terms “halogen” or “halo” refer to chlorine, bromine, fluorine, or iodine.

[0110] 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 CF3or 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)(Re)2, S(=O)2ORe, P(=O)(ORe)2, NRbRc, NRbS(=O)2Re, NRbP(=O)(Re)2, S(=O)2NRbRc, P(=O)(NRbRc)2, 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)(NRbRc)2, NRbC(=O)Ra, or NRbP(=O)(Re)2, wherein each occurrence of Ra is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; each occurrence of Rb, Rc, and Rdis independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or said Rband Rctogether 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.

[0111] Unless otherwise indicated, any heteroatom with unsatisfied valences is assumed to have hydrogen atoms sufficient to satisfy the valences.

[0112] 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.

[0113] The compounds of the present invention which contain a basic moiety, such as but not limited to an amine, a pyridine ring, or an imidazole ring, may form salts with a variety oforganic 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.

[0114] 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, and 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.

[0115] 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.

[0116] 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.

[0117] 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 as 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, 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.

[0118] 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% or 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.

[0119] 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.

[0120] Throughout the specification, groups and substituents thereof may be chosen to provide stable moieties and compounds.

[0121] 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, 75thEd., 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.

[0122] 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.

[0123] 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) or in a ratio in a range bounded by any two ratios disclosed herein 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.

[0124] 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 as2H (D),3H (T),13C,11C,14C,15N,18O,17O,31P,32P,35S,18F, and36Cl, 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 as3H and14C 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 theprocedures disclosed in the Schemes and / or in the Examples below, by substituting a readily available isotopically labeled reagent for a non-isotopically-labeled reagent.

[0125] 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 is 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 chromatographic means well known in the art, and subsequent recovery of the pure enantiomers.

[0126] 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, and 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.

[0127] 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; and 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.

[0128] 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.

[0129] 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

[0130] Novel compounds as potassium channel (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 disclosedherein selectively block KCa3.1 and do not block the hERG channel and thus, have desirable cardiovascular safety profiles.

[0131] In one aspect, a compound having a structure of Formula I is describedthe various substituents are defined herein. Thecompounds 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. Further described herein are pharmaceutical compositions and methods of using these compounds and compositions, e.g., as 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 treatment of 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.

[0132] In one aspect, a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a tautomer thereof, is described:wherein A is O, S, or C(R11)2; B is C(R12)2 or absent, wherein when B is absent, A and E are connected by a bond; E is O, S, or C(R13)2;X is N or CR14; Y is N or CR15; R1is H, D, halogen, -CN, alkyl, halogenated alkyl, cycloalkyl, halogenated cycloalkyl, -ORa, -SRa, -C1-4alkyl-ORa, or -C1-4alkyl-SRa; R2 is H, D, or halogen; R3is -(CR8R9)mR10; R4is H, D, halogen, or alkyl; R5 is H, D, halogen, -CN, alkyl, halogenated alkyl, cycloalkyl, halogenated cycloalkyl, -ORa, -SRa, -C1-4alkyl-ORa, or -C1-4alkyl-SRa; R6is H, D, halogen, -CN, alkyl, halogenated alkyl, cycloalkyl, halogenated cycloalkyl, -ORa, -SRa, -C1-4alkyl-ORa, or -C1-4alkyl-SRa; R7 is H, D, halogen, or alkyl; each occurrence of R8is independently H, D, or alkyl; each occurrence of R9 is independently H, D, or alkyl; R10 is -CN, saturated heterocycle, heteroaryl, -CORa, -CO2Ra, -CONRaRb, -ORa, - SORa, or -SO2Ra; each occurrence of R11is independently H, D, or alkyl; each occurrence of R12 is independently H, D, or alkyl; each occurrence of R13is independently H, D, or alkyl; R14is H, D, halogen, -CN, alkyl, halogenated alkyl, cycloalkyl, halogenated cycloalkyl, -ORa, -SRa, -C1-4alkyl-ORa, or -C1-4alkyl-SRa; R15is 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 Ra and Rb is independently selected from the group consisting of H, D, alkyl, cycloalkyl, halogenated alkyl, heteroalkyl, halogenated heteroalkyl, or halogenated cycloalkyl; or alternatively, Ra and Rb, together with the nitrogen atom that theyare 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, cycloalkyl, heteroalkyl, saturated heterocycle, aryl, and / or heteroaryl in R1, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, Ra, or Rb, where applicable, are each optionally and independently substituted by 1-4 substituents each independently selected from the group consisting of alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, halogen, -ORx, -(CH2)1-2ORx, 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.

[0133] In some embodiments, the compound of Formula I is not in a salt form or a tautomer form. In some embodiments, the compound of Formula I is in a salt form or a tautomer form. In some embodiments, the compound of Formula I is in a salt form. In some embodiments, the compound of Formula I is in a tautomer form.

[0134] In some embodiments, A is O, S, or C(R11)2. In some embodiments, A is O or S. In some embodiments, A is O or C(R11)2. In some embodiments, A is S or C(R11)2. In some embodiments, A is O. In some embodiments, A is S. In some embodiments, A is C(R11)2.

[0135] In some embodiments, B is C(R12)2or absent, wherein when B is absent, A and E are connected by a bond. In some embodiments, B is C(R12)2. In some embodiments, B is absent and A and E are connected by a bond.

[0136] In some embodiments, E is O, S, or C(R13)2. In some embodiments, E is O or S. In some embodiments, E is O or C(R13)2. In some embodiments, E is S or C(R13)2. In some embodiments, E is O. In some embodiments, E is S. In some embodiments, E is C(R13)2.

[0137] In some embodiments, X is N or CR14. In some embodiments, X is N. In some embodiments, X is CR14.

[0138] In some embodiments, Y is N or CR15. In some embodiments, Y is N. In some embodiments, Y is CR15.

[0139] In some embodiments, when X is N, Y is CR15. In some embodiments, when X is CR14, Y is N. In some embodiments, both X and Y are N. In some embodiments, X is CR14 and Y is CR15.

[0140] In some embodiments, the structural moietyhas the structure ofembodiments, the structural moiety.

[0141] In some embodiments, R1 is H, D, halogen, -CN, alkyl, halogenated alkyl, cycloalkyl, halogenated cycloalkyl, -ORa, -SRa, -C1-4alkyl-ORa, or -C1-4alkyl-SRa.

[0142] In some embodiments, R1 is H or D. In some embodiments, R1 is H. In some embodiments, R1 is D.

[0143] In some embodiments, R1is halogen. In some embodiments, R1is F, Cl, Br, or I. In some embodiments, R1is F or Cl. In some embodiments, R1is F. In some embodiments, R1is Cl. In some embodiments, R1 is Br or I. In some embodiments, R1 is Br. In some embodiments, R1is I.

[0144] In some embodiments, R1is alkyl. In some embodiments, R1is C1-4alkyl. In some embodiments, R1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl. In some embodiments, R1 is halogenated alkyl. In some embodiments, R1 is C1-4alkyl with oneor more of its hydrogen atoms substituted with one or more halogen atoms (e.g., F and / or Cl), as valence permits. In some embodiments, R1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl with one or more of its hydrogen atoms substituted with one or more halogen atoms (e.g., F and / or Cl), as valence permits. In some embodiments, R1 is C1-4alkyl with one or more of its hydrogen atoms substituted with F and / or Cl, as valence permits. In some embodiments, R1is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl with one or more of its hydrogen atoms substituted with F and / or Cl, as valence permits. In some embodiments, R1 is CF3 or CCl3. In certain embodiments, the alkyl or C1-4alkyl of R1 may be optionally substituted by groups other than or in addition to halogen.

[0145] In some embodiments, R1is cycloalkyl. In some embodiments, R1is C3-7cycloalkyl. In some embodiments, R1 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. In some embodiments, R1 is halogenated cycloalkyl. In some embodiments, R1 is C3-7cycloalkyl with one or more of its hydrogen atoms substituted with one or more halogen atoms (e.g., F and / or Cl), as valence permits. In some embodiments, R1 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl with one or more of its hydrogen atoms substituted with one or more halogen atoms (e.g., F and / or Cl), as valence permits. In some embodiments, R1is C3-7cycloalkyl with one or more of its hydrogen atoms substituted with F and / or Cl, as valence permits. In some embodiments, R1 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl with one or more of its hydrogen atoms substituted with F and / or Cl, as valence permits. In certain embodiments, the cycloalkyl or C3-7cycloalkyl of R1 may be optionally substituted by groups other than or in addition to halogen.

[0146] In some embodiments, R1is -ORaor -SRa. In some embodiments, R1is -ORa. In some embodiments, R1 is -OH. In some embodiments, R1 is -O-alkyl. In some embodiments, R1 is -OC1-4alkyl. In some embodiments, R1 is -OCH3, -OCH2CH3, - OCH2CH2CH3, -OCH(CH3)2, -OCH2CH2CH2CH3, -OCH2CH(CH3)2, or -OC(CH3)3. In some embodiments, R1 is -OCH3 or -OCH2CH3. In some embodiments, R1 is -SH. In some embodiments, R1 is -S-alkyl. In some embodiments, R1 is -SC1-4alkyl. In some embodiments, R1is -SCH3, -SCH2CH3, -SCH2CH2CH3, -SCH(CH3)2, -SCH2CH2CH2CH3, - SCH2CH(CH3)2, or -SC(CH3)3. In some embodiments, R1is -SCH3or -SCH2CH3. In certain embodiments, the alkyl and C1-4alkyl of R1 may be optionally substituted (e.g., by one or more halogen atoms, such as by one or more F and / or Cl atoms).

[0147] In some embodiments, R1 is -C1-4alkyl-ORa or -C1-4alkyl-SRa. In some embodiments, R1 is -C1-4alkyl-ORa. In some embodiments, R1 is -C1-4alkyl-O-alkyl. In some embodiments, R1is -C1-4alkyl-OC1-4alkyl. In some embodiments, R1is -(CH2)1-4OCH3, -(CH2)1-4OCH2CH3, -(CH2)1-4OCH2CH2CH3, -(CH2)1-4OCH(CH3)2, -(CH2)1-4OCH2CH2CH2CH3, -(CH2)1- 4OCH2CH(CH3)2, -(CH2)1-4OC(CH3)3. In some embodiments, R1 is -(CH2)1-2OCH3, -(CH2)1-2OCH2CH3, -(CH2)1-2OCH2CH2CH3, -(CH2)1-2OCH(CH3)2, -(CH2)1-2OCH2CH2CH2CH3, - (CH2)1-2OCH2CH(CH3)2, -(CH2)1-2OC(CH3)3. In some embodiments, R1is -CH2OCH3, - CH2OCH2CH3, -CH2CH2OCH3, or -CH2CH2OCH2CH3. In some embodiments, R1 is -C1-4alkyl-SRa. In some embodiments, R1is -C1-4alkyl-S-alkyl. In some embodiments, R1is -C1-4alkyl-SC1-4alkyl. In some embodiments, R1is -(CH2)1-4SCH3, -(CH2)1-4SCH2CH3, -(CH2)1-4SCH2CH2CH3, -(CH2)1-4SCH(CH3)2, -(CH2)1-4SCH2CH2CH2CH3, -(CH2)1-4SCH2CH(CH3)2, -(CH2)1-4SC(CH3)3. In some embodiments, R1 is -(CH2)1-2SCH3, -(CH2)1-2SCH2CH3, -(CH2)1-2SCH2CH2CH3, -(CH2)1-2SCH(CH3)2, -(CH2)1-2SCH2CH2CH2CH3, -(CH2)1-2SCH2CH(CH3)2, -(CH2)1-2SC(CH3)3. In some embodiments, R1 is -CH2SCH3, -CH2SCH2CH3, -CH2CH2SCH3, or -CH2CH2SCH2CH3. In certain embodiments, the alkyl and C1-4alkyl of R1 may be optionally substituted (e.g., by one or more halogen atoms, such as by one or more F and / or Cl atoms).

[0148] In some embodiments, R1 is -CN.

[0149] In some embodiments, R1is H, D, halogen, -ORa, or -C1-4alkyl-ORa. In some embodiments, R1is H, F, Cl, -OCH3, or -OCH2CH3. In some embodiments, R1is H, F, or Cl. In some embodiments, R1 is H, -OCH3, or -OCH2CH3.

[0150] In some embodiments, R2is H, D, or halogen. In some embodiments, R2is H or D. In some embodiments, R2is H. In some embodiments, R2is D. In some embodiments, R2is halogen. In some embodiments, R2 is F, Cl, Br, or I. In some embodiments, R2 is F or Cl. In some embodiments, R2 is F. In some embodiments, R2 is Cl.

[0151] In some embodiments, R14is H, D, halogen, -CN, alkyl, halogenated alkyl, cycloalkyl, halogenated cycloalkyl, -ORa, -SRa, -C1-4alkyl-ORa, or -C1-4alkyl-SRa.

[0152] In some embodiments, R14 is H or D. In some embodiments, R14 is H. In some embodiments, R14is D.

[0153] In some embodiments, R14is halogen. In some embodiments, R14is F, Cl, Br, or I. In some embodiments, R14 is F or Cl. In some embodiments, R14 is F. In some embodiments,R14 is Cl. In some embodiments, R14 is Br or I. In some embodiments, R14 is Br. In some embodiments, R14 is I.

[0154] In some embodiments, R14is alkyl. In some embodiments, R14is C1-4alkyl. In some embodiments, R14 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl. In some embodiments, R14 is halogenated alkyl. In some embodiments, R14 is C1-4alkyl with one or more of its hydrogen atoms substituted with one or more halogen atoms (e.g., F and / or Cl), as valence permits. In some embodiments, R14is methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, or tert-butyl with one or more of its hydrogen atoms substituted with one or more halogen atoms (e.g., F and / or Cl), as valence permits. In some embodiments, R14is C1-4alkyl with one or more of its hydrogen atoms substituted with F and / or Cl, as valence permits. In some embodiments, R14 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl with one or more of its hydrogen atoms substituted with F and / or Cl, as valence permits. In some embodiments, R14is CF3or CCl3. In certain embodiments, the alkyl or C1-4alkyl of R14 may be optionally substituted by groups other than or in addition to halogen.

[0155] In some embodiments, R14 is cycloalkyl. In some embodiments, R14 is C3-7cycloalkyl. In some embodiments, R14is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. In some embodiments, R14is halogenated cycloalkyl. In some embodiments, R14 is C3-7cycloalkyl with one or more of its hydrogen atoms substituted with one or more halogen atoms (e.g., F and / or Cl), as valence permits. In some embodiments, R14is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl with one or more of its hydrogen atoms substituted with one or more halogen atoms (e.g., F and / or Cl), as valence permits. In some embodiments, R14is C3-7cycloalkyl with one or more of its hydrogen atoms substituted with F and / or Cl, as valence permits. In some embodiments, R14is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl with one or more of its hydrogen atoms substituted with F and / or Cl, as valence permits. In certain embodiments, the cycloalkyl or C3-7cycloalkyl of R14may be optionally substituted by groups other than or in addition to halogen.

[0156] In some embodiments, R14 is -ORa or -SRa. In some embodiments, R14 is -ORa. In some embodiments, R14is -OH. In some embodiments, R14is -O-alkyl. In some embodiments, R14is -OC1-4alkyl. In some embodiments, R14is -OCH3, -OCH2CH3, - OCH2CH2CH3, -OCH(CH3)2, -OCH2CH2CH2CH3, -OCH2CH(CH3)2, or -OC(CH3)3. In some embodiments, R14is -OCH3or -OCH2CH3. In some embodiments, R14is -SH. In some embodiments, R14is -S-alkyl. In some embodiments, R14is -SC1-4alkyl. In someembodiments, R14 is -SCH3, -SCH2CH3, -SCH2CH2CH3, -SCH(CH3)2, -SCH2CH2CH2CH3, - SCH2CH(CH3)2, or -SC(CH3)3. In some embodiments, R14 is -SCH3 or -SCH2CH3. In certain embodiments, the alkyl or C1-4alkyl of R14may be optionally substituted (e.g., by one or more halogen atoms, such as by one or more F and / or Cl atoms).

[0157] In some embodiments, R14 is -C1-4alkyl-ORa or -C1-4alkyl-SRa. In some embodiments, R14is -C1-4alkyl-ORa. In some embodiments, R14is -C1-4alkyl-O-alkyl. In some embodiments, R14is -C1-4alkyl-OC1-4alkyl. In some embodiments, R14is -(CH2)1-4OCH3, -(CH2)1-4OCH2CH3, -(CH2)1-4OCH2CH2CH3, -(CH2)1-4OCH(CH3)2, -(CH2)1-4OCH2CH2CH2CH3, -(CH2)1-4OCH2CH(CH3)2, -(CH2)1-4OC(CH3)3. In some embodiments, R14is -(CH2)1-2OCH3, -(CH2)1-2OCH2CH3, -(CH2)1-2OCH2CH2CH3, -(CH2)1-2OCH(CH3)2, - (CH2)1-2OCH2CH2CH2CH3, -(CH2)1-2OCH2CH(CH3)2, -(CH2)1-2OC(CH3)3. In some embodiments, R14 is -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, or -CH2CH2OCH2CH3. In some embodiments, R14is -C1-4alkyl-SRa. In some embodiments, R14is -C1-4alkyl-S-alkyl. In some embodiments, R14 is -C1-4alkyl-SC1-4alkyl. In some embodiments, R14 is -(CH2)1- 4SCH3, -(CH2)1-4SCH2CH3, -(CH2)1-4SCH2CH2CH3, -(CH2)1-4SCH(CH3)2, -(CH2)1-4SCH2CH2CH2CH3, -(CH2)1-4SCH2CH(CH3)2, -(CH2)1-4SC(CH3)3. In some embodiments, R14is -(CH2)1-2SCH3, -(CH2)1-2SCH2CH3, -(CH2)1-2SCH2CH2CH3, -(CH2)1-2SCH(CH3)2, - (CH2)1-2SCH2CH2CH2CH3, -(CH2)1-2SCH2CH(CH3)2, -(CH2)1-2SC(CH3)3. In some embodiments, R14is -CH2SCH3, -CH2SCH2CH3, -CH2CH2SCH3, or -CH2CH2SCH2CH3. In certain embodiments, the alkyl and C1-4alkyl of R14may be optionally substituted (e.g., by one or more halogen atoms, such as by one or more F and / or Cl atoms).

[0158] In some embodiments, R14is -CN.

[0159] In some embodiments, R14is H, halogen, -ORa, or -C1-4alkyl-ORa. In some embodiments, R14 is H, F, Cl, -OCH3, -OCH2CH3, -C1-4alkyl-OCH3, or -C1-4alkyl-OCH2CH3. In some embodiments, R14 is H, F, or Cl. In some embodiments, R14 is H, -OCH3, or - OCH2CH3. In some embodiments, R14is H, F, Cl, -OCH3, or -OCH2CH3. In some embodiments, R14 is H, F, Cl, or -OCH3. In some embodiments, R14 is H, -CH2OCH3, - CH2CH2OCH3, -CH2CH2CH2OCH3, -CH2CH2CH2CH2OCH3, -CH2OCH2CH3, - CH2CH2OCH2CH3, -CH2CH2CH2OCH2CH3, or -CH2CH2CH2CH2OCH2CH3. In some embodiments, R14is H, -CH2OCH3, -CH2CH2OCH3, -CH2OCH2CH3, or -CH2CH2OCH2CH3.

[0160] In some embodiments, R15 is H, D, halogen, -CN, alkyl, halogenated alkyl, cycloalkyl, halogenated cycloalkyl, -ORa, -SRa, -C1-4alkyl-ORa, or -C1-4alkyl-SRa.

[0161] In some embodiments, R15 is H or D. In some embodiments, R15 is H. In some embodiments, R15 is D.

[0162] In some embodiments, R15is halogen. In some embodiments, R15is F, Cl, Br, or I. In some embodiments, R15 is F or Cl. In some embodiments, R15 is F. In some embodiments, R15 is Cl. In some embodiments, R15 is Br or I. In some embodiments, R15 is Br. In some embodiments, R15is I.

[0163] In some embodiments, R15is alkyl. In some embodiments, R15is C1-4alkyl. In some embodiments, R15 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl. In some embodiments, R15is halogenated alkyl. In some embodiments, R15is C1-4alkyl with one or more of its hydrogen atoms substituted with one or more halogen atoms (e.g., F and / or Cl), as valence permits. In some embodiments, R15 is methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, or tert-butyl with one or more of its hydrogen atoms substituted with one or more halogen atoms (e.g., F and / or Cl), as valence permits. In some embodiments, R15is C1-4alkyl with one or more of its hydrogen atoms substituted with F and / or Cl, as valence permits. In some embodiments, R15 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl with one or more of its hydrogen atoms substituted with F and / or Cl, as valence permits. In some embodiments, R15is CF3or CCl3. In certain embodiments, the alkyl or C1-4alkyl of R15 may be optionally substituted by groups other than or in addition to halogen.

[0164] In some embodiments, R15is cycloalkyl. In some embodiments, R15is C3-7cycloalkyl. In some embodiments, R15is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. In some embodiments, R15 is halogenated cycloalkyl. In some embodiments, R15is C3-7cycloalkyl with one or more of its hydrogen atoms substituted with one or more halogen atoms (e.g., F and / or Cl), as valence permits. In some embodiments, R15is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl with one or more of its hydrogen atoms substituted with one or more halogen atoms (e.g., F and / or Cl), as valence permits. In some embodiments, R15is C3-7cycloalkyl with one or more of its hydrogen atoms substituted with F and / or Cl, as valence permits. In some embodiments, R15 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl with one or more of its hydrogen atoms substituted with F and / or Cl, as valence permits. In these embodiments, the cycloalkyl or C3-7cycloalkyl of R15may be optionally substituted by groups other than or in addition to halogen.

[0165] In some embodiments, R15 is -ORa or -SRa. In some embodiments, R15 is -ORa. In some embodiments, R15 is -OH. In some embodiments, R15 is -O-alkyl. In some embodiments, R15is -OC1-4alkyl. In some embodiments, R15is -OCH3, -OCH2CH3, - OCH2CH2CH3, -OCH(CH3)2, -OCH2CH2CH2CH3, -OCH2CH(CH3)2, or -OC(CH3)3. In some embodiments, R15 is -OCH3 or -OCH2CH3. In some embodiments, R15 is -SH. In some embodiments, R15is -S-alkyl. In some embodiments, R15is -SC1-4alkyl. In some embodiments, R15is -SCH3, -SCH2CH3, -SCH2CH2CH3, -SCH(CH3)2, -SCH2CH2CH2CH3, - SCH2CH(CH3)2, or -SC(CH3)3. In some embodiments, R15 is -SCH3 or -SCH2CH3. In certain embodiments, the alkyl or C1-4alkyl of R15may be optionally substituted (e.g., by one or more halogen atoms, such as by one or more F and / or Cl atoms).

[0166] In some embodiments, R15 is -C1-4alkyl-ORa or -C1-4alkyl-SRa. In some embodiments, R15 is -C1-4alkyl-ORa. In some embodiments, R15 is -C1-4alkyl-O-alkyl. In some embodiments, R15is -C1-4alkyl-OC1-4alkyl. In some embodiments, R15is -(CH2)1-4OCH3, -(CH2)1-4OCH2CH3, -(CH2)1-4OCH2CH2CH3, -(CH2)1-4OCH(CH3)2, -(CH2)1- 4OCH2CH2CH2CH3, -(CH2)1-4OCH2CH(CH3)2, -(CH2)1-4OC(CH3)3. In some embodiments, R15is -(CH2)1-2OCH3, -(CH2)1-2OCH2CH3, -(CH2)1-2OCH2CH2CH3, -(CH2)1-2OCH(CH3)2, - (CH2)1-2OCH2CH2CH2CH3, -(CH2)1-2OCH2CH(CH3)2, -(CH2)1-2OC(CH3)3. In some embodiments, R15 is -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, or -CH2CH2OCH2CH3. In some embodiments, R15is -C1-4alkyl-SRa. In some embodiments, R15is -C1-4alkyl-S-alkyl. In some embodiments, R15is -C1-4alkyl-SC1-4alkyl. In some embodiments, R15is -(CH2)1-4SCH3, -(CH2)1-4SCH2CH3, -(CH2)1-4SCH2CH2CH3, -(CH2)1-4SCH(CH3)2, -(CH2)1-4SCH2CH2CH2CH3, -(CH2)1-4SCH2CH(CH3)2, -(CH2)1-4SC(CH3)3. In some embodiments, R15is -(CH2)1-2SCH3, -(CH2)1-2SCH2CH3, -(CH2)1-2SCH2CH2CH3, -(CH2)1-2SCH(CH3)2, - (CH2)1-2SCH2CH2CH2CH3, -(CH2)1-2SCH2CH(CH3)2, -(CH2)1-2SC(CH3)3. In some embodiments, R15 is -CH2SCH3, -CH2SCH2CH3, -CH2CH2SCH3, or -CH2CH2SCH2CH3. In certain embodiments, the alkyl or C1-4alkyl of R15may be optionally substituted (e.g., by one or more halogen atoms, such as by one or more F and / or Cl atoms).

[0167] In some embodiments, R15 is -CN.

[0168] In some embodiments, R15is H, halogen, -ORa, or -C1-4alkyl-ORa. In some embodiments, R15is H, F, Cl, -OCH3, -OCH2CH3, -C1-4alkyl-OCH3, or -C1-4alkyl-OCH2CH3. In some embodiments, R15 is H, F, or Cl. In some embodiments, R15 is H, -OCH3, or - OCH2CH3. In some embodiments, R15is H, F, Cl, -OCH3, or -OCH2CH3. In some embodiments, R15is H, F, Cl, or -OCH3. In some embodiments, R15is H, -CH2OCH3, -CH2CH2OCH3, -CH2CH2CH2OCH3, -CH2CH2CH2CH2OCH3, -CH2OCH2CH3, - CH2CH2OCH2CH3, -CH2CH2CH2OCH2CH3, or -CH2CH2CH2CH2OCH2CH3. In some embodiments, R15is H, -CH2OCH3, -CH2CH2OCH3, -CH2OCH2CH3, or -CH2CH2OCH2CH3.

[0169] In some embodiments, the structural moietyhas the structure of ,.

[0170] In some embodiments, the structural moietyhas the structure of, , , , , , ,

[0171] In some embodiments, the structural moietyhas the structure of

[0172] In some embodiments, the structural moietyhas the structure of

[0173] In some embodiments, the structural moietyhas the structure of

[0174] In some embodiments, the structural moietyhas the structure of

[0175] In some embodiments, R3 is -(CR8R9)mR10.

[0176] In some embodiments, m is 1 or 2. In some embodiments, m is 1. In some embodiments, m is 2.

[0177] In some embodiments, each occurrence of R8is independently H, D, or alkyl. In some embodiments, each occurrence of R8 is independently H or D. In some embodiments,each occurrence of R8 is H. In some embodiments, each occurrence of R8 is D. In some embodiments, at least one occurrence of R8 is H. In some embodiments, at least one occurrence of R8is D. In some embodiments, each occurrence of R8is independently H or alkyl. In some embodiments, each occurrence of R8 is independently H or C1-4alkyl. In some embodiments, at least one occurrence of R8 is alkyl. In some embodiments, at least one occurrence of R8is C1-4alkyl. In some embodiments, at least one occurrence of R8is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl. In some embodiments, at least one occurrence of R8 is methyl or ethyl. In these embodiments, the alkyl or C1-4alkyl of R8 may be optionally substituted with one or more halogen atom (e.g., F and / or Cl).

[0178] In some embodiments, each occurrence of R9is independently H, D, or alkyl. In some embodiments, each occurrence of R9 is independently H or D. In some embodiments, each occurrence of R9 is H. In some embodiments, each occurrence of R9 is D. In some embodiments, at least one occurrence of R9is H. In some embodiments, at least one occurrence of R9 is D. In some embodiments, each occurrence of R9 is independently H or alkyl. In some embodiments, each occurrence of R9 is independently H or C1-4alkyl. In some embodiments, at least one occurrence of R9is alkyl. In some embodiments, at least one occurrence of R9is C1-4alkyl. In some embodiments, at least one occurrence of R9is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl. In some embodiments, at least one occurrence of R9is methyl or ethyl. In these embodiments, the alkyl or C1-4alkyl of R9may be optionally substituted with one or more halogen atom (e.g., F and / or Cl).

[0179] In some embodiments, the structural moiety -(CR8R9)m- has the structure of -CH2-, - CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH(CH3)CH2-, -CH(CH3)CH(CH3)-, or - C(CH3)2C(CH3)2-. In some embodiments, the structural moiety -(CR8R9)m- has the structure of -CH2-, -CH2CH2-, -CH(CH3)-, -CH(CH3)CH2-, or -CH(CH3)CH(CH3)-. In some embodiments, the structural moiety -(CR8R9)m- has the structure of -CH2-, -CHD-, -CD2-, - CH2CH2-, -CHDCH2-, -CHDCHD-, -CD2CH2-, -CD2CHD-, or -CD2CD2-. In some embodiments, the structural moiety -(CR8R9)m- has the structure of -CH2- or -CH2CH2-. In some embodiments, the structural moiety -(CR8R9)m- has the structure of -CH2-. In some embodiments, the structural moiety -(CR8R9)m- has the structure of -CH2CH2-.

[0180] In some embodiments, R10is -CN, saturated heterocycle, heteroaryl, -CORa, -CO2Ra, -CONRaRb, -ORa, -SORa, or -SO2Ra.

[0181] In some embodiments, R10 is saturated heterocycle or heteroaryl. In some embodiments, R10 is saturated heterocycle. In some embodiments, R10 is heteroaryl. In certain embodiments, the heterocycle or heteroaryl of R10may be optionally substituted with halogen, -OH, or -O-alkyl (e.g., -OCH3 and / or -OCH2CH3). In some embodiments, R10 is saturated heterocycle optionally substituted by one or more halogens (e.g., F and / or Cl), -OH, or -O-alkyl (e.g., -OCH3and / or -OCH2CH3). In some embodiments, R10is heteroaryl optionally substituted by one or more halogen (e.g., F and / or Cl), -OH, or -O-alkyl (e.g., - OCH3 and / or -OCH2CH3). In some embodiments, R10 is ethylene oxide, tetrahydrofuran, tetrahydropyran, 1,4-dioxane, aziridine, pyrrolidine, piperidine, or morpholine, each of which may be optionally substituted by one or more halogen (e.g., F and / or Cl), -OH, or -O-alkyl (e.g., -OCH3 and / or -OCH2CH3). In some embodiments, R10 is furan, thiophene, imidazole, oxazole, indole, thiazole, pyridine, pyrrole, benzofuran, quinoline, pyrazole, pyrimidine, pyridazine, isoquinoline, triazole, pyrazine, or purine, each of which may be optionally substituted by one or more halogen (e.g., F and / or Cl), -OH, or -O-alkyl (e.g., -OCH3 and / or - OCH2CH3).

[0182] In some embodiments, R10is -CN, -CO2Ra, -CORa, -CONRaRb, -ORa, -SORa, or - SO2Ra. In some embodiments, R10is -CN. In some embodiments, R10is -CO2Raor -CORa. In some embodiments, R10 is -CO2H, -CO2C1-4alkyl, -COH, or -COC1-4alkyl. In some embodiments, R10is -CO2H, -CO2CH3, -COH, or -COCH3. In some embodiments, R10is - SORaor -SO2Ra. In some embodiments, R10is -SOH, -SOC1-4alkyl, -SO2H, or -SO2C1-4alkyl. In some embodiments, R10 is -SOH, -SOCH3, -SO2H, or -SO2CH3. In some embodiments, R10is -ORa. In some embodiments, R10is -OH or -OC1-4alkyl. In some embodiments, R10is -OH, -OCH3, or -OCH2CH3.

[0183] In some embodiments, R10 is -CONRaRb. In some embodiments, R10 is -CONH2, - CONRaH, or -CONHRb. In some embodiments, R10 is -CONH2, -CONHC1-4alkyl, -CON(C1-4alkyl)2, -CONHC3-7cycloalkyl, -CON(C3-7cycloalkyl)2, or -CON(C3-7cycloalkyl)(C1-4alkyl). In some embodiments, R10 is -CONH2, -CONHC1-4alkyl, -CON(C1-4alkyl)2. In some embodiments, R10 is -CONH2, -CONHCH3, -CON(CH3)2. In some embodiments, R10 is - CONH2. In certain embodiments, the C1-4alkyl and C3-7cycloalkyl may be optionally and independently substituted with one or more halogens (e.g., F and / or Cl), -OH, or -O-alkyl (e.g., -OCH3 or -OCH2CH3).

[0184] In some embodiments, R10is (CH2)1-2CONRaRb. In some embodiments, R10is (CH2)1-2CONH2, (CH2)1-2CONRaH, or (CH2)1-2CONHRb. In some embodiments, R10is(CH2)1-2CONH2, (CH2)1-2CONHC1-4alkyl, (CH2)1-2CON(C1-4alkyl)2, (CH2)1-2CONHC3- 7cycloalkyl, (CH2)1-2CON(C3-7cycloalkyl)2, or (CH2)1-2CON(C3-7cycloalkyl)(C1-4alkyl). In some embodiments, R10is (CH2)1-2CONH2, (CH2)1-2CONHC1-4alkyl, (CH2)1-2CON(C1-4alkyl)2. In some embodiments, R10 is (CH2)1-2CONH2, (CH2)1-2CONHCH3, (CH2)1- 2CON(CH3)2. In these embodiments, the C1-4alkyl and C3-7cycloalkyl may be optionally and independently substituted with one or more halogens (e.g., F, Cl, Br, and / or I), OH, or O- alkyl (e.g., OCH3or OCH2CH3). In some embodiments, R10is (CH2)1-2CONH2. In some embodiments, R10 is CH2CONH2 or CH2CH2CONH2. In some embodiments, R10 is CH2CONH2.

[0185] In some embodiments, R4is H, D, halogen, or alkyl. In some embodiments, R4is H or D. In some embodiments, R4 is H. In some embodiments, R4 is D.

[0186] In some embodiments, R4 is H or halogen. In some embodiments, R4 is halogen. In some embodiments, R4is F, Cl, Br, or I. In some embodiments, R4is F or Cl. In some embodiments, R4 is F. In some embodiments, R4 is Cl. In some embodiments, R4 is H, F, or Cl. In some embodiments, R4 is H or F. In some embodiments, R4 is H or Cl.

[0187] In some embodiments, R4is H or alkyl. In some embodiments, R4is alkyl. In some embodiments, R4is H or C1-4alkyl. In some embodiments, R4is C1-4alkyl. In some embodiments, R4 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl. In some embodiments, R4is methyl or ethyl. In some embodiments, the alkyl or C1-4alkyl of R4may be optionally substituted (e.g., by one or more halogen atoms, such as F and / or Cl).

[0188] In some embodiments, R5 is H, D, halogen, -CN, alkyl, halogenated alkyl, cycloalkyl, halogenated cycloalkyl, -ORa, -SRa, -C1-4alkyl-ORa, or -C1-4alkyl–SRa.

[0189] In some embodiments, R5is H or D. In some embodiments, R5is H. In some embodiments, R5 is D.

[0190] In some embodiments, R5 is halogen. In some embodiments, R5 is F, Cl, Br, or I. In some embodiments, R5is F or Cl. In some embodiments, R5is F. In some embodiments, R5is Cl. In some embodiments, R5 is Br or I. In some embodiments, R5 is Br. In some embodiments, R5 is I.

[0191] In some embodiments, R5is alkyl. In some embodiments, R5is C1-4alkyl. In some embodiments, R5is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl. In some embodiments, R5 is halogenated alkyl. In some embodiments, R5 is C1-4alkyl with oneor more of its hydrogen atoms substituted with one or more halogen atoms (e.g., F and / or Cl), as valence permits. In some embodiments, R5 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl with one or more of its hydrogen atoms substituted with one or more halogen atoms (e.g., F and / or Cl), as valence permits. In some embodiments, R5 is C1-4alkyl with one or more of its hydrogen atoms substituted with F and / or Cl, as valence permits. In some embodiments, R5is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl with one or more of its hydrogen atoms substituted with F and / or Cl, as valence permits. In some embodiments, R5 is CF3 or CCl3. In certain embodiments, the alkyl or C1-4alkyl of R5 may be optionally substituted by groups other than or in addition to halogen.

[0192] In some embodiments, R5is cycloalkyl. In some embodiments, R5is C3-7cycloalkyl. In some embodiments, R5 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. In some embodiments, R5 is halogenated cycloalkyl. In some embodiments, R5 is C3-7cycloalkyl with one or more of its hydrogen atoms substituted with one or more halogen atoms (e.g., F and / or Cl), as valence permits. In some embodiments, R5 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl with one or more of its hydrogen atoms substituted with one or more halogen atoms (e.g., F and / or Cl), as valence permits. In some embodiments, R5is C3-7cycloalkyl with one or more of its hydrogen atoms substituted with F and / or Cl, as valence permits. In some embodiments, R5 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl with one or more of its hydrogen atoms substituted with F and / or Cl, as valence permits. In these embodiments, the cycloalkyl or C3-7cycloalkyl of R5 may be optionally substituted by groups other than or in addition to halogen.

[0193] In some embodiments, R5is -ORaor -SRa. In some embodiments, R5is -ORa. In some embodiments, R5is -OH. In some embodiments, R5is -O-alkyl. In some embodiments, R5 is -OC1-4alkyl. In some embodiments, R5 is -OCH3, -OCH2CH3, - OCH2CH2CH3, -OCH(CH3)2, -OCH2CH2CH2CH3, -OCH2CH(CH3)2, or -OC(CH3)3. In some embodiments, R5is -OCH3or -OCH2CH3. In some embodiments, R5is -SH. In some embodiments, R5 is -S-alkyl. In some embodiments, R5 is -SC1-4alkyl. In some embodiments, R5 is -SCH3, -SCH2CH3, -SCH2CH2CH3, -SCH(CH3)2, -SCH2CH2CH2CH3, - SCH2CH(CH3)2, or -SC(CH3)3. In some embodiments, R5is -SCH3or -SCH2CH3. In certain embodiments, the alkyl or C1-4alkyl of R5may be optionally substituted (e.g., by one or more halogen atoms, such as by one or more F and / or Cl atoms).

[0194] In some embodiments, R5is -C1-4alkyl-ORaor -C1-4alkyl-SRa. In some embodiments, R5is -C1-4alkyl-ORa. In some embodiments, R5is -C1-4alkyl-O-alkyl. In some embodiments,R5 is -C1-4alkyl-OC1-4alkyl. In some embodiments, R5 is -(CH2)1-4OCH3, -(CH2)1-4OCH2CH3, -(CH2)1-4OCH2CH2CH3, -(CH2)1-4OCH(CH3)2, -(CH2)1-4OCH2CH2CH2CH3, -(CH2)1-4OCH2CH(CH3)2, -(CH2)1-4OC(CH3)3. In some embodiments, R5is -(CH2)1-2OCH3, -(CH2)1-2OCH2CH3, -(CH2)1-2OCH2CH2CH3, -(CH2)1-2OCH(CH3)2, -(CH2)1-2OCH2CH2CH2CH3, - (CH2)1-2OCH2CH(CH3)2, -(CH2)1-2OC(CH3)3. In some embodiments, R5 is -CH2OCH3, - CH2OCH2CH3, -CH2CH2OCH3, or -CH2CH2OCH2CH3. In some embodiments, R5is -C1-4alkyl-SRa. In some embodiments, R5is -C1-4alkyl-S-alkyl. In some embodiments, R5is -C1-4alkyl-SC1-4alkyl. In some embodiments, R5 is -(CH2)1-4SCH3, -(CH2)1-4SCH2CH3, -(CH2)1-4SCH2CH2CH3, -(CH2)1-4SCH(CH3)2, -(CH2)1-4SCH2CH2CH2CH3, -(CH2)1-4SCH2CH(CH3)2, -(CH2)1-4SC(CH3)3. In some embodiments, R5is -(CH2)1-2SCH3, -(CH2)1-2SCH2CH3, -(CH2)1-2SCH2CH2CH3, -(CH2)1-2SCH(CH3)2, -(CH2)1-2SCH2CH2CH2CH3, -(CH2)1-2SCH2CH(CH3)2, -(CH2)1-2SC(CH3)3. In some embodiments, R5 is -CH2SCH3, -CH2SCH2CH3, -CH2CH2SCH3, or -CH2CH2SCH2CH3. In certain embodiments, the alkyl or C1-4alkyl of R5may be optionally substituted (e.g., by one or more halogen atoms, such as by one or more F and / or Cl atoms).

[0195] In some embodiments, R5is -CN.

[0196] In some embodiments, R5is H, halogen, -ORa, or -C1-4alkyl-ORa. In some embodiments, R5 is H, F, Cl, -OCH3, or -OCH2CH3. In some embodiments, R5 is H, F, or Cl. In some embodiments, R5is H, -OCH3, or -OCH2CH3.

[0197] In some embodiments, R6is H, D, halogen, -CN, alkyl, halogenated alkyl, cycloalkyl, halogenated cycloalkyl, -ORa, -SRa, -C1-4alkyl-ORa, or -C1-4alkyl-SRa.

[0198] In some embodiments, R6is H or D. In some embodiments, R6is H. In some embodiments, R6is D.

[0199] In some embodiments, R6 is halogen. In some embodiments, R6 is F, Cl, Br, or I. In some embodiments, R6 is F or Cl. In some embodiments, R6 is F. In some embodiments, R6 is Cl. In some embodiments, R6is Br or I. In some embodiments, R6is Br. In some embodiments, R6 is I.

[0200] In some embodiments, R6 is alkyl. In some embodiments, R6 is C1-4alkyl. In some embodiments, R6is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl. In some embodiments, R6is halogenated alkyl. In some embodiments, R6is C1-4alkyl with one or more of its hydrogen atoms substituted with one or more halogen atoms (e.g., F and / or Cl), as valence permits. In some embodiments, R6is methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, or tert-butyl with one or more of its hydrogen atoms substituted with one or more halogen atoms (e.g., F and / or Cl), as valence permits. In some embodiments, R6 is C1-4alkyl with one or more of its hydrogen atoms substituted with F and / or Cl, as valence permits. In some embodiments, R6 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl with one or more of its hydrogen atoms substituted with F and / or Cl, as valence permits. In some embodiments, R6is CF3or CCl3. In certain embodiments, the alkyl or C1-4alkyl of R6may be optionally substituted by groups other than or in addition to halogen.

[0201] In some embodiments, R6 is cycloalkyl. In some embodiments, R6 is C3-7cycloalkyl. In some embodiments, R6is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. In some embodiments, R6is halogenated cycloalkyl. In some embodiments, R6is C3-7cycloalkyl with one or more of its hydrogen atoms substituted with one or more halogen atoms (e.g., F and / or Cl), as valence permits. In some embodiments, R6 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl with one or more of its hydrogen atoms substituted with one or more halogen atoms (e.g., F and / or Cl), as valence permits. In some embodiments, R6 is C3-7cycloalkyl with one or more of its hydrogen atoms substituted with F and / or Cl, as valence permits. In some embodiments, R6is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl with one or more of its hydrogen atoms substituted with F and / or Cl, as valence permits. In these embodiments, the cycloalkyl or C3-7cycloalkyl of R6may be optionally substituted by groups other than or in addition to halogen.

[0202] In some embodiments, R6is -ORaor -SRa. In some embodiments, R6is -ORa. In some embodiments, R6 is -OH. In some embodiments, R6 is -O-alkyl. In some embodiments, R6is -OC1-4alkyl. In some embodiments, R6is -OCH3, -OCH2CH3, - OCH2CH2CH3, -OCH(CH3)2, -OCH2CH2CH2CH3, -OCH2CH(CH3)2, or -OC(CH3)3. In some embodiments, R6 is -OCH3 or -OCH2CH3. In some embodiments, R6 is -SH. In some embodiments, R6 is -S-alkyl. In some embodiments, R6 is -SC1-4alkyl. In some embodiments, R6is -SCH3, -SCH2CH3, -SCH2CH2CH3, -SCH(CH3)2, -SCH2CH2CH2CH3, - SCH2CH(CH3)2, or -SC(CH3)3. In some embodiments, R6 is -SCH3 or -SCH2CH3. In certain embodiments, the alkyl or C1-4alkyl of R6 may be optionally substituted (e.g., by one or more halogen atoms, such as by one or more F and / or Cl atoms).

[0203] In some embodiments, R6is -C1-4alkyl-ORaor -C1-4alkyl-SRa. In some embodiments, R6 is -C1-4alkyl-ORa. In some embodiments, R6 is -C1-4alkyl-O-alkyl. In some embodiments, R6is -C1-4alkyl-OC1-4alkyl. In some embodiments, R6is -(CH2)1-4OCH3, -(CH2)1-4OCH2CH3, -(CH2)1-4OCH2CH2CH3, -(CH2)1-4OCH(CH3)2, -(CH2)1-4OCH2CH2CH2CH3, -(CH2)1-4OCH2CH(CH3)2, -(CH2)1-4OC(CH3)3. In some embodiments, R6 is -(CH2)1-2OCH3, -(CH2)1- 2OCH2CH3, -(CH2)1-2OCH2CH2CH3, -(CH2)1-2OCH(CH3)2, -(CH2)1-2OCH2CH2CH2CH3, - (CH2)1-2OCH2CH(CH3)2, -(CH2)1-2OC(CH3)3. In some embodiments, R6is -CH2OCH3, - CH2OCH2CH3, -CH2CH2OCH3, or -CH2CH2OCH2CH3. In some embodiments, R6 is -C1- 4alkyl-SRa. In some embodiments, R6 is -C1-4alkyl-S-alkyl. In some embodiments, R6 is -C1-4alkyl-SC1-4alkyl. In some embodiments, R6is -(CH2)1-4SCH3, -(CH2)1-4SCH2CH3, -(CH2)1-4SCH2CH2CH3, -(CH2)1-4SCH(CH3)2, -(CH2)1-4SCH2CH2CH2CH3, -(CH2)1-4SCH2CH(CH3)2, -(CH2)1-4SC(CH3)3. In some embodiments, R6 is -(CH2)1-2SCH3, -(CH2)1-2SCH2CH3, -(CH2)1-2SCH2CH2CH3, -(CH2)1-2SCH(CH3)2, -(CH2)1-2SCH2CH2CH2CH3, -(CH2)1-2SCH2CH(CH3)2, -(CH2)1-2SC(CH3)3. In some embodiments, R6is -CH2SCH3, -CH2SCH2CH3, -CH2CH2SCH3, or -CH2CH2SCH2CH3. In certain embodiments, the alkyl or C1-4alkyl of R6 may be optionally substituted (e.g., by one or more halogen atoms, such as by one or more F and / or Cl atoms).

[0204] In some embodiments, R6 is -CN.

[0205] In some embodiments, R6 is H, halogen, -ORa, or -C1-4alkyl-ORa. In some embodiments, R6is H, F, Cl, -OCH3, or -OCH2CH3. In some embodiments, R6is H, F, or Cl. In some embodiments, R6is H, -OCH3, or -OCH2CH3.

[0206] In some embodiments, R7 is H, D, halogen, or alkyl. In some embodiments, R7 is H or D. In some embodiments, R7is H. In some embodiments, R7is D.

[0207] In some embodiments, R7is H or halogen. In some embodiments, R7is halogen. In some embodiments, R7 is F, Cl, Br, or I. In some embodiments, R7 is F or Cl. In some embodiments, R7is F. In some embodiments, R7is Cl. In some embodiments, R7is H, F, or Cl. In some embodiments, R7is H or F. In some embodiments, R7is H or Cl.

[0208] In some embodiments, R7 is H or alkyl. In some embodiments, R7 is alkyl. In some embodiments, R7 is H or C1-4alkyl. In some embodiments, R7 is C1-4alkyl. In some embodiments, R7is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl. In some embodiments, R7 is methyl or ethyl. In certain embodiments, the alkyl or C1-4 alkyl of R7 may be optionally substituted (e.g., by one or more halogen atoms, such as F and / or Cl).

[0209] In some embodiments, the structural moietyhas the structure of

[0210] In some embodiments, the structural moietyhas the structure of

[0211] In some embodiments, each occurrence of R11is independently H, D, or alkyl. In some embodiments, each occurrence of R11 is independently H or D. In some embodiments, each occurrence of R11 is independently H or alkyl. In some embodiments, each occurrence of R11is independently H or C1-4alkyl. In some embodiments, each occurrence of R11is H. In some embodiments, each occurrence of R11is alkyl. In some embodiments, each occurrence of R11 is D. In some embodiments, at least one occurrence of R11 is H. In some embodiments, at least one occurrence of R11 is D. In some embodiments, at least one occurrence of R11is alkyl. In some embodiments, at least one occurrence of R11is C1-4alkyl. In some embodiments, at least one occurrence of R11 is methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, or tert-butyl. In some embodiments, at least one occurrence of R11 is methyl or ethyl. In certain embodiments, the alkyl or C1-4alkyl of R11may be optionally substituted with one or more halogen atom (e.g., F and / or Cl).

[0212] In some embodiments, each occurrence of R12 is independently H, D, or alkyl. In some embodiments, each occurrence of R12is independently H or D. In some embodiments, each occurrence of R12is independently H or alkyl. In some embodiments, each occurrence of R12 is independently H or C1-4alkyl. In some embodiments, each occurrence of R12 is H. In some embodiments, each occurrence of R12 is alkyl. In some embodiments, each occurrence of R12is D. In some embodiments, at least one occurrence of R12is H. In some embodiments, at least one occurrence of R12 is D. In some embodiments, at least oneoccurrence of R12 is alkyl. In some embodiments, at least one occurrence of R12 is C1-4alkyl. In some embodiments, at least one occurrence of R12 is methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, or tert-butyl. In some embodiments, at least one occurrence of R12is methyl or ethyl. In certain embodiments, the alkyl or C1-4alkyl of R12 may be optionally substituted with one or more halogen atom (e.g., F, Cl, Br, and / or I).

[0213] In some embodiments, each occurrence of R13is independently H, D, or alkyl. In some embodiments, each occurrence of R13is independently H or D. In some embodiments, each occurrence of R13 is independently H or alkyl. In some embodiments, each occurrence of R13is independently H or C1-4alkyl. In some embodiments, each occurrence of R13is H. In some embodiments, each occurrence of R13is alkyl. In some embodiments, each occurrence of R13 is D. In some embodiments, at least one occurrence of R13 is H. In some embodiments, at least one occurrence of R13 is D. In some embodiments, at least one occurrence of R13is alkyl. In some embodiments, at least one occurrence of R13is C1-4alkyl. In some embodiments, at least one occurrence of R13 is methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, or tert-butyl. In some embodiments, at least one occurrence of R13 is methyl or ethyl. In these embodiments, the alkyl or C1-4alkyl of R13may be optionally substituted with one or more halogen atom (e.g., F, Cl, Br, and / or I).

[0214] In some embodiments, 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, and saturated heterocycle, or alternatively, Raand Rb, together with the 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.

[0215] In some embodiments, each occurrence of Ra and Rb is independently H, D, alkyl, or halogenated alkyl. In some embodiments, each occurrence of Ra and Rb is independently H or D. In some embodiments, each occurrence of Raand Rbis H. In some embodiments, each occurrence of Ra and Rb is D. In some embodiments, at least one occurrence of Ra and Rb is H. In some embodiments, at least one occurrence of Ra and Rb is D.

[0216] In some embodiments, each occurrence of Raand Rbis independently H, alkyl, or halogenated alkyl. In some embodiments, each occurrence of Raand Rbis independently H or alkyl. In some embodiments, each occurrence of Ra and Rb is independently H or C1-4alkyl. In some embodiments, each occurrence of Raand Rbis alkyl. In some embodiments,at least one occurrence of Ra and Rb is alkyl. In some embodiments, at least one occurrence of Ra and Rb is C1-4alkyl. In some embodiments, at least one occurrence of Ra and Rb is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl. In some embodiments, each occurrence of Ra and Rb is halogenated alkyl. In some embodiments, at least one occurrence of Ra and Rb is halogenated alkyl. In some embodiments, at least one occurrence of Raand Rbis C1-4alkyl with one or more of its hydrogen atoms substituted with one or more halogen atoms (e.g., F and / or Cl), as valence permits. In some embodiments, at least one occurrence of Ra and Rb is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl with one or more of its hydrogen atoms substituted with one or more halogen atoms (e.g., F and / or Cl), as valence permits. In some embodiments, at least one occurrence of Raand Rbis C1-4alkyl with one or more of its hydrogen atoms substituted with F and / or Cl, as valence permits. In some embodiments, at least one occurrence of Ra and Rb is methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, or tert-butyl with one or more of its hydrogen atoms substituted with F and / or Cl, as valence permits. In some embodiments, at least one occurrence of Ra and Rb is CF3 or CCl3. In certain embodiments, the alkyl or C1-4alkyl of Ra and / or Rbmay be optionally substituted by groups other than or in addition to halogen.

[0217] In some embodiments, each occurrence of Raand Rbis independently H, cycloalkyl, or halogenated cycloalkyl. In some embodiments, each occurrence of Ra and Rb is independently H or cycloalkyl. In some embodiments, each occurrence of Raand Rbis cycloalkyl. In some embodiments, at least one occurrence of Raand Rbis cycloalkyl. In some embodiments, at least one occurrence of Ra and Rb is C3-7cycloalkyl. In some embodiments, at least one occurrence of Raand Rbis cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. In some embodiments, each occurrence of Raand Rbis halogenated cycloalkyl. In some embodiments, at least one occurrence of Ra and Rb is halogenated cycloalkyl. In some embodiments, at least one occurrence of Ra and Rb is C3-7cycloalkyl with one or more of its hydrogen atoms substituted with one or more halogen atoms (e.g., F and / or Cl), as valence permits. In some embodiments, at least one occurrence of Ra and Rb is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl with one or more of its hydrogen atoms substituted with one or more halogen atoms (e.g., F and / or Cl), as valence permits. In some embodiments, at least one occurrence of Raand Rbis C3-7cycloalkyl with one or more of its hydrogen atoms substituted with F and / or Cl, as valence permits. In some embodiments, at least one occurrence of Raand Rbis cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl with one or more of its hydrogen atomssubstituted with F and / or Cl, as valence permits. In certain embodiments, the cycloalkyl or C3-7cycloalkyl of Ra and / or Rb may be optionally substituted by groups other than or in addition to halogen.

[0218] In some embodiments, each occurrence of Ra and Rb is independently H.

[0219] In some embodiments, each occurrence of Ra and Rb is independently H, heteroalkyl, or halogenated heteroalkyl. In some embodiments, each occurrence of Raand Rbis heteroalkyl. In some embodiments, at least one occurrence of Raand Rbis heteroalkyl. In some embodiments, each occurrence of Ra and Rb is halogenated heteroalkyl. In some embodiments, at least one occurrence of Raand Rbis halogenated heteroalkyl. In some embodiments, at least one occurrence of Raand Rbis C1-6alkyl where one or more carbon atoms are substituted for O (resulting in, e.g., an ether, an alcohol, or a peroxide), N (resulting in, e.g., an amine), and / or S (resulting in, e.g., a thioether, thiol, or disulfide).

[0220] In some embodiments, Raand Rb, together with the 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. In some embodiments, Raand Rb, together with the nitrogen atom that they are connected to form a 3- 7-membered cycloalkyl or a 3-7-membered saturated heterocycle (e.g., aziridine, azetidine, pyrrolidine, imidazolidine, oxazolidine, thiazolidine, pyrazolidine, piperidine, piperazine, morpholine, and thiomorpholine).

[0221] In some embodiments, each occurrence of Raand Rbis independently H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, or C(CH3)3. In some embodiments, each occurrence of Ra and Rbis independently H, CH3, or CH2CH3. In some embodiments, each occurrence of Raand Rbis independently H or CH3.

[0222] In some embodiments, the alkyl, cycloalkyl, heteroalkyl, saturated heterocycle, aryl, and / or heteroaryl in R1, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, Ra, or Rb, where applicable, are each optionally and independently substituted by 1-4 substituents each independently selected from the group consisting of alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, halogen, -ORx, -(CH2)1-2ORx, and oxo, where valence permits. In some embodiments, each occurrence of Rxis independently H, D, alkyl, halogenated alkyl, or heterocycle optionally substituted by alkyl, halogen, or -OH.

[0223] In some embodiments, the alkyl, cycloalkyl, heteroalkyl, saturated heterocycle, aryl, and / or heteroaryl in R1, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, Ra, or Rb, whereapplicable, are each optionally and independently substituted by 1-4 halogen atoms. In some embodiments, the alkyl, cycloalkyl, heteroalkyl, saturated heterocycle, aryl, and / or heteroaryl in R1, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, Ra, or Rb, where applicable, are each optionally and independently substituted by 1-4 F, Cl, Br, and / or I atoms. In some embodiments, the alkyl, cycloalkyl, heteroalkyl, saturated heterocycle, aryl, and / or heteroaryl in R1, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, Ra, or Rb, where applicable, are each optionally and independently substituted by 1-4 F and / or Cl atoms.

[0224] In some embodiments, the alkyl, cycloalkyl, heteroalkyl, saturated heterocycle, aryl, and / or heteroaryl in R1, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, Ra, or Rb, where applicable, are each optionally and independently substituted by 1-4 substituents each independently selected from the group consisting of alkyl or halogenated alkyl. In some embodiments, the alkyl, cycloalkyl, heteroalkyl, saturated heterocycle, aryl, and / or heteroaryl in R1, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, Ra, or Rb, where applicable, are each optionally and independently substituted by 1-4 alkyl substituents. In some embodiments, the alkyl, cycloalkyl, heteroalkyl, saturated heterocycle, aryl, and / or heteroaryl in R1, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, Ra, or Rb, where applicable, are each optionally and independently substituted by 1-4 C1-4alkyl substituents. In some embodiments, the alkyl, cycloalkyl, heteroalkyl, saturated heterocycle, aryl, and / or heteroaryl in R1, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, Ra, or Rb, where applicable, are each optionally and independently substituted by 1-4 methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert- butyl substituents. In some embodiments, the alkyl, cycloalkyl, heteroalkyl, saturated heterocycle, aryl, and / or heteroaryl in R1, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, Ra, or Rb, where applicable, are each optionally and independently substituted by 1-4 halogenated alkyl substituents. In some embodiments, the alkyl, cycloalkyl, heteroalkyl, saturated heterocycle, aryl, and / or heteroaryl in R1, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, Ra, or Rb, where applicable, are each optionally and independently substituted by 1- 4 C1-4alkyl with one or more of its hydrogen atoms substituted with one or more halogen atoms (e.g., F and / or Cl), as valence permits. In some embodiments, the alkyl, cycloalkyl, heteroalkyl, saturated heterocycle, aryl, and / or heteroaryl in R1, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, Ra, or Rb, where applicable, are each optionally and independently substituted by 1-4 methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl with one or more of its hydrogen atoms substituted with one or more halogen atoms (e.g., F and / or Cl), as valence permits. In some embodiments, the alkyl, cycloalkyl, heteroalkyl, saturatedheterocycle, aryl, and / or heteroaryl in R1, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, Ra, or Rb, where applicable, are each optionally and independently substituted by 1-4 C1-4alkyl with one or more of its hydrogen atoms substituted with F and / or Cl, as valence permits. In some embodiments, the alkyl, cycloalkyl, heteroalkyl, saturated heterocycle, aryl, and / or heteroaryl in R1, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, Ra, or Rb, where applicable, are each optionally and independently substituted by 1-4 methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl with one or more of its hydrogen atoms substituted with F and / or Cl, as valence permits.

[0225] In some embodiments, the alkyl, cycloalkyl, heteroalkyl, saturated heterocycle, aryl, and / or heteroaryl in R1, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, Ra, or Rb, where applicable, are each optionally and independently substituted by 1-4 substituents each independently selected from the group consisting of cycloalkyl or halogenated cycloalkyl. In some embodiments, the alkyl, cycloalkyl, heteroalkyl, saturated heterocycle, aryl, and / or heteroaryl in R1, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, Ra, or Rb, where applicable, are each optionally and independently substituted by 1-4 C3-7cycloalkyl. In some embodiments, the alkyl, cycloalkyl, heteroalkyl, saturated heterocycle, aryl, and / or heteroaryl in R1, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, Ra, or Rb, where applicable, are each optionally and independently substituted by 1-4 cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. In some embodiments, the alkyl, cycloalkyl, heteroalkyl, saturated heterocycle, aryl, and / or heteroaryl in R1, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, Ra, or Rb, where applicable, are each optionally and independently substituted by 1- 4 halogenated cycloalkyl substituents. In some embodiments, the alkyl, cycloalkyl, heteroalkyl, saturated heterocycle, aryl, and / or heteroaryl in R1, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, Ra, or Rb, where applicable, are each optionally and independently substituted by 1-4 C3-7cycloalkyl with one or more of its hydrogen atoms substituted with one or more halogen atoms (e.g., F and / or Cl), as valence permits. In some embodiments, the alkyl, cycloalkyl, heteroalkyl, saturated heterocycle, aryl, and / or heteroaryl in R1, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, Ra, or Rb, where applicable, are each optionally and independently substituted by 1-4 cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl with one or more of its hydrogen atoms substituted with one or more halogen atoms (e.g., F and / or Cl), as valence permits. In some embodiments, the alkyl, cycloalkyl, heteroalkyl, saturated heterocycle, aryl, and / or heteroaryl in R1, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, Ra, or Rb, where applicable, are each optionally and independentlysubstituted by 1-4 C3-7cycloalkyl with one or more of its hydrogen atoms substituted with F and / or Cl, as valence permits. In some embodiments, the alkyl, cycloalkyl, heteroalkyl, saturated heterocycle, aryl, and / or heteroaryl in R1, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, Ra, or Rb, where applicable, are each optionally and independently substituted by 1- 4 cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl with one or more of its hydrogen atoms substituted with F and / or Cl, as valence permits.

[0226] In some embodiments, the alkyl, cycloalkyl, heteroalkyl, saturated heterocycle, aryl, and / or heteroaryl in R1, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, Ra, or Rb, where applicable, are each optionally and independently substituted by 1-4 -ORxor -(CH2)1-2ORxsubstituents, where valence permits. In some embodiments, the alkyl, cycloalkyl, heteroalkyl, saturated heterocycle, aryl, and / or heteroaryl in R1, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, Ra, or Rb, where applicable, are each optionally and independently substituted by 1-4 -ORx, where valence permits. In some embodiments, the alkyl, cycloalkyl, heteroalkyl, saturated heterocycle, aryl, and / or heteroaryl in R1, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, Ra, or Rb, where applicable, are each optionally and independently substituted by 1-4 -OH or -OC1-4alkyl, where valence permits. In some embodiments, the alkyl, cycloalkyl, heteroalkyl, saturated heterocycle, aryl, and / or heteroaryl in R1, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, Ra, or Rb, where applicable, are each optionally and independently substituted by 1-4 -OH, -OCH3or -OCH2CH3, where valence permits. In some embodiments, the alkyl, cycloalkyl, heteroalkyl, saturated heterocycle, aryl, and / or heteroaryl in R1, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, Ra, or Rb, where applicable, are each optionally and independently substituted by 1-4 -(CH2)1-2ORxsubstituents, where valence permits. In some embodiments, the alkyl, cycloalkyl, heteroalkyl, saturated heterocycle, aryl, and / or heteroaryl in R1, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, Ra, or Rb, where applicable, are each optionally and independently substituted by 1-4 -(CH2)1-2OH or -(CH2)1-2OC1-4alkyl. In some embodiments, the alkyl, cycloalkyl, heteroalkyl, saturated heterocycle, aryl, and / or heteroaryl in R1, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, Ra, or Rb, where applicable, are each optionally and independently substituted by 1-4 -(CH2)1-2OH, -(CH2)1-2OCH3, or -(CH2)1-2OCH2CH3.

[0227] In some embodiments, the alkyl, cycloalkyl, heteroalkyl, saturated heterocycle, aryl, and / or heteroaryl in R1, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, Ra, or Rb, where applicable, are each optionally and independently substituted by 1-4 oxo substituents, where valence permits.

[0228] In some embodiments, the alkyl, cycloalkyl, heteroalkyl, saturated heterocycle, aryl, and / or heteroaryl in R1, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, Ra, or Rb, where applicable, are each optionally and independently substituted by 1-4 substituents selected from the group consisting of F, Cl, -CH3, -CH2CH3, -CF3, -CCl3, -OH, -OCH3, -OCH2CH3, - CH2F, -CH2Cl, -CH2OH, -CH2OCH3, and -CH2OCH2CH3, where valence permits.

[0229] In some embodiments, each occurrence of Rxis independently H, D, alkyl, halogenated alkyl, or heterocycle optionally substituted by alkyl, halogen, or -OH. In some embodiments, each occurrence of Rx is independently H or D. In some embodiments, each occurrence of Rxis independently H. In some embodiments, each occurrence of Rxis independently D.

[0230] In some embodiments, each occurrence of Rx is independently H, alkyl, or halogenated alkyl. In some embodiments, each occurrence of Rx is independently H or alkyl. In some embodiments, each occurrence of Rxis independently H or halogenated alkyl. In some embodiments, each occurrence of Rx is independently alkyl or halogenated alkyl. In some embodiments, each occurrence of Rx is independently H, C1-4alkyl, or C1-4halogenated alkyl. In some embodiments, each occurrence of Rxis independently H, methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, or tert-butyl. In some embodiments, each occurrence of Rx is independently H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl, optionally substituted by one or more halogens (e.g., F and / or Cl). In some embodiments, each occurrence of Rxis independently H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl, optionally substituted by one or more F and / or Cl.

[0231] In some embodiments, each occurrence of Rxis independently H or heterocycle. In some embodiments, each occurrence of Rxis independently H or heterocycle optionally substituted by alkyl, halogen, or -OH. In some embodiments, each occurrence of Rx is independently heterocycle optionally substituted by alkyl, halogen, or -OH. In some embodiments, each occurrence of Rxis independently 3-7-membered heterocycle (e.g., ethylene oxide, tetrahydrofuran, tetrahydropyran, 1,4-dioxane, aziridine, pyrrolidine, piperidine, morpholine, furan, thiophene, imidazole, oxazole, indole, thiazole, pyridine, pyrrole, benzofuran, quinoline, pyrazole, pyrimidine, pyridazine, isoquinoline, triazole, pyrazine, and / or purine) optionally substituted by C1-4alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and / or tert-butyl), halogen (e.g., F and / or Cl), or -OH.

[0232] In some embodiments, each occurrence of Rx is independently H, alkyl, or heterocycle. In some embodiments, each occurrence of Rx is independently H or alkyl. In some embodiments, each occurrence of Rxis independently H or C1-4alkyl. In some embodiments, each occurrence of Rx is independently H, CH3, or CH2CH3.

[0233] In some embodiments, the compound has the structure of Formula Ia:

[0234] In some embodiments, the structural moietysome embodiments, the structural moiety; wherein A, when present, is C(R11)2; B is C(R12)2; and E, when present, is C(R13)2.

[0235] In some embodiments, the structural moietyhas the structure ofindependently H or C1-4alkyl. In some embodiments, the structural moietyhas thewherein each occurrence of R11, R12, and R13 is independently H, CH3, or CH2CH3. In some embodiments, the structural moietyembodiments, the structural moietyembodiments, the structural moietyembodiments, the structural moietyhas the structure.

[0236] In some embodiments, the compound has the structure of Formula Ib:

[0237] In some embodiments, the structural moietyhas the structure ofstructural moietyhas the structure of, , , or; wherein A, when present, is C(R11)2; and E, when present, is C(R13)2.

[0238] In some embodiments, the structural moietyhas the structure ofembodiments, the structural moietywherein each occurrence of R11 and R13 is independently H or C1-4alkyl. In some embodiments, the structural moietywherein each occurrence of R11 and R13 is independently H, CH3, or CH2CH3. In some embodiments, the structural moietyhas the structure of, , , , ,embodiments, the structural moietyembodiments, the structural moietyhas the structure ofsome embodiments, the structural moietysome embodiments, the structural moietysome embodiments, the structural moietysome embodiments, the structural moiety.

[0239] In some embodiments, the compound has the structure of Formula II:II wherein A is O, S, or C(R11)2; B is C(R12)2 or absent, wherein when B is absent, A and E are connected by a bond; E is O or C(R13)2; X is N or CR14; Y is N or CR15; R1 is H, D, or halogen; R3is -(CR8R9)mR10; R5is H, D, or halogen; R6 is H, D, or halogen; each occurrence of R8 is independently H, D, or alkyl; each occurrence of R9is independently H, D, -ORa, or alkyl; R10 is–CN, saturated heterocycle, heteroaryl, -CORa, -CO2Ra; -CONRaRb, -ORa, - SORa, or -SO2Ra; each occurrence of R11is independently H or alkyl;each occurrence of R12 is independently H or alkyl; each occurrence of R13 is independently H or alkyl; R14is H, D, halogen, alkyl, ORa, or -C1-4alkyl-ORa; R15 is H, D, halogen, alkyl, ORa, or -C1-4alkyl-ORa; m is 1 or 2; each occurrence of Raand Rbis independently selected from the group consisting of H, alkyl, cycloalkyl, halogenated alkyl, heteroalkyl, halogenated heteroalkyl, halogenated cycloalkyl; or alternatively, Ra and Rb, together with the 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, cycloalkyl, heteroalkyl, saturated heterocycle, aryl, and / or heteroaryl in R8, R9, R10, R11, R12, R13, R14, R15, Ra, or Rb, where applicable, are each optionally and independently substituted by 1-4 substituents each independently selected from the group consisting of alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, halogen, -ORx, - (CH2)1-2ORx, and oxo, where valence permits; and each occurrence of Rxis independently H, D, alkyl, halogenated alkyl, or heterocycle optionally substituted by alkyl, halogen, or OH.

[0240] In some embodiments, A is O, S, or C(R11)2; B is C(R12)2or absent, wherein when B is absent, A and E are connected by a bond; E is O or C(R13)2; X is N or CR14; Y is N or CR15; R1 is H or halogen; R3 is -(CR8R9)1-2R10; R5is H or halogen; R6 is H or halogen; each occurrence of R8 is independently H or alkyl;each occurrence of R9 is independently H or alkyl; R10 is –CONRaRb; each occurrence of R11is independently H or alkyl; each occurrence of R12 is independently H or alkyl; each occurrence of R13 is independently H or alkyl; R14is H, halogen, ORa, or -C1-4alkyl-ORa; R15is H, halogen, ORa, or -C1-4alkyl-ORa; and each occurrence of Ra and Rb is independently selected from the group consisting of H or alkyl.

[0241] In some embodiments, the compound has the structure of Formula IIa:wherein A is O, S, or CH2; E is O or CHR13; X is N or CR14; Y is N or CR15; R1 is H or halogen; R3is -(CR8R9)1-2R10; R5is H or halogen; R6 is H or halogen; each occurrence of R8is independently H or alkyl; each occurrence of R9is independently H or alkyl; R10 is –CONRaRb;R13 is H or alkyl; R14 is H, halogen, ORa, or -C1-4alkyl–ORa; R15is H, halogen, ORa, or -C1-4alkyl-ORa; and each occurrence of Ra and Rb is independently selected from the group consisting of H or alkyl.

[0242] In some embodiments, the compound has the structure of Formula IIb:IIb wherein A is O or CH2;E is O or CHR13; X is N or CR14; Y is N or CR15; R1 is H or halogen; R3 is -(CR8R9)1-2R10; R5is H or halogen; R6is H or halogen; each occurrence of R8 is independently H or alkyl; each occurrence of R9is independently H or alkyl; R10is -CONRaRb; each occurrence of R13 is independently H or alkyl; R14is H, halogen, ORa, or -C1-4alkyl-ORa; R15is H, halogen, ORa, or -C1-4alkyl-ORa; andeach occurrence of Ra and Rb is independently selected from the group consisting of H or alkyl.

[0243] In some embodiments, the compound has the structure of Formula I and is selected ,, , , ,,the structure of Formula I and is selected from the group consisting of, , , ,the structure of Formula I and is selected from the group consisting of Compounds 1-40 in Table 3.

[0244] In some embodiments, the compound has the structure of Formula II and is selected,the structure of Formula II and is selected from the group consisting of ,,the structure of Formula II and is selected from the group consisting of Compounds 1-40 in Table 3.

[0245] In some embodiments, the compound has the structure of Formula Ia and is selectedand is selected from the group consisting of Compounds 38-40 in Table 3.

[0246] In some embodiments, the compound has the structure of Formula IIa and is selected from the group consisting. In some embodiments, the compound has the structure of Formula IIa and is selected from the group consistingand is selected from the group consisting of Compounds 38-40 in Table 3.

[0247] In some embodiments, the compound has the structure of Formula Ib and is selected from the group consistingembodiments, the compound has the structure of Formula Ib and is selected from the groupembodiments, the compound has the structure of Formula Ib and is selected from the group consisting of Compounds 1-37 in Table 3.

[0248] In some embodiments, the compound has the structure of Formula IIb and is selected from the group consistingembodiments, the compound has the structure of Formula IIb and is selected from the group consisting of Compounds 1-37 in Table 3.

[0249] The enumerated compounds in Table 3 and Examples 1-11 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, tautomers thereof, or enantiomers thereof. Abbreviations ACN / MeCN Acetonitrile AcOH Acetic acid AIBN Azobisisobutyronitrile Aq. Aqueous n-BuLi n-Butyl lithium DCE 1,2-Dichloroethane DCM Dichloromethane DIBAL Diisobutylaluminium hydride DMF Dimethyl formamide DMSO Dimethyl sulfoxide EA / EtOAc Ethyl acetate ESI Electrospray ionizationEt3N / TEA Triethylamine Et3SiH Triethylsilane EtOH Ethanol Im Imidazole Ir(dtb- [4,4′-Bis(1,1-dimethylethyl)-2,2′-bipyridine-N1,N1′]bis[2-(2-pyridinyl- bpy)(ppy)2PF6 N)phenyl-C]iridium(III) hexafluorophosphate LCMS Liquid chromatography–mass spectrometry MeOH Methanol MsCl Methanesulfonyl chloride or mesyl chloride NBS N-Bromosuccinimide NMR Nuclear magnetic resonance Pd(dppf)Cl2- [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex CH2Cl2with dichloromethane PE Petroleum ether PG Protecting group PhMe Toluene PMB Para-methoxybenzyl PMBCl Para-methoxybenzyl chloride Py Pyridine SEM 2-(Trimethylsilyl)ethoxymethyl TBAF Tetra-n-butylammonium fluoride TBS tert-Butyldimethylsilyl TBSCl tert-Butyldimethylsilyl chloride TFA Trifluoroacetic acid TsOH / pTsOH Para-Toluenesulfonic acid THF Tetrahydrofuran Methods of Preparation

[0250] 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.

[0251] 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 Formulas I, Ia, Ib,II, IIa, and IIb, or precursors thereof. Various modifications to these methods may be envisioned by those skilled in the art to achieve similar results to that of the inventions given below. In the embodiments below, the synthetic route is described using compounds having the structure of Formulas I, Ia, Ib, II, IIa, and IIb, or precursors 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.

[0252] Compounds of Formula I may be synthesized by several different methods depending on the nature of A, B, and E in the ring. For example, compounds of Formula I where A is O, B is absent and A and E are connected by a bond, and E is C(R13)2can be obtained as shown in Scheme 1.

[0253] As shown in Scheme 1, reaction of a 2-bromoarylamine G-1 with a benzofuran acid chloride G-2 and a base, such as triethylamine, in a solvent, such as DCM, gives amide G-3. Alternatively, pyridine can be used as both base and solvent, optionally with heating. The amide nitrogen is then protected with a group such as PMB. Treatment of G-3 with a base, such as sodium hydride, in a solvent, such as DMF, and addition of the appropriate halide provides G-4. Conversion of G-4 to the spirocycle G-5 is carried out by radical cyclizationof G-4 with tributyltin hydride and an initiator, such as AIBN, in a solvent, such as toluene. The cyclization may also be carried out by photoredox chemistry using Ir(dtb-bpy)(ppy)2PF6 as catalyst in a solvent, such as acetonitrile, a base, such as triethylamine, and irradiation with white LED light. Removal of the protecting group (PG) gives G-6. When PG is PMB trifluoromethanesulfonic acid, a mixture of TFA and DCM may be used for deprotection. Installation of the R3sidechain by reaction of G-6 with a halide R3X, and a base, such as potassium carbonate, in a solvent, such as DMF, provides G-7.

[0254] Compounds of Formula I where A is O, B is absent and A and E are connected by a bond, and E is C(R13)2can also be obtained as shown in Scheme 2 (route to G-9). Compounds of Formula I where A is C(R11)2, B is absent and A and E are connected by a bond, and E is O can be obtained as shown in Scheme 2 (route to G-17).

[0255] As shown in Scheme 2, isatin G-8 is reacted with a protected 2-bromophenol G-10 using n-butyl lithium in a solvent, such as THF, at low temperature to give the 3- hydroxyindolinone G-11. SEM is one suitable protecting group for the phenol. The indolinone nitrogen is then protected with a different protecting group. PMB is one such protecting group. PMB is added by treating G-11 with PMBCl and a base, such as potassium carbonate, in a solvent, such as DMF, to give G-12. Treatment of G-12 with triethylsilane and TFA removes the hydroxyl group and the SEM protecting group to form phenol G-13. Reaction of G-13 with chloroiodomethane and a base, such as cesium carbonate, in a solvent, such as DMF, provides spirocycle G-14. Deprotection as above then yields G-9.

[0256] Also as shown in Scheme 2, reaction of 2-bromobenzylalcohol G-15 with n- butyllithium at low temperature and addition of isatin G-8 gives diol G-16. Heating G-16 with an acid, such as tosic acid, in a solvent, such as toluene, affords the spirocycle G-17.

[0257] Compounds of Formula I where A is C(R11)2, B is absent and A and E are connected by a bond, and E is C(R13)2 can be obtained as shown in Scheme 3.Scheme 3

[0258] As shown in Scheme 3, reaction of 3-arylindolinone G-18 with ethyl bromoacetate and a base, such a potassium carbonate, in a solvent, such as DMF, gives ester G-19. Ester G-19 is protected on the indole N with a protecting group, such as PMB, that is introduced by treatment with the appropriate halide under the same conditions to provide G-20. The ester is then hydrolyzed with a base, such as lithium hydroxide, and converted to the acid chloride G- 21 with thionyl chloride. Friedel-Crafts cyclization of G-21 in the presence of a Lewis acid, such as aluminum chloride, in a solvent, such as DCM, forms ketone G-22. The carbonyl is removed by sequential reaction with sodium borohydride to give the alcohol, mesyl chloride and triethylamine to give a mixture of mesylate and eliminated product, and finally hydrogenation over Pd / C to provide spirocyclic indane G-23, that is then deprotected to G- 24.

[0259] Compounds of Formula I where A is C(R11)2, B is C(R12)2, and E is C(R13)2 can be obtained as shown in Scheme 4.

[0260] As shown in Scheme 4, reaction of isatin G-8 with Grignard reagent G-25 in a solvent, such as THF, gives alcohol G-26. Treatment of G-26 with a Lewis acid, such as boron trifluoride etherate, in a solvent, such as DCM, results in cyclization to G-27.

[0261] Compounds of Formula I where A is O, B is C(R12)2, and E is C(R13)2 can be obtained as shown in Scheme 5.

[0262] As shown in Scheme 5, indolinone G-13, where PG is a protecting group, such as PMB, is protected on the phenol with an orthogonal protecting group, such as TBS, to give G-28. Reaction of G-28 with ethyl bromoacetate and a base, such as potassium carbonate, in a solvent, such as DMF, provides ester G-29. Reduction of the ester with a reducing agent,such as DIBAL, in a solvent such as toluene, followed by treatment with TBAF in THF forms diol G-30. Heating G-30 with an acid, such as tosic acid, in a solvent, such as toluene, affords the spirocycle G-31. Deprotection then yields G-32.

[0263] Compounds of Formula I where A is S, B is C(R12)2, and E is C(R13)2 can be obtained as shown in Scheme 6.

[0264] As shown in Scheme 6, 2-bromothiophenol G-33 is reacted with a protected bromoethanol and a base, such a cesium carbonate, in a solvent such, as DMF, to form G-34. One suitable protecting group is TBS. Lithiation of G-34 using n-butyllithium in a solvent, such as THF, at low temperature and reaction with isatin G-8 gives alcohol G-35. The hydroxyl group is removed by converting to the chloride G-36 with thionyl chloride and a base, such as triethylamine, followed by reduction with zinc in acetic acid and removal of the TBS group with aqueous HCl in methanol to provide G-37. Reaction of G-37 with iodine and triphenylphosphine in the presence of imidazole forms iodide G-38. Cyclization of G-38 is carried out with a base, such a sodium hydride, in a solvent, such as DMF, to yield spirocycle G-39. Pharmaceutical Compositions

[0265] 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.

[0266] In another aspect, the present invention provides 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. In another aspect, the present invention provides a pharmaceutical composition comprising at least one compound according to Formulas I, Ia, Ib, II, IIa, and IIb, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.

[0267] In some 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.

[0268] 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.

[0269] As set out above, certain embodiments of the present pharmaceutical agents may be provided in the form of pharmaceutically acceptable salts. The term “pharmaceuticallyacceptable 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).

[0270] 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.

[0271] 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).

[0272] 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.

[0273] 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%.

[0274] 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.

[0275] 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, as a solution or a suspension in an aqueous or non-aqueous liquid, 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.

[0276] 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 asglycerol; 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.

[0277] 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.

[0278] 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.

[0279] 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.

[0280] 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.

[0281] 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.

[0282] 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.

[0283] 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.

[0284] 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.

[0285] 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.

[0286] Ophthalmic formulations, eye ointments, powders, solutions, and the like, are also contemplated as being within the scope of this invention.

[0287] 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.

[0288] 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 material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution. 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.

[0289] 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.

[0290] 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.

[0291] 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).

[0292] 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.

[0293] 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

[0294] In yet another aspect, the present invention provides 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 the embodiments described herein, or a pharmaceutically acceptable salt 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. In yet another aspect, the present invention provides a method of treating a condition in a mammalian species in need thereof, comprising administering to the mammalian species atherapeutically effective amount of at least one compound according to Formulas I, Ia, Ib, II, IIa, and IIb, or a pharmaceutically acceptable salt 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.

[0295] In some embodiments, 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.

[0296] In some embodiments, the autoimmune disease is rheumatoid arthritis or multiple sclerosis. In some embodiments, the central nervous system (CNS) 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).

[0297] In some embodiments, the mammalian species is human.

[0298] In yet another aspect, 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 the embodiments described herein, or a pharmaceutically acceptable salt thereof. In yet another aspect, 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 Formulas I, Ia, Ib, II, IIa, and IIb, or a pharmaceutically acceptable salt thereof.

[0299] 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.

[0300] Some aspects of the invention involve administering an effective amount of a composition to a subject to achieve a specific outcome. The small molecule compositionsuseful according to the methods of the present invention thus can be formulated in any manner suitable for pharmaceutical use.

[0301] 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.

[0302] 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.

[0303] 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.

[0304] 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.

[0305] 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.

[0306] 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, sulfuric, nitric, phosphoric, maleic, acetic, salicylic, p-toluene sulfonic, tartaric, citric, methane sulfonic, formic, malonic, succinic, naphthalene-2-sulfonic, and benzene sulfonic. 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.

[0307] 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).

[0308] 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.

[0309] 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.

[0310] A variety of administration routes are 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.

[0311] 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.

[0312] 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- based 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. Inaddition, pump-based hardware delivery systems can be used, some of which are adapted for implantation. Assays for Effectiveness of KCa3.1 Channel Inhibitors

[0313] In some embodiments, the compounds as described herein were tested for their activities against the 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

[0314] 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

[0315] Examples 1-10 describe various intermediates used in the syntheses of representative compounds of Formulas I, Ia, Ib, II, IIa, and IIb, as disclosed herein. Example 1. Intermediate 1 (5,6-difluoro-2-methyl-1-benzofuran-3-carboxylic acid)Step a:

[0316] To a solution of 4,5-difluoro-2-iodophenol (2.00 g, 7.81 mmol) and but-2-ynoic acid ethyl ester (1.05 g, 9.38 mmol) in MeCN (20 mL) was added DABCO (0.175 g, 1.56 mmol). The reaction mixture was stirred at 70 °C for 16 h under nitrogen, cooled, diluted with water(50 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 (10 / 1) to afford ethyl (2E)-3-(4,5-difluoro-2-iodophenoxy)but-2-enoate as a colorless liquid (2.00 g, 70.0%): LCMS (ESI) calc’d for C12H11F2IO3 [M + H]+: 369 found 369;1H NMR (300 MHz, DMSO-d6) δ 8.09 (dd, J = 9.93, 8.76 Hz, 1H), 7.57 (dd, J = 11.11, 7.27 Hz, 1H), 4.65 (s, 1H), 4.04 (q, J = 7.10 Hz, 2H), 2.45 (s, 3H), 1.15 (t, J = 7.12 Hz, 3H). Step b:

[0317] To a solution of ethyl (2E)-3-(4,5-difluoro-2-iodophenoxy)but-2-enoate (1.80 g, 4.89 mmol) and TEA (0.990 g, 9.78 mmol) in MeCN (20 mL) was added Pd(dppf)Cl2•CH2Cl2(0.797 g, 0.978 mmol). The reaction mixture was degassed under reduced pressure, purged with nitrogen three times, and stirred at 70 °C for 16 h under nitrogen. After cooling down to room temperature, the resulting mixture was concentrated under reduced pressure and the residue purified by silica gel column chromatography, eluting with PE / EA (10 / 1) to afford ethyl 5,6-difluoro-2-methyl-1-benzofuran-3-carboxylate as a light yellow solid (0.800 g, 68.0%): LCMS (ESI) calc’d for C12H10F2O3[M + H]+: 241 found 241;1H NMR (400 MHz, DMSO-d6) δ 7.93 (dd, J = 10.29, 6.59 Hz, 1H), 7.75 (dd, J = 10.42, 8.09 Hz, 1H), 4.35 (q, J = 7.10 Hz, 2H), 2.74 (s, 3H), 1.37 (t, J = 7.07 Hz, 3H). Step c:

[0318] To a solution of ethyl 5,6-difluoro-2-methyl-1-benzofuran-3-carboxylate (0.800 g, 3.33 mmol) in MeOH (10 mL) and H2O (1 mL) was added LiOH (0.160 g, 6.66 mmol). The reaction mixture was stirred at 60 °C for 2 h. The cooled mixture was acidified to pH 3 with aq. HCl (3 mL, 2 N) and filtered. The filter cake was washed with EA (5 x 2 mL) and dried under reduced pressure to afford Intermediate 1 (5,6-difluoro-2-methyl-1-benzofuran-3- carboxylic acid) as an off-white solid (0.610 g, 86.0%): LCMS (ESI) calc’d for C10H6F2O3 [M - H]-: 211, found 211;1H NMR (300 MHz, DMSO-d6) δ 13.14 (s, 1H), 7.88 (dd, J = 10.33, 6.59 Hz, 1H), 7.74 (dd, J = 10.47, 8.18 Hz, 1H), 2.73 (s, 3H). Example 2. Intermediate 2 (3-bromo-4,5-difluoropyridin-2-amine)Step a:

[0319] To a stirred solution of 4,5-difluoropyridin-2-amine (1.00 g, 7.69 mmol) in DCM (20 mL) was added NBS (1.64 g, 9.21 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 h and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with PE / EA (4 / 1) to afford Intermediate 2 (3-bromo-4,5-difluoropyridin-2-amine) as a light orange solid (0.600 g, 37.0%): LCMS (ESI) calc’d for C5H3BrF2N2[M + H]+: 209, 211 (1 : 1) found 209, 211 (1 : 1);1H NMR (400 MHz, DMSO-d6) δ 8.11 (dd, J = 9.52, 1.49 Hz, 1H), 6.49 (s, 2H). Synthesis of Spirocyclic Cores Example 3. Intermediate 3 (4',5,5'-trifluoro-2-methyl-1'H,2H-spiro[1-benzofuran-3,3'- pyrrolo[2,3-b]pyridin]-2'-one)

[0320] To a solution of 5-fluoro-2-methyl-1-benzofuran-3-carboxylic acid (1.40 g, 7.21 mmol) in DCM (30 mL) was added (COCl)2(1.30 g, 10.2 mmol) and DMF (40.0 mg, 0.547 mmol) dropwise at room temperature. The reaction mixture was stirred for 2 h and concentrated under reduced pressure to afford 5-fluoro-2-methyl-1-benzofuran-3-carbonyl chloride as a light yellow solid (1.50 g, crude). To a solution of 3-bromo-4,5-difluoropyridin- 2-amine (0.890 g, 4.26 mmol) in THF (10 mL) was added NaH (0.426 g, 10.6 mmol, 60% wt% in oil) in portions at room temperature. After 30 min, a solution of 5-fluoro-2-methyl-1- benzofuran-3-carbonyl chloride (1.09 g, 5.11 mmol) in THF (15 mL) was added dropwise and the mixture was stirred for a further 2 h at room temperature. The resulting mixture was quenched with water (30 mL) at 0oC and extracted with EA (3 x 50 mL). The combinedorganic 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 47% MeCN in water (plus 20 mM NH4HCO3) to afford N-(3- bromo-4,5-difluoropyridin-2-yl)-5-fluoro-2-methyl-1-benzofuran-3-carboxamide as a light yellow solid (0.900 g, 55.0%): LCMS (ESI) calc’d for C15H8BrF3N2O2 [M + H]+: 385, 387 (1 : 1) found 385, 387 (1 : 1);1H NMR (400 MHz, DMSO-d6) δ 10.71 (s, 1H), 8.73 (d, J = 8.94 Hz, 1H), 7.67 (dd, J = 9.0, 4.2 Hz, 1H), 7.51 (dd, J = 9.0, 2.8 Hz, 1H), 7.35-7.10 (m, 1H), 2.73 (s, 3H). Step b:

[0321] To a solution of N-(3-bromo-4,5-difluoropyridin-2-yl)-5-fluoro-2-methyl-1- benzofuran-3-carboxamide (0.300 g, 0.779 mmol) and PMBCl (0.366 g, 2.34 mmol) in MeCN (10 mL) was added TEA (0.236 g, 2.34 mmol). The reaction mixture was stirred at 80 °C for 16 h, cooled, 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 (5 / 1) to afford N-(3-bromo-4,5-difluoropyridin- 2-yl)-5-fluoro-N-(4-methoxybenzyl)-2-methyl-1-benzofuran-3-carboxamide as a light yellow semi-solid (0.250 g, 64.0%): LCMS (ESI) calc’d for C23H16BrF3N2O3 [M + H]+: 505, 507 (1 : 1) found 505, 507 (1 : 1);1H NMR (300 MHz, DMSO-d6) δ 8.76 (dd, J = 9.06, 1.05 Hz, 1H), 7.57-7.44 (m, 1H), 7.32-7.22 (m, 2H), 7.21-7.04 (m, 2H), 6.88-6.80 (m, 2H), 5.05 (s, 2H), 3.72 (s, 3H), 2.38 (s, 3H). Step c:

[0322] To a solution of N-(3-bromo-4,5-difluoropyridin-2-yl)-5-fluoro-N-(4- methoxybenzyl)-2-methyl-1-benzofuran-3-carboxamide (0.440 g, 0.871 mmol) and tributyltinhydride (0.760 g, 2.61 mmol) in toluene (10 mL) was added AIBN (0.143 g, 0.871 mmol). The reaction mixture was degassed under reduced pressure and purged with nitrogen three times, then stirred at 100 °C for 4 h. The cooled mixture was filtered and the filtrate concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (5 / 1) to afford 4',5,5'-trifluoro-1'-(4-methoxybenzyl)-2- methyl-2H-spiro[1-benzofuran-3,3'-pyrrolo[2,3-b]pyridin]-2'-one as a light yellow semi-solid (0.260 g, 70.0%): LCMS (ESI) calc’d for C23H17F3N2O3 [M + H]+: 427 found 427;1H NMR (300 MHz, DMSO-d6) δ 8.61-8.41 (m, 1H), 7.38-7.22 (m, 2H), 7.20-7.08 (m, 1H), 7.06-6.97(m, 1H), 6.95-6.86 (m, 3H), 5.31-5.10 (m, 1H), 5.01-4.72 (m, 2H), 3.76-3.66 (m, 3H), 1.32- 1.23 (m, 3H). Step d:

[0323] To a solution of 4',5,5'-trifluoro-1'-(4-methoxybenzyl)-2-methyl-2H-spiro[1- benzofuran-3,3'-pyrrolo[2,3-b]pyridin]-2'-one (0.100 g, 0.235 mmol) in DCM (2 mL) and TFA (2 mL) was added trifluoromethanesulfonic acid (0.352 g, 2.35 mmol). The reaction mixture was stirred at 40 °C for 16 h, basified to pH 8 with saturated aq. Na2CO3(30 mL), and extracted with EA (2 x 30 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 silica gel column chromatography, eluting with PE / EA (2 / 1) to afford Intermediate 3 (4',5,5'-trifluoro-2-methyl-1'H,2H-spiro[1-benzofuran-3,3'-pyrrolo[2,3- b]pyridin]-2'-one) as a light yellow solid (35.0 mg, 49.0%): LCMS (ESI) calc’d for C15H9F3N2O2[M + H]+: 307 found 307;1H NMR (400 MHz, DMSO-d6) δ 11.84-11.43 (m, 1H), 8.42 (dd, J = 9.59, 3.31 Hz, 1H), 7.15-7.03 (m, 2H), 7.00-6.96 (m, 1H), 5.25-5.05 (m, 1H), 1.43-1.27 (m, 3H). Example 4. Intermediate 4 (4',7'-difluoro-2-methyl-1'H,2H-spiro[1-benzofuran-3,3'- indol]-2'-one)Step a:

[0324] To a stirred solution of N-(2,4-dibromo-3,6-difluorophenyl)-N-(4-methoxybenzyl)-2- methyl-1-benzofuran-3-carboxamide (1.26 g, 2.23 mmol) and [Ir(dtbbpy)(ppy)2][PF6] (0.102 g, 0.111 mmol) in MeCN (10 mL) was added TEA (2.26 g, 22.3 mmol) dropwise at room temperature. The reaction mixture was degassed under reduced pressure, purged with argon three times, and irradiated with white LED at 25 °C for 16 h under argon. The resulting mixture was concentrated under reduced pressure and the residue purified by prep-TLC (PE / EA = 10 / 1) to afford 4',7'-difluoro-1'-(4-methoxybenzyl)-2-methyl-2H-spiro[1- benzofuran-3,3'-indol]-2'-one as an off-white solid (0.250 g, 27.5%): LCMS (ESI) calc’d forC24H19F2NO3 [M + H]+: 408 found 408;1H NMR (400 MHz, DMSO-d6) δ 7.42-7.25 (m, 2H), 7.25-7.17 (m, 3H), 7.07-6.98 (m, 1H), 6.98-6.93 (m, 2H), 6.93-6.84 (m, 2H), 5.25-4.84 (m, 3H), 3.75-3.72 (m, 3H), 1.42-1.25 (m, 3H). Step b:

[0325] To a stirred solution of 4',7'-difluoro-1'-(4-methoxybenzyl)-2-methyl-2H-spiro[1- benzofuran-3,3'-indol]-2'-one (0.250 g, 0.614 mmol) in TFA (2 mL) and DCE (2 mL) was added trifluoromethanesulfonic acid (0.460 g, 3.07 mmol) dropwise at 25 °C. The reaction mixture was stirred at 50 °C for 16 h, cooled, and concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluting with 40% MeCN in water (plus 10 mM NH4HCO3) to afford Intermediate 4 (4',7'-difluoro-2-methyl-1'H,2H-spiro[1- benzofuran-3,3'-indol]-2'-one) as an off-white solid (65.0 mg, 22.1%): LCMS (ESI) calc’d for C16H11F2NO2 [M + H]+: 288 found 288;1H NMR (400 MHz, DMSO-d6) δ 11.62-11.25 (m, 1H), 7.42-7.14 (m, 2H), 6.96-6.73 (m, 4H), 5.24-4.92 (m, 1H), 1.46-1.14 (m, 3H). Example 5. Intermediate 5 (4',5',6-trifluoro-1'H,2H-spiro[1-benzofuran-3,3'-indol]-2'- one)Step a:

[0326] To a stirred solution of [2-(2-bromo-5-fluorophenoxymethoxy)ethyl]trimethylsilane (2.63 g, 8.19 mmol) in THF (30 mL) was added n-BuLi (5.50 mL, 13.8 mmol, 2.5 M in hexane) dropwise at -78 °C under nitrogen. The reaction solution was stirred at -78 °C for 30 min then a solution of 4,5-difluoro-1H-indole-2,3-dione (1.00 g, 5.46 mmol) in THF (10 mL) was added dropwise and the mixture stirred at -78 °C for an additional 2 h. After warming to room temperature, the mixture was quenched with saturated aq. NH4Cl (80 mL) andextracted with EA (3 x 80 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 reverse phase chromatography, eluting with 45% MeCN in water (plus 10 mM NH4HCO3) to afford 4,5-difluoro-3-(4-fluoro-2-{[2- (trimethylsilyl)ethoxy]methoxy}phenyl)-3-hydroxy-1H-indol-2-one as a yellow solid (0.980 g, 42.0%): LCMS (ESI) calc’d for C20H22F3NO4Si [M - H]-: 424 found 424;1H NMR (300 MHz, DMSO-d6) δ 10.51 (s, 1H), 7.91-7.82 (m, 1H), 7.28-7.16 (m, 1H), 6.99-6.84 (m, 2H), 6.80 (dd, J = 11.10, 2.51 Hz, 1H), 6.67-6.59 (m, 1H), 5.07 (d, J = 7.05 Hz, 1H), 4.89 (d, J = 7.10 Hz, 1H), 3.29-3.21 (m, 1H), 3.14-3.03 (m, 1H), 0.74-0.65 (m, 2H), -0.09 (s, 9H). Step b:

[0327] To a stirred mixture of 4,5-difluoro-3-(4-fluoro-2-{[2- (trimethylsilyl)ethoxy]methoxy}phenyl)-3-hydroxy-1H-indol-2-one (0.600 g, 1.41 mmol) and K2CO3(0.586 g, 4.23 mmol) in DMF (8 mL) was added PMBCl (0.221 g, 1.41 mmol). The reaction mixture was stirred at 50 °C for 16 h, cooled, diluted with water (40 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 silica gel column chromatography, eluting with PE / EA (3 / 1) to afford 4,5-difluoro-3-(4-fluoro-2-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)-3-hydroxy-1-(4- methoxybenzyl)indol-2-one as a yellow solid (0.680 g, 88.0%): LCMS (ESI) calc’d for C28H30F3NO5Si [M - H]-: 544 found 544;1H NMR (300 MHz, DMSO-d6) δ 7.92 (dd, J = 8.75, 6.90 Hz, 1H), 7.44-7.36 (m, 2H), 7.35-7.19 (m, 1H), 7.15 (s, 1H), 7.00-6.91 (m, 3H), 6.91-6.72 (m, 2H), 5.05-4.93 (m, 1H), 4.92-4.76 (m, 2H), 4.37 (d, J = 7.32 Hz, 1H), 3.75 (s, 3H), 3.05-2.81 (m, 2H), 0.68-0.51 (m, 2H), -0.14 (s, 9H). Step c:

[0328] To a stirred solution of 4,5-difluoro-3-(4-fluoro-2-{[2- (trimethylsilyl)ethoxy]methoxy}phenyl)-3-hydroxy-1-(4-methoxybenzyl)indol-2-one (0.400 g, 0.733 mmol) in TFA (4 mL) was added Et3SiH (0.256 g, 2.19 mmol) dropwise at room temperature. The reaction mixture was stirred at 80 °C for 2 h, cooled, and concentrated under reduced pressure. The residue was 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 4,5-difluoro-3-(4-fluoro-2-hydroxyphenyl)-1-(4-methoxybenzyl)-3H-indol-2-one as an off-white solid (0.200 g, 68.0%): LCMS (ESI) calc’d for C22H16F3NO3 [M + H]+: 400 found 400;1H NMR (300 MHz, DMSO-d6) δ 10.07 (s, 1H), 7.36-7.17 (m, 4H), 6.95-6.85 (m, 2H), 6.72- 6.61 (m, 2H), 6.57 (dd, J = 10.67, 2.61 Hz, 1H), 5.17 (s, 1H), 4.99-4.73 (m, 2H), 3.74 (s, 3H). Step d:

[0329] To a stirred solution of 4,5-difluoro-3-(4-fluoro-2-hydroxyphenyl)-1-(4- methoxybenzyl)-3H-indol-2-one (0.170 g, 0.426 mmol) and chloroiodomethane (0.750 g, 4.26 mmol) in THF (4 mL) was added Cs2CO3 (0.346 g, 1.06 mmol). The reaction mixture was stirred at room temperature for 16 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 (3 / 1) to afford 4',5',6- trifluoro-1'-(4-methoxybenzyl)-2H-spiro[1-benzofuran-3,3'-indol]-2'-one as an off-white solid (60.0 mg, 34.0%): LCMS (ESI) calc’d for C23H16F3NO3 [M + H]+: 412 found 412;1H NMR (300 MHz, CD3OD) δ 7.34-7.27 (m, 2H), 7.27-7.13 (m, 1H), 6.95-6.86 (m, 2H), 6.83- 6.77 (m, 1H), 6.75-6.65 (m, 2H), 6.65-6.54 (m, 1H), 5.03-4.76 (m, 4H), 3.77 (s, 3H). Step e:

[0330] To a stirred solution of 4',5',6-trifluoro-1'-(4-methoxybenzyl)-2H-spiro[1-benzofuran- 3,3'-indol]-2'-one (60.0 mg, 0.146 mmol) in TFA (1 mL) and DCM (1 mL) was added trifluoromethanesulfonic acid (0.219 g, 1.46 mmol). The reaction mixture was stirred at room temperature for 16 h and concentrated under reduced pressure to afford Intermediate 5 (4',5',6-trifluoro-2H-spiro[benzofuran-3,3'-indolin]-2'-one) as a purple liquid (60.0 mg, crude), which was used in the next step directly without purification: LCMS (ESI) calc’d for C15H8F3NO2 [M - H]-: 290 found 290. Example 6. Intermediate 6 (4',5,5'-trifluoro-1'H,3H-spiro[2-benzofuran-1,3'-indol]-2'- one)Step a:

[0331] To a stirred solution of (2-bromo-5-fluorophenyl)methanol (0.840 g, 4.10 mmol) in THF (20 mL) was added n-BuLi (3.28 mL, 8.19 mmol, 2.5 M in hexane) dropwise at -78 °C under nitrogen. After 0.5 h, a solution of 4,5-difluoro-1H-indole-2,3-dione (0.500 g, 2.73 mmol) in THF (3 mL) was added at -78 °C. The resulting mixture was stirred at room temperature for an additional 2 h. The reaction was quenched with saturated aq. NH4Cl (100 mL) at 0 °C 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 30% MeCN in water (plus 10 mM NH4HCO3) to afford 4,5-difluoro-3-[4-fluoro-2- (hydroxymethyl)phenyl]-3-hydroxy-1H-indol-2-one as a brown solid (0.280 g, 33.2%): LCMS (ESI) calc’d for C15H10F3NO3 [M + H]+: 310 found 310;1H NMR (400 MHz, DMSO- d6) δ 10.79 (s, 1H), 7.73-7.60 (m, 1H), 7.43-7.29 (m, 2H), 7.14 (s, 1H), 7.13-7.06 (m, 1H), 6.78-6.71 (m, 1H), 5.24 (t, J = 5.66 Hz, 1H), 4.39 (dd, J = 15.10, 5.66 Hz, 1H), 4.18-4.09 (m, 1H). Step b:

[0332] To a stirred solution of 4,5-difluoro-3-[4-fluoro-2-(hydroxymethyl)phenyl]-3- hydroxy-1H-indol-2-one (0.100 g, 0.323 mmol) in toluene (30 mL) was added TsOH (0.167 g, 0.969 mmol). The reaction mixture was stirred at 110 °C for 2 h, cooled, and concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluting with 50% MeCN in water (plus 10 mM NH4HCO3) to afford Intermediate 6 (4',5,5'-trifluoro- 1'H,3H-spiro[2-benzofuran-1,3'-indol]-2'-one) as an off-white solid (80.0 mg, 85.0%): LCMS (ESI) calc’d for C15H8F3NO2[M - H]-: 290 found 290;1H NMR (400 MHz, DMSO-d6) δ 10.81 (s, 1H), 7.46-7.38 (m, 1H), 7.36 (dd, J = 8.83, 2.33 Hz, 1H), 7.16-7.10 (m, 1H), 7.10- 7.02 (m, 1H), 6.77 (dd, J = 8.57, 3.21 Hz, 1H), 5.41-5.28 (m, 2H). Example 7. Intermediate 7 (4',5,5'-trifluoro-2,3-dihydro-1'H-spiro[indene-1,3'-indol]- 2'-one)Intermediate 7Step a:

[0333] To a stirred solution of 4,5-difluoro-3-(4-fluorophenyl)-1,3-dihydroindol-2-one (0.500 g, 1.90 mmol) and ethyl bromoacetate (0.317 g, 1.90 mmol) in DMF (5 mL) was added K2CO3 (0.525 g, 3.80 mmol). The reaction mixture was stirred at 110 °C for 2 h, cooled, diluted with water (50 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 under reduced pressure. The residue was purified by reverse phase chromatography, eluting with 45% MeCN in water (plus 0.05% FA) to afford ethyl 2-[4,5-difluoro-3-(4-fluorophenyl)-2- oxo-1H-indol-3-yl]acetate as a yellow solid (0.510 g, 76.9%): LCMS (ESI) calc’d for C18H14F3NO3 [M + H]+: 350 found 350;1H NMR (400 MHz, DMSO-d6) δ 10.79 (s, 1H), 7.42-7.33 (m, 1H), 7.33-7.25 (m, 2H), 7.24-7.14 (m, 2H), 6.75 (dd, J = 8.59, 3.30 Hz, 1H), 3.89 (q, J = 7.08 Hz, 2H), 3.60 (d, J = 15.57 Hz, 1H), 3.22 (d, J = 15.60 Hz, 1H), 0.95 (t, J = 7.06 Hz, 3H). Step b:

[0334] To a stirred solution of ethyl 2-[4,5-difluoro-3-(4-fluorophenyl)-2-oxo-1H-indol-3- yl]acetate (0.300 g, 0.859 mmol) and PMBCl (0.269 g, 1.72 mmol) in DMF (0.5 mL) was added K2CO3 (0.237 g, 1.72 mmol). The reaction mixture was stirred at room temperature for 3 h, diluted with water (20 mL), and extracted with EA (3 x 30 mL). The combinedorganic layers were washed with brine (2 x 30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluting with 45% MeCN in water (plus 0.05% FA) to afford ethyl 2-[4,5- difluoro-3-(4-fluorophenyl)-1-(4-methoxybenzyl)-2-oxoindol-3-yl]acetate as a light yellow liquid (0.370 g, 94.6%): LCMS (ESI) calc’d for C26H22F3NO4 [M + H]+: 470 found 470. Step c:

[0335] A mixture of ethyl 2-[4,5-difluoro-3-(4-fluorophenyl)-1-(4-methoxybenzyl)-2- oxoindol-3-yl]acetate (0.400 g, 0.852 mmol) and LiOH (40.8 mg, 1.70 mmol) in MeOH (4 mL) and H2O (1 mL) was stirred at room temperature for 3 h and concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluting with 30% MeCN in water (plus 0.05% FA) to afford [4,5-difluoro-3-(4-fluorophenyl)-1-(4- methoxybenzyl)-2-oxoindol-3-yl]acetic acid as a light yellow liquid (0.350 g, 93.1%): LCMS (ESI) calc’d for C24H18F3NO4[M + H]+: 442 found 442;1H NMR (300 MHz, CDCl3) δ 7.40- 7.30 (m, 2H), 7.24-7.15 (m, 2H), 7.13-7.00 (m, 3H), 6.88-6.80 (m, 2H), 6.52-6.43 (m, 1H), 4.95-4.74 (m, 2H), 3.80 (s, 3H), 3.76-3.67 (m, 1H), 3.51-3.43 (m, 1H). Step d:

[0336] To a stirred solution of [4,5-difluoro-3-(4-fluorophenyl)-1-(4-methoxybenzyl)-2- oxoindol-3-yl]acetic acid (0.260 g, 0.589 mmol) and oxalyl chloride (0.374 g, 2.95 mmol) in DCM (5 mL) was added DMF (0.430 mg, 0.00600 mmol) dropwise at room temperature. The reaction mixture was stirred for 2 h and concentrated under reduced pressure to afford [4,5-difluoro-3-(4-fluorophenyl)-1-(4-methoxybenzyl)-2-oxoindol-3-yl]acetyl chloride as a yellow liquid (0.260 g, 96.0%), which was used in the next step directly without purification. Step e:

[0337] A solution of [4,5-difluoro-3-(4-fluorophenyl)-1-(4-methoxybenzyl)-2-oxoindol-3- yl]acetyl chloride (0.260 g, 0.565 mmol) in DCE (2 mL) was added dropwise to AlCl3 (0.226 g, 1.70 mmol) with stirring at 0 °C under nitrogen. The reaction mixture was stirred at room temperature for 16 h and concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluting with 55% MeCN in water (plus 10 mM NH4HCO3) to afford 4',5,5'-trifluoro-1'-(4-methoxybenzyl)-2H-spiro[indene-1,3'-indole]-2',3-dione as an off-white solid (0.140 g, 58.5%): LCMS (ESI) calc’d for C24H16F3NO3[M - H]-: 422 found 422;1H NMR (400 MHz, DMSO-d6) δ 7.67-7.54 (m, 2H), 7.52-7.40 (m, 1H), 7.37-7.26 (m,2H), 7.17-7.11 (m, 1H), 7.02-6.96 (m, 1H), 6.96-6.89 (m, 2H), 4.97-4.84 (m, 2H), 3.74 (s, 3H), 3.37-3.32 (m, 1H) 3.25-3.15 (m, 1H). Step f:

[0338] To a stirred solution of 4',5,5'-trifluoro-1'-(4-methoxybenzyl)-2H-spiro[indene-1,3'- indole]-2',3-dione (0.140 g, 0.331 mmol) in MeOH (2 mL) was added NaBH4 (37.5 mg, 0.993 mmol) in portions at 0 °C. The reaction mixture was stirred at 25 °C for 2 h, quenched with saturated aq. NH4Cl (20 mL) at 0 °C, 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 reverse phase chromatography, eluting with 60% MeCN in water (plus 10 mM NH4HCO3) to afford 4',5,5'- trifluoro-3-hydroxy-1'-(4-methoxybenzyl)-2,3-dihydrospiro[indene-1,3'-indol]-2'-one as an off-white solid (0.130 g, 92.4%): LCMS (ESI) calc’d for C24H18F3NO3 [M + H]+: 426 found 426;1H NMR (400 MHz, DMSO-d6) δ 7.46-7.17 (m, 4H), 7.12-6.99 (m, 1H), 6.97-6.82 (m, 3H), 6.79-6.68 (m, 1H), 5.87 (dd, J = 50.76, 6.60 Hz, 1H), 5.64-5.42 (m, 1H), 5.02-4.73 (m, 2H), 3.73 (d, J = 7.60 Hz, 3H), 2.89-2.74 (m, 1H), 2.49-2.42 (m, 1H). Step g:

[0339] To a stirred solution of 4',5,5'-trifluoro-3-hydroxy-1'-(4-methoxybenzyl)-2,3- dihydrospiro[indene-1,3'-indol]-2'-one (0.100 g, 0.235 mmol) and methanesulfonic anhydride (61.4 mg, 0.352 mmol) in DCM (2 mL) was added TEA (71.4 mg, 0.705 mmol) dropwise at 25 °C. The reaction mixture was stirred for 16 h, diluted with water (20 mL) and EA (20 mL), and extracted with more 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 to afford 4',5,5'-trifluoro-1'-(4-methoxybenzyl)spiro[indene-1,3'-indol]-2'- one as a brown solid (60.0 mg, 62.7%), which was used in the next step directly without purification: LCMS (ESI) calc’d for C24H16F3NO2 [M + H]+: 408 found 408;1H NMR (400 MHz, DMSO-d6) δ 7.75-7.37 (m, 2H), 7.36-7.30 (m, 1H), 7.30-7.14 (m, 2H), 6.98-6.88 (m, 4H), 6.89-6.83 (m, 1H), 6.50-6.36 (m, 1H), 4.97-4.82 (m, 2H), 3.77-3.71 (m, 3H). Step h:

[0340] To a stirred solution of 4',5,5'-trifluoro-1'-(4-methoxybenzyl)spiro[indene-1,3'-indol]- 2'-one (60.0 mg, 0.147 mmol) in EA (3 mL) was added Pd / C (3.13 mg, 0.0290 mmol). The reaction mixture was degassed under reduced pressure, purged with hydrogen three times, and stirred at 25 °C for 16 h. The resulting mixture was filtered and the filter cake washedwith EA (3 x 10 mL). The filtrate was concentrated under reduced pressure and the residue purified by reverse phase chromatography, eluting with 60% MeCN in water (plus 0.05% TFA) to afford 4',5,5'-trifluoro-1'-(4-methoxybenzyl)-2,3-dihydrospiro[indene-1,3'-indol]-2'- one as a light brown solid (50.0 mg, 82.9%): LCMS (ESI) calc’d for C24H18F3NO2 [M + H]+: 410 found 410;1H NMR (400 MHz, DMSO-d6) δ 7.42-7.20 (m, 4H), 7.02-6.85 (m, 4H), 6.74-6.69(m, 1H), 4.94-4.80 (m, 2H), 3.74 (s, 3H), 3.37-3.29 (m, 1H), 3.28-3.17 (m, 1H), 2.71-2.54 (m, 2H). Step i:

[0341] To a stirred solution of 4',5,5'-trifluoro-1'-(4-methoxybenzyl)-2,3- dihydrospiro[indene-1,3'-indol]-2'-one (50.0 mg, 0.122 mmol) and TFA (2 mL) in DCE (2 mL) was added trifluoromethanesulfonic acid (0.183 g, 1.22 mmol) dropwise. The reaction mixture was stirred at 50 °C for 2 h, cooled, and concentrated under reduced pressure to afford Intermediate 7 (4',5,5'-trifluoro-2,3-dihydro-1'H-spiro[indene-1,3'-indol]-2'-one) as a brown liquid (60.0 mg, crude), which was used to the next step directly without purification: LCMS (ESI) calc’d for C16H10F3NO [M + H]+: 290 found 290;1H NMR (400 MHz, DMSO- d6) δ 10.72 (s, 1H), 7.37-7.27 (m, 1H), 7.25-7.20 (m, 1H), 6.96-6.91 (m, 1H), 6.82-6.78 (m, 1H), 6.78-6.71 (m, 1H), 3.34-3.13 (m, 2H), 2.63-2.53 (m, 2H). Example 8. Intermediate 8 (4,5-difluoro-3',4'-dihydro-1H,2'H-spiro[indole-3,1'- naphthalen]-2-one)Step a:

[0342] To a stirred solution of 4,5-difluoro-1H-indole-2,3-dione (0.300 g, 1.64 mmol) in THF (3 mL) was added a solution of 3-phenyl-1-propylmagnesium bromide (9.83 mL, 4.91 mmol, 0.5 M in THF) dropwise at 0 °C. The reaction mixture was stirred at room temperature for 1 h under nitrogen, quenched with saturated aq. NH4Cl (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. Theresidue was purified by silica gel column chromatography, eluting with PE / EA (1 / 1) to afford 4,5-difluoro-3-hydroxy-3-(3-phenylpropyl)-1H-indol-2-one as a brown yellow solid (0.230 g, 46.0%): LCMS (ESI) calc’d for C17H15F2NO2[M - H]-: 302 found 302;1H NMR (300 MHz, DMSO-d6) δ 10.46 (s, 1H), 7.33-7.19 (m, 3H), 7.19-7.12 (m, 1H), 7.12-7.06 (m, 2H), 6.63- 6.56 (m, 1H), 6.25 (s, 1H), 2.55-2.53 (m, 2H), 2.02-1.79 (m, 2H), 1.41-1.19 (m, 2H). Step b:

[0343] To a stirred solution of 4,5-difluoro-3-hydroxy-3-(3-phenylpropyl)-1H-indol-2-one (0.200 g, 0.659 mmol) in DCE (3 mL) was added BF3 etherate (0.262 g, 1.85 mmol) dropwise. The reaction mixture was stirred at 80 °C for 16 h, cooled, diluted with water (30 mL), and extracted with EA (3 x 10 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 prep-TLC (PE / EA = 1 / 1) to afford Intermediate 8 (4,5- difluoro-3',4'-dihydro-1H,2'H-spiro[indole-3,1'-naphthalen]-2-one) as an off-white solid (0.135 g, 72.0%): LCMS (ESI) calc’d for C17H13F2NO [M + H]+: 286 found 286;1H NMR (400 MHz, DMSO-d6) δ 10.69 (s, 1H), 7.37-7.24 (m, 1H), 7.24-7.14 (m, 2H), 7.07-6.99 (m, 1H), 6.76 (dd, J = 8.63, 3.42 Hz, 1H), 6.53 (d, J = 7.74 Hz, 1H), 2.89 (t, J = 6.26 Hz, 2H), 2.39-2.25 (m, 1H), 2.18-2.05 (m, 2H), 1.95-1.82 (m, 1H). Example 9. Intermediate 9 (4',5'-difluorospiro[chromane-4,3'-indolin]-2'-one)Step a:

[0344] To a stirred solution of 4,5-difluoro-3-(2-hydroxyphenyl)-1-(4-methoxybenzyl)-3H- indol-2-one (0.250 g, 0.656 mmol) and imidazole (0.223 g, 3.28 mmol) in DMF (5 mL) was added TBSCl (0.987 g, 6.56 mmol). The reaction mixture was stirred at room temperature for 16 h, diluted with water (30 mL), and extracted with EA (3 x 20 mL). The combinedorganic 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 (10 / 1) to afford 3-{2-[(tert- butyldimethylsilyl)oxy]phenyl}-4,5-difluoro-1-(4-methoxybenzyl)-3H-indol-2-one as a light yellow liquid (0.300 g, 92.3%): LCMS (ESI) calc’d for C28H31F2NO3Si [M + H]+: 496, found 496;1H NMR (300 MHz, CDCl3) δ 7.32-7.23 (m, 3H), 7.26-7.14 (m, 1H), 7.06-6.97 (m, 1H), 6.97-6.92 (m, 1H), 6.92-6.84 (m, 3H), 6.56-6.44 (m, 1H), 5.34 (s, 1H), 4.89 (s, 2H), 3.82 (s, 3H), 1.03 (s, 9H), 0.13 (s, 3H), 0.03 (s, 3H). Step b:

[0345] To a stirred solution of 3-{2-[(tert-butyldimethylsilyl)oxy]phenyl}-4,5-difluoro-1-(4- methoxybenzyl)-3H-indol-2-one (0.300 g, 0.605 mmol) and ethyl bromoacetate (0.707 g, 4.24 mmol) in DMF (5 mL) was added Cs2CO3 (0.591 g, 1.82 mmol). The reaction mixture was stirred at room temperature for 16 h, diluted with water (30 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 to afford ethyl 2-(3-{2- [(tert-butyldimethylsilyl)oxy]phenyl}-4,5-difluoro-1-(4-methoxybenzyl)-2-oxoindol-3- yl)acetate as a light yellow liquid (0.280 g, crude), which was used in the next step directly without purification: LCMS (ESI) calc’d for C32H37F2NO5Si [M + H]+: 582 found 582. Step c:

[0346] To a stirred solution of ethyl 2-(3-{2-[(tert-butyldimethylsilyl)oxy]phenyl}-4,5- difluoro-1-(4-methoxybenzyl)-2-oxoindol-3-yl)acetate (0.300 g, 0.516 mmol) in THF (5 mL) was added DIBAL-H (1.55 mL, 2.33 mmol, 1.5 M in toluene) dropwise at 0oC. The reaction mixture was stirred at room temperature for 30 min, diluted with EA (20 mL), and quenched with aq. NaOH (2 M, 1 mL). The mixture was filtered and the filter cake washed with EA (3 x 10 mL). The filtrate was concentrated under reduced pressure to afford 3-{2-[(tert- butyldimethylsilyl)oxy]phenyl}-4,5-difluoro-3-(2-hydroxyethyl)-1-(4-methoxybenzyl)indol- 2-one as a light yellow solid (0.199 g, crude), which was used in the next step directly without purification: LCMS (ESI) calc’d for C30H35F2NO4Si [M + H]+: 540 found 540. Step d:

[0347] A solution of 3-{2-[(tert-butyldimethylsilyl)oxy]phenyl}-4,5-difluoro-3-(2- hydroxyethyl)-1-(4-methoxybenzyl)indol-2-one (0.200 g, 0.371 mmol) and TBAF (0.193 g, 0.742 mmol) in THF (5 mL) was stirred at room temperature for 2 h then concentrated underreduced pressure. The residue was purified by reversed phase chromatography, eluting with 65% MeCN in water (plus 0.1% FA) to afford 4,5-difluoro-3-(2-hydroxyethyl)-3-(2- hydroxyphenyl)-1-(4-methoxybenzyl)indol-2-one as a light yellow liquid (0.120 g, 76.1%): LCMS (ESI) calc’d for C24H21F2NO4 [M - H]-: 424 found 424;1H NMR (300 MHz, DMSO- d6) δ 9.44 (s, 1H), 7.54 (dd, J = 8.03, 1.57 Hz, 1H), 7.42-7.33 (m, 2H), 7.27-7.08 (m, 2H), 6.98-6.81 (m, 3H), 6.71 (dd, J = 8.05, 1.25 Hz, 1H), 6.65 (dd, J = 8.64, 3.25 Hz, 1H), 4.91- 4.73 (m, 2H), 4.54 (s, 1H), 3.75 (s, 3H), 3.31-3.13 (m, 1H), 3.10-2.98 (m, 1H), 2.64-2.54 (m, 1H), 2.46-2.34 (m, 1H). Step e:

[0348] A solution of 4,5-difluoro-3-(2-hydroxyethyl)-3-(2-hydroxyphenyl)-1-(4- methoxybenzyl)indol-2-one (0.100 g, 0.235 mmol) and TsOH (0.121 g, 0.705 mmol) in toluene (5 mL) was stirred at 110 ℃ for 16 h under nitrogen atmosphere. After cooling down to room temperature, the cooled mixture was concentrated under reduced pressure and the residue purified by reversed phase chromatography, eluting with 40% MeCN in water (plus 0.1% FA) to afford Intermediate 9 (4',5'-difluoro-2,3-dihydro-1'H-spiro[1-benzopyran-4,3'- indol]-2'-one) as a light yellow solid (30.0 mg, 31.3%): LCMS (ESI) calc’d for C16H11F2NO2[M - H]-: 286 found 286;1H NMR (400 MHz, DMSO-d6) δ 10.85 (s, 1H), 7.42-7.31 (m, 1H), 7.23-7.14 (m, 1H), 6.91 (dd, J = 8.27, 1.26 Hz, 1H), 6.84-6.75 (m, 2H), 6.54 (dd, J = 7.80, 1.64 Hz, 1H), 4.73-4.62 (m, 1H), 4.38-4.28 (m, 1H), 2.43-2.33 (m, 1H), 2.29-2.20 (m, 1H). Example 10. Intermediate 10 (4',5'-difluoro-2,3-dihydro-1'H-spiro[1-benzothiopyran- 4,3'-indol]-2'-one)Step a:

[0349] To a solution of 2-bromobenzenethiol (2.00 g, 10.6 mmol) in DMF (20 mL) were added K2CO3(4.39 g, 31.7 mmol) and (2-bromoethoxy)(tert-butyl)dimethylsilane (3.04 g, 12.7 mmol). The reaction mixture was stirred at room temperature for 16 h, diluted with water (100 mL), and extracted with EA (3 x 50 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 purified by silica gel column chromatography, eluting with PE / EA (20 / 1) to afford {2-[(2-bromophenyl)thio]ethoxy}(tert- butyl)dimethylsilane as a colorless liquid (3.50 g, 95.0%):1H NMR (300 MHz, CDCl3) δ 7.59-7.53 (m, 1H), 7.38-7.29 (m, 1H), 7.28-7.23 (m, 1H), 7.09-7.00 (m, 1H), 3.91-3.83 (m, 2H), 3.12 (t, J = 7.06 Hz, 2H), 0.92 (s, 9H), 0.08 (s, 6H). Step b:

[0350] To a solution of {2-[(2-bromophenyl)thio]ethoxy}(tert-butyl)dimethylsilane (1.90 g, 5.46 mmol) in THF (10 mL) was added n-BuLi (2.40 mL, 6.01 mmol, 2.5 M in hexane) dropwise at -65 °C over 20 min under nitrogen. After 50 min, a solution of 4,5-difluoro-1H- indole-2,3-dione (0.500 g, 2.73 mmol) in THF (10 mL) was added dropwise at -65 °C and the reaction mixture was stirred at -65 °C for a further 1 h. After warming to 0 °C, the resulting mixture was quenched with saturated aq. NH4Cl (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 silica gel column chromatography, eluting with PE / EA (2 / 1) to afford 3-[2-({2-[(tert- butyldimethylsilyl)oxy]ethyl}thio)phenyl]-4,5-difluoro-3-hydroxy-1H-indol-2-one as a light yellow semi-solid (0.600 g, 49.0%): LCMS (ESI) calc’d for C22H27F2NO3SSi [M + Na]+: 474 found 474;1H NMR (300 MHz, DMSO-d6) δ 10.64 (s, 1H), 8.01 (dd, J = 7.68, 1.85 Hz, 1H), 7.50 (dd, J = 7.49, 1.56 Hz, 1H), 7.44-7.23 (m, 3H), 7.05 (s, 1H), 6.69-6.60 (m, 1H), 3.42- 3.32 (m, 1H), 3.30-3.20 (m, 1H), 2.81-2.62 (m, 2H), 0.79 (s, 9H), 0.07 (s, 6H). Step c:

[0351] To a solution of 3-[2-({2-[(tert-butyldimethylsilyl)oxy]ethyl}thio)phenyl]-4,5- difluoro-3-hydroxy-1H-indol-2-one (0.600 g, 1.33 mmol) and TEA (0.403 g, 3.99 mmol) in DCM (12 mL) was added SOCl2(0.395 g, 3.32 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 2 h, diluted with DCM (20 mL), washed with brine (2 x 20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure toafford 3-[2-({2-[(tert-butyldimethylsilyl)oxy]ethyl}thio)phenyl]-3-chloro-4,5-difluoro-1H- indol-2-one as a light yellow liquid (0.650 g, crude), which was used in the next step directly without purification: LCMS (ESI) calc’d for C22H26ClF2NO2SSi [M + Na]+: 492, 494 (3 : 1) found 492, 494 (3 : 1). Step d:

[0352] To a solution of 3-[2-({2-[(tert-butyldimethylsilyl)oxy]ethyl}thio)phenyl]-3-chloro- 4,5-difluoro-1H-indol-2-one (0.650 g, 1.18 mmol) in THF (12 mL) and AcOH (4 mL) was added Zn (0.768 g, 11.75 mmol) in portions over 10 min at room temperature. The reaction mixture was stirred for 2 h, filtered, and the filtrate concentrated under reduced pressure to afford 3-[2-({2-[(tert-butyldimethylsilyl)oxy]ethyl}thio)phenyl]-4,5-difluoroindolin-2-one as a light yellow liquid (0.500 g, crude), which was used to next step directly without further purification: LCMS (ESI) calc’d for C22H27F2NO2SSi [M + Na]+: 458 found 458. Step e:

[0353] To a solution of 3-[2-({2-[(tert-butyldimethylsilyl)oxy]ethyl}thio)phenyl]-4,5- difluoroindolin-2-one (0.500 g, crude) in MeOH (6 mL) was added HCl (g) (4 N in MeOH, 3 mL). The solution was stirred at room temperature for 1 h and concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluting with 40% MeCN in water (plus 10 mM NH4HCO3) to afford 4,5-difluoro-3-{2-[(2- hydroxyethyl)thio]phenyl}indolin-2-one as a light yellow solid (0.200 g, 64.0%): LCMS (ESI) calc’d for C16H13F2NO2S [M + H]+: 322 found 322;1H NMR (300 MHz, DMSO-d6) δ 10.77 (s, 1H), 7.73-7.44 (m, 1H), 7.41-7.11 (m, 3H), 6.79-6.58 (m, 2H), 5.77-5.02 (m, 1H), 5.01-4.61 (m, 1H), 3.65-3.48 (m, 1H), 3.28-3.14 (m, 1H), 3.14-2.95 (m, 1H), 2.84-2.61 (m, 1H). Step f:

[0354] To a stirred mixture of PPh3 (0.245 g, 0.930 mmol) and imidazole (0.127 g, 1.87 mmol) in THF (4 mL) was added I2(0.269 g, 1.06 mmol) at 0 °C. Five min later, a solution of 4,5-difluoro-3-{2-[(2-hydroxyethyl)thio]phenyl}indolin-2-one (0.200 g, 0.620 mmol) in THF (4 mL) was added at 0 °C. The reaction mixture was stirred at room temperature for 1 h, diluted with EA (25 mL), and washed with a solution of saturated aq. NaHCO3and saturated aq. Na2SO3(3 x 30 mL, v / v=1 / 1). 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 40%MeCN in water (plus 10 mM NH4HCO3) to afford 4,5-difluoro-3-{2-[(2- iodoethyl)thio]phenyl}indolin-2-one as a light brown solid (0.170 g, 63.0%): LCMS (ESI) calc’d for C16H12F2INOS [M + H]+: 432 found 432. Step g:

[0355] To a solution of 4,5-difluoro-3-{2-[(2-iodoethyl)thio]phenyl}indolin-2-one (0.170 g, 0.390 mmol) in DMF (5 mL) was added NaH (31.5 mg, 0.790 mmol, 60% wt% in oil) at room temperature. The reaction mixture was stirred at room temperature for 2 h, quenched with water (30 mL), and extracted with EA (3 x 25 mL). The combined organic layers were washed with brine (5 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 / 3) to afford Intermediate 10 (4',5'-difluoro-2,3-dihydro-1'H-spiro[1- benzothiopyran-4,3'-indol]-2'-one) as an off-white foam (0.100 g, 84.0%): LCMS (ESI) calc’d for C16H11F2NOS [M + H]+: 304 found 304;1H NMR (400 MHz, DMSO-d6) δ 10.85 (s, 1H), 7.42-7.31 (m, 1H), 7.23-7.11 (m, 2H), 6.98-6.90 (m, 1H), 6.82-6.75 (m, 1H), 6.61- 6.55 (m, 1H), 3.70-3.59 (m, 1H), 3.09-2.97 (m, 1H), 2.44-2.32 (m, 2H).

[0356] Example 11 describes the exemplified syntheses of representative compounds of Formulas I, Ia, Ib, II, IIa, and IIb, as disclosed herein. Example 11. Compound 1 (2-[(3S)-4',5,5'-trifluoro-2-methyl-2'-oxo-2H-spiro[1- benzofuran-3,3'-pyrrolo[2,3-b]pyridin]-1'-yl]acetamide isomer 1); Compound 2 (2-[(3S)- 4',5,5'-trifluoro-2-methyl-2'-oxo-2H-spiro[1-benzofuran-3,3'-pyrrolo[2,3-b]pyridin]-1'- yl]acetamide isomer 2); Compound 3 (2-[(3R)-4',5,5'-trifluoro-2-methyl-2'-oxo-2H- spiro[1-benzofuran-3,3'-pyrrolo[2,3-b]pyridin]-1'-yl]acetamide isomer 1); Compound 4 (2-[(3S)-4',5,5'-trifluoro-2-methyl-2'-oxo-2H-spiro[1-benzofuran-3,3'-pyrrolo[2,3- b]pyridin]-1'-yl]acetamide isomer 2)

[0357] To a stirred solution of Intermediate 3 (4',5,5'-trifluoro-2-methyl-1'H,2H-spiro[1- benzofuran-3,3'-pyrrolo[2,3-b]pyridin]-2'-one) (90.0 mg, 0.294 mmol) and bromoacetamide (60.8 mg, 0.441 mmol) in DMF (2 mL) was added K2CO3(81.2 mg, 0.588 mmol). The reaction mixture was stirred at room temperature for 2 h, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluting with 40% MeCN in water (plus 10 mM NH4HCO3) to afford 2-{4',5,5'-trifluoro-2-methyl-2'- oxo-2H-spiro[1-benzofuran-3,3'-pyrrolo[2,3-b]pyridin]-1'-yl}acetamide as an off-white solid (75.0 mg, 70.0%): LCMS (ESI) calc’d for C17H12F3N3O3 [M + H]+: 364 found 364. Step b:

[0358] 2-{4',5,5'-trifluoro-2-methyl-2'-oxo-2H-spiro[1-benzofuran-3,3'-pyrrolo[2,3- b]pyridin]-1'-yl}acetamide (75.0 mg, 0.206 mmol) was separated by prep Chiral-HPLC with the following conditions: Column: CHIRALPAK IC, 2 x 25 cm, 5 μm; Mobile Phase A: Hex (plus 0.5% 2 M NH3-MeOH), Mobile Phase B: EtOH : DCM = 1 : 1; Flow rate: 20 mL / min; Gradient: 60% B to 60% B in 18 min; Wavelength: 220 / 254 nm; Retention Time 1: 3.59 min; Retention Time 2: 7.08 min; Retention Time 3: 13.03 min; Retention Time 4: 15.76 min.

[0359] The first-eluting isomer at 3.59 min was obtained Compound 1 (2-[(3S)-4',5,5'- trifluoro-2-methyl-2'-oxo-2H-spiro[1-benzofuran-3,3'-pyrrolo[2,3-b]pyridin]-1'-yl]acetamide isomer 1) as an off-white solid (20.1 mg, 27.0%): LCMS (ESI) calc’d for C17H12F3N3O3 [M + H]+: 364 found 364;1H NMR (400 MHz, DMSO-d6) δ 8.49 (dd, J = 9.23, 3.16 Hz, 1H), 7.76 (s, 1H), 7.31 (s, 1H), 7.17-7.09 (m, 1H), 7.05 (dd, J = 8.03, 2.79 Hz, 1H), 7.01 (dd, J = 8.83, 4.16 Hz, 1H), 5.16-5.09 (m, 1H), 4.47-4.36 (m, 2H), 1.34 (d, J = 6.49 Hz, 3H).

[0360] The second-eluting isomer at 7.08 min was obtained Compound 2 (2-[(3S)-4',5,5'- trifluoro-2-methyl-2'-oxo-2H-spiro[1-benzofuran-3,3'-pyrrolo[2,3-b]pyridin]-1'-yl]acetamide isomer 2) as an off-white solid (6.30 mg, 8.00%): LCMS (ESI) calc’d for C17H12F3N3O3[M + H]+: 364 found 364;1H NMR (400 MHz, DMSO-d6) δ 8.49 (dd, J = 9.23, 3.28 Hz, 1H), 7.68 (s, 1H), 7.24 (s, 1H), 7.17-7.09 (m, 1H), 7.03-6.96 (m, 2H), 5.31 (q, J = 6.37 Hz, 1H), 4.38- 4.27 (m, 2H), 1.43 (d, J = 6.40 Hz, 3H).

[0361] The third-eluting isomer at 13.03 min was obtained Compound 3 (2-[(3R)-4',5,5'- trifluoro-2-methyl-2'-oxo-2H-spiro[1-benzofuran-3,3'-pyrrolo[2,3-b]pyridin]-1'-yl]acetamide isomer 1) as an off-white solid (5.80 mg, 8.00%): LCMS (ESI) calc’d for C17H12F3N3O3[M + H]+: 364 found 364;1H NMR (400 MHz, DMSO-d6) δ 8.49 (dd, J = 9.21, 3.26 Hz, 1H), 7.68 (s, 1H), 7.24 (s, 1H), 7.17-7.09 (m, 1H), 7.04-6.96 (m, 2H), 5.31 (q, J = 6.38 Hz, 1H), 4.38- 4.26 (m, 2H), 1.43 (d, J = 6.39 Hz, 3H).

[0362] The forth-eluting isomer at 15.76 min was obtained Compound 4 (2-[(3S)-4',5,5'- trifluoro-2-methyl-2'-oxo-2H-spiro[1-benzofuran-3,3'-pyrrolo[2,3-b]pyridin]-1'-yl]acetamide isomer 2) as an off-white solid (19.0 mg, 25.0%): LCMS (ESI) calc’d for C17H12F3N3O3 [M + H]+: 364 found 364;1H NMR (400 MHz, DMSO-d6) δ 8.49 (dd, J = 9.31, 3.16 Hz, 1H), 7.76 (s, 1H), 7.31 (s, 1H), 7.17-7.10 (m, 1H), 7.05 (dd, J = 8.02, 2.81 Hz, 1H), 7.01 (dd, J = 8.84, 4.16 Hz, 1H), 5.16-5.09 (m, 1H), 4.48-4.35 (m, 2H), 1.34 (d, J = 6.49 Hz, 3H).

[0363] The compounds in the following Tables were synthesized by the method of Example 11, by alkylation of the appropriate spirocyclic indolinone. Table 1. Preparation of Compounds 5-35.Table 2. Preparation of Compounds 36-40.Example 12. Evaluation of KCa3.1 Inhibitor Activities

[0364] This assay was used to evaluate the disclosed compounds’ inhibition activities against the human KCa3.1 channel. Cell Culture

[0365] 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

[0366] 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

[0367] 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

[0368] Data analysis was performed using DataControl384 (Nanion’s proprietary software). To determine IC50values, 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: (1) 1 − ^^^(^^^^^௨^ௗ)ି^^^(^௨^^ ^^^^^)^^^(^^^௧^^^)ି^^^(^௨^^ ^^^^^)(2) 1 − ^^^^(^^^^^௨^ௗ)ି^^^^(^௨^^ ^^^^^)^^^^(^^^௧^^^)ି^^^^(^௨^^ ^^^^^)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 versus 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 13. Evaluation of hERG Activities

[0369] This assay was used to evaluate the disclosed compounds’ inhibition activities against the hERG channel. Cell Culture

[0370] 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 plasticculture flasks and grown at 37°C in a 5% CO2-humidified incubator per ChanPharm SOP. Stocks were maintained in cryogenic storage. Solutions

[0371] 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

[0372] 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

[0373] 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:

[0374] Table 3 provides a summary of the inhibition activities (IC50 (μM) values) of certain exemplified compounds against KCa3.1 channel and hERG channel. Table 3. IC50(μM) Values of Certain Exemplified Compounds Against KCa3.1 Channel and hERG Channel.

Claims

CLAIMS 1. A compound of Formula I, or a pharmaceutically acceptable salt thereof, or a tautomer thereof:wherein A is O, S, or C(R11)2; B is C(R12)2or absent, wherein when B is absent, A and E are connected by a bond; E is O, S, or C(R13)2; X is N or CR14; Y is N or CR15; R1 is H, D, halogen, –CN, alkyl, halogenated alkyl, cycloalkyl, halogenated cycloalkyl, –ORa, –SRa, –C1-4alkyl–ORa, or –C1-4alkyl–SRa; R2is H, D, or halogen; R3 is –(CR8R9)mR10; R4 is H, D, halogen, or alkyl; R5is 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; R7is H, D, halogen, or alkyl; each occurrence of R8 is independently H, D, or alkyl; each occurrence of R9is independently H, D, or alkyl;R10 is –CN, saturated heterocycle, heteroaryl, –CORa, –CO2Ra, –CONRaRb, –ORa, – SORa, or –SO2Ra; each occurrence of R11is independently H, D, or alkyl; each occurrence of R12 is independently H, D, or alkyl; each occurrence of R13 is independently H, D, or alkyl; R14is H, D, halogen, –CN, alkyl, halogenated alkyl, cycloalkyl, halogenated cycloalkyl, –ORa, –SRa, –C1-4alkyl–ORa, or –C1-4alkyl–SRa; R15 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 Ra and Rb is independently selected from the group consisting of H, alkyl, cycloalkyl, halogenated alkyl, heteroalkyl, halogenated heteroalkyl, or halogenated cycloalkyl; or alternatively, Raand Rb, together with the 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, cycloalkyl, heteroalkyl, saturated heterocycle, aryl, and / or heteroaryl in R1, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, Ra, or Rb, where applicable, are each optionally and independently substituted by 1-4 substituents each independently selected from the group consisting of alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, halogen, –ORx, –(CH2)1-2ORx, 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.

2. The compound of claim 1, wherein the structural moiety3. The compound of claim 1 or 2, wherein R1 is H, halogen, –ORa, or –C1-4alkyl– ORa.

4. The compound of any one of claims 1-3, wherein R1is H, F, Cl, OCH3, or OCH2CH3.

5. The compound of any one of claims 1-4, wherein R1 is H, F, or Cl.

6. The compound of any one of claims 1-4, wherein R2is H or halogen.

7. The compound of any one of claims 1-6, wherein R2is H, F, or Cl.

8. The compound of any one of claims 1-7, wherein R14 is H, halogen, –ORa, or –C1-4alkyl–ORa.

9. The compound of any one of claims 1-8, wherein R14is H, F, Cl, –OCH3, – OCH2CH3, –C1-4alkyl–OCH3, or –C1-4alkyl–OCH2CH3.

10. The compound of any one of claims 1-9, wherein R14 is H, F, Cl, or –OCH3.

11. The compound of any one of claims 1-10, wherein R15is H, halogen, –ORa, or –C1-4alkyl–ORa.

12. The compound of any one of claims 1-11, wherein R15 is H, F, Cl, –OCH3, or –OCH2CH3.

13. The compound of any one of claims 1-12, wherein R15is H, F, or Cl.

14. The compound of any one of claims 1-4 or 6-13, wherein the structural moiety, , , , , ,,15. The compound of any one of claims 1-14, wherein the structural moiety16. The compound of any one of claims 1-15, wherein m is 1.

17. The compound of any one of claims 1-15, wherein m is 2.

18. The compound of any one of claims 1-17, wherein each occurrence of R8is independently H or alkyl.

19. The compound of any one of claims 1-18, wherein each occurrence of R9 is independently H or alkyl.

20. The compound of any one of claims 1-19, wherein the structural moiety –(CR8R9)m– has the structure of –CH2–, –CH2CH2–, –CH(CH3)–, -CH(CH3)CH2–, or –CH(CH3)CH(CH3)–.

21. The compound of any one of claims 1-20, wherein each occurrence of R8is H.

22. The compound of any one of claims 1-21, wherein each occurrence of R9 is H.

23. The compound of any one of claims 1-22, wherein the structural moiety –(CR8R9)m– has the structure of –CH2– or –CH2CH2–.

24. The compound of any one of claims 1-23, wherein R10 is CN, –CO2Ra, – CORa, –CONRaRb, –ORa, –SORa, or –SO2Ra.

25. The compound of any one of claims 1-24, wherein R10is saturated heterocycle or heteroaryl, wherein R10is optionally substituted with halogen or OH.

26. The compound of any one of claims 1-24, wherein R10 is –CONRaRb.

27. The compound of any one of claims 1-24 and 26, wherein R3is –(CH2)1-2CONRaRb.

28. The compound of any one of claims 1-27, wherein R4 is H, F, or Cl.

29. The compound of any one of claims 1-28, wherein R4 is H.

30. The compound of any one of claims 1-29, wherein R5is H, F, Cl, OCH3, or OCH2CH3.

31. The compound of any one of claims 1-30, wherein R5 is H, F, or Cl.

32. The compound of any one of claims 1-31, wherein R6is H, F, Cl, –OCH3, or – OCH2CH3.

33. The compound of any one of claims 1-32, wherein R6 is H, F, or Cl.

34. The compound of any one of claims 1-33, wherein R7is H, F, or Cl.

35. The compound of any one of claims 1-34, wherein the structural moiety36. The compound of any one of claims 1-34, wherein the structural moiety.

37. The compound of any one of claims 1-34 and 36, wherein R5 and R6 are each independently H, F, or Cl.

38. The compound of any one of claims 1-34 and 36-37, wherein the structural39. The compound of any one of claims 1-38, wherein each occurrence of R11 is independently H or alkyl.

40. The compound of any one of claims 1-39, wherein each occurrence of R12 is independently H or alkyl.

41. The compound of any one of claims 1-40, wherein each occurrence of R13is independently H or alkyl.

42. The compound of claim 1, wherein the compound has the structure of Formula43. The compound of any one of claims 1-38, wherein the structural moietyand E, when present, is C(R13)2.

44. The compound of any one of claims 1-38 and 43, wherein the structuralCH2CH3.

45. The compound of any one of claims 1-38 and 43-44, wherein the structural.

46. The compound of any one of claims 1-38 and 43-45, wherein the structural47. The compound of claim 1, wherein the compound has the structure of Formula Ib:

48. The compound of any one of claims 1-38, wherein the structural moietywherein A, when present, is (R11)2; and E, when present, is C(R13)2.

49. The compound of any one of claims 1-38 and 48, wherein the structural; wherein each occurrence of R11 and R13 is independently H, – CH3, or –CH2CH3.

50. The compound of any one of claims 1-38 and 48-49, wherein the structural ,.

51. The compound of any one of claims 1-38 and 48-50, wherein the structural52. The compound of any one of claims 1-51, wherein each occurrence of Ra or Rb is independently H, D, alkyl, or halogenated alkyl.

53. The compound of any one of claims 1-51, wherein each occurrence of Ra or Rb is independently H, D, or cycloalkyl.

54. The compound of any one of claims 1-52, wherein each occurrence of Raor Rbis independently H or alkyl.

55. The compound of any one of claims 1-51, wherein each occurrence of Ra or Rb is independently H, –CH3, –CH2CH3, –CH2CH2CH3, –CH(CH3)2, or –C(CH3)3.

56. The compound of any one of claims 1-52 and 54-55, wherein each occurrence of Ra or Rb is independently H, –CH3, or –CH2CH3.

57. The compound of any one of claims 1-51, 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.

58. The compound of any one of claims 1-57, wherein each occurrence of Rxis independently H, alkyl, or heterocycle.

59. The compound of any one of claims 1-58, wherein each occurrence of Rx is independently H, –CH3, or –CH2CH3.

60. The compound of claim 1, wherein the compound has the structure of Formula II:II wherein A is O, S, or C(R11)2; B is C(R12)2 or absent, wherein when B is absent, A and E are connected by a bond; E is O or C(R13)2; X is N or CR14; Y is N or CR15; R1 is H, D, or halogen; R3is –(CR8R9)mR10; R5is H, D, or halogen; R6 is H, D, or halogen; each occurrence of R8is independently H, D, or alkyl; each occurrence of R9is independently H, D, or alkyl; R10 is –CN, saturated heterocycle, heteroaryl, –CORa, –CO2Ra, –CONRaRb, –ORa, – SORa, or –SO2Ra; each occurrence of R11is independently H or alkyl; each occurrence of R12 is independently H or alkyl; each occurrence of R13 is independently H or alkyl; R14is H, D, halogen, alkyl, –ORa, or –C1-4alkyl–ORa; R15 is H, D, halogen, alkyl, –ORa, or –C1-4alkyl–ORa; m is 1 or 2; each occurrence of Raand Rbis independently selected from the group consisting of H, D, alkyl, cycloalkyl, halogenated alkyl, heteroalkyl, halogenated heteroalkyl, halogenatedcycloalkyl; or alternatively, Ra and Rb, together with the 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, cycloalkyl, heteroalkyl, saturated heterocycle, aryl, and / or heteroaryl in R8, R9, R10, R11, R12, R13, R14, R15, Ra, or Rb, where applicable, are each optionally and independently substituted by 1-4 substituents each independently selected from the group consisting of alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, halogen, –ORx, – (CH2)1-2ORx, and oxo, where valence permits; and each occurrence of Rxis independently H, D, alkyl, halogenated alkyl, or heterocycle optionally substituted by alkyl, halogen, or OH.

61. The compound of claim 1 or claim 60, wherein A is O, S, or C(R11)2; B is C(R12)2or absent, wherein when B is absent, A and E are connected by a bond; E is O or C(R13)2; X is N or CR14; Y is N or CR15; R1is H or halogen; R3 is –(CR8R9)1-2R10; R5is H or halogen; R6is H or halogen; each occurrence of R8 is independently H or alkyl; each occurrence of R9is independently H or alkyl; R10is –CONRaRb; each occurrence of R11 is independently H or alkyl; each occurrence of R12 is independently H or alkyl; each occurrence of R13is independently H or alkyl; R14 is H, halogen, –ORa, or –C1-4alkyl–ORa;R15 is H, halogen, –ORa, or –C1-4alkyl–ORa; and each occurrence of Ra and Rb is independently selected from the group consisting of H or alkyl.

62. The compound of any one of claims 1 and 60-61, wherein the compound has the structure of Formula IIa:wherein A is O, S, or CH2; E is O or CHR13; X is N or CR14; Y is N or CR15; R1is H or halogen; R3is –(CR8R9)1-2R10; R5 is H or halogen; R6 is H or halogen; each occurrence of R8is independently H or alkyl; each occurrence of R9 is independently H or alkyl; R10 is –CONRaRb; R13is H or alkyl; R14 is H, halogen, –ORa, or –C1-4alkyl–ORa; R15 is H, halogen, –ORa, or –C1-4alkyl–ORa; and each occurrence of Raand Rbis independently selected from the group consisting of H or alkyl.

63. The compound of any one of claims 1 and 60-61, wherein the compound has the structure of Formula IIb:IIb wherein A is O or CH2; E is O or CHR13; X is N or CR14; Y is N or CR15; R1is H or halogen; R3is –(CR8R9)1-2R10; R5 is H or halogen; R6is H or halogen; each occurrence of R8is independently H or alkyl; each occurrence of R9 is independently H or alkyl; R10 is –CONRaRb; each occurrence of R13is independently H or alkyl; R14 is H, halogen, –ORa, or –C1-4alkyl–ORa; R15 is H, halogen, –ORa, or –C1-4alkyl–ORa; and each occurrence of Raand Rbis independently selected from the group consisting of H or alkyl.,, , , ,,65. The compound of claim 1, wherein the compound is selected from the group consisting of Compounds 1-40 in Table 3.

66. The compound of any one of claims 1-65, wherein the compound is not in a salt form or a tautomer form.

67. A pharmaceutical composition comprising at least one compound according to any one of claims 1-66 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent.

68. 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 1-66 or a pharmaceutically acceptable salt 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.

69. The method of claim 68, 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.

70. The method of claim 68, wherein the autoimmune disease is rheumatoid arthritis or multiple sclerosis.

71. The method of claim 68, wherein the CNS disorder is acute ischemic stroke, traumatic brain injury, peripheral nerve injury, glioblastoma multiforme, or spinal cord injury.

72. The method of claim 68, wherein the fibrotic disease is liver fibrosis, kidney fibrosis, cardiac fibrosis, eye injury-related corneal fibrosis, or lung fibrosis.

73. The method of claim 68, wherein the neurodegenerative disease is Alzheimer’s disease, Parkinson’s disease, or amyotrophic lateral sclerosis (ALS).

74. The method of claim 68, wherein the mammalian species is human.

75. 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- 66 or a pharmaceutically acceptable salt thereof.

76. The method of claim 75, wherein the mammalian species is human.

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