Caspase 6 inhibitors and uses thereof

Abstract

To provide compounds and methods for inhibiting Caspase 6 and treating diseases.SOLUTION: Disclosed herein are a pharmaceutical composition including a specific compound exemplified by the following structural formula and a pharmaceutically acceptable excipient and methods of inhibiting human Caspase 6 protein activity, the method including: contacting the human Caspase 6 protein with a compound as disclosed herein.SELECTED DRAWING: Figure 1A

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 62 / 939,263, filed November 22, 2019, which is incorporated herein by reference in its entirety for all purposes.

[0002] Reference to a "Sequence Listing," table, or computer program listing appendix submitted as an ASCII file The sequence listing set forth in file 048536-664001WO_Sequence_Listing_ST25.txt, 9,466 bytes, machine format IBM-PC, MS Windows operating system, created on November 16, 2020, is incorporated herein by reference. [Background technology]

[0003] Caspase 6 is an enzyme that is encoded by the CASP6 gene in humans. Caspase 6 has known functions in apoptosis, early immune response, and neurodegeneration in Huntington's disease and Alzheimer's disease. It has proven difficult to identify an inhibitor of caspase 6. In particular, solutions to these and other problems known in the art are disclosed herein. Summary of the Invention

[0004] In one aspect, a compound is provided having the formula: [ka]

[0005] R 1 are independently halogen, -CX 1 3. -CHX 1 2. -CH2X 1 , -OCX 1 3. -OCH2X 1 , -OCHX 1 2, -CN, -SOn1 R 1D , -SO v1 NR 1A R 1B , -NR 1C NR 1A R 1B , -ONR 1A R 1B , -NHC(O)NR 1C NR 1A R 1B , -NHC(O)NR 1A R 1B , -N(O) m1 , -NR 1A R 1B , -C(O)R 1C , -C(O)-OR 1C , -C(O)NR 1A R 1B , -OR 1D , -NR 1A SO2R 1D , -NR 1A C(O)R 1C , -NR 1A C(O)OR 1C , -NR 1A OR 1C , -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and two adjacent R on adjacent carbons 1 The substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl, or two R 1 The substituents may optionally be combined to form a substituted or unsubstituted alkyl or a substituted or unsubstituted heterocycloalkyl.

[0006] z1 is an integer from 0 to 9.

[0007] R 2 are independently oxo, halogen, -CX 2 3. -CHX 22. -CH2X 2 , -OCX 2 3. -OCH2X 2 , -OCHX 2 2, -CN, -SO n2 R 2D , -SO v2 NR 2A R 2B , -NR 2C NR 2A R 2B , -ONR 2A R 2B , -NHC(O)NR 2C NR 2A R 2B , -NHC(O)NR 2A R 2B , -N(O) m2 , -NR 2A R 2B , -C(O)R 2C , -C(O)-OR 2C , -C(O)NR 2A R 2B , -OR 2D , -NR 2A SO2R 2D , -NR 2A C(O)R 2C , -NR 2A C(O)OR 2C , -NR 2A OR 2C , -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and two adjacent R on adjacent carbons 2 The substituents may optionally be combined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted heteroaryl.

[0008] z2 is an integer of 2 to 6.

[0009] L 3 is a bond, -S(O)2-, -NR 3-, -NH-, -O-, -S-, -C(O)-, -C(O)NR 3 -, -NR 3 C(O)-, -N(R 3 )CH2-, -NR 3 C(O)NH-, -NHC(O)NR 3 -, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene.

[0010] L 4 is a bond, -NH-, -NR 4 -, or substituted or unsubstituted alkylene.

[0011] L 6 is -N(R 6 )-L 3 - or -C(O)NH-.

[0012] W 5 is CH or N.

[0013] z6 is either 1 or 2.

[0014] R 3 , R 4 , and R 6 are independently hydrogen, —CCl3, —CBr3, —CF3, —CI3, CHCl2, —CHBr2, —CHF2, —CHI2, —CH2Cl, —CH2Br, —CH2F, —CH2I, —CN, —OH, —NH2, —COOH, —CO(C1-C6 alkyl), —CONH2, —OCCl3, —OCF3, —OCBr3, —OCI3, —OCHCl2, —OCHBr2, —OCHI2, —OCHF2, —OCH2Cl, —OCH2Br, —OCH2I, —OCH2F, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, or unsubstituted heterocycloalkyl.

[0015] R 7 , R 8 , R 9 , and R 10 are independently hydrogen or unsubstituted C-C 10 It is alkyl.

[0016] Ring B is aryl or heteroaryl.

[0017] R 5 is an electrophilic moiety.

[0018] R 1A , R 1B , R 1C , R 1D , R 2A , R 2B , R 2C , and R 2D are independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and R attached to the same nitrogen atom are independently substituted or unsubstituted. 1A and R 1B The substituents may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R 2A and R 2B The substituents may optionally be combined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

[0019] X 1 and X 2 are independently -F, -Cl, -Br, or -I.

[0020] n1 and n2 are independently an integer of 0 to 4.

[0021] m1, m2, v1, and v2 are independently 1 or 2.

[0022] In one aspect, a pharmaceutical composition is provided comprising a compound described herein and a pharmaceutically acceptable excipient.

[0023] In one aspect, a method of inhibiting the activity of human caspase-6 protein is provided, the method comprising contacting the human caspase-6 protein with a compound described herein.

[0024] In one aspect, a method of treating a neurodegenerative disease is provided, the method comprising administering to a subject in need thereof an effective amount of a compound disclosed herein.

[0025] In one aspect, a method of treating memory loss is provided, the method comprising administering to a subject in need thereof an effective amount of a compound disclosed herein.

[0026] In one aspect, a method of treating axonal degeneration is provided, the method comprising administering to a subject in need thereof an effective amount of a compound disclosed herein.

[0027] In one aspect, a method of treating an inflammatory disease is provided, the method comprising administering to a subject in need thereof an effective amount of a compound disclosed herein.

[0028] In one aspect, a method of treating neuroinflammation is provided, the method comprising administering to a subject in need thereof an effective amount of a compound disclosed herein.

[0029] In one aspect, a method of treating liver disease is provided, the method comprising administering to a subject in need thereof an effective amount of a compound disclosed herein.

[0030] In one aspect, a method of treating non-alcoholic steatohepatitis or non-alcoholic fatty liver disease is provided, the method comprising administering to a subject in need thereof an effective amount of a compound disclosed herein.

[0031] In one aspect, a method of treating fibrosis is provided, the method comprising administering to a subject in need thereof an effective amount of a compound disclosed herein. [Brief explanation of the drawings]

[0032] [Figure 1A] Figure 1A: Compound SU20667-0134-01 inhibits the VEIDase activity of purified caspase-6 (IC50 = 10 nM). Assay method: 1 nM caspase-6, 5 μM z-VEID-Glo, and various compound doses are mixed. After 30 minutes, luciferase detection reagent is added and the plate is read in a luminometer. In Figure 1A, the axis label "0134-01" refers to compound SU20667-0134-01. [Figure 1B] Figure 1B: Compound SU20667-0134-01 inhibits caspase-6-mediated cleavage of lamin A after staurosporine (STS) treatment in SKNAS cells (IC50 = 6 nM). For assay methods, see Mintzer, et al. PLoS One, 2012, 7, e30376. In Figure 1B, the axis label "0134-01" refers to compound SU20667-0134-01. [Figure 2-1]The compound SU20667-0134-01 inhibits z-VEID-ase activity (z-VEID-Glo) and LDHA release after treatment with staurosporine (STS) in iPSC-derived neurons from patients with frontotemporal dementia tau mutation (V337M) and wild-type tau (control). The pan-caspase inhibitor z-VAD-FMK also blocks VEID-ase activity and LDHA release. Assay Method: Induced neurons (iNs) derived from iPSCs carrying heterozygous V337M MAPT mutation and WT isogenic controls were generated and differentiated as previously described (Sohn et al., Neuron 2019, 104, 458-470; Wang et al., Stem Cell Reports 2017, 9, 1221-1233). After differentiation, cells were grown for 12 weeks and then treated with 40 μM staurosporine (STS) for 48 hours. Where indicated, 50–200 μM SU20667-0134-01 or z-VAD-FMK was added simultaneously with STS. After 6 h of treatment, caspase-6 and caspase-3 / 7 levels were examined using Caspase-Glo 6 and 3 / 7 (Promega), respectively, according to the manufacturer's instructions. Cytotoxicity was measured using a lactate dehydrogenase (LDH) release assay (Promega) after 48 h of treatment, according to the manufacturer's instructions. In Figure 2, the label "134" refers to compound SU20667-0134-01, and the label "STS / 134" refers to STS combined with compound SU20667-0134-01. In Figure 2 (continued), the label "134" refers to compound SU20667-0134-01, and the labels "STS / 134_1," "STS / 134_2," and "STS / 134_3" refer to STS in combination with compound SU20667-0134-01. [Figure 2-2]The compound SU20667-0134-01 inhibits z-VEID-ase activity (z-VEID-Glo) and LDHA release after treatment with staurosporine (STS) in iPSC-derived neurons from patients with frontotemporal dementia tau mutation (V337M) and wild-type tau (control). The pan-caspase inhibitor z-VAD-FMK also blocks VEID-ase activity and LDHA release. Assay Method: Induced neurons (iNs) derived from iPSCs carrying heterozygous V337M MAPT mutation and WT isogenic controls were generated and differentiated as previously described (Sohn et al., Neuron 2019, 104, 458-470; Wang et al., Stem Cell Reports 2017, 9, 1221-1233). After differentiation, cells were grown for 12 weeks and then treated with 40 μM staurosporine (STS) for 48 hours. Where indicated, 50–200 μM SU20667-0134-01 or z-VAD-FMK was added simultaneously with STS. After 6 h of treatment, caspase-6 and caspase-3 / 7 levels were examined using Caspase-Glo 6 and 3 / 7 (Promega), respectively, according to the manufacturer's instructions. Cytotoxicity was measured using a lactate dehydrogenase (LDH) release assay (Promega) after 48 h of treatment, according to the manufacturer's instructions. In Figure 2, the label "134" refers to compound SU20667-0134-01, and the label "STS / 134" refers to STS combined with compound SU20667-0134-01. In Figure 2 (continued), the label "134" refers to compound SU20667-0134-01, and the labels "STS / 134_1," "STS / 134_2," and "STS / 134_3" refer to STS in combination with compound SU20667-0134-01. [Figure 3]The compound SU20667-0134-01 inhibits spontaneous cell death in iPSC-derived mixed cortical cultures from patients with frontotemporal dementia tau mutation (V337M). The level of death is similar to that from cells with wild-type tau (V337V). Assay method: Cells were differentiated into postmitotic neurons using previously reported methods (Karch, et al., Stem Cell Reports. 2019, 13, 930-55; van de Leemput J., et al. Neuron. 2014, 83, 51-68; Chambers SM, et al. Nat Biotechnol. 2009, 27, 275-80). Ninety-day-old V337M and control cortical cultures were treated with SU20667-0134-01 at defined doses, and cell death was assessed 48 hours after treatment using the ethidium homodimer (EtHD) assay. Cells were incubated with EtHD (4 μM) for 30 minutes, rinsed with 1x PBS, incubated with Hoechst (1 μg / mL) for 5 minutes, and washed with PBS. Warm culture medium was added to the plate, and then the plate was imaged under a microscope. The percentage of dead cells was defined as the number of EtHD nuclei / the number of Hoechst-positive nuclei. In Figure 3, the label "134" refers to compound SU20667-0134-01. [Figure 4-1] Compound SU20667-0134-01 inhibits the cell death phenotype after treatment with staurosporine (STS) in iPSC-derived neurons from patients with frontotemporal dementia tau mutation (V337M) and wild-type tau (control). The pan-caspase inhibitor z-VAD-FMK also inhibits the cell death phenotype. Cell methods as described for Figure 2; cells are stained for MAP2 and NeuN. In Figure 4 (continued), the label "Inhibitor 134" refers to compound SU20667-0134-01. [Figure 4-2]Compound SU20667-0134-01 inhibits the cell death phenotype after treatment with staurosporine (STS) in iPSC-derived neurons from patients with frontotemporal dementia tau mutation (V337M) and wild-type tau (control). The pan-caspase inhibitor z-VAD-FMK also inhibits the cell death phenotype. Cell methods as described for Figure 2; cells are stained for MAP2 and NeuN. In Figure 4 (continued), the label "Inhibitor 134" refers to compound SU20667-0134-01. DETAILED DESCRIPTION OF THE INVENTION

[0033] I. Definition The abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulas set forth herein are constructed according to the standard rules of chemical valency known to the chemical arts.

[0034] Substituents, when specified by their conventional chemical formula written from left to right, equally encompass the chemically identical substituents that would result from writing the structure from right to left, e.g., -CH2O- is equivalent to -OCH2-.

[0035] The term "alkyl," by itself or as part of another substituent, means, unless otherwise stated, a straight-chain (i.e., unbranched) or branched carbon chain (or carbons), or combinations thereof, which may be fully saturated, mono- or polyunsaturated, and can include monovalent, divalent, and polyvalent radicals. An alkyl can contain the number of carbons specified (e.g., C-C 10(meaning 1 to 10 carbons). Alkyl is a non-cyclized chain. Examples of saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, methyl, and homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. Unsaturated alkyl groups are those containing one or more double or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologs and isomers. Alkoxy is an alkyl attached to the remainder of the molecule via an oxygen linker (-O-). The alkyl moiety may also be an alkenyl moiety. The alkyl moiety may be an alkynyl moiety. The alkyl moiety may be fully saturated. The alkenyl may contain, in addition to one or more double bonds, more than one double bond and / or one or more triple bonds. The alkynyl may contain, in addition to one or more triple bonds, more than one triple bond and / or one or more double bonds. In embodiments, the alkyl is fully saturated. In embodiments, the alkyl is monounsaturated. In embodiments, the alkyl is polyunsaturated.

[0036] The term "alkylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from alkyl, exemplified by, but not limited to, -CHCHCHCH-. Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with groups having 10 or fewer carbon atoms being preferred herein. A "lower alkyl" or "lower alkylene" is a shorter chain alkyl or alkylene group, generally having 8 or fewer carbon atoms. The term "alkenylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkene. In embodiments, an alkylene is fully saturated. In embodiments, an alkylene is monounsaturated. In embodiments, an alkylene is polyunsaturated. In embodiments, an alkenylene contains one or more double bonds. In embodiments, an alkynylene contains one or more triple bonds.

[0037] The term "heteroalkyl," by itself or in combination with another term, means, unless otherwise stated, a stable linear or branched chain, or combination thereof, containing at least one carbon atom and at least one heteroatom (e.g., O, N, P, Si, and S), wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. The heteroatom(s) (e.g., O, N, S, Si, or P) may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. A heteroalkyl is a non-cyclizing chain. Examples include, but are not limited to, -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-S-CH2, -S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, -O-CH3, -O-CH-2-CH3, and -CN. Up to two or three heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. The heteroalkyl moiety may contain one heteroatom (e.g., O, N, S, Si, or P). A heteroalkyl moiety may contain two optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may contain three optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may contain four optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may contain five optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may contain up to eight optionally different heteroatoms (e.g., O, N, S, Si, or P). The term "heteroalkenyl," by itself or in combination with another term, means, unless otherwise stated, a heteroalkyl containing at least one double bond.A heteroalkenyl may optionally contain, in addition to one or more double bonds, more than one double bond and / or one or more triple bonds. The term "heteroalkynyl," by itself or in combination with another term, means, unless otherwise specified, a heteroalkyl containing at least one triple bond. A heteroalkynyl may optionally contain, in addition to one or more triple bonds, more than one triple bond and / or one or more double bonds. In embodiments, a heteroalkyl is fully saturated. In embodiments, a heteroalkyl is monounsaturated. In embodiments, a heteroalkyl is polyunsaturated.

[0038] Similarly, the term "heteroalkylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from heteroalkyl, exemplified by, but not limited to, -CH-CH-S-CH-CH- and -CH-S-CH-CH-NH-CH-. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, etc.). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula -C(O)R'- represents both -C(O)R'- and -R'C(O)-. As noted above, heteroalkyl groups, as used herein, include groups attached to the remainder of the molecule via a heteroatom, such as -C(O)R', -C(O)NR', ​​-NR'R'', -OR', -SR', and / or -SOR'. When "heteroalkyl" is recited followed by a specific heteroalkyl group, e.g., -NR'R'', it is understood that the terms heteroalkyl and -NR'R'' are not redundant or mutually exclusive. Rather, the specific heteroalkyl group is recited for clarity. Thus, the term "heteroalkyl" should not be construed herein to exclude specific heteroalkyl groups, e.g., -NR'R'', etc. The term "heteroalkenylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from a heteroalkene. The term "heteroalkynylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from a heteroalkyne. In embodiments, a heteroalkylene is fully saturated. In embodiments, a heteroalkylene is monounsaturated. In embodiments, the heteroalkylene is polyunsaturated. In embodiments, the heteroalkenylene contains one or more double bonds. In embodiments, the heteroalkynylene contains one or more triple bonds.

[0039] The terms "cycloalkyl" and "heterocycloalkyl," by themselves or in combination with other terms, mean, unless otherwise stated, cyclic versions of "alkyl" and "heteroalkyl," respectively. Cycloalkyl and heterocycloalkyl are not aromatic. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkyl include, but are not limited to, 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like. A "cycloalkylene" and a "heterocycloalkylene," alone or as part of another substituent, mean a divalent radical derived from a cycloalkyl and a heterocycloalkyl, respectively. In embodiments, the cycloalkyl is fully saturated. In embodiments, the cycloalkyl is monounsaturated. In embodiments, the cycloalkyl is polyunsaturated. In embodiments, the heterocycloalkyl is fully saturated. In embodiments, the heterocycloalkyl is monounsaturated. In embodiments, the cycloalkyl is polyunsaturated.

[0040] In embodiments, the term "cycloalkyl" refers to a monocyclic, bicyclic, or polycyclic cycloalkyl ring system. In embodiments, a monocyclic ring system is a cyclic hydrocarbon group containing 3 to 8 carbon atoms; such groups can be saturated or unsaturated, but are not aromatic. In embodiments, a cycloalkyl group is fully saturated. In embodiments, a bicyclic or polycyclic cycloalkyl ring system refers to multiple rings fused together, where at least one of the fused rings is a cycloalkyl ring, and the multiple rings are attached to the parent molecular moiety through any carbon atom contained within the cycloalkyl ring of the multiple rings. Examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. A bicyclic cycloalkyl ring system is a bridged monocyclic ring or a fused bicyclic ring. In embodiments, a bridged monocyclic ring is a ring in which two non-adjacent carbon atoms of a monocyclic ring are joined by an alkylene bridge of 1 to 3 additional carbon atoms (i.e., of the form (CH)). wwhere w is 1, 2, or 3. Representative examples of bicyclic ring systems include, but are not limited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, and bicyclo[4.2.1]nonane. In embodiments, the fused bicyclic cycloalkyl ring system comprises a monocyclic cycloalkyl ring fused to either a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocyclyl, or a monocyclic heteroaryl. In embodiments, the bridged or fused bicyclic cycloalkyl is attached to the parent molecular moiety through any carbon atom contained within the monocyclic cycloalkyl ring. In embodiments, the cycloalkyl group is optionally substituted with one or two groups, independently oxo or thia. In embodiments, the fused bicyclic cycloalkyl is a 5- or 6-membered monocyclic cycloalkyl ring fused to either a phenyl ring, a 5- or 6-membered monocyclic cycloalkyl, a 5- or 6-membered monocyclic cycloalkenyl, a 5- or 6-membered monocyclic heterocyclyl, or a 5- or 6-membered monocyclic heteroaryl, optionally substituted with one or two groups, independently oxo or thia. In embodiments, the polycyclic cycloalkyl ring system is (i) one ring system selected from the group consisting of bicyclic aryl, bicyclic heteroaryl, bicyclic cycloalkyl, bicyclic cycloalkenyl, and bicyclic heterocyclyl, or (ii) a monocyclic cycloalkyl ring (base ring) fused to either of two other ring systems independently selected from the group consisting of phenyl, bicyclic aryl, monocyclic or bicyclic heteroaryl, monocyclic or bicyclic cycloalkyl, monocyclic or bicyclic cycloalkenyl, and monocyclic or bicyclic heterocyclyl. In embodiments, the polycyclic cycloalkyl is attached to the parent molecular moiety through any carbon atom contained within the base ring.In embodiments, the polycyclic cycloalkyl ring system is a monocyclic cycloalkyl ring (base ring) fused to either (i) one ring system selected from the group consisting of bicyclic aryl, bicyclic heteroaryl, bicyclic cycloalkyl, bicyclic cycloalkenyl, and bicyclic heterocyclyl, or (ii) two other ring systems independently selected from the group consisting of phenyl, monocyclic heteroaryl, monocyclic cycloalkyl, monocyclic cycloalkenyl, and monocyclic heterocyclyl. Examples of polycyclic cycloalkyl groups include, but are not limited to, tetradecahydrophenanthrenyl, perhydrophenothiazin-1-yl, and perhydrophenoxazin-1-yl.

[0041] In embodiments, cycloalkyl is cycloalkenyl. The term "cycloalkenyl" is used according to its plain and ordinary meaning. In embodiments, cycloalkenyl is a monocyclic, bicyclic, or polycyclic cycloalkenyl ring system. In embodiments, a bicyclic or polycyclic cycloalkenyl ring system refers to multiple rings fused together, at least one of the fused rings being a cycloalkenyl ring, and the multiple rings are attached to the parent molecular moiety through any carbon atom contained within the cycloalkenyl ring of the multiple rings. In embodiments, a monocyclic cycloalkenyl ring system is a cyclic hydrocarbon group containing 3 to 8 carbon atoms; such groups are unsaturated (i.e., contain at least one cyclic carbon-carbon double bond) but are not aromatic. Examples of monocyclic cycloalkenyl ring systems include cyclopentenyl and cyclohexenyl. In embodiments, a bicyclic cycloalkenyl ring is a bridged monocyclic ring or a fused bicyclic ring. In embodiments, a bridged monocyclic ring is one in which two non-adjacent carbon atoms of the monocyclic ring are joined by an alkylene bridge (i.e., of the form (CH)) between 1 to 3 additional carbon atoms. wwhere w is 1, 2, or 3. Representative examples of bicyclic cycloalkenyls include, but are not limited to, norbornenyl and bicyclo[2.2.2]oct2enyl. In embodiments, the fused bicyclic cycloalkenyl ring system comprises a monocyclic cycloalkenyl ring fused to either a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocyclyl, or a monocyclic heteroaryl. In embodiments, the bridged or fused bicyclic cycloalkenyl is attached to the parent molecular moiety through any carbon atom contained within the monocyclic cycloalkenyl ring. In embodiments, the cycloalkenyl group is optionally substituted with one or two groups, independently oxo or thia. In embodiments, the polycyclic cycloalkenyl ring comprises a monocyclic cycloalkenyl ring (base ring) fused to either (i) one ring system selected from the group consisting of bicyclic aryl, bicyclic heteroaryl, bicyclic cycloalkyl, bicyclic cycloalkenyl, and bicyclic heterocyclyl, or (ii) two ring systems independently selected from the group consisting of phenyl, bicyclic aryl, monocyclic or bicyclic heteroaryl, monocyclic or bicyclic cycloalkyl, monocyclic or bicyclic cycloalkenyl, and monocyclic or bicyclic heterocyclyl. In embodiments, the polycyclic cycloalkenyl is attached to the parent molecular moiety through any carbon atom contained within the base ring. In embodiments, the polycyclic cycloalkenyl ring comprises a monocyclic cycloalkenyl ring (base ring) fused to either (i) one ring system selected from the group consisting of bicyclic aryl, bicyclic heteroaryl, bicyclic cycloalkyl, bicyclic cycloalkenyl, and bicyclic heterocyclyl, or (ii) two ring systems independently selected from the group consisting of phenyl, monocyclic heteroaryl, monocyclic cycloalkyl, monocyclic cycloalkenyl, and monocyclic heterocyclyl.

[0042] In embodiments, the term "heterocycloalkyl" refers to a monocyclic, bicyclic, or polycyclic heterocycloalkyl ring system. In embodiments, the heterocycloalkyl group is fully saturated. In embodiments, a bicyclic or polycyclic heterocycloalkyl ring system refers to multiple rings fused together, where at least one of the fused rings is a heterocycloalkyl ring, and the rings are attached to the parent molecular moiety through any atom contained within the heterocycloalkyl ring of the multiple rings. In embodiments, a heterocycloalkyl is a heterocyclyl. As used herein, the term "heterocyclyl" refers to a monocyclic, bicyclic, or polycyclic heterocycle. A heterocyclyl monocyclic heterocycle is a 3-, 4-, 5-, 6-, or 7-membered ring, where the ring is saturated or unsaturated but not aromatic, and contains at least one heteroatom independently selected from the group consisting of O, N, and S. The 3- or 4-membered ring contains one heteroatom selected from the group consisting of O, N, and S. A 5-membered ring can contain zero or one double bond and one, two, or three heteroatoms selected from the group consisting of O, N, and S. A 6- or 7-membered ring can contain zero, one, or two double bonds and one, two, or three heteroatoms selected from the group consisting of O, N, and S. A heterocyclyl monocyclic heterocycle is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the heterocyclyl monocyclic heterocycle.Representative examples of heterocyclyl monocyclic heterocycles include azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, Examples of heterocyclic heterocycles include, but are not limited to, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxidethiomorpholinyl (thiomorpholine sulfone), thiopyranyl, and trithianyl. Heterocyclyl bicyclic heterocycles are monocyclic heterocycles fused to either phenyl, monocyclic cycloalkyl, monocyclic cycloalkenyl, monocyclic heterocycle, or monocyclic heteroaryl. Heterocyclyl bicyclic heterocycles are connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the monocyclic heterocycle portion of the bicyclic ring system. Representative examples of bicyclic heterocyclyls include, but are not limited to, 2,3-dihydrobenzofuran-2-yl, 2,3-dihydrobenzofuran-3-yl, indolin-1-yl, indolin-2-yl, indolin-3-yl, 2,3-dihydrobenzothien-2-yl, decahydroquinolinyl, decahydroisoquinolinyl, octahydro-1H-indolyl, and octahydrobenzofuranyl. In embodiments, the heterocyclyl group is optionally substituted with one or two groups, independently oxo or thia. In certain embodiments, the bicyclic heterocyclyl is a 5- or 6-membered monocyclic heterocyclyl ring fused to a phenyl ring, a 5- or 6-membered monocyclic cycloalkyl, a 5- or 6-membered monocyclic cycloalkenyl, a 5- or 6-membered monocyclic heterocyclyl, or a 5- or 6-membered monocyclic heteroaryl, optionally substituted by one or two groups that are independently oxo or thia.A polycyclic heterocyclyl ring system is a monocyclic heterocyclyl ring (base ring) fused to either (i) one ring system selected from the group consisting of bicyclic aryl, bicyclic heteroaryl, bicyclic cycloalkyl, bicyclic cycloalkenyl, and bicyclic heterocyclyl, or (ii) two other ring systems independently selected from the group consisting of phenyl, bicyclic aryl, monocyclic or bicyclic heteroaryl, monocyclic or bicyclic cycloalkyl, monocyclic or bicyclic cycloalkenyl, and monocyclic or bicyclic heterocyclyl. The polycyclic heterocyclyl is attached to the parent molecular moiety through any carbon atom or nitrogen atom contained within the base ring. In embodiments, the polycyclic heterocyclyl ring system is a monocyclic heterocyclyl ring (base ring) fused to either (i) one ring system selected from the group consisting of bicyclic aryl, bicyclic heteroaryl, bicyclic cycloalkyl, bicyclic cycloalkenyl, and bicyclic heterocyclyl, or (ii) two other ring systems independently selected from the group consisting of phenyl, monocyclic heteroaryl, monocyclic cycloalkyl, monocyclic cycloalkenyl, and monocyclic heterocyclyl. Examples of polycyclic heterocyclyl groups include, but are not limited to, 10H-phenothiazin-10-yl, 9,10-dihydroacridin-9-yl, 9,10-dihydroacridin-10-yl, 10H-phenoxazin-10-yl, 10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl, 1,2,3,4-tetrahydropyrido[4,3-g]isoquinolin-2-yl, 12H-benzo[b]phenoxazin-12-yl, and dodecahydro-1H-carbazol-9-yl.

[0043] The terms "halo" or "halogen," by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as "haloalkyl" are meant to include monohaloalkyl and polyhaloalkyl. For example, the term "halo(C1-C4)alkyl" includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

[0044] The term "acyl," unless otherwise specified, means -C(O)R, where R is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0045] The term "aryl," unless otherwise specified, refers to a polyunsaturated aromatic hydrocarbon substituent, which may be a single ring or multiple rings (preferably 1 to 3 rings) fused together (i.e., fused-ring aryl) or covalently linked together. Fused-ring aryl refers to multiple rings fused together, at least one of which is an aryl ring. In embodiments, fused-ring aryl refers to multiple rings fused together, at least one of which is an aryl ring, and the multiple rings are bonded to the parent molecular moiety through any carbon atom contained within the aryl ring of the multiple rings. The term "heteroaryl" refers to an aryl group (or ring) containing at least one heteroatom, such as N, O, or S, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom is optionally quaternized. Thus, the term "heteroaryl" includes fused-ring heteroaryl groups (i.e., multiple rings fused together, at least one of which is an aromatic heterocycle). In embodiments, the term "heteroaryl" refers to a fused-ring heteroaryl group (i.e., multiple rings fused together, where at least one of the fused rings is a heteroaromatic ring and the rings are bonded to the parent molecular moiety through any atom contained within the heteroaromatic ring of the multiple rings). 5,6-fused-ring heteroarylene refers to two rings fused together, where one ring has 5 members and the other has 6 members, and at least one ring is a heteroaryl ring. Similarly, 6,6-fused-ring heteroarylene refers to two rings fused together, where one ring has 6 members and the other has 6 members, and at least one ring is a heteroaryl ring. Also, 6,5-fused-ring heteroarylene refers to two rings fused together, where one ring has 6 members and the other has 5 members, and at least one ring is a heteroaryl ring. Heteroaryl groups can be bonded to the remainder of the molecule through a carbon atom or a heteroatom.Non-limiting examples of aryl and heteroaryl groups include phenyl, naphthyl, pyrrolyl, pyrazolyl, pyridazinyl, triazinyl, pyrimidinyl, imidazolyl, pyrazinyl, purinyl, oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzofuran, isobenzofuranyl, indolyl, isoindolyl, benzothiophenyl, isoquinolyl, quinoxalinyl, quinolyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, and the like. aryl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl. Substituents for each of the above noted aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below. An "arylene" and a "heteroarylene," alone or as part of another substituent, mean a divalent radical derived from an aryl and heteroaryl, respectively. The heteroaryl group substituent may be -O-bonded to a ring heteroatom nitrogen.

[0046] A fused-ring heterocycloalkyl-aryl is an aryl fused to a heterocycloalkyl. A fused-ring heterocycloalkyl-heteroaryl is a heteroaryl fused to a heterocycloalkyl. A fused-ring heterocycloalkyl-cycloalkyl is a heterocycloalkyl fused to a cycloalkyl. A fused-ring heterocycloalkyl-heterocycloalkyl is a heterocycloalkyl fused to another heterocycloalkyl. Each fused-ring heterocycloalkyl-aryl, fused-ring heterocycloalkyl-heteroaryl, fused-ring heterocycloalkyl-cycloalkyl, or fused-ring heterocycloalkyl-heterocycloalkyl can independently be unsubstituted or substituted with one or more of the substituents described herein.

[0047] Spirocyclic rings are two or more rings in which adjacent rings are connected via a single atom. The individual rings in a spirocyclic ring can be the same or different. The individual rings in a spirocyclic ring can be substituted or unsubstituted, and can have different substituents from the other individual rings in a set of spirocyclic rings. The possible substituents of the individual rings in a spirocyclic ring are the possible substituents of the same ring (e.g., the substituents of a cycloalkyl ring or heterocycloalkyl ring) when they are not part of a spirocyclic ring. The spirocyclic ring can be substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted heterocycloalkylene, and the individual rings in a spirocyclic ring group can be any of the rings in the previous list, including all rings of one type (e.g., all rings are substituted heterocycloalkylene, and each ring can be the same or different substituted heterocycloalkylene). When referring to a spirocyclic ring system, a heterocyclic spirocyclic ring means a spirocyclic ring in which at least one ring is a heterocyclic ring, and each ring can be a different ring. When referring to a spirocyclic ring system, a substituted spirocyclic ring means that at least one ring is substituted, and each substituent can optionally be different.

[0048] symbol [ka] indicates the point of attachment of the chemical moiety to the rest of the molecule or chemical formula.

[0049] The term "oxo" as used herein means an oxygen that is double bonded to a carbon atom.

[0050] As used herein, the term "alkylsulfonyl" refers to a moiety having the formula -S(O2)-R', where R' is a substituted or unsubstituted alkyl group as defined above. R' can have a specified number of carbon atoms (e.g., "C1-C4 alkylsulfonyl").

[0051] The term "alkylarylene" as an arylene moiety covalently linked to an alkylene moiety (also referred to herein as an alkylene linker). In embodiments, the alkylarylene group has the formula: [ka]

[0052] The alkylarylene moiety can be substituted (e.g., by a substituent) at the alkylene portion or arylene linker (e.g., at carbon 2, 3, 4, or 6) with halogen, oxo, -N, -CF, -CCl, -CBr, -CI, -CN, -CHO, -OH, -NH, -COOH, -CONH, -NO, -SH, -SOCH-SOH, -OSOH, -SONH, -NHNH, -ONH, -NHC(O)NHNH, substituted or unsubstituted C-C alkyl, or substituted or unsubstituted 2-5 membered heteroalkyl). In embodiments, the alkylarylene is unsubstituted.

[0053] Each of the above terms (e.g., "alkyl," "heteroalkyl," "cycloalkyl," "heterocycloalkyl," "aryl," and "heteroaryl") includes both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided below.

[0054] Substituents for alkyl and heteroalkyl radicals (including those groups often referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) range in number from 0 to (2m'+1), where m' is the total number of carbon atoms in such radical, and include, but are not limited to, -OR', ═O, ═NR', ═N-OR', -NR'R'', -SR', -halogen, -SiR'R''R''', -OC(O)R', -C(O)R', -COR', -CONR'R ", -OC(O)NR'R", -NR"C(O)R', -NR'-C(O)NR"R"', -NR"C(O)R', -NR-C(NR'R"R'")=NR"", -NR-C(NR'R")=NR"', -S(O)R', -S(O)R', -S(O)NR'R", -NRSO2R', -NR'NR"R"', -ONR'R", -NR'C(O)NR"NR'"R"", -CN, -NO2, -NR'S02R", -NR'C(O)R", -NR'C(O)-OR", -NR'OR". R, R', R'', R''', and R'''' each preferably independently refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1 to 3 halogens), substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, alkoxy, or thioalkoxy group, or arylalkyl group. When a compound described herein includes more than one R group, for example, each of the R groups is independently selected as each R', R'', R''', and R'''' group when more than one of these groups is present. R' and R'', when attached to the same nitrogen atom, may combine with the nitrogen atom to form a 4-, 5-, 6-, or 7-membered ring. For example, -NR'R'' includes, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl.From the above discussion of substituents, one of skill in the art will understand that the term "alkyl" is intended to include groups that contain carbon atoms bonded to groups other than hydrogen groups, such as haloalkyl (e.g., -CF and -CHCF) and acyl (e.g., -C(O)CH, -C(O)CF, -C(O)CHOCH, etc.).

[0055] Similar to the substituents described for the alkyl radical, the substituents for the aryl and heteroaryl groups vary and include, for example, —OR′, —NR′R″, —SR′, -halogen, —SiR′R″R′′, —OC(O)R′, —C(O)R′, —COR′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′-C(O)NR″R′′′, —NR″C(O)R′, —NR-C(NR′R″R′′)═NR′″, —NR-C(NR′R″)═NR′″, —S(O)R′, —S(O)R′, —S(O)NR′R″, —NRSOR′, —NR′ and R'" are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. When the compounds described herein include more than one R group, for example, each of the R groups is independently selected for each R', R", R'", and R"" group when more than one of these groups is present.

[0056] Substituents for a ring (e.g., cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene) can be shown as substituents on the ring (commonly referred to as floating substituents) rather than on a specific atom of the ring. In such cases, the substituent may be attached to any of the ring atoms (according to the rules of chemical valence), and in the case of a fused or spirocyclic ring, a substituent shown as attached to one member of the fused or spirocyclic ring (a floating substituent on a single ring) can be a substituent on either the fused or spirocyclic ring (a floating substituent on a polycyclic ring). When a substituent is attached to a ring rather than to a specific atom (a floating substituent), and the substituent subscript is an integer greater than 1, multiple substituents may be on the same atom, the same ring, different atoms, different fused rings, or different spirocyclic rings, and each substituent may optionally be different. When the point of attachment of a ring to the rest of the molecule is not limited to a single atom (a floating substituent), the point of attachment may be any atom of the ring, or, in the case of a fused or spirocyclic ring, any atom of the fused or spirocyclic ring, according to the rules of chemical valence. When a ring, fused ring, or spirocyclic ring contains one or more ring heteroatoms and the ring, fused ring, or spirocyclic ring is shown with another floating substituent (including, but not limited to, the point of attachment to the rest of the molecule), the floating substituent may be attached to the heteroatom. When a ring heteroatom is shown attached to one or more hydrogens in a structure or formula with a floating substituent (e.g., a ring nitrogen with two bonds to ring atoms and a third bond to a hydrogen), it will be understood that when the heteroatom is attached to the floating substituent, the substituent replaces the hydrogen, according to the rules of chemical valence.

[0057] Two or more substituents on adjacent carbons may optionally combine to form an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group. These so-called ring-forming substituents are typically, but not necessarily, found attached to a cyclic base structure. In one embodiment, the ring-forming substituents are attached to adjacent members of the base structure. For example, two ring-forming substituents attached to adjacent members of a cyclic base structure form a fused ring structure. In another embodiment, the ring-forming substituents are attached to a single member of the base structure. For example, two ring-forming substituents attached to a single member of a cyclic base structure form a spirocyclic structure. In yet another embodiment, the ring-forming substituents are attached to non-adjacent members of the base structure.

[0058] Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be of the formula -TC(O)-(CRR') q -U-, where T and U are independently -NR-, -O-, -CRR'-, or a single bond, and q is an integer from 0 to 3. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally form a ring of the formula -A-(CH2) r A and B may be optionally replaced with a substituent of the formula -B-, where A and B are independently -CRR'-, -O-, -NR-, -S-, -S(O)-, -S(O)2-, -S(O)2NR'-, or a single bond, and r is an integer from 1 to 4. One of the single bonds in the new ring so formed may optionally be replaced with a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -(CRR') s -X'-(C''R''R'') d-, where s and d are independently integers from 0 to 3, and X' is -O-, -NR'-, -S-, -S(O)-, -S(O)2-, or -S(O)2NR'-. The substituents R, R', R'', and R''' are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0059] As used herein, the term "heteroatom" or "ring heteroatom" is meant to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).

[0060] As used herein, a "substituent" means a group selected from the following moieties: (A) Oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO 2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2 Cl, -OCH2Br, -OCHI, -OCH2F, -N3, unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C 10 Aryl, C10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl), and (B) alkyl (e.g., C1-C 20 Alkyl, C1-C 12 alkyl, C1-C8 alkyl, C1-C6 alkyl, C1-C4 alkyl, or C1-C2 alkyl), heteroalkyl (e.g., 2-20 membered heteroalkyl, 2-12 membered heteroalkyl, 2-8 membered heteroalkyl, 2-6 membered heteroalkyl, 4-6 membered heteroalkyl, 2-3 membered heteroalkyl, or 4-5 membered heteroalkyl), cycloalkyl (e.g., C3-C 10 cycloalkyl, C3-C8 cycloalkyl, C3-C6 cycloalkyl, C4-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl (e.g., 3-10 membered heterocycloalkyl, 3-8 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, 4-6 membered heterocycloalkyl, 4-5 membered heterocycloalkyl, or 5-6 membered heterocycloalkyl), aryl (e.g., C6-C 12 Aryl, C6-C 10 aryl, or phenyl), or heteroaryl (e.g., 5-12 membered heteroaryl, 5-10 membered heteroaryl, 5-9 membered heteroaryl, or 5-6 membered heteroaryl), substituted with at least one substituent selected from the following: alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl: (i) Oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO 2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2 Cl, -OCH2Br, -OCHI, -OCH2F, -N3, unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl), and (ii) alkyl (e.g., C1-C 20 Alkyl, C1-C 12 alkyl, C1-C8 alkyl, C1-C6 alkyl, C1-C4 alkyl, or C1-C2 alkyl), heteroalkyl (e.g., 2-20 membered heteroalkyl, 2-12 membered heteroalkyl, 2-8 membered heteroalkyl, 2-6 membered heteroalkyl, 4-6 membered heteroalkyl, 2-3 membered heteroalkyl, or 4-5 membered heteroalkyl), cycloalkyl (e.g., C3-C 10cycloalkyl, C3-C8 cycloalkyl, C3-C6 cycloalkyl, C4-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl (e.g., 3-10 membered heterocycloalkyl, 3-8 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, 4-6 membered heterocycloalkyl, 4-5 membered heterocycloalkyl, or 5-6 membered heterocycloalkyl), aryl (e.g., C6-C 12 Aryl, C6-C 10 aryl, or phenyl), or heteroaryl (e.g., 5-12 membered heteroaryl, 5-10 membered heteroaryl, 5-9 membered heteroaryl, or 5-6 membered heteroaryl), substituted with at least one substituent selected from the following: alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl: (a) Oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO 2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2 Cl, -OCH2Br, -OCHI, -OCH2F, -N3, unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C 10 Aryl, C 10aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl), and (b) alkyl (e.g., C1-C 20 Alkyl, C1-C 12 alkyl, C1-C8 alkyl, C1-C6 alkyl, C1-C4 alkyl, or C1-C2 alkyl), heteroalkyl (e.g., 2-20 membered heteroalkyl, 2-12 membered heteroalkyl, 2-8 membered heteroalkyl, 2-6 membered heteroalkyl, 4-6 membered heteroalkyl, 2-3 membered heteroalkyl, or 4-5 membered heteroalkyl), cycloalkyl (e.g., C3-C 10 cycloalkyl, C3-C8 cycloalkyl, C3-C6 cycloalkyl, C4-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl (e.g., 3-10 membered heterocycloalkyl, 3-8 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, 4-6 membered heterocycloalkyl, 4-5 membered heterocycloalkyl, or 5-6 membered heterocycloalkyl), aryl (e.g., C6-C 12 Aryl, C6-C 10aryl, or phenyl), or heteroaryl (e.g., 5-12 membered heteroaryl, 5-10 membered heteroaryl, 5-9 membered heteroaryl, or 5-6 membered heteroaryl), including the following: oxo, halogen, —CCl3, —CBr3, —CF3, —CI3, —CHCl2, —CHBr2, —CHF2, —CHI2, —CH2Cl, —CH2Br, —CH2F, —CH2I, —CN, —OH, —NH2, —COOH, —CONH2, —NO2, —SH, —SO3H, —SO4H, —SON2NH2, —NHNH2, —ONH2, —NHC(O)NHNH2, —NHC(O)NH2, —NHSO2H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl3, —OCF3, —OCB r3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0061] As used herein, "size-limited substituent" or "size-limited substituent" means a group selected from all of the substituents described above for "substituent," wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C-C 20each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2- to 20-membered heteroalkyl; each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C8 cycloalkyl; each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3- to 8-membered heterocycloalkyl; and each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C8 10 aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5- to 10-membered heteroaryl.

[0062] As used herein, a "lower substituent" or "lower substituent group" means a group selected from all of the substituents described above for "substituent," wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C8 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2- to 8-membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C7 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3- to 7-membered heterocycloalkyl, and each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C8 10 aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5- to 9-membered heteroaryl.

[0063] In some embodiments, each substituent described in the compounds herein is substituted with at least one substituent. More specifically, in some embodiments, each substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene described in the compounds herein is substituted with at least one substituent. In other embodiments, at least one or all of these groups are substituted with at least one size-limited substituent. In other embodiments, at least one or all of these groups are substituted with at least one lower-rank substituent.

[0064] In other embodiments of the compounds herein, each substituted or unsubstituted alkyl is a substituted or unsubstituted C-C 20 each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2- to 20-membered heteroalkyl; each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C8 cycloalkyl; each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3- to 8-membered heterocycloalkyl; and each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C8 10 aryl, and / or each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5-10 membered heteroaryl. In some embodiments of the compounds herein, each substituted or unsubstituted alkylene is a substituted or unsubstituted C-C 20 each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2- to 20-membered heteroalkylene; each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C3-C8 cycloalkylene; each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3- to 8-membered heterocycloalkylene; and each substituted or unsubstituted arylene is a substituted or unsubstituted C6-C8 10arylene, and / or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5- to 10-membered heteroarylene.

[0065] In some embodiments, each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C8 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2-8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C7 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3-7 membered heterocycloalkyl, and each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C7 10 In some embodiments, each substituted or unsubstituted alkylene is a substituted or unsubstituted C1-C8 alkylene, each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2-8 membered heteroalkylene, each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C3-C7 cycloalkylene, each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3-7 membered heterocycloalkylene, and each substituted or unsubstituted arylene is a substituted or unsubstituted C6-C8 10 and / or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5- to 9-membered heteroarylene. In some embodiments, the compound is a species described in the Examples section, Figures, or Tables below.

[0066] In embodiments, a substituted or unsubstituted moiety (e.g., substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, and / or substituted or unsubstituted heteroarylene) is unsubstituted (e.g., unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted alkylene, unsubstituted heteroalkylene, unsubstituted cycloalkylene, unsubstituted heterocycloalkylene, unsubstituted arylene, and / or unsubstituted heteroarylene, respectively). In embodiments, a substituted or unsubstituted moiety (e.g., substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, and / or substituted or unsubstituted heteroarylene) is substituted (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene, respectively).

[0067] In embodiments, a substituted moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene) is substituted with at least one substituent, and when a substituted moiety is substituted with multiple substituents, each substituent can optionally be different. In embodiments, when a substituted moiety is substituted with multiple substituents, each substituent is different.

[0068] In embodiments, a substituted moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene) is substituted with at least one size-limiting substituent, and when a substituted moiety is substituted with multiple size-limiting substituents, each size-limiting substituent can optionally be different. In embodiments, when a substituted moiety is substituted with multiple size-limiting substituents, each size-limiting substituent is different.

[0069] In embodiments, a substituted moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene) is substituted with at least one lower substituent, and when a substituted moiety is substituted with multiple lower substituents, each lower substituent may optionally be different. In embodiments, when a substituted moiety is substituted with multiple lower substituents, each lower substituent is different.

[0070] In embodiments, a substituted moiety (e.g., a substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene) is substituted with at least one substituent, size-limiting substituent, or lower substituent, and when a substituted moiety is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent can optionally be different. In embodiments, when a substituted moiety is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent is different.

[0071] Certain compounds of the present disclosure possess asymmetric carbon atoms (optical or chiral centers) or double bonds and can be defined in terms of absolute stereochemistry as (R)- or (S)-, or for amino acids, as (D)- or (L). Enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisomeric forms, and individual isomers are encompassed within the scope of the present disclosure. The compounds of the present disclosure do not include compounds known in the art to be too unstable to synthesize and / or isolate. The present disclosure is intended to include compounds in racemic and optically pure form. Optically active (R)- and (S)- or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents or resolved using conventional techniques. When the compounds described herein contain olefinic bonds or other centers of geometric asymmetry, unless otherwise specified, it is intended that the compounds include both E and Z geometric isomers.

[0072] As used herein, the term "isomers" refers to compounds that have the same number and kind of atoms, and therefore the same molecular weight, but differ with regard to the structural arrangement or configuration of the atoms.

[0073] The term "tautomer," as used herein, refers to one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another.

[0074] It will be apparent to one of ordinary skill in the art that certain compounds of the present disclosure may exist in tautomeric forms, all such tautomeric forms of the compounds being within the scope of the disclosure.

[0075] Unless otherwise stated, structures depicted herein are also intended to include all stereochemical forms of the structure, i.e., R and S configurations for each asymmetric center. Accordingly, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the disclosure.

[0076] Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms, for example, the replacement of a hydrogen by deuterium or tritium, or 13 C or 14 Compounds having this structure, except for the replacement of a carbon with a C-enriched carbon, are within the scope of this disclosure.

[0077] The compounds of the present disclosure may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may contain unnatural proportions of atomic isotopes, such as tritium ( 3 H), iodine-125( 125 I), or carbon-14 ( 14 C). All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure.

[0078] It should be noted that throughout this application, options, e.g., each amino acid position containing more than one possible amino acid, are described in terms of a Markush group. Specifically, it is intended that each member of a Markush group should be considered individually, thereby encompassing alternative embodiments, and that the Markush group should not be read as a single unit.

[0079] As used herein, the terms "bioconjugate" and "bioconjugate linker" refer to the resulting association between atoms or molecules of a "bioconjugate reactive group" or "bioconjugate reactive moiety." The association can be direct or indirect. For example, as provided herein, a conjugate between a first bioconjugate reactive group (e.g., -NH, -C(O)OH, -N-hydroxysuccinimide, or -maleimide) and a second bioconjugate reactive group (e.g., sulfhydryl, sulfur-containing amino acid, amine, amine side chain containing amino acid, or carboxylate) can be direct, e.g., via a covalent bond or linker (e.g., a first linker of a second linker), or indirect, e.g., via a non-covalent bond (e.g., electrostatic interactions (e.g., ionic bonds, hydrogen bonds, halogen bonds), van der Waals interactions (e.g., dipole-dipole, dipole-induced dipole, London dispersion), ring stacking (pi effect), hydrophobic interactions, etc.). In embodiments, bioconjugates or bioconjugate linkers are formed using bioconjugate chemistry (i.e., the association of two bioconjugate reactive groups), including, but not limited to, nucleophilic substitution (e.g., reaction of amines and alcohols with acyl halides, activated esters), electrophilic substitution (e.g., enamine reaction), and addition to carbon-carbon and carbon-heteroatom multiple bonds (e.g., Michael reaction, Diels-Alder addition). These and other useful reactions are discussed, for example, in March, ADVANCED ORGANIC CHEMISTRY, 3rd Ed., John Wiley & Sons, New York, 1985; Hermanson, BIOCONJUGATE TECHNIQUES, Academic Press, San Diego, 1996; and Feeney et al., MODIFICATION OF PROTEINS; Advances in Chemistry Series, Vol. 198, American Chemical Society, Washington, DC, 1982.In embodiments, a first bioconjugate reactive group (e.g., a maleimide moiety) is covalently linked to a second bioconjugate reactive group (e.g., a sulfhydryl). In embodiments, a first bioconjugate reactive group (e.g., a haloacetyl moiety) is covalently linked to a second bioconjugate reactive group (e.g., a sulfhydryl). In embodiments, a first bioconjugate reactive group (e.g., a pyridyl moiety) is covalently linked to a second bioconjugate reactive group (e.g., a sulfhydryl). In embodiments, a first bioconjugate reactive group (e.g., an -N-hydroxysuccinimide moiety) is covalently linked to a second bioconjugate reactive group (e.g., an amine). In embodiments, a first bioconjugate reactive group (e.g., a maleimide moiety) is covalently linked to a second bioconjugate reactive group (e.g., a sulfhydryl). In embodiments, a first bioconjugate reactive group (eg, a -sulfo-N-hydroxysuccinimide moiety) is covalently attached to a second bioconjugate reactive group (eg, an amine).

[0080] Useful bioconjugate reactive moieties for use in the bioconjugate chemistry herein include, for example: (a) Carboxyl groups and their various derivatives, including, but not limited to, N-hydroxysuccinimide esters, N-hydroxybenztriazole esters, acid halides, acylimidazoles, thioesters, p-nitrophenyl esters, alkyls, alkenyls, alkynyls, and esters; (b) hydroxyl groups that can be converted into esters, ethers, aldehydes, etc.; (c) haloalkyl groups in which the halide is subsequently replaced by a nucleophilic group, such as an amine, a carboxylate anion, a thiol anion, a carbanion, or an alkoxide ion, thereby resulting in the covalent attachment of a new group at the site of the halogen atom; (d) dienophile groups capable of participating in Diels-Alder reactions, such as maleimide or maleimido groups; (e) aldehyde or ketone groups that are capable of subsequent derivatization, for example, via formation of carbonyl derivatives such as imines, hydrazones, semicarbazones, or oximes, or via mechanisms such as Grignard addition or alkyllithium addition; (f) sulfonyl halide groups for subsequent reaction with amines to form, for example, sulfonamides; (g) thiol groups, which can be converted to disulfides, react with acyl halides, conjugated to metals such as gold, or reacted with maleimides; (h) amine or sulfhydryl groups (e.g., those present in cysteine) that can be, for example, acylated, alkylated, or oxidized; (i) alkenes, which can undergo, for example, cycloaddition, acylation, Michael addition, etc.; (j) epoxides, which may react with, for example, amines and hydroxyl compounds; (k) phosphoramidites and other standard functional groups useful in nucleic acid synthesis; (l) metal-silicon oxide bond; (m) metal binding to reactive phosphorus groups (e.g., phosphines), for example, to form phosphodiester bonds; (n) an azide coupled to an alkyne using copper-catalyzed cycloaddition click chemistry; and (o) a biotin conjugate capable of reacting with avidin or streptavidin to form an avidin-biotin complex or a streptavidin-biotin complex;

[0081] Bioconjugate reactive groups can be selected so that they do not contribute to or interfere with the chemical stability of the conjugates described herein. Alternatively, reactive functional groups can be protected from participating in crosslinking reactions by the presence of a protecting group. In embodiments, bioconjugates include molecular entities resulting from the reaction of an unsaturated bond, such as a maleimide, with a sulfhydryl group.

[0082] "Analog" or "analogue" is used according to its plain and ordinary meaning within chemistry and biology to refer to a chemical compound that is structurally similar to another compound (i.e., a so-called "reference" compound) but differs in composition, e.g., the replacement of one atom with an atom of a different element, or the presence of a particular functional group, or the replacement of one functional group with another functional group, or the absolute stereochemistry of one or more chiral centers of the reference compound. Thus, an analog is a compound that is similar or equivalent in function and appearance to the reference compound, but differs in structure or origin.

[0083] As used herein, the terms "a" or "an" mean one or more. Additionally, as used herein, the phrase "substituted with a[n]" means that the specified group can be substituted with one or more of any or all of the specified substituents. For example, when a group such as an alkyl group or heteroaryl group is "unsubstituted C-C 20 When "substituted with alkyl or unsubstituted 2-20 membered heteroalkyl," the group is substituted with one or more unsubstituted C-C 20 It may contain alkyl and / or one or more unsubstituted 2- to 20-membered heteroalkyl.

[0084] Furthermore, when a moiety is substituted with an R substituent, the group may be referred to as "R-substituted." When a moiety is R-substituted, the moiety is substituted with at least one R substituent, and each R substituent is optionally different. When a particular R group occurs in a description of a chemical species (such as formula (I)), Roman alphabet symbols may be used to distinguish between each occurrence of that particular R group. For example, multiple R 13 When substituents are present, each R 13 The substituents are R 13.1 , R 13.2 , R 13.3 , R 13.4 can be distinguished from R 13.1 , R 13.2 , R 13.3 , R 13.4 etc. are R 13 are defined within the definition of and optionally differ from.

[0085] A "detectable agent" or "detectable moiety" is a composition, substance, element, or compound, or portion thereof, that is detectable by appropriate means, such as spectroscopic, photochemical, biochemical, immunochemical, chemical, magnetic resonance imaging, or other physical means. For example, useful detectable agents include: 18 F, 32 P, 33 P, 45 Ti, 47 Sc, 52 Fe, 59 Fe, 62 Cu, 64 Cu, 67 Cu, 67 Ga, 68 Ga, 77 As, 86 Y, 90 Y, 89 Sr, 89 Zr, 94 Tc, 94 Tc, 99m Tc, 99 Mo, 105 Pd, 105 Rh, 111 Ag, 111 In, 123 I, 124 I, 125 I, 131 I, 142 Pr, 143 Pr, 149 Pm, 153 Sm, 154-1581 Gd, 161 Tb, 166 Dy, 166 Ho, 169 Er, 175 Lu, 177 Lu, 186 Re, 188 Re, 189 Re, 194 Ir, 198 Au, 199 Au, 211 At, 211 Pb, 212 Bi, 212 Pb, 213 Bi, 223 Ra,225 Ac, Cr, V, Mn, Fe, Co, Ni, Cu, La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, Lu, 32 P, fluorophores (such as fluorescent dyes), electron-dense reagents, enzymes (e.g., those commonly used in ELISA), biotin, digoxigenin, paramagnetic molecules, paramagnetic nanoparticles, ultrasmall superparamagnetic iron oxide ("USPIO") nanoparticles, USPIO nanoparticle aggregates, superparamagnetic iron oxide ("SPIO") nanoparticles, SPIO nanoparticle aggregates, single-crystal iron oxide nanoparticles, single-crystal iron oxide, nanoparticle contrast agents, liposomes, or other delivery vehicles containing gadolinium chelate ("Gd-chelate") molecules, gadolinium, radioisotopes, radionuclides (e.g., carbon-11, nitrogen-13, oxygen-15, fluorine-18, rubidium-82), fluorodeoxyglucose (e.g., fluorine-18 labeled), any gamma-emitting radionuclide, positron-emitting radionuclide, radiolabeled glucose, radiolabeled water, radiolabeled ammonia, biological colloids , microbubbles (e.g., microbubble shells comprising albumin, galactose, lipids, and / or polymers; microbubble gas cores comprising air, heavy gas(es), perfluorocarbon, nitrogen, octafluoropropane, perflexane lipid microspheres, perflutren, etc.), iodinated contrast agents (e.g., iohexol, iodixanol, ioversol, iopamidol, ioxilan, iopromide, diatrizoate, metrizoate, ioxaglate), barium sulfate, thorium dioxide, gold, gold nanoparticles, gold nanoparticle aggregates, fluorophores, two-photon fluorophores, or haptens and proteins, or other entities that can be made detectable, for example, by incorporating a radioactive label into a peptide or antibody that specifically reacts with a target peptide. The detectable moiety is a monovalent detectable agent or a detectable agent that can form a bond with another composition.

[0086] Radioactive substances (e.g., radioisotopes) that may be used as imaging and / or labeling agents according to embodiments of the present disclosure include: 18 F, 32 P,33 P、 45 Home, 47 Sc、 52 Fe、 59 Fe、 62 Cu、 64 Cu、 67 Cu、 67 Ga、 68 Ga、 77 As、 86 Y、 90 Y、 89 Sr、 89 Zr、 94 Tc、 94 Tc、 99m Tc、 99 I、 105 Pd、 105 Rh、 111 Ag、 111 In、 123 I、 124 I、 125 I、 131 I、 142 Pr、 143 Pr、 149 Pm、 153 Sm、 154-1581 Gd、 161 Tb、 166 Dy、 166 Your, 169 Er、 175 Ridiculous, 177 Ridiculous, 186 Too, 188 Too, 189 Too, 194 They、 198 I、 199 I、 211 And、 211 Pb、 212 Bi、 212 Pb、 213 Bi、 223 Raおよび 225Paramagnetic ions that can be used as additional imaging agents in accordance with embodiments of the present disclosure include, but are not limited to, ions of transition metals and lanthanide metals (e.g., metals with atomic numbers 21-29, 42, 43, 44, or 57-71). These metals include ions of Cr, V, Mn, Fe, Co, Ni, Cu, La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, and Lu.

[0087] The description of the compound of the present disclosure is limited by the principles of chemical bonding known to those skilled in the art.Therefore, when group can be substituted with one or more of several substituents, such substitution is selected to comply with the principles of chemical bonding and to bring about a compound that is not inherently unstable and / or is known to those skilled in the art to be likely to be unstable under ambient conditions, such as aqueous, neutral and some known physiological conditions.For example, heterocycloalkyl or heteroaryl is bonded to the rest of the molecule through ring heteroatom according to the principles of chemical bonding known to those skilled in the art, thereby avoiding inherently unstable compounds.

[0088] Those of skill in the art will understand that when a variable (e.g., a moiety or linker) of a compound or compound genus (e.g., a genus described herein) is described by the name or formula of a stand-alone compound with all valences satisfied, the unsatisfied valences of that variable will be determined by the context in which the variable is used. For example, when a variable of a compound described herein is connected (e.g., bonded) to the remainder of the compound through a single bond, that variable will be understood to represent the monovalent form of the stand-alone compound (i.e., capable of forming a single bond due to unsatisfied valences). (For example, if a variable is named "methane" in one embodiment, but that variable is known to be connected to the remainder of the compound by a single bond, those of skill in the art will understand that that variable is actually the monovalent form of methane, i.e., methyl or -CH3.) Similarly, linker variables (e.g., L as described herein) will be understood to represent the monovalent form of the stand-alone compound (i.e., capable of forming a single bond due to unsatisfied valences).1 , L 2 or L 3 ), one of skill in the art will understand that the variable is a divalent form of the stand-alone compound (e.g., if a variable is assigned to "PEG" or "polyethylene glycol" in one embodiment, but that variable is connected to the remainder of the compound by two separate bonds, one of skill in the art will understand that the variable is a divalent (i.e., capable of forming two bonds via two unsatisfied valences) form of PEG, rather than the stand-alone compound PEG.

[0089] The term "exogenous" refers to a molecule or substance (e.g., a compound, nucleic acid, or protein) that originates from outside a given cell or organism. For example, an "exogenous promoter" as referred to herein is a promoter that does not originate from the plant in which it is expressed. Conversely, the terms "endogenous" or "endogenous promoter" refer to a molecule or substance that is naturally present in or originates from within a given cell or organism.

[0090] A charged moiety refers to a functional group that has abundant electron density (i.e., electronegative) or deficient electron density (i.e., electropositive). Non-limiting examples of charged moieties include carboxylic acids, alcohols, phosphates, aldehydes, and sulfonamides. In embodiments, charged moieties are capable of forming hydrogen bonds.

[0091] As used herein, the terms "bind" and "bound" are used according to their plain and ordinary meaning to refer to an association between atoms or molecules. The association can be direct or indirect. For example, the bound atoms or molecules can be direct, e.g., through a covalent bond or linker (e.g., a first linker or a second linker), or indirect, e.g., through a non-covalent bond (e.g., electrostatic interactions (e.g., ionic bonds, hydrogen bonds, halogen bonds), van der Waals interactions (e.g., dipole-dipole, dipole-induced dipole, London dispersion forces), ring stacking (π effect), hydrophobic interactions, etc.).

[0092] As used herein, the term "capable of binding" refers to a moiety (e.g., a compound described herein) that can measurably bind to a target (e.g., NF-κB, Toll-like receptor). In embodiments where a moiety is capable of binding to a target, the moiety can bind with a Kd of less than about 10 μM, 5 μM, 1 μM, 500 nM, 250 nM, 100 nM, 75 nM, 50 nM, 25 nM, 15 nM, 10 nM, 5 nM, 1 nM, or about 0.1 nM.

[0093] As used herein, the term "salt" refers to an acid or base salt of a compound used in the method of the present invention. Illustrative examples of acceptable salts are salts of mineral acids (such as hydrochloric acid, hydrobromic acid, and phosphoric acid), salts of organic acids (such as acetic acid, propionic acid, glutamic acid, and citric acid), and salts of quaternary ammonium salts (such as methyl iodide and ethyl iodide).

[0094] The term "pharmaceutically acceptable salts" is intended to include salts of active compounds prepared using relatively non-toxic acids or bases, depending on the specific substituents found in the compounds described herein.When a compound of the present disclosure contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired base, either directly or in a suitable inert solvent.Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salts, or similar salts.When a compound of the present disclosure contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired acid, either directly or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphate, dihydrogenphosphate, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, or phosphorous acid, as well as salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, oxalic acid, methanesulfonic acid, etc. Also included are amino acid salts such as arginate salts, and organic acid salts such as glucuronic acid or galacturonic acid (see, for example, Berge et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present disclosure contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

[0095] Therefore, the compounds of the present disclosure may exist as salts with pharmaceutically acceptable acids, etc. The present disclosure includes such salts. Non-limiting examples of such salts include hydrochloride, hydrobromide, sulfate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, propionate, tartrate (e.g., (+)-tartrate, (-)-tartrate, or a mixture thereof, including a racemic mixture), succinate, benzoate, and salts with amino acids, such as glutamic acid, and quaternary ammonium salts (e.g., methyl iodide, ethyl iodide, etc.). These salts may be prepared by methods known to those skilled in the art.

[0096] The neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound may differ from the various salt forms in certain physical properties, such as solubility in polar solvents.

[0097] In addition to salt forms, the present disclosure provides compounds in prodrug form.Prodrugs of the compounds described herein are compounds that easily undergo chemical changes under physiological conditions to produce the compounds of the present disclosure.Prodrugs of the compounds described herein can be converted in vivo after administration.In addition, prodrugs can be converted to the compounds of the present disclosure by chemical or biochemical methods in an ex vivo environment, for example, when contacted with suitable enzymes or chemical reagents.

[0098] Certain compounds of the present disclosure can exist in unsolvated form and solvated form, including hydrated form.In general, solvated form is equivalent to unsolvated form and is included within the scope of the present disclosure.Certain compounds of the present disclosure may exist in multiple crystalline or amorphous forms.In general, all physical forms are equivalent for the use contemplated by the present disclosure and are intended to be within the scope of the present disclosure.

[0099] "Pharmaceutically acceptable excipients" and "pharmaceutically acceptable carriers" refer to substances that aid in the administration and absorption of active agents by a subject and can be included in the compositions of the present disclosure without causing significant adverse toxicological effects to the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline, lactated Ringer's solution, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coating agents, sweeteners, flavoring agents, saline (such as Ringer's solution), alcohol, oils, gelatin, carbohydrates such as lactose, amylose, or starch, fatty acid esters, hydroxymethylcellulose, polyvinylpyrrolidine, and coloring agents. Such preparations can be sterilized and, if desired, mixed with auxiliary substances such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring agents, and / or aromatic substances that do not adversely react with the compounds of the present disclosure. Those of skill in the art will recognize that other pharmaceutical excipients are useful in the present disclosure.

[0100] The term "preparation" is intended to include a formulation of an active compound with an encapsulating material as a carrier to provide a capsule, in which the active ingredient, with or without other carriers, is surrounded by the carrier and thus associated with the carrier. Also included are cachets and lozenges. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.

[0101] As used herein, the term "about" refers to a range of values ​​that includes the specified value, which one of ordinary skill in the art would consider to be reasonably similar to the specified value. In embodiments, about refers to within a standard deviation using measurements generally accepted in the art. In embodiments, about refers to a range that covers + / - 10% of the specified value. In embodiments, about includes the specified value.

[0102] As used herein, a "synergistic amount" refers to the sum of a first amount (e.g., an amount of a caspase-6 inhibitor) and a second amount (e.g., a therapeutic agent) that results in a synergistic effect (i.e., an effect that is greater than additive). Thus, the terms "synergy," "synergism," "synergistic," "combined synergistic amount," and "synergistic therapeutic effect," used interchangeably herein, refer to a measured effect of a caspase-6 inhibitor in combination with a second agent (e.g., an anticancer agent), where the measured effect is greater than the sum of the individual effects of a caspase-6 inhibitor provided herein and the second agent (e.g., an anticancer agent) administered alone as a single agent.

[0103] In embodiments, a synergistic amount is about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.10, 4.11, 4.12, 4.13, 4.14, 4.15, 4.16, 4.17, 4.18, 4.19, 4.20, 4.21, 4.22, 4.23, 4.24, 4.25, 4.26, 4.27, 4.28, 4.29, 5.30, 5.31, 5.32, 5.33, 5.34, 5.35, 5.36, 5.37, 5.38, 5.39, 5.40, 5.41, 5.42, 5.43, 5.44, 5.45, 5.46, 5.47, 5.48, 5.49, 5.50, 5.51, 5.52, 5.53, 5.54, 5.55, 5.56, 5.57, 5.58, 5.59, .3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, It can be 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%.In embodiments, a synergistic amount is an amount of a therapeutic agent that is about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.10, 4.11, 4.12, 4.13, 4.14, 4.15, 4.16, 4.17, 4.18, 4.19, 4.20, 4.21, 4.22, 4.23, 4.24, 4.25, 4.26, 4.27, 4.28, 4.29, 5.30, 5.31, 5.32, 5.33, 5.34, 5.35, 5.36, 5.37, 5.38, 5.39, 5.40, 5.41, 5.42, 5.43, 5.44, 5.45, 5.46, 5.47, 5.48, 5.49, 5.50, 5.51, 5.52, 5.53, 5.54, 5.55, 5.56, 5.57, 5.5 3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, It can be 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%.

[0104] As used herein, the term "EC50" or "half-maximal effective concentration" refers to the concentration of a molecule (e.g., a small molecule, antibody, chimeric antigen receptor, or bispecific antibody) that can induce a response that is halfway between the baseline response and the maximum response after a specified exposure time. In embodiments, the EC50 is the concentration of a molecule (e.g., a small molecule, antibody, chimeric antigen receptor, or bispecific antibody) that produces 50% of the molecule's maximum possible effect.

[0105] As used herein, "IC 50 The term "half-maximal inhibitory concentration" or "half-maximal inhibitory concentration" refers to the concentration of an inhibitory molecule (e.g., a small molecule, antibody, chimeric antigen receptor, or bispecific antibody) required to inhibit a given biological process or biological component by 50%.

[0106] The term "small molecule" is used in accordance with its well-understood meaning to refer to a low molecular weight organic compound that can modulate a biological process. In embodiments, a small molecule is a compound weighing less than 1000 daltons. In embodiments, a small molecule is a compound weighing less than 900 daltons. In embodiments, a small molecule weighs less than 800 daltons. In embodiments, a small molecule weighs less than 700 daltons. In embodiments, a small molecule weighs less than 600 daltons. In embodiments, a small molecule weighs less than 500 daltons. In embodiments, a small molecule weighs less than 450 daltons. In embodiments, a small molecule weighs less than 400 daltons.

[0107] "Contacting" is used according to its plain and ordinary meaning to refer to a process that allows at least two different species (e.g., compounds, including biomolecules or cells) to come into sufficient proximity to react, interact, or physically contact. However, it should be understood that the resulting reaction product may be produced directly from the reaction between the added reagents or from an intermediate derived from one or more of the added reagents that may be produced in the reaction mixture.

[0108] The term "contacting" can include allowing two species to react, interact, or come into physical contact, and the two species can be a compound described herein and a protein or enzyme. In some embodiments, contacting includes allowing a compound described herein to interact with a protein or enzyme involved in a signal transduction pathway.

[0109] As defined herein, the terms "activation," "activate," "activating," "activator," and the like, with respect to protein-inhibitor interactions, refer to positively affecting (e.g., increasing) the activity or function of a protein compared to the activity or function of the protein in the absence of the activator. In embodiments, activation refers to positively affecting (e.g., increasing) the concentration or level of a protein compared to the concentration or level of the protein in the absence of the activator. These terms may refer to activating, activating, sensitizing, or upregulating signal transduction or enzymatic activity or the amount of a protein that is decreased in a disease. Thus, activation may include, at least in part, partially or completely increasing stimulation, increasing signal transduction or enzymatic activity, or the amount of a protein associated with a disease (e.g., a protein that is decreased in a disease compared to an unaffected control), or enabling activation, activating, sensitizing, or upregulating signal transduction or enzymatic activity, or the amount of a protein. Activation may include, at least in part, partially or completely increasing stimulation, increasing signal transduction or enzymatic activity, or the amount of a protein, or enabling activation, activating, sensitizing, or upregulating.

[0110] The terms "agonist," "activator," "up-regulator," and the like refer to a substance capable of detectably increasing the expression or activity of a given gene or protein. An agonist can increase expression or activity by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or more compared to a control in the absence of the agonist. In certain instances, expression or activity is 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, or more higher than expression or activity in the absence of the agonist.

[0111] As defined herein, the terms "inhibition," "inhibit," "inhibiting," and the like, with respect to a protein-inhibitor interaction, refer to adversely affecting (e.g., reducing) the activity or function of a protein compared to the activity or function of the protein in the absence of the inhibitor. In embodiments, inhibition refers to negatively affecting (e.g., decreasing) the concentration or level of a protein compared to the concentration or level of the protein in the absence of the inhibitor. In embodiments, inhibition refers to the reduction of a disease or disease symptom. In embodiments, inhibition refers to the reduction of the activity of a specific protein target. Thus, inhibition includes at least partially, partially, or completely blocking a stimulus, reducing, preventing, or delaying activation, or inactivating, desensitizing, or downregulating signaling or enzymatic activity or the amount of a protein. In embodiments, inhibition refers to a reduction in the activity of a target protein due to a direct interaction (e.g., an inhibitor binds to the target protein). In embodiments, inhibition refers to a reduction in the activity of a target protein due to an indirect interaction (e.g., an inhibitor binds to a protein that activates the target protein, thereby preventing activation of the target protein).

[0112] "Caspase 6 inhibitor" refers to a compound (e.g., a compound described herein) that reduces the activity of caspase 6 compared to a control, such as no compound or a compound with a known inactivity.

[0113] The terms "inhibitor," "suppressor," or "antagonist," or "down-regulator" refer interchangeably to a substance that can detectably reduce the expression or activity of a given gene or protein. Antagonists can reduce expression or activity by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or more compared to a control in the absence of the antagonist. In certain instances, expression or activity is 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, or more lower than the expression or activity in the absence of the antagonist.

[0114] The term "caspase 6" or "caspase-6" refers to proteins (including homologs, isoforms, and functional fragments thereof) that are members of the cysteine-aspartic acid protease (caspase) family. Caspase 6 cleaves substrates (e.g., HTT in Huntington's disease, APP in Alzheimer's disease, and tau in Alzheimer's disease) and can cause protein aggregation of the fragments. In embodiments, caspase 6 cleaves substrates that lead to inflammation (e.g., neuroinflammation) and cell death. In embodiments, cell death leads to cirrhosis and fibrosis (e.g., in the liver or other organs). In one embodiment, caspase 6 is involved in axonal degeneration. The term includes any recombinant or naturally occurring form of caspase 6 variant that maintains caspase 6 activity (e.g., within at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% activity compared to wild-type caspase 6). In embodiments, caspase 6 is encoded by the CASP6 gene. In embodiments, caspase 6 has an amino acid sequence described in or corresponding to Entrez 839, UniProt P55212, RefSeq(protein)NP_001217.2, or RefSeq(protein)NP_116787.1. In embodiments, caspase 6 has the following sequence: MSSASGLRRGHPAGGEENMTETDAFYKREMFDPAEKYKMDHRRRGIALIFNHERFFWHLT LPERRGTCADRDNLTRRFSDLGFEVKCFNDLKAEELLLKIHEVSTVSHADADCFVCVFLS HGEGNHIYAYDAKIEIQTLTGLFKGDKCHSLVGKPKIFIIQACRGNQHDVPVIPLDVVDN QTEKLDTNITEVDAASVYTLPAGADFLMCYSVAEGYYSHRETVNGSWYIQDLCEMLGKYG SSLEFTELLTLVNRKVSQRRVDFCKDPSAIGKKQVPCFASMLTKKLHFFPKSN (SEQ ID NO: 1)

[0115] The term "caspase 3" or "caspase-3" refers to a protein (including homologs, isoforms, and functional fragments thereof) that is a member of the cysteine-aspartic acid protease (caspase) family and cleaves substrates following aspartic acid residues. The term includes any recombinant or naturally occurring form of that caspase 3 variant that maintains caspase 3 activity (e.g., within at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% activity compared to wild-type caspase 3). In embodiments, caspase 3 is encoded by the CASP3 gene. In embodiments, caspase 3 has an amino acid sequence set forth in or corresponding to Entrez 836, UniProt P42574, RefSeq(protein)NP_004337.2, RefSeq(protein)NP_116786.1, RefSeq(protein)NP_001341706, RefSeq(protein)NP_001341707, RefSeq(protein)NP_001341708, or XP_011530603.1. In embodiments, caspase 3 has the following sequence: MENTENSVDSKSIKNLEPKIIHGSESMDSGISLDNSYKMDYPEMGLCIIINNKNFHKSTG MTSRSGTDVDAANLRETFRNLKYEVRNKNDLTREEIVELMRDVSKEDHSKRSSFVCVLLS HGEEGIIFGTNGPVDLKKITNFFRGDRCRSLTGKPKLFIIQACRGTELDCGIETDSGVDD DMACHKIPVEADFLYAYSTAPGYYSWRNSKDGSWFIQSLCAMLKQYADKLEFMHILTRVN RKVATEFESFSFDATFHAKKQIPCIVSMLTKELYFYH (SEQ ID NO: 2)

[0116] The term "caspase 2" or "caspase-2" refers to a protein (including homologs, isoforms, and functional fragments thereof) that is a member of the cysteine-aspartic acid protease (caspase) family and cleaves substrates following aspartic acid residues. The term includes any recombinant or naturally occurring form of that caspase 2 variant that maintains caspase 2 activity (e.g., within at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% activity compared to wild-type caspase 2). In embodiments, caspase 2 is encoded by the CASP2 gene. In embodiments, caspase-2 has an amino acid sequence set forth in or corresponding to Entrez 835, UniProt P42575, RefSeq(protein)NP_001215.1, RefSeq(protein)NP_116764.2, or RefSeq(protein)NP_116765.2. In embodiments, caspase-2 has the following sequence: MAAPSAGSWSTFQHKELMAADRGRRILGVCGMHPHHQETLKKNRVVLAKQLLLSELLEHL LEKDIITLEMRELIQAKVGSFSQNVELLNLLPKRGPQAFDAFCEALRETKQGHLEDMLLT TLSGLQHVLPPLSCDYDLSLPFPVCESCPLYKKLRLSTDTVEHSLDNKDGPVCLQVKPCT PEFYQTHFQLAYRLQSRPRGLALVLSNVHFTGEKELEFRSGGDVDHSTLVTLFKLLGYDV HVLCDQTAQEMQEKLQNFAQLPAHRVTDSCIVALLSHGVEGAIYGVDGKLLQLQEVFQLF DNANCPSLQNKPKMFFIQACRGDETDRGVDQQDGKNHAGSPGCEESDAGKEKLPKMRLPT RSDMICGYACLKGTAAMRNTKRGSWYIEALAQVFSERACDMHVADMLVKVNALIKDREGY APGTEFHRCKEMSEYCSTLCRHLYLFPGHPPT (SEQ ID NO: 3)

[0117] The term "expression" includes any step involved in polypeptide production, including, but not limited to, transcription, post-transcriptional modification, translation, post-translational modification, and secretion. Expression can be detected using conventional techniques for detecting proteins (e.g., ELISA, Western blotting, flow cytometry, immunofluorescence, immunohistochemistry, etc.).

[0118] The term "modulator" refers to a composition that increases or decreases the level of a target molecule, or the function of a target molecule, or the physical state of a molecular target compared to the absence of the modulator. In some embodiments, a caspase-6-associated disease modulator is a compound that reduces the severity of one or more symptoms of a caspase-6-associated disease (e.g., a neurodegenerative disease, a liver disease, or cancer). A caspase-6 modulator is a compound that increases or decreases the activity or function or level of activity or function of caspase-6.

[0119] The term "modulate" is used according to its plain and ordinary meaning and refers to the act of changing or varying one or more properties. "Modulation" refers to the process of changing or varying one or more properties. For example, as applied to the effect of a modulator on a target protein, modulating means changing the property or function of the target molecule or the amount of the target molecule by increasing or decreasing it.

[0120] In the context of a substance or the activity or function of a substance associated with a disease (e.g., a protein-related disease, a cancer associated with caspase 6 activity, a caspase 6-related cancer, a caspase 6-related disease (e.g., a neurodegenerative disease, a liver disease, a cancer, an inflammatory disease, an autoimmune disease, or an infectious disease)), the term "associated" or "associated with" means that the disease (e.g., a neurodegenerative disease, a liver disease, a cancer, an inflammatory disease, an autoimmune disease, or an infectious disease) is caused (in whole or in part) or a symptom of the disease is caused (in whole or in part) by the substance or the activity or function of the substance. For example, a cancer associated with caspase 6 activity or function can be a cancer that results (in whole or in part) from aberrant caspase 6 function (e.g., enzymatic activity, protein-protein interaction, signaling pathway), or a cancer in which a particular symptom of the disease is caused (in whole or in part) by aberrant caspase 6 activity or function. As used herein, something described as associated with a disease, if it is a causative agent, can be a target for disease treatment. For example, cancers associated with caspase 6 activity or function, or caspase 6-associated diseases (e.g., neurodegenerative diseases, liver diseases, cancer, inflammatory diseases, autoimmune diseases, or infectious diseases) can be treated with caspase 6 modulators or caspase 6 inhibitors when increased caspase 6 activity or function (e.g., signal transduction pathway activity) causes the disease (e.g., neurodegenerative diseases, liver diseases, cancer, inflammatory diseases, autoimmune diseases, or infectious diseases).

[0121] As used herein, the term "abnormal" refers to something that is different from normal. When used to describe enzyme activity or protein function, abnormal refers to an activity or function that is higher or lower than the average of a normal control or normal, non-disease control sample. Abnormal activity can refer to the amount of activity that causes disease, and restoring the abnormal activity to a normal or non-disease-related amount (e.g., by administering a compound or using the methods described herein) results in a reduction of the disease or one or more symptoms.

[0122] As used herein, the term "signal transduction pathway" refers to a series of interactions between cellular and optional extracellular components (e.g., proteins, nucleic acids, small molecules, ions, lipids) that transmit a change in one component to one or more other components, which in turn transmit the change to additional components, which are optionally propagated to other signal transduction pathway components. For example, binding of caspase 6 with a compound described herein may reduce the level of a product of a caspase 6-catalyzed reaction, or the level or binding of a downstream derivative of the product may reduce the interaction between the caspase 6 enzyme or caspase 6 reaction product and a downstream effector or signal transduction pathway component (e.g., the epigenetic regulatory protein MLL and the transcription factor (TF) IIA family of nuclear proteins), resulting in a change in cell growth, proliferation, or survival.

[0123] In this disclosure, "comprises," "comprising," "containing," "having," and the like can have the meaning ascribed to them in U.S. patent law and can mean "includes," "including," etc. "Consisting essentially of" or "consists essentially" likewise have the meaning ascribed to them in U.S. patent law, and the term is open-ended and allows for the presence of more than what is recited, but does not include prior art embodiments, so long as the basic or novel characteristics of what is recited are not changed by the presence of more than what is recited.

[0124] The term "disease" or "condition" refers to an existence or state of health of a patient or subject that can be treated with the compounds or methods provided herein. The disease can be a neurodegenerative disease. The disease can be a liver disease. The disease can be cancer. The disease can be an autoimmune disease. The disease can be an inflammatory disease. The disease can be an infectious disease. In some further examples, "cancer" refers to human cancers and carcinomas, sarcomas, adenocarcinomas, lymphomas, leukemias, etc., including solid and lymphatic cancers, kidney cancer, breast cancer, lung cancer, bladder cancer, colon cancer, ovarian cancer, prostate cancer, pancreatic cancer, stomach cancer, brain cancer, head and neck cancer, skin cancer, uterine cancer, testicular cancer, glioma, esophageal cancer, and liver cancer, including hepatocellular carcinoma, lymphoma, including B acute lymphoblastic lymphoma, non-Hodgkin's lymphoma (e.g., Burkitt's, small cell, and large cell lymphoma), Hodgkin's lymphoma, leukemia (including AML, ALL, and CML), or multiple myeloma.

[0125] As used herein, the term "inflammatory disease" refers to a disease or condition characterized by abnormal inflammation (e.g., increased levels of inflammation compared to a control, such as a healthy individual without the disease). Examples of inflammatory diseases include autoimmune diseases, arthritis, rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, multiple sclerosis, systemic lupus erythematosus (SLE), myasthenia gravis, juvenile-onset diabetes, type 1 diabetes mellitus, Guillain-Barré syndrome, Hashimoto's encephalopathy, Hashimoto's thyroiditis, ankylosing spondylitis, psoriasis, Sjogren's syndrome, vasculitis, glomerulonephritis, autoimmune thyroiditis, Behcet's disease, Crohn's disease, These include ulcerative colitis, bullous pemphigoid, sarcoidosis, ichthyosis, Graves' ophthalmopathy, inflammatory bowel disease, Addison's disease, vitiligo, asthma, allergic asthma, acne vulgaris, celiac disease, chronic prostatitis, inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, ischemia-reperfusion injury, stroke, sarcoidosis, transplant rejection, interstitial cystitis, atherosclerosis, scleroderma, and atopic dermatitis.

[0126] As used herein, the term "cancer" refers to all types of cancer, neoplasm, or malignant tumor found in mammals (e.g., humans), including leukemia, lymphoma, carcinoma, and sarcoma. Exemplary cancers that can be treated using the compounds or methods provided herein include brain cancer, glioma, glioblastoma, neuroblastoma, prostate cancer, colorectal cancer, pancreatic cancer, medulloblastoma, melanoma, cervical cancer, gastric cancer, ovarian cancer, lung cancer, head cancer, Hodgkin's disease, and non-Hodgkin's lymphoma. Exemplary cancers that can be treated using the compounds or methods provided herein include thyroid cancer, endocrine system cancer, brain cancer, breast cancer, cervical cancer, colon cancer, head and neck cancer, liver cancer, kidney cancer, lung cancer, ovarian cancer, pancreatic cancer, rectal cancer, gastric cancer, and uterine cancer. Further examples include thyroid cancer, bile duct cancer, pancreatic adenocarcinoma, cutaneous melanoma of the skin, colon adenocarcinoma, rectal adenocarcinoma, gastric adenocarcinoma, esophageal cancer, squamous cell carcinoma of the head and neck, invasive carcinoma of the breast, lung adenocarcinoma, squamous cell carcinoma of the lung, non-small cell lung cancer, mesothelioma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, primary thrombocythemia, primary macroglobulinemia, primary brain tumors, malignant pancreatic insulinoma, malignant carcinoid, bladder cancer, premalignant skin lesions, testicular cancer, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary cancer, malignant hypercalcemia, endometrial cancer, adrenocortical carcinoma, endocrine or exocrine pancreatic neoplasms, medullary thyroid cancer, and medullary thyroid cancer. carcinoma), melanoma, colorectal cancer, papillary thyroid cancer, hepatocellular carcinoma, or prostate cancer.

[0127] As used herein, the term "autoimmune disease" refers to a disease or condition in which a subject's immune system mounts an abnormal immune response to a substance that does not normally elicit an immune response in a healthy individual. Examples of autoimmune diseases that can be treated with the compounds, pharmaceutical compositions, or methods described herein include acute disseminated encephalomyelitis (ADEM), acute necrotizing hemorrhagic leukoencephalitis, Addison's disease, agammaglobulinemia, skin rash, amyloidosis, ankylosinating spondylomyelitis, anti-GBM / anti-TBM nephritis, antiphospholipid syndrome (APS), autoimmune angioedema, autoimmune aplastic anemia, autoimmune dysautonomia, autoimmune hepatitis, autoimmune hyperlipidemia, autoimmune immunodeficiency, autoimmune inner ear disease (AIED), autoimmune encephalopathy, and autoimmune vasculopathy. Infectious myocarditis, autoimmune oophoritis, autoimmune pancreatitis, autoimmune retinitis, autoimmune pancreatic hormonopathy thrombocytopenic purpura (ATP), autoimmune thyroid disease, autoimmune urticaria, axonal or neuronal neuropathy, Barot's disease, Behcet's disease, bullous pephigoid, cardiomyopathy, Castleman's disease, celiac disease, Chagas' disease, chronic fatigue syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic relapsing granulomatosis with polyangiitis (CRMO), Churg-Strauss syndrome, cicatricial scaly / benign mucous membrane amygdala, Crohn's disease, Cogan's syndrome, cold agglutinin disease, congenital heart block, Coxsackie myocarditis, CREST disease, essential mixed cryoglobulinemia, demyelinating neuropathy, dermatitis herpetiformis, dermatomyositis, Devic's disease (neuromyelitis optica), discoid lupus erythematosus, Dressler's syndrome, endometriosis, eosinophilic esophagitis, eosinophilic fasciitis, conjunctivitis, experimental allergic encephalomyelitis, Evans syndrome, fibromyalgia, fibrosing alveolitis, giant cell arteritis (temporal arteritis), giant cell myocarditis, glomerulonephritis, Goodpasture's syndrome, polyangiitis Graves' disease, Guillain-Barr syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, hemolytic anemia, Henoch-Schoenfeld disease, hemolytic anemia, hypogammaglobulinemia, idiopathic thrombocytopenic purpura (ITP), IgA nephropathy, IgG4-related sclerosing disease, immunomodulatory lipoproteins, inclusion body myositis, interstitial cystitis, juvenile arthritis, juvenile diabetes mellitus (type 1 diabetes), juvenile myositis, Kawasaki syndrome, Lambert-Eaton vasculitis, leukemic lichen planus, lichen sclerosus, lymphocytic conjunctivitis,Linear immunoglobulin A disease (LAD), lupus (SLE), Lyme disease, chronic, Meniere's disease, microscopic polyangiitis, mixed connective tissue disease (MCTD), Mooren's ulcer, Mucha-Habermann disease, multiple sclerosis, severe myositis, myositis, narcolepsy, neuromyelitis optica (Devic's), neutropenia, ocular cicatricial uveitis, ocular neuritis, relapsing rheumatoid arthritis, PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection), paraneoplastic Cerebellar degeneration, paroxysmal nocturnal hemoglobinuria (PNH), Parry-Romberg syndrome, Parsonage-Turner syndrome, Persplanitis (peripheral uveitis), Pemphigus, peripheral neuropathy, pericardium encephalomyelitis, pernicious anemia, POEMS syndrome, polyarteritis nodosa, autoimmune polyglandular syndrome type I, II, III, polymyalgia rheumatica, polymyositis, post-myocardial infarction syndrome, post-pericardiotomy syndrome, progesterone Psoriatic dermatitis, primary angina, psoriatic arthritis, primary sclerosing cholangitis, psoriasis, psoriatic arthritis, idiopathic pulmonary fibrosis, ganglionic pyoderma, pure red cell aplasia, Raynaud's phenomenon, reactive arthritis, reflex sympathetic dystrophy, Reiter's syndrome, relapsing polychondritis, restless leg syndrome, retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, sarcoid arthritis, Schmidt's syndrome, scleritis, scleroderma, Sjögren's syndrome, sperm and testes These include autoimmune, stiff-neck syndrome, subacute bacterial endocarditis (SBE), Sazac syndrome, sympathetic ophthalmia, Takayasu's arteritis, temporal arteritis-giant cell arteritis, thrombocytopenic purpura (TTP), Tolosa-Hunt syndrome, transverse myelitis, type 1 diabetes, ulcerative colitis, undifferentiated connective tissue disease (UCTD), uveitis, vasculitis, bullous dermatoses, vitiligo, or Wegener's granulomatosis (i.e., granulomatosis with polyangiitis (GPA)).

[0128] As used herein, the term "inflammatory disease" refers to a disease or condition characterized by abnormal inflammation (e.g., increased levels of inflammation compared to a control, such as a healthy individual not afflicted with the disease). Examples of inflammatory diseases include traumatic brain injury, arthritis, rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, multiple sclerosis, systemic lupus erythematosus (SLE), myasthenia gravis, juvenile-onset diabetes, type 1 diabetes mellitus, Guillain-Barré syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, ankylosing spondylitis, psoriasis, Sjögren's syndrome, vasculitis, glomerulonephritis, autoimmune thyroiditis, Behçet's disease, Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, ichthyosis, Graves' ophthalmopathy, inflammatory bowel disease, Addison's disease, vitiligo, asthma, allergic asthma, acne vulgaris, celiac disease, chronic prostatitis, inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, sarcoidosis, transplant rejection, interstitial cystitis, atherosclerosis, and atopic dermatitis.

[0129] As used herein, the term "neurodegenerative disorder" or "neurodegenerative disease" refers to a disease or condition in which the function of a subject's nervous system is impaired. Examples of neurodegenerative diseases that may be treated by the compounds, pharmaceutical compositions, or methods described herein include Alexander disease, Alper's disease, Alzheimer's disease, amyotrophic lateral sclerosis, ataxia-telangiectasia, Batten disease (also known as Spielmeyer-Voigt-Sjogren-Batten disease), bovine spongiform encephalopathy (BSE), Canavan disease, chronic fatigue syndrome, Cockayne syndrome, corticobasal degeneration, Creutzfeldt-Jakob disease, frontotemporal dementia, Gerstmann-Sträussler-Scheinker syndrome, Huntington's disease, HIV-associated dementia, Kennedy disease, Krauss disease, and others. These include: Behr's disease, kuru, Lewy body disease, dementia with Lewy bodies, Machado-Joseph disease (Spinocerebellar ataxia type 3), multiple sclerosis, multiple system atrophy, myalgic encephalomyelitis, narcolepsy, neuroborreliosis, Parkinson's disease, Pelizaeus-Merzbach disease, Pick's disease, primary lateral sclerosis, prion diseases, progressive supranuclear palsy, Refsum disease, Sandhoff disease, Schilder's disease, subacute combined spinal degeneration secondary to pernicious anemia, schizophrenia, spinocerebellar ataxia (various types with varying features), spinal muscular atrophy, Steele-Richardson-Olszewski disease, progressive supranuclear palsy, or tabes dorsalis.

[0130] The term "treating" or "treatment" refers to an indication of success in treating or ameliorating an injury, disease, condition, or state, and includes any objective or subjective parameter, such as remission, remission, alleviating symptoms, or making the injury, disease, or state more tolerable to the patient, slowing the rate of degeneration or decline; making the end point of degeneration less debilitating; or improving the patient's physical or mental health. The treatment or amelioration of symptoms can be based on objective or subjective parameters, including the results of a physical examination, neuropsychiatric testing, and / or psychiatric evaluation. The term "treating" and its conjugations can include prevention of an injury, disease, condition, or disease. In embodiments, treating is preventing. In embodiments, treating does not include preventing.

[0131] As used herein (and as is well understood in the art), "treating" or "treatment" broadly encompasses any approach to achieving beneficial or desired results in a subject's condition, including clinical outcomes. Beneficial or desired clinical outcomes may include, but are not limited to, alleviating or ameliorating one or more symptoms or conditions, whether partial or complete, and whether detectable or undetectable, reducing the extent of the disease, stabilizing (i.e., not worsening) the condition, preventing the spread or transmission of the disease, delaying or slowing disease progression, improving or alleviating the condition, reducing disease recurrence, and remission. In other words, "treatment" as used herein includes any cure, amelioration, or prevention of a disease. Treatment may prevent the disease from developing, inhibit the spread of the disease, relieve symptoms of the disease (e.g., eye pain, seeing halos around lights, bloodshot eyes, high intraocular pressure), completely or partially eliminate the underlying cause of the disease, shorten the duration of the disease, or a combination thereof.

[0132] As used herein, "treating" and "treatment" include prophylactic treatment. A therapeutic method involves administering a therapeutically effective amount of an active agent to a subject. The administration step can consist of a single administration or can include a series of administrations. The length of the treatment period depends on various factors, such as the severity of the condition, the age of the patient, the concentration of the active agent, the activity of the composition used for treatment, or a combination thereof. It will also be understood that the effective dosage of an agent used for treatment or prevention can increase or decrease during a particular treatment or prevention regimen. Dosage changes can be determined and made evident by standard diagnostic assays known in the art. In some cases, chronic administration may be required. For example, a composition is administered to a subject in an amount and for a duration sufficient to treat the patient. In embodiments, the treating or treatment is not prophylactic (e.g., the patient has a disease or is suffering from a disease).

[0133] The term "preventing" refers to a reduction in the occurrence of caspase 6 disease symptoms in a patient. As noted above, prevention can be complete (no detectable symptoms) or partial, such that fewer symptoms are observed than would likely develop without treatment.

[0134] "Patient" or "subject in need of treatment" refers to an organism suffering from or susceptible to a disease or condition that can be treated by administration of a pharmaceutical composition as provided herein. Non-limiting examples include humans, other mammals, cows, rats, mice, dogs, monkeys, goats, sheep, cattle, deer, and other non-mammals. In some embodiments, the patient is a human.

[0135] An "effective amount" is an amount of a compound sufficient to achieve a specified purpose (e.g., achieve the effect of being administered, treat a disease, reduce enzyme activity, increase enzyme activity, reduce a signal transduction pathway, or reduce one or more symptoms of a disease or condition) compared to the absence of the compound. An example of an "effective amount" is an amount sufficient to contribute to the treatment, prevention, or reduction of a symptom(s) of a disease, which may also be referred to as a "therapeutically effective amount." "Reduction" of a symptom(s) (and grammatical equivalents of this phrase) refers to a decrease in the severity or frequency of the symptom(s), or the elimination of the symptom(s). A "prophylactically effective amount" of a drug is an amount of a drug that, when administered to a subject, will have the intended preventative effect, for example, an amount of a drug that prevents or delays the onset (or recurrence) of an injury, disease, pathology, or condition, or reduces the likelihood of the onset (or recurrence) of an injury, disease, pathology, or condition, or a symptom thereof. A complete preventative effect does not necessarily occur by administration of a single dose, but may occur only after administration of a series of doses. Therefore, a prophylactically effective amount can be administered in one or more doses. As used herein, "activity-reducing amount" refers to the amount of antagonist required to reduce the activity of an enzyme compared to the absence of the antagonist. As used herein, "function-disrupting amount" refers to the amount of antagonist required to disrupt the function of an enzyme or protein compared to the absence of the antagonist. The exact amount depends on the purpose of treatment and can be determined by those skilled in the art using known techniques (see, for example, Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).

[0136] For any compound described herein, the therapeutically effective amount can be initially determined from cell culture assays. The target concentration will be the concentration of active compound that is capable of achieving the methods described herein, as measured using the methods described herein or known in the art.

[0137] As is well known in the art, the therapeutically effective amount used in humans can also be determined from animal models.For example, human dosage can be formulated to achieve the concentration found to be effective in animals.As described above, human dosage can be adjusted by monitoring the effectiveness of compound and adjusting dosage upward or downward.Based on the above method and other methods, it is well within the ability of those skilled in the art to adjust dosage to achieve maximum effectiveness in humans.

[0138] The term "therapeutically effective amount" as used herein refers to an amount of a therapeutic agent sufficient to improve a disorder, as described above. For example, for a given parameter, a therapeutically effective amount would exhibit an increase or decrease of at least 5%, 10%, 15%, 20%, 25%, 40%, 50%, 60%, 75%, 80%, 90%, or at least 100%. Therapeutic effectiveness can also be expressed as a "-fold" increase or decrease. For example, a therapeutically effective amount can be at least 1.2-fold, 1.5-fold, 2-fold, 5-fold, or more effective than a control.

[0139] Dosage may vary depending on the patient's requirements and the compound used. In light of the present disclosure, the dose administered to a patient should be sufficient to produce a beneficial therapeutic response in the patient over time. The size of the dose will also be determined by the existence, nature, and extent of any adverse side effects. Determining the appropriate dosage for a particular situation is within the capabilities of those skilled in the art. Generally, treatment is initiated with a lower dosage that is less than the optimal dose of the compound. Thereafter, the dosage is gradually increased until the optimal effect is reached under the circumstances. Dosage amount and interval can be individually adjusted to provide a level of the administered compound that is effective for the specific clinical indication being treated. This will provide a treatment plan that is appropriate for the severity of the individual's condition.

[0140] As used herein, the term "administering" refers to oral administration, administration as a suppository, topical contact, intravenous, parenteral, intraperitoneal, intramuscular, intralesional, intrathecal, intranasal, or subcutaneous administration, or implantation of a sustained-release device, e.g., a mini-osmotic pump, to a subject. Administration is by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal). Parenteral administration includes, for example, intravenous, intramuscular, intraarteriolar, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial administration. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, and the like. In embodiments, administration does not include administration of any active agent other than the listed active agent.

[0141] "Co-administered" means that the compositions described herein are administered simultaneously with, immediately before, or immediately after the administration of one or more additional therapeutic agents. The compounds provided herein can be administered alone or simultaneously to a patient. Co-administration is intended to include simultaneous or sequential administration of compounds, individually or in combination (two or more compounds). Thus, the preparation can also be combined with other active substances, if desired (e.g., to reduce metabolic degradation). The compositions of the present disclosure can be delivered transdermally by topical routes or formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols.

[0142] As used herein, "cell" refers to a cell that performs metabolic or other functions sufficient to preserve or replicate its genomic DNA. Cells can be identified by methods well known in the art, including, for example, the presence of an intact membrane, staining with a particular dye, the ability to produce progeny, or, in the case of gametes, the ability to combine with a second gamete to produce viable progeny. Cells can include prokaryotic and eukaryotic cells. Prokaryotic cells include, but are not limited to, bacteria. Eukaryotic cells include, but are not limited to, yeast cells and cells derived from plants and animals, such as mammalian cells, insect cells (e.g., Spodoptera), and human cells. Cells can be useful if they are naturally non-adherent or have been treated to prevent them from adhering to surfaces, for example, by trypsinization.

[0143] "Control" or "control experiment" is used according to its plain and ordinary meaning to refer to an experiment in which the experimental subject or reagent is treated the same as in a parallel experiment except for the omission of an experimental procedure, reagent, or variable. In some cases, a control is used as a standard of comparison in evaluating experimental efficacy. In some embodiments, a control is a measurement of protein activity in the absence of a compound described herein (including embodiments and examples).

[0144] The term "irreversible covalent bond" is used according to its plain and ordinary meaning in the art to refer to an association obtained between atoms or molecules that have a low probability of dissociation (e.g., an electrophilic chemical moiety and a nucleophilic moiety). In embodiments, an irreversible covalent bond does not readily dissociate under normal biological conditions. In embodiments, an irreversible covalent bond is formed through a chemical reaction between two species (e.g., an electrophilic chemical moiety and a nucleophilic moiety).

[0145] The term "electrophilic chemical moiety" is used according to its plain and ordinary chemical meaning to refer to a chemical group (e.g., a monovalent chemical group) that is electrophilic. In embodiments, the electrophilic chemical moiety is referred to herein as a "warhead" or "E." In embodiments, E is: [ka] where R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , and R 20 is as described herein, including the embodiments. 17 is -F, Cl, -Br, or -I. In embodiments, the electrophilic moiety is a covalent cysteine ​​modifier moiety.

[0146] As used herein, the term "covalent cysteine ​​modifier moiety" refers to a monovalent electrophilic moiety capable of measurably binding to a cysteine ​​amino acid. In embodiments, the covalent cysteine ​​modifier moiety is attached via an irreversible covalent bond. In embodiments, the covalent cysteine ​​modifier moiety is capable of binding with a Kd of less than about 10 μM, 5 μM, 1 μM, 500 nM, 250 nM, 100 nM, 75 nM, 50 nM, 25 nM, 15 nM, 10 nM, 5 nM, 1 nM, or about 0.1 nM. In embodiments, the covalent cysteine ​​modifier moiety is attached via a covalent bond.

[0147] The term "nucleophilic chemical moiety" is used according to its plain and ordinary meaning to refer to a chemical group (eg, a monovalent chemical group) that is nucleophilic.

[0148] An amino acid residue in a protein "corresponds" to a given residue if it occupies the same essential structural position within the protein as the given residue. Instead of primary sequence alignment, three-dimensional structural alignment can also be used; for example, the structure of a selected protein is aligned for maximum correspondence with a human protein, and the overall structure is compared. In this case, an amino acid that occupies the same essential position in the structural model as a particular amino acid is said to correspond to the particular residue. For example, a selected residue in a selected protein corresponds to C264 in a caspase 6 protein (e.g., human caspase 6 protein) if the selected residue occupies the same essential spatial or other structural relationship as C264 in the caspase 6 protein (e.g., human caspase 6 protein). In some embodiments, when the selected protein is aligned for maximum homology with the caspase 6 protein (e.g., human caspase 6 protein), the position in the aligned selected protein that aligns with C264 is said to correspond to C264 in the caspase 6 protein (e.g., human caspase 6 protein). Instead of primary sequence alignment, three-dimensional structural alignment can also be used. For example, the structure of a selected protein is aligned for maximum correspondence with a human caspase 6 protein (e.g., human caspase 6 protein or SEQ ID NO: 1), and the overall structures are compared. In this case, an amino acid occupying the same essential position in the structural model as C264 of a caspase 6 protein (e.g., human caspase 6 protein) is said to correspond to the C264 residue. In another example, if a selected residue (e.g., a cysteine ​​residue) occupies essentially the same sequence, spatial, or other structural position within the same protein as C264 of a caspase 6 protein (e.g., human caspase 6 protein), the selected residue of the selected protein corresponds to C264 of a caspase 6 protein (e.g., human caspase 6 protein).

[0149] The term "amino acid" refers to naturally occurring and synthetic amino acids, as well as amino acid analogs and amino acid mimetics that function similarly to naturally occurring amino acids. Naturally occurring amino acids are those encoded by the genetic code, as well as those that are later modified, such as hydroxyproline, γ-carboxyglutamate, and O-phosphoserine. Amino acid analogs refer to compounds that have the same basic chemical structure as a naturally occurring amino acid, i.e., an α-carbon bonded to a hydrogen, a carboxyl group, an amino group, and an R group, such as homoserine, norleucine, methionine sulfoxide, and methionine methylsulfonium. Such analogs have modified R groups (e.g., norleucine) or modified peptide backbones, but retain the same basic chemical structure as a naturally occurring amino acid. Amino acid mimetics refer to compounds that have a structure different from the general chemical structure of an amino acid but function similarly to a naturally occurring amino acid. The terms "non-naturally occurring amino acid" and "unnatural amino acid" refer to amino acid analogs, synthetic amino acids, and amino acid mimetics that are not found in nature.

[0150] Amino acids may be referred to herein by either their commonly known three letter symbols or by the one-letter symbols recommended by the IUPAC-IUB Biochemical Nomenclature Commission. Similarly, nucleotides may be referred to by their commonly accepted single-letter codes.

[0151] The terms "polypeptide," "peptide," and "protein" are used interchangeably herein to refer to a polymer of amino acid residues, which may, in embodiments, be conjugated to moieties not composed of amino acids. The term applies to amino acid polymers in which one or more amino acid residues are artificial chemical mimetics of a corresponding naturally occurring amino acid, as well as to naturally occurring and non-naturally occurring amino acid polymers.

[0152] The "position" of an amino acid or nucleotide base is indicated by a number sequentially identifying each amino acid (or nucleotide base) in a reference sequence based on its position relative to the N-terminus (or 5'-terminus). Because of deletions, insertions, truncations, fusions, etc., which must be considered when determining optimal alignment, the number of amino acid residues in a test sequence, determined simply by counting from the N-terminus, is generally not necessarily the same as the number of corresponding positions in the reference sequence. For example, if a variant has a deletion compared to the aligned reference sequence, no amino acid in the variant will correspond to the position in the reference sequence at the deletion site. If the aligned reference sequence has an insertion, the insertion will not correspond to a numbered amino acid position in the reference sequence. In the case of a truncation or fusion, there may be a stretch of amino acids in either the reference sequence or the aligned sequence that does not correspond to any amino acid in the corresponding sequence.

[0153] When used in the context of the numbering of a given amino acid or polynucleotide sequence, the term "numbered with reference to" or "corresponding to" refers to the numbering of residues in a particular reference sequence when the given amino acid or polynucleotide sequence is compared to the reference sequence.

[0154] II. Compounds In one aspect, a compound is provided having the formula: [ka] In one aspect, provided herein are compounds of Formula (I), (II), and / or (III), including embodiments thereof, or metabolites thereof.

[0155] R 1 are independently halogen, -CX 1 3. -CHX 1 2. -CH2X 1 , -OCX 1 3. -OCH2X 1 , -OCHX 1 2, -CN, -SO n1 R 1D , -SOv1 NR 1A R 1B , -NR 1C NR 1A R 1B , -ONR 1A R 1B , -NHC(O)NR 1C NR 1A R 1B , -NHC(O)NR 1A R 1B , -N(O) m1 , -NR 1A R 1B , -C(O)R 1C , -C(O)-OR 1C , -C(O)NR 1A R 1B , -OR 1D , -NR 1A SO2R 1D , -NR 1A C(O)R 1C , -NR 1A C(O)OR 1C , -NR 1A OR 1C , -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and two adjacent R on adjacent carbons 1 The substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl, or two R 1 The substituents may optionally be combined to form a substituted or unsubstituted alkyl or a substituted or unsubstituted heterocycloalkyl.

[0156] z1 is an integer from 0 to 9.

[0157] R 2 are independently oxo, halogen, -CX 2 3. -CHX 2 2. -CH2X 2 , -OCX2 3. -OCH2X 2 , -OCHX 2 2, -CN, -SO n2 R 2D , -SO v2 NR 2A R 2B , -NR 2C NR 2A R 2B , -ONR 2A R 2B , -NHC(O)NR 2C NR 2A R 2B , -NHC(O)NR 2A R 2B , -N(O) m2 , -NR 2A R 2B , -C(O)R 2C , -C(O)-OR 2C , -C(O)NR 2A R 2B , -OR 2D , -NR 2A SO2R 2D , -NR 2A C(O)R 2C , -NR 2A C(O)OR 2C , -NR 2A OR 2C , -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and two adjacent R on adjacent carbons 2 The substituents may optionally be combined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted heteroaryl.

[0158] z2 is an integer of 0 to 6.

[0159] L 3 is a bond, -S(O)2-, -NR 3 -, -NH-, -O-, -S-, -C(O)-, -C(O)NR 3 -, -NR3 C(O)-, -N(R 3 )CH2-, -NR 3 C(O)NH-, -NHC(O)NR 3 -, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene.

[0160] L 4 is a bond, -NH-, -NR 4 -, or substituted or unsubstituted alkylene.

[0161] L 6 is -N(R 6 )-L 3 - or -C(O)NH-.

[0162] W 5 is CH or N.

[0163] z6 is either 1 or 2.

[0164] R 3 , R 4 , and R 6 are independently hydrogen, —CCl3, —CBr3, —CF3, —CI3, CHCl2, —CHBr2, —CHF2, —CHI2, —CH2Cl, —CH2Br, —CH2F, —CH2I, —CN, —OH, —NH2, —COOH, —CO(C1-C6 alkyl), —CONH2, —OCCl3, —OCF3, —OCBr3, —OCI3, —OCHCl2, —OCHBr2, —OCHI2, —OCHF2, —OCH2Cl, —OCH2Br, —OCH2I, —OCH2F, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, or unsubstituted heterocycloalkyl.

[0165] R 7 , R 8 , R 9 , and R 10 are independently hydrogen or unsubstituted C-C 10 It is alkyl.

[0166] Ring B is aryl or heteroaryl.

[0167] R 5 is an electrophilic moiety.

[0168] R 1A , R 1B , R 1C , R 1D , R 2A , R 2B , R 2C , and R 2D are independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and R attached to the same nitrogen atom are independently substituted or unsubstituted. 1A and R 1B The substituents may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R 2A and R 2B The substituents may optionally be combined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

[0169] X 1 and X 2 are independently -F, -Cl, -Br, or -I.

[0170] n1 and n2 are independently an integer of 0 to 4.

[0171] m1, m2, v1, and v2 are independently 1 or 2.

[0172] In embodiments, the formula: [ka] Compounds having rings B, R 1 , z1, R 2 , z2, R 5 , L 3 , L 4 , L 6 , z6, and W 5 is as described herein, including embodiments. In embodiments, [ka] Compounds having rings B, R 1 , z1, R 2 , z2, R 5 , L 3 , L 4 , z6, and W 5 is as described herein, including embodiments. In embodiments, [ka] Compounds having rings B, R 2 , z2, R 5 , L 4 , and L 6 is as described herein, including embodiments. In embodiments, [ka] Compounds having rings B, R 2 , z2, R 5 , R 7 , R 8 , R 9 , R 10 , L 4 , and L 6 is as described herein, including the embodiments.

[0173] In embodiments, R 3 , R 4 , and R 6are independently hydrogen, —CCl3, —CBr3, —CF3, —CI3, CHCl2, —CHBr2, —CHF2, —CHI2, —CH2Cl, —CH2Br, —CH2F, —CH2I, —CN, —OH, —NH2, —COOH, —COCH3, —CONH2, —OCCl3, —OCF3, —OCBr3, —OCI3, —OCHCl2, —OCHBr2, —OCHI2, —OCHF2, —OCH2Cl, —OCH2Br, —OCH2I, —OCH2F, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, or unsubstituted heterocycloalkyl.

[0174] In embodiments, R 3 , R 4 , and R 6 are independently hydrogen, —CCl3, —CBr3, —CF3, —CI3, CHCl2, —CHBr2, —CHF2, —CHI2, —CH2Cl, —CH2Br, —CH2F, —CH2I, —CN, —OH, —NH2, —COOH, —CONH2, —OCCl3, —OCF3, —OCBr3, —OCI3, —OCHCl2, —OCHBr2, —OCHI2, —OCHF2, —OCH2Cl, —OCH2Br, —OCH2I, —OCH2F, unsubstituted alkyl, or unsubstituted heteroalkyl.

[0175] In embodiments, the electrophilic moiety is a covalent cysteine ​​modifier moiety. 5 is a covalent cysteine ​​modifier moiety.

[0176] In embodiments, R 5 is independent, [ka] is.

[0177] R 14 are independently =O or =NR 19 is.

[0178] R 15 are independently =O or =NR 20 is.

[0179] R 16 , R 17 , and R 18 are independently hydrogen, oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -C(O)N(CH3)2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H , -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0180] R 19 and R 20 are independently hydrogen, —CCl3, —CBr3, —CF3, —CI3, CHCl2, —CHBr2, —CHF2, —CHI2, —CH2Cl, —CH2Br, —CH2F, —CH2I, —CN, —COOH, —CONH2, —C(O)N(CH3)2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0181] In embodiments, there is provided a compound having the formula: [ka] R 1 are independently halogen, -CX 1 3. -CHX 1 2. -CH2X 1 , -OCX1 3. -OCH2X 1 , -OCHX 1 2, -CN, -SO n1 R 1D , -SO v1 NR 1A R 1B , -NR 1C NR 1A R 1B , -ONR 1A R 1B , -NHC(O)NR 1C NR 1A R 1B , -NHC(O)NR 1A R 1B , -N(O) m1 , -NR 1A R 1B , -C(O)R 1C , -C(O)-OR 1C , -C(O)NR 1A R 1B , -OR 1D , -NR 1A SO2R 1D , -NR 1A C(O)R 1C , -NR 1A C(O)OR 1C , -NR 1A OR 1C , -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and two adjacent R on adjacent carbons 1 The substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl, or two R 1 The substituents may optionally be joined to form a substituted or unsubstituted alkyl or a substituted or unsubstituted heterocycloalkyl, z1 is an integer from 0 to 9, and R 2 are independently oxo, halogen, -CX 2 3. -CHX 2 2. -CH2X2 , -OCX 2 3. -OCH2X 2 , -OCHX 2 2, -CN, -SO n2 R 2D , -SO v2 NR 2A R 2B , -NR 2C NR 2A R 2B , -ONR 2A R 2B , -NHC(O)NR 2C NR 2A R 2B , -NHC(O)NR 2A R 2B , -N(O) m2 , -NR 2A R 2B , -C(O)R 2C , -C(O)-OR 2C , -C(O)NR 2A R 2B , -OR 2D , -NR 2A SO2R 2D , -NR 2A C(O)R 2C , -NR 2A C(O)OR 2C , -NR 2A OR 2C , -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and two adjacent R on adjacent carbons 2 The substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted heteroaryl; z2 is an integer from 0 to 6; L 3 is a bond, -S(O)2-, -NR 3 -, -NH-, -O-, -S-, -C(O)-, -C(O)NR 3 -, -NR 3 C(O)-, -N(R 3 )CH2-, -NR 3C(O)NH-, -NHC(O)NR 3 -, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene; 4 is a bond, -NH-, -NR 4 - or substituted or unsubstituted alkylene, and L 6 is a bond, -N(R 6 )-L 3 - or -C(O)NH-, and W 5 is CH or N, z6 is 1 or 2, and R 3 , R 4 , and R 6 are independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CO(C1-C6 alkyl), -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, or unsubstituted heterocycloalkyl; and R 7 , R 8 , R 9 , and R 10 are independently hydrogen or unsubstituted C-C 10 alkyl, ring B is aryl or heteroaryl, and R 5 is independent, [ka] where R 14 are independently =O or =NR 19 and R 15 are independently =O or =NR 20 and R 16 , R 17 , and R 18are independently hydrogen, oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -C(O)N(CH3)2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H , -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and R 19 and R 20 are independently hydrogen, —CCl3, —CBr3, —CF3, —CI3, CHCl2, —CHBr2, —CHF2, —CHI2, —CH2Cl, —CH2Br, —CH2F, —CH2I, —CN, —COOH, —CONH2, —C(O)N(CH3)2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 1A , R 1B , R 1C , R 1D , R 2A , R 2B , R 2C , and R 2Dare independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and R attached to the same nitrogen atom are independently substituted or unsubstituted. 1A and R 1B The substituents may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R 2A and R 2B The substituents may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and X 1 and X 2 are independently -F, -Cl, -Br, or -I; n1 and n2 are independently an integer of 0 to 4; m1, m2, v1, and v2 are independently 1 or 2.

[0182] In embodiments, R 5 is independent, [ka] where R 16 , R 17 , and R 18 is as described herein, including the embodiments.

[0183] In embodiments, R 5 is independent, [ka] is.

[0184] In embodiments, there is provided a compound having the formula: [ka] R 1 are independently halogen, -CX 1 3. -CHX 1 2. -CH2X 1 , -OCX 1 3. -OCH2X 1 , -OCHX 1 2, -CN, -SO n1 R 1D , -SO v1 NR 1A R 1B , -NR 1C NR 1A R 1B , -ONR 1A R 1B , -NHC(O)NR 1C NR 1A R 1B , -NHC(O)NR 1A R 1B , -N(O) m1 , -NR 1A R 1B , -C(O)R 1C , -C(O)-OR 1C , -C(O)NR 1A R 1B , -OR 1D , -NR 1A SO2R 1D , -NR 1A C(O)R 1C , -NR 1A C(O)OR 1C , -NR 1A OR 1C , -SF5, -N3, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 2- to 6-membered heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted C6-C 10 aryl, or substituted or unsubstituted 5- to 10-membered heteroaryl, and two adjacent R 1The substituents may optionally be joined to form a substituted or unsubstituted C3-C6 cycloalkyl, a substituted or unsubstituted 3- to 6-membered heterocycloalkyl, a substituted or unsubstituted phenyl, or a substituted or unsubstituted 5- to 6-membered heteroaryl, or two R 1 The substituents may optionally be joined to form a substituted or unsubstituted C3-C6 cycloalkyl or a substituted or unsubstituted 3- to 6-membered heterocycloalkyl, z1 is an integer from 0 to 9, and R 2 are independently oxo, halogen, -CX 2 3. -CHX 2 2. -CH2X 2 , -OCX 2 3. -OCH2X 2 , -OCHX 2 2, -CN, -SO n2 R 2D , -SO v2 NR 2A R 2B , -NR 2C NR 2A R 2B , -ONR 2A R 2B , -NHC(O)NR 2C NR 2A R 2B , -NHC(O)NR 2A R 2B , -N(O) m2 , -NR 2A R 2B , -C(O)R 2C , -C(O)-OR 2C , -C(O)NR 2A R 2B , -OR 2D , -NR 2A SO2R 2D , -NR 2A C(O)R 2C , -NR 2A C(O)OR 2C , -NR 2A OR 2C, -SF5, -N3, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 2- to 6-membered heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted C6-C 10 aryl, or substituted or unsubstituted 5- to 10-membered heteroaryl, and two adjacent R 2 The substituents may optionally be joined to form a substituted or unsubstituted C3-C6 cycloalkyl, a substituted or unsubstituted 3- to 6-membered heterocycloalkyl, a substituted or unsubstituted phenyl, or a substituted or unsubstituted 5- to 6-membered heteroaryl, z2 is an integer from 0 to 6, and L 3 is a bond, -S(O)2-, -NR 3 -, -NH-, -O-, -S-, -C(O)-, -C(O)NR 3 -, -NR 3 C(O)-, -N(R 3 )CH2-, -NR 3 C(O)NH-, -NHC(O)NR 3 -, -C(O)O-, -OC(O)-, substituted or unsubstituted C1-C6 alkylene, or substituted or unsubstituted 2- to 6-membered heteroalkylene; 4 is a bond, -NH-, -NR 4 - or substituted or unsubstituted C1-C2 alkylene, and L 6 is a bond, -N(R 6 )-L 3 - or -C(O)NH-, and W 5 is CH or N, z6 is 1 or 2, and R 3 , R 4 , and R 6are independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -COCH3, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, unsubstituted C1-C6 alkyl, unsubstituted 2- to 6-membered heteroalkyl, unsubstituted cycloalkyl, or unsubstituted heterocycloalkyl; and R 7 , R 8 , R 9 , and R 10 are independently hydrogen or unsubstituted C-C 10 alkyl, and ring B is C-C 10 aryl or 5- to 10-membered heteroaryl, and R 5 is independent, [ka] and R 14 are independently =O or =NR 19 and R 15 are independently =O or =NR 20 and R 16 , R 17 , and R 18are independently hydrogen, oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -C(O)N(CH3)2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC( O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 2-6 membered heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted C6-C 12 aryl, or substituted or unsubstituted 5- to 12-membered heteroaryl; R 19 and R 20 are independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -COOH, -CONH2, -C(O)N(CH3)2, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 2- to 6-membered heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted C6-C 12 aryl, or substituted or unsubstituted 5- to 12-membered heteroaryl; R 1A , R 1B , R 1C , R 1D , R 2A , R 2B , R 2C , and R 2Dare independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and R attached to the same nitrogen atom are independently substituted or unsubstituted. 1A and R 1B The substituents may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R 2A and R 2B The substituents may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and X 1 and X 2 are independently -F, -Cl, -Br, or -I; n1 and n2 are independently an integer of 0 to 4; m1, m2, v1, and v2 are independently 1 or 2.

[0185] In embodiments, there is provided a compound having the formula: [ka] ;R 1 are independently halogen, -CX 1 3. -CHX 1 2. -CH2X 1 , -OCX 1 3. -OCH2X 1 , -OCHX 1 2, -CN, -SO n1 R 1D , -SO v1 NR 1A R 1B , -NR 1C NR 1A R1B , -ONR 1A R 1B , -NHC(O)NR 1C NR 1A R 1B , -NHC(O)NR 1A R 1B , -N(O) m1 , -NR 1A R 1B , -C(O)R 1C , -C(O)-OR 1C , -C(O)NR 1A R 1B , -OR 1D , -NR 1A SO2R 1D , -NR 1A C(O)R 1C , -NR 1A C(O)OR 1C , -NR 1A OR 1C , -SF5, -N3, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 2- to 6-membered heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted C6-C 10 aryl, or substituted or unsubstituted 5- to 10-membered heteroaryl, and two adjacent R 1 The substituents may optionally be joined to form a substituted or unsubstituted C3-C6 cycloalkyl, a substituted or unsubstituted 3- to 6-membered heterocycloalkyl, a substituted or unsubstituted phenyl, or a substituted or unsubstituted 5- to 6-membered heteroaryl, or two R 1 The substituents may optionally be joined to form a substituted or unsubstituted C3-C6 cycloalkyl or a substituted or unsubstituted 3- to 6-membered heterocycloalkyl, z1 is an integer from 0 to 9, and R 2 are independently oxo, halogen, -CX 2 3. -CHX 2 2. -CH2X 2 , -OCX 2 3. -OCH2X 2 , -OCHX 2 2, -CN, -SO n2 R 2D , -SOv2 NR 2A R 2B , -NR 2C NR 2A R 2B , -ONR 2A R 2B , -NHC(O)NR 2C NR 2A R 2B , -NHC(O)NR 2A R 2B , -N(O) m2 , -NR 2A R 2B , -C(O)R 2C , -C(O)-OR 2C , -C(O)NR 2A R 2B , -OR 2D , -NR 2A SO2R 2D , -NR 2A C(O)R 2C , -NR 2A C(O)OR 2C , -NR 2A OR 2C , -SF5, -N3, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 2- to 6-membered heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted C6-C 10 aryl, or substituted or unsubstituted 5- to 10-membered heteroaryl, and two adjacent R 2 The substituents may optionally be joined to form a substituted or unsubstituted C3-C6 cycloalkyl, a substituted or unsubstituted 3- to 6-membered heterocycloalkyl, a substituted or unsubstituted phenyl, or a substituted or unsubstituted 5- to 6-membered heteroaryl, z2 is an integer from 0 to 6, and L 3 is a bond, -S(O)2-, -NR 3 -, -NH-, -O-, -S-, -C(O)-, -C(O)NR 3 -, -NR 3 C(O)-, -N(R 3 )CH2-, -NR 3 C(O)NH-, -NHC(O)NR 3-, -C(O)O-, -OC(O)-, substituted or unsubstituted C1-C6 alkylene, or substituted or unsubstituted 2- to 6-membered heteroalkylene; 4 is a bond, -NH-, -NR 4 - or substituted or unsubstituted C1-C2 alkylene, and L 6 is -N(R 6 )-L 3 - or -C(O)NH-, W 5 is CH or N, z6 is 1 or 2, and R 3 , R 4 , and R 6 are independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, unsubstituted C1-C6 alkyl, or unsubstituted 2- to 6-membered heteroalkyl; and ring B is C6-C 10 aryl or 5- to 10-membered heteroaryl, and R 5 is independent, [ka] and R 16 , R 17 , and R 18are independently hydrogen, oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -C(O)N(CH3)2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC( O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 2-6 membered heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted C6-C 12 aryl, or substituted or unsubstituted 5- to 12-membered heteroaryl; R 1A , R 1B , R 1C , R 1D , R 2A , R 2B , R 2C , and R 2D are independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and R attached to the same nitrogen atom are independently substituted or unsubstituted. 1A and R 1B The substituents may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R2A and R 2B The substituents may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and X 1 and X 2 are independently -F, -Cl, -Br, or -I; n1 and n2 are independently an integer of 0 to 4; m1, m2, v1, and v2 are independently 1 or 2.

[0186] In embodiments, there is provided a compound having the formula: [ka] ;R 1 are independently halogen, -CX 1 3. -CHX 1 2. -CH2X 1 , -OCX 1 3. -OCH2X 1 , -OCHX 1 2, -CN, -SO n1 R 1D , -SO v1 NR 1A R 1B , -NR 1C NR 1A R 1B , -ONR 1A R 1B , -NHC(O)NR 1C NR 1A R 1B , -NHC(O)NR 1A R 1B , -N(O) m1 , -NR 1A R 1B , -C(O)R 1C , -C(O)-OR 1C , -C(O)NR 1A R 1B , -OR 1D , -NR 1A SO2R 1D , -NR 1A C(O)R 1C , -NR 1A C(O)OR 1C , -NR 1A OR 1C, -SF5, -N3, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 2- to 6-membered heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted C6-C 10 aryl, or substituted or unsubstituted 5- to 10-membered heteroaryl, and two adjacent R 1 The substituents may optionally be joined to form a substituted or unsubstituted C3-C6 cycloalkyl, a substituted or unsubstituted 3- to 6-membered heterocycloalkyl, a substituted or unsubstituted phenyl, or a substituted or unsubstituted 5- to 6-membered heteroaryl, or two R 1 The substituents may optionally be joined to form a substituted or unsubstituted C3-C6 alkyl or a substituted or unsubstituted 3- to 6-membered heterocycloalkyl, z1 is an integer from 0 to 9, and R 2 are independently oxo, halogen, -CX 2 3. -CHX 2 2. -CH2X 2 , -OCX 2 3. -OCH2X 2 , -OCHX 2 2, -CN, -SO n2 R 2D , -SO v2 NR 2A R 2B , -NR 2C NR 2A R 2B , -ONR 2A R 2B , -NHC(O)NR 2C NR 2A R 2B , -NHC(O)NR 2A R 2B , -N(O) m2 , -NR 2A R 2B , -C(O)R 2C , -C(O)-OR 2C , -C(O)NR 2A R 2B , -OR 2D , -NR 2A SO2R 2D , -NR 2A C(O)R2C , -NR 2A C(O)OR 2C , -NR 2A OR 2C , -SF5, -N3, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 2- to 6-membered heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted C6-C 10 aryl, or substituted or unsubstituted 5- to 10-membered heteroaryl, and two adjacent R 2 The substituents may optionally be joined to form a substituted or unsubstituted C3-C6 cycloalkyl, a substituted or unsubstituted 3- to 6-membered heterocycloalkyl, a substituted or unsubstituted phenyl, or a substituted or unsubstituted 5- to 6-membered heteroaryl, z2 is an integer from 0 to 6, and L 3 is a bond, -S(O)2-, -NR 3 -, -NH-, -O-, -S-, -C(O)-, -C(O)NR 3 -, -NR 3 C(O)-, -N(R 3 )CH2-, -NR 3 C(O)NH-, -NHC(O)NR 3 -, -C(O)O-, -OC(O)-, substituted or unsubstituted C1-C6 alkylene, or substituted or unsubstituted 2- to 6-membered heteroalkylene; 4 is a bond, -NH-, -NR 4 - or substituted or unsubstituted C1-C2 alkylene, and L 6 is -N(R 6 )-L 3 - or -C(O)NH-, W 5 is CH or N, z6 is 1 or 2, and R 3 , R 4 , and R 6are independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, unsubstituted C1-C6 alkyl, or unsubstituted 2- to 6-membered heteroalkyl; and ring B is C6-C 10 aryl or 5- to 10-membered heteroaryl, and R 5 is independent, [ka] and R 16 , R 17 , and R 18 are independently hydrogen, oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -C(O)N(CH3)2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC( O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 2-6 membered heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted C6-C 12 aryl, or substituted or unsubstituted 5- to 12-membered heteroaryl; R 1A , R 1B , R 1C , R 1D , R 2A , R 2B , R 2C , and R 2Dare independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and R attached to the same nitrogen atom are independently substituted or unsubstituted. 1A and R 1B The substituents may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R 2A and R 2B The substituents may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and X 1 and X 2 are independently -F, -Cl, -Br, or -I; n1 and n2 are independently an integer of 0 to 4; m1, m2, v1, and v2 are independently 1 or 2.

[0187] In embodiments, the compound has the formula: [ka] wherein R 1 , R 2 , R 5 , z1, z2, L 3 , L 4 and Ring B are as described herein, including embodiments.

[0188] In embodiments, the compound has the formula: [ka] R 1.2 , R1.3 , R 1.4 , and R 1.5 is hydrogen or any value of R as described herein, including embodiments. 1 It could be.

[0189] In embodiments, R 1.2 and R 1.3 are independently hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)N H2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl, or R on adjacent carbons 1.2 and R 1.3 The substituents are optionally linked and are substituted or unsubstituted phenyl, or substituted or unsubstituted heteroaryl.

[0190] In embodiments, R 1.2 and R 1.3are independently hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, - NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted 2- to 6-membered heteroalkyl, or R on adjacent carbons 1.2 and R 1.3 The substituents are optionally linked and are substituted or unsubstituted phenyl, or substituted or unsubstituted 5-6 membered heteroaryl.

[0191] In embodiments, R 1.4 and R 1.5 are independently hydrogen, halogen, —CCl3, —CBr3, —CF3, —CI3, CHCl2, —CHBr2, —CHF2, —CHI2, —CH2Cl, —CH2Br, —CH2F, —CH2I, —CN, —OH, —NH2, —COOH, —CONH2, —NO2, —SH, —SOH, —SOH, —SONH2, —NHNH2, —ONH2, —NHC(O)NHNH2, —NHC(O)NH2, —NHS02H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl3, —OCF3, —OCBr3, —OCI3, —OCHCl2, —OCHBr2, —OCHI2, —OCHF2, —OCH2Cl, —OCH2Br, —OCHI, —OCH2F, —N3, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.

[0192] In embodiments, R 1.4 and R 1.5are independently hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O )NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted 2- to 6-membered heteroalkyl.

[0193] In embodiments, the compound has the formula: [ka] wherein R 1.2 , R 1.3 , R 1.4 , R 1.5 , R 2 , z2, R 5 , L 3 , and L 4 is as described herein, including the embodiments.

[0194] W 1 are independently -O-, -NH-, or -NR 2 -It is.

[0195] W 2 and W 3 are independently =N-, =CH-, or =CR 2 -It is.

[0196] R 11 are independently oxo, halogen, -CX 11 3. -CHX 11 2. -CH2X 11 , -OCX 11 3. -OCH2X 11 , -OCHX11 2, -CN, -OH, -NH2, -COOH, -CONH2, -C(O)N(CH3)2, -NO2, -SH, -S03H, -S04H, -SON2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHS02H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0197] R 21 are independently oxo, halogen, -CX 21 3. -CHX 21 2. -CH2X 21 , -OCX 21 3. -OCH2X 21 , -OCHX 21 2, -CN, -OH, -NH2, -COOH, -CONH2, -C(O)N(CH3)2, -NO2, -SH, -S03H, -S04H, -SON2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHS02H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0198] X 11 and X 21 are independently -F, -Cl, -Br, or -I.

[0199] z11 is an integer of 0 to 4.

[0200] z21 is an integer of 0 to 5.

[0201] In embodiments, R 2 are independently oxo, halogen, -CX 2 3. -CHX2 2. -CH2X 2 , -OCX 2 3. -OCH2X 2 , -OCHX 2 2, -CN, -OH, -NH2, -COOH, -CONH2, -C(O)N(CH3)2, -NO2, -SH, -SO3H, -SO4H, -SON2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, SF5, -N3, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 2- to 6-membered heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted C6-C 12 It is aryl, or substituted or unsubstituted 5- to 12-membered heteroaryl.

[0202] In embodiments, R 2 are independently halogen, -OCX 2 3. -OCH2X 2 , -OCHX 2 2. unsubstituted C1-C3 alkyl or unsubstituted 5- to 6-membered heteroaryl, R 11 are independently halogen, -OCX 11 3. -OCH2X 11 , -OCHX 11 2. unsubstituted C1-C3 alkyl or unsubstituted 5- to 6-membered heteroaryl, R 21 are independently halogen, -OCX 21 3. -OCH2X 21 , -OCHX 21 2. Unsubstituted C1-C3 alkyl, or unsubstituted 5- to 6-membered heteroaryl.

[0203] In embodiments, R 1.2 , R 1.3 , R 1.4 , and R 1.5 are independently hydrogen or halogen.

[0204] In embodiments, the compound has the formula: [ka] wherein R 1.2 , R 1.3 , R 1.4 , R 1.5 , R 2 , z2, R 21 , z21, R 5 , L 3 , L 4 , W 1 , W 2 , and W 3 is as described herein, including embodiments. In embodiments, the compound has the formula: [ka] wherein R 1.2 , R 1.3 , R 1.4 , R 1.5 , R 2 , z2, R 5 , L 3 , L 4 , W 1 , and W 2 is as described herein, including embodiments. In embodiments, the compound has the formula: [ka] wherein R 1.2 , R 1.3 , R 1.4 , R 1.5 , R 2 , z2, R 5 , L 3 , and L 4 is as described herein, including embodiments. In embodiments, the compound has the formula: [ka] wherein R 1.4 , R 1.5 , R 2 , z2, R 5 , R 11 , z11, L 3 , and L 4 is as described herein, including the embodiments.

[0205] In an embodiment, L 3 is —C(O)—, —CH—, —C(O)NH—, —NHC(O)—, —NHCH—, —CHCHNH—, —C(O)CHNH—, or —CHC(O)NH—.

[0206] In an embodiment, L 4 is a bond, —NH—, or —CH—. In embodiments, L 4 -NH-, -NR 4 -, or -CH2-. In embodiments, L 4 is a bond. In embodiments, L 4 is —NH—. In embodiments, L 4 is -NR 4 In an embodiment, L 4 is -CH2-.

[0207] In embodiments, R 5 is independent, [ka] where R 16 , R 17 , and R 18 is as described herein, including the embodiments.

[0208] In embodiments, R 16 , R 17 , and R 18 are independently hydrogen, —C(O)N(CH3)2, or unsubstituted C1-C3 alkyl.

[0209] In embodiments, R 5 is independent, [ka] where R 16 , R 17 , and R 18 are independently hydrogen, —C(O)N(CH3)2, or unsubstituted C1-C3 alkyl.

[0210] In embodiments, R 5 is independent, [ka] where R 16 , R 17 , and R 18 is as described herein, including the embodiments.

[0211] In embodiments, the compound has the formula: [ka] R 1.2 , R 1.3 , R 1.4 , R 1.5 , R 5 , R 11 , z11, W 1 , W 2 , L 3 , and L 4 is as described herein, including embodiments. 2.1 and R 2.2 are independently hydrogen or any value of R as described herein, including embodiments. 2 is.

[0212] In embodiments, the compound has the formula: [ka] R 1.2 , R 1.3 , R 1.4 , R 1.5 , R 2.1 , R 2.2 , R 5 , W 1 , W 2 , L 3 , and L 4 is as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 1.2 , R 1.3 , R 1.4 , R 1.5 , R 2.1 , R 2.2 , R 5 , L 3 , and L 4 is as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 1.4 , R 1.5 , R 2.1 , R 2.2 , R 5 , R 11 , z11, L 3 , and L 4 is as described herein, including the embodiments.

[0213] In embodiments, R 2.1 are independently hydrogen, -OCX 2 3, or unsubstituted 5- to 6-membered heteroaryl.

[0214] In embodiments, R 2.2 are independently hydrogen or halogen.

[0215] In embodiments, R 11 are independently halogen.

[0216] In embodiments, the compound has the formula: [ka] R 2 , z2, R 5 , R 6 , L 3 , and L 4 is as described herein, including the embodiments.

[0217] In embodiments, the compound has the formula: [ka] R 2 , z2, R 21 , z21, R 5 , W 1 , W 2 , W 3 , L 3 , and L 4 is as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 2 , z2, R 21 , z21, R 5 , W 1 , W 2 , W 3 , L 3 , and L 4 is as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 2 , z2, R 5 , W 1 , W 2 , L 3 , and L 4 is as described herein, including the embodiments.

[0218] In an embodiment, W 1 are independently -O-, -NH-, or -NR 2 -It is.

[0219] In embodiments, R 2 are independently halogen, -OCX 2 3. -OCH2X 2 , -OCHX 2 2. Unsubstituted C1-C3 alkyl, or unsubstituted 5- to 6-membered heteroaryl.

[0220] In embodiments, R 21 are independently halogen, -OCX 2 3. -OCH2X 2, -OCHX 2 2. Unsubstituted C1-C3 alkyl, or unsubstituted 5- to 6-membered heteroaryl.

[0221] In an embodiment, L 3 is —C(O)— or —CH2—.

[0222] In an embodiment, L 4 -NH-, -NR 4 -, or -CH2-.

[0223] In embodiments, R 16 are independently hydrogen, —C(O)N(CH), or unsubstituted C-C alkyl. 17 are independently hydrogen, —C(O)N(CH), or unsubstituted C-C alkyl. 18 are independently hydrogen, —C(O)N(CH3)2, or unsubstituted C1-C3 alkyl.

[0224] In embodiments, R 5 is independent, [ka] where R 16 , R 17 , and R 18 are independently hydrogen, —C(O)N(CH3)2, or unsubstituted C1-C3 alkyl.

[0225] In embodiments, the compound has the formula: [ka] R 2.1 , R 2.2 , R 5 , R 21 , z21, W 1 , W 2 , W 3 , L 3 , and L 4 is as described herein, including the embodiments.

[0226] In embodiments, the compound has the formula: [ka] R 2.1 , R 2.2 , R 5 , W 1 , W 2 , L 3 , and L 4 is as described herein, including the embodiments.

[0227] In embodiments, the compound has the formula: [ka] R 5 , R 21 , z21, W 1 , W 2 , W 3 , L 3 , and L 4 is as described herein, including the embodiments.

[0228] In embodiments, the compound has the formula: [ka] R 1.2 , R 1.3 , R 1.4 , R 1.5 , R 2 , R 3 , R 5 , R 21 , L 4 , W 1 , W 2 , W, z2, and z21 are as described herein, including the embodiments.

[0229] In embodiments, the compound has the formula: [ka] R 1.2 , R 1.3 , R 1.4, R 1.5 , R 2 , R 5 , R 21 , L 4 , W 1 , W 2 , W, z2, and z21 are as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 1.2 , R 1.3 , R 1.4 , R 1.5 , R 2 , R 5 , R 21 , L 4 , W 1 , W 2 , W 3 , z2, and z21 are as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 1.2 , R 1.3 , R 1.4 , R 1.5 , R 2 , R 3 , R 5 , R 21 , L 4 , W 1 , W 2 , W 3 , z2, and z21 are as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 1.2 , R 1.3 , R 1.4 , R 1.5 , R 2 , R 3 , R 5 , R 21 , L 4 , W 1 , W 2 , W 3, z2, and z21 are as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 1.2 , R 1.3 , R 1.4 , R 1.5 , R 2 , R 3 , R 5 , R 21 , L 4 , W 1 , W 2 , W 3 , z2, and z21 are as described herein, including embodiments.

[0230] In embodiments, the compound has the formula: [ka] R 1.2 , R 1.3 , R 1.4 , R 1.5 , R 2 , R 3 , R 5 , L 4 , W 1 , W 2 , and z2 are as described herein, including embodiments.

[0231] In embodiments, the compound has the formula: [ka] R 1.2 , R 1.3 , R 1.4 , R 1.5 , R 2 , R 5 , L 4 , W 1 , W 2 and z2 is as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 1.2 , R 1.3 , R 1.4 , R 1.5 , R 2 , R 5 , L 4 , W 1 , W 2 and z2 is as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 1.2 , R 1.3 , R 1.4 , R 1.5 , R 2 , R 3 , R 5 , L 4 , W 1 , W 2 and z2 is as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 1.2 , R 1.3 , R 1.4 , R 1.5 , R 2 , R 3 , R 5 , L 4 , W 1 , W 2 and z2 is as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 1.2 , R 1.3 , R 1.4 , R 1.5 , R 2 , R 3 , R 5 , L 4 , W 1 , W 2and z2 is as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 1.2 , R 1.3 , R 1.4 , R 1.5 , R 2 , R 3 , R 5 , L 4 , W 1 , W 2 , and z2 are as described herein, including embodiments.

[0232] In embodiments, the compound has the formula: [ka] R 1.4 , R 1.5 , R 3 , R 5 , L 4 , W 1 , and W 2 is as described herein, including the embodiments.

[0233] In embodiments, the compound has the formula: [ka] R 1.4 , R 1.5 , R 5 , L 4 , W 1 , and W 2 is as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 1.4 , R 1.5 , R 5 , L 4 , W 1 , and W 2is as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 1.4 , R 1.5 , R 3 , R 5 , L 4 , W 1 , and W 2 is as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 1.4 , R 1.5 , R 3 , R 5 , L 4 , W 1 , and W 2 is as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 1.4 , R 1.5 , R 3 , R 5 , L 4 , W 1 , and W 2 is as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 1.4 , R 1.5 , R 3 , R 5 , L 4 , W 1 , and W 2 is as described herein, including the embodiments.

[0234] In embodiments, the compound has the formula: [ka] R 1.4 , R 1.5 , R 3 , R 5 , L 4 , W 1 , and W 2 is as described herein, including the embodiments.

[0235] In embodiments, the compound has the formula: [ka] R 1.4 , R 1.5 , R 5 , L 4 , W 1 , and W 2 is as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 1.4 , R 1.5 , R 5 , L 4 , W 1 , and W 2 is as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 1.4 , R 1.5 , R 3 , R 5 , L 4 , W 1 , and W 2 is as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 1.4 , R 1.5 , R 3 , R 5 , L 4 , W 1, and W 2 is as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 1.4 , R 1.5 , R 3 , R 5 , L 4 , W 1 , and W 2 is as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 1.4 , R 1.5 , R 3 , R 5 , L 4 , W 1 , and W 2 is as described herein, including the embodiments.

[0236] In embodiments, the compound has the formula: [ka] R 1.2 , R 1.3 , R 1.4 , R 1.5 , R 2 , R 3 , R 5 , L 4 , and z2 are as described herein, including embodiments.

[0237] In embodiments, the compound has the formula: [ka] R 1.2 , R 1.3 , R 1.4 , R 1.5 , R 2 , R 5 , L 4and z2 is as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 1.2 , R 1.3 , R 1.4 , R 1.5 , R 2 , R 5 , L 4 and z2 is as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 1.2 , R 1.3 , R 1.4 , R 1.5 , R 2 , R 3 , R 5 , L 4 and z2 is as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 1.2 , R 1.3 , R 1.4 , R 1.5 , R 2 , R 3 , R 5 , L 4 and z2 is as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 1.2 , R 1.3 , R 1.4 , R 1.5 , R 2 , R 3 , R 5 , L 4 and z2 is as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 1.2 , R 1.3 , R 1.4 , R 1.5 , R 2 , R 3 , R 5 , L 4 , and z2 are as described herein, including embodiments.

[0238] In embodiments, the compound has the formula: [ka] R 1.4 , R 1.5 , R 3 , R 5 , and L 4 is as described herein, including embodiments

[0239] In embodiments, the compound has the formula: [ka] R 1.4 , R 1.5 , R 5 , and L 4 is as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 1.4 , R 1.5 , R 3 , R 5 , and L 4 is as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 1.4 , R 1.5 , R 3 , R 5 , and L 4is as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 1.4 , R 1.5 , R 3 , R 5 , and L 4 is as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 1.4 , R 1.5 , R 3 , R 5 , and L 4 is as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 1.4 , R 1.5 , R 3 , R 5 , and L 4 is as described herein, including the embodiments.

[0240] In embodiments, the compound has the formula: [ka] R 1.4 , R 1.5 , R 3 , R 5 , and L 4 is as described herein, including the embodiments.

[0241] In embodiments, the compound has the formula: [ka] R 1.4 , R 1.5 , R 5 , and L4 is as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 1.4 , R 1.5 , R 5 , and L 4 is as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 1.4 , R 1.5 , R 3 , R 5 , and L 4 is as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 1.4 , R 1.5 , R 3 , R 5 , and L 4 is as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 1.4 , R 1.5 , R 3 , R 5 , and L 4 is as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 1.4 , R 1.5 , R 3 , R 5 , and L 4 is as described herein, including the embodiments.

[0242] In embodiments, the compound has the formula: [ka] R 1.4 , R 1.5 , R 2 , R 3 , R 5 , R 11 , L 4 , z2, and z11 are as described herein, including embodiments.

[0243] In embodiments, the compound has the formula: [ka] R 1.4 , R 1.5 , R 2 , R 5 , R 11 , L 4 , z2, and z11 are as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 1.4 , R 1.5 , R 2 , R 5 , R 11 , L 4 , z2, and z11 are as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 1.4 , R 1.5 , R 2 , R 3 , R 5 , R 11 , L 4 , z2, and z11 are as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 1.4 , R 1.5 , R 2 , R 3 , R 5 , R 11 , L 4 , z2, and z11 are as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 1.4 , R 1.5 , R 2 , R 3 , R 5 , R 11 , L 4 , z2, and z11 are as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 1.4 , R 1.5 , R 2 , R 3 , R 5 , R 11 , L 4 , z2, and z11 are as described herein, including embodiments.

[0244] In embodiments, the compound has the formula: [ka] R 1.4 , R 1.5 , R 3 , R 5 , and L 4 is as described herein, including embodiments. 11.1 are independently hydrogen or any value of R as described herein, including embodiments. 11 is.

[0245] In embodiments, the compound has the formula: [ka] R 1.4 , R 1.5 , R 5 , R 11.1 , and L 4 is as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 1.4 , R 1.5 , R 5 , R 11.1 , and L 4 is as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 1.4 , R 1.5 , R 3 , R 5 , R 11.1 , and L 4 is as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 1.4 , R 1.5 , R 3 , R 5 , R 11.1 , and L 4 is as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 1.4 , R 1.5 , R 3 , R 5 , R 11.1 , and L 4 is as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 1.4 , R 1.5 , R 3 , R 5 , R 11.1 , and L 4 is as described herein, including the embodiments.

[0246] In embodiments, the compound has the formula: [ka] R 1.4 , R 1.5 , R 3 , R 5 , R 11.1 , and L 4 is as described herein, including the embodiments.

[0247] In embodiments, the compound has the formula: [ka] R 1.4 , R 1.5 , R 5 , R 11.1 , and L 4 is as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 1.4 , R 1.5 , R 5 , R 11.1 , and L 4 is as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 1.4 , R 1.5 , R 3 , R 5 , R 11.1 , and L 4is as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 1.4 , R 1.5 , R 3 , R 5 , R 11.1 , and L 4 is as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 1.4 , R 1.5 , R 3 , R 5 , R 11.1 , and L 4 is as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 1.4 , R 1.5 , R 3 , R 5 , R 11.1 , and L 4 is as described herein, including the embodiments.

[0248] In embodiments, the compound has the formula: [ka] R 1.2 , R 1.3 , R 1.4 , R 1.5 , R 21 , L 3 , W 1 , W 2 , W 3 , and z21 are as described herein, including embodiments.

[0249] In embodiments, the compound has the formula: [ka] R 1.2 , R 1.3 , R 1.4 , R 1.5 , R 21 , L 3 , W 1 , W 2 , W 3 and z21 are as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 1.2 , R 1.3 , R 1.4 , R 1.5 , R 21 , L 3 , W 1 , W 2 , W 3 and z21 are as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 1.2 , R 1.3 , R 1.4 , R 1.5 , R 21 , L 3 , W 1 , W 2 , W 3 and z21 are as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 1.2 , R 1.3 , R 1.4 , R 1.5 , R 21 , L 3 , W 1 , W 2 , W 3 , and z21 are as described herein, including embodiments.

[0250] In embodiments, the compound has the formula: [ka] R 1.2 , R 1.3 , R 1.4 , R 1.5 , R 2.1 , R 2.2 , L 3 , W 1 , and W 2 is as described herein, including the embodiments.

[0251] In embodiments, the compound has the formula: [ka] R 1.2 , R 1.3 , R 1.4 , R 1.5 , R 2.1 , R 2.2 , L 3 , W 1 , and W 2 is as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 1.2 , R 1.3 , R 1.4 , R 1.5 , R 2.1 , R 2.2 , L 3 , W 1 , and W 2 is as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 1.2 , R 1.3 , R 1.4 , R 1.5 , R 2.1 , R 2.2 , L 3, W 1 , and W 2 is as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 1.2 , R 1.3 , R 1.4 , R 1.5 , R 2.1 , R 2.2 , L 3 , W 1 , and W 2 is as described herein, including the embodiments.

[0252] In embodiments, the compound has the formula: [ka] R 1.2 , R 1.3 , R 1.4 , R 1.5 , R 2.1 , R 2.2 , and L 3 is as described herein, including the embodiments.

[0253] In embodiments, the compound has the formula: [ka] R 1.2 , R 1.3 , R 1.4 , R 1.5 , R 2.1 , R 2.2 , and L 3 is as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 1.2 , R 1.3 , R 1.4 , R 1.5 , R 2.1 , R 2.2, and L 3 is as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 1.2 , R 1.3 , R 1.4 , R 1.5 , R 2.1 , R 2.2 , and L 3 is as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 1.2 , R 1.3 , R 1.4 , R 1.5 , R 2.1 , R 2.2 , and L 3 is as described herein, including the embodiments.

[0254] In embodiments, the compound has the formula: [ka] R 1.4 , R 1.5 , R 11 , R 2.1 , R 2.2 , L 3 , and z11 are as described herein, including embodiments.

[0255] In embodiments, the compound has the formula: [ka] R 1.4 , R 1.5 , R 11 , R 2.1 , R 2.2 , L 3 and z11 is as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 1.4 , R 1.5 , R 11 , R 2.1 , R 2.2 , L 3 and z11 is as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 1.4 , R 1.5 , R 11 , R 2.1 , R 2.2 , L 3 and z11 is as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 1.4 , R 1.5 , R 11 , R 2.1 , R 2.2 , L 3 , and z11 are as described herein, including embodiments.

[0256] In embodiments, the compound has the formula: [ka] R 2 , R 5 , R 11 , L 3 , L 4 , and z11 are as described herein, including embodiments.

[0257] In embodiments, the compound has the formula: [ka] R 2 , R 5 , R 11 , L3 , L 4 , z2, and z11 are as described herein, including embodiments.

[0258] In embodiments, the compound has the formula: [ka] R 2 , R 5 , L 3 , L 4 and z2 is as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 2 , R 5 , L 3 , L 4 and z2 is as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 2 , R 5 , L 3 , L 4 and z2 is as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 2 , R 5 , R 11 , L 3 , L 4 , z2, and z11 are as described herein, including embodiments.

[0259] In embodiments, the compound has the formula: [ka] R 5 , R 11 , L 3 , L4 , R 2.1 , R 2.2 , and z11 are as described herein, including embodiments.

[0260] In embodiments, the compound has the formula: [ka] R 5 , L 3 , L 4 , R 2.1 , and R 2.2 is as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 5 , L 3 , L 4 , R 2.1 , and R 2.2 is as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 5 , L 3 , L 4 , R 2.1 , and R 2.2 is as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 5 , R 11 , L 3 , L 4 , R 2.1 , R 2.2 , and z11 are as described herein, including embodiments.

[0261] In embodiments, the compound has the formula: [ka] R 5 , R 11 , L 3 , L 4 , and z11 are as described herein, including embodiments. 2.1 and R 2.2 are independently hydrogen, -F, or -OCF3.

[0262] In embodiments, the compound has the formula: [ka] R 5 , L 3 , and L 4 is as described herein, including embodiments. 2.1 and R 2.2 is independently hydrogen, -F, or -OCF. In embodiments, the compound has the formula: [ka] R 5 , L 3 , and L 4 is as described herein, including embodiments. 2.1 and R 2.2 is independently hydrogen, -F, or -OCF. In embodiments, the compound has the formula: [ka] R 5 , L 3 , and L 4 is as described herein, including embodiments. 2.1 and R 2.2 is independently hydrogen, -F, or -OCF. In embodiments, the compound has the formula: [ka] R 5 , R 11 , L 3 , L 4, and z11 are as described herein, including embodiments. 2.1 and R 2.2 are independently hydrogen, -F, or -OCF3.

[0263] In embodiments, the compound has the formula: [ka] R 1.2 , R 1.3 , R 1.4 , R 1.5 , R 2 , R 3 , R 16 , R 17 , R 18 , L 4 , ring B, and z2 are as described herein, including embodiments.

[0264] In embodiments, the compound has the formula: [ka] R 1.2 , R 1.3 , R 1.4 , R 1.5 , R 2 , R 16 , R 17 , R 18 , L 4 , ring B, and z2 are as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 1.2 , R 1.3 , R 1.4 , R 1.5 , R 2 , R 16 , R 17 , R 18 , L 4 , ring B, and z2 are as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 1.2 , R 1.3 , R 1.4 , R 1.5 , R 2 , R 3 , R 16 , R 17 , R 18 , L 4 , ring B, and z2 are as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 1.2 , R 1.3 , R 1.4 , R 1.5 , R 2 , R 3 , R 16 , R 17 , R 18 , L 4 , ring B, and z2 are as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 1.2 , R 1.3 , R 1.4 , R 1.5 , R 2 , R 3 , R 16 , R 17 , R 18 , L 4 , ring B, and z2 are as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 1.2 , R 1.3 , R 1.4 , R 1.5 , R 2 , R 3 , R 16 , R 17 , R 18 , L 4, ring B, and z2 are as described herein, including embodiments.

[0265] In embodiments, the compound has the formula: [ka] R 1.2 , R 1.3 , R 1.4 , R 1.5 , R 2 , R 3 , R 5 , L 4 , and z2 are as described herein, including embodiments.

[0266] In embodiments, the compound has the formula: [ka] R 1.2 , R 1.3 , R 1.4 , R 1.5 , R 2 , R 5 , L 4 and z2 is as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 1.2 , R 1.3 , R 1.4 , R 1.5 , R 2 , R 5 , L 4 and z2 is as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 1.2 , R 1.3 , R 1.4 , R 1.5 , R 2 , R 3 , R 5 , L 4and z2 is as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 1.2 , R 1.3 , R 1.4 , R 1.5 , R 2 , R 3 , R 5 , L 4 and z2 is as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 1.2 , R 1.3 , R 1.4 , R 1.5 , R 2 , R 3 , R 5 , L 4 and z2 is as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 1.2 , R 1.3 , R 1.4 , R 1.5 , R 2 , R 3 , R 5 , L 4 , and z2 are as described herein, including embodiments.

[0267] In embodiments, the compound has the formula: [ka] R 1.2 , R 1.3 , R 1.4 , R 1.5 , R 2 , R 3 , R 5 , L 4, and z2 are as described herein, including embodiments.

[0268] In embodiments, the compound has the formula: [ka] R 1.2 , R 1.3 , R 1.4 , R 1.5 , R 2 , R 5 , L 4 and z2 is as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 1.2 , R 1.3 , R 1.4 , R 1.5 , R 2 , R 5 , L 4 and z2 is as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 1.2 , R 1.3 , R 1.4 , R 1.5 , R 2 , R 3 , R 5 , L 4 and z2 is as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 1.2 , R 1.3 , R 1.4 , R 1.5 , R 2 , R 3 , R 5 , L 4and z2 is as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 1.2 , R 1.3 , R 1.4 , R 1.5 , R 2 , R 3 , R 5 , L 4 and z2 is as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 1.2 , R 1.3 , R 1.4 , R 1.5 , R 2 , R 3 , R 5 , L 4 , and z2 are as described herein, including embodiments.

[0269] In embodiments, the compound has the formula: [ka] R 1.4 , R 1.5 , R 3 , R 5 , and L 4 is as described herein, including the embodiments.

[0270] In embodiments, the compound has the formula: [ka] R 1.4 , R 1.5 , R 5 , and L 4 is as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 1.4 , R 1.5 , R 5 , and L 4 is as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 1.4 , R 1.5 , R 3 , R 5 , and L 4 is as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 1.4 , R 1.5 , R 3 , R 5 , and L 4 is as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 1.4 , R 1.5 , R 3 , R 5 , and L 4 is as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 1.4 , R 1.5 , R 3 , R 5 , and L 4 is as described herein, including the embodiments.

[0271] In embodiments, the compound has the formula: [ka] R1.4 , R 1.5 , R 3 , R 5 , and L 4 is as described herein, including the embodiments.

[0272] In embodiments, the compound has the formula: [ka] R 1.4 , R 1.5 , R 5 , and L 4 is as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 1.4 , R 1.5 , R 5 , and L 4 is as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 1.4 , R 1.5 , R 3 , R 5 , and L 4 is as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 1.4 , R 1.5 , R 3 , R 5 , and L 4 is as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 1.4 , R 1.5 , R 3 , R5 , and L 4 is as described herein, including embodiments, the compound has the formula: [ka] R 1.4 , R 1.5 , R 3 , R 5 , and L 4 is as described herein, including embodiments

[0273] In embodiments, the compound has the formula: [ka] R 1.4 , R 1.5 , R 3 , R 5 , and L 4 is as described herein, including the embodiments.

[0274] In embodiments, the compound has the formula: [ka] R 1.4 , R 1.5 , R 5 , and L 4 is as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 1.4 , R 1.5 , R 5 , and L 4 is as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 1.4 , R 1.5 , R 3 , R 5, and L 4 is as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 1.4 , R 1.5 , R 3 , R 5 , and L 4 is as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 1.4 , R 1.5 , R 3 , R 5 , and L 4 is as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 1.4 , R 1.5 , R 3 , R 5 , and L 4 is as described herein, including the embodiments.

[0275] In embodiments, the compound has the formula: [ka] R 1.4 , R 1.5 , R 3 , R 5 , and L 4 is as described herein, including the embodiments.

[0276] In embodiments, the compound has the formula: [ka] R 1.4 , R 1.5 , R5 , and L 4 is as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 1.4 , R 1.5 , R 5 , and L 4 is as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 1.4 , R 1.5 , R 3 , R 5 , and L 4 is as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 1.4 , R 1.5 , R 3 , R 5 , and L 4 is as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 1.4 , R 1.5 , R 3 , R 5 , and L 4 is as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 1.4 , R 1.5 , R 3 , R 5 , and L 4 is as described herein, including the embodiments.

[0277] In embodiments, the compound has the formula: [ka] wherein R 1 , R 2 , R 5 , z1, z2, L 3 , L 4 and Ring B are as described herein, including embodiments.

[0278] In embodiments, the compound has the formula: [ka] wherein R 1.2 , R 1.3 , R 1.4 , R 1.5 , R 2 , R 5 , z2, L 3 , L 4 and Ring B are as described herein, including embodiments.

[0279] In embodiments, the compound has the formula: [ka] wherein R 1.2 , R 1.3 , R 1.4 , R 1.5 , R 2 , z2, R 11 , z11, R 21 , z21, R 5 , L 3 , L 4 , W 1 , W 2 , and W 3 is as described herein, including the embodiments.

[0280] In embodiments, the compound has the formula: [ka] R1.2 , R 1.3 , R 1.4 , R 1.5 , R 2 , z2, R 21 , z21, R 5 , L 3 , L 4 , W 1 , W 2 , and W 3 is as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 1.2 , R 1.3 , R 1.4 , R 1.5 , R 2 , z2, R 5 , L 3 , L 4 , W 1 , and W 2 is as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 1.2 , R 1.3 , R 1.4 , R 1.5 , R 2 , z2, R 5 , L 3 , and L 4 is as described herein, including embodiments. In embodiments, the compound has the formula: [ka] R 1.4 , R 1.5 , R 2 , z2, R 11 , z11, R 5 , L 3 , and L 4 is as described herein, including the embodiments.

[0281] In embodiments, the compound has the formula: [ka] wherein ring B is phenyl, 5- to 6-membered heteroaryl, or 9-membered heteroaryl; and R 2 , z2, R 5 , L 4 , and L 6 is as described herein, including embodiments. In embodiments, the compound has the formula: [ka] wherein ring B is phenyl, 5- to 6-membered heteroaryl, or 9-membered heteroaryl; and L 4 is -NH- or -NR 4 - and R 5 teeth, [ka] and R 2 , z2, R 4 , and L 6 is as described herein, including embodiments. In embodiments, the compound has the formula: [ka] wherein ring B is phenyl, 5- to 6-membered heteroaryl, or 9-membered heteroaryl; and L 4 is -NH- or -NR 4 - and R 5 is the expression: [ka] and R 2 , z2, R 4 , and L 6 is as described herein, including the embodiments.

[0282] In embodiments, the compound has the formula: [ka] wherein W5 is CH, Ring B is phenyl, and R 2 , z1, R 2 , z2, z6, R 5 , L 3 , and L 4 is as described herein, including embodiments. In embodiments, the compound has the formula: [ka] wherein W 5 is CH, Ring B is phenyl, and R 2 , z2, R 5 , L 3 , and L 4 is as described herein, including embodiments. In embodiments, the compound has the formula: [ka] wherein W 5 is CH, ring B is phenyl, and L 4 is -NH- and R 5 teeth, [ka] and R 2 , z2, and L 3 is as described herein, including the embodiments.

[0283] In embodiments, (Ring B)-(R 2 ) z2 teeth, [ka] is.

[0284] In embodiments, (Ring B)-(R 2 ) z2 teeth, [ka] In an embodiment, (Ring B)-(R 2 ) z2 teeth, [ka] In an embodiment, (Ring B)-(R 2 ) z2 [ka] In an embodiment, (Ring B)-(R 2 ) z2 [ka] In an embodiment, (Ring B)-(R 2 ) z2 [ka] In an embodiment, (Ring B)-(R 2 ) z2 [ka] In an embodiment, (Ring B)-(R 2 ) z2 [ka] In an embodiment, (Ring B)-(R 2 ) z2 [ka] In an embodiment, (Ring B)-(R 2 ) z2 [ka] .

[0285] R 1 are independently halogen, -CX 1 3. -CHX 1 2. -CH2X 1 , -OCX 1 3. -OCH2X 1, -OCHX 1 2, -CN, -SO n1 R 1D , -SO v1 NR 1A R 1B , -NR 1C NR 1A R 1B , -ONR 1A R 1B , -NHC(O)NR 1C NR 1A R 1B , -NHC(O)NR 1A R 1B , -N(O) m1 , -NR 1A R 1B , -C(O)R 1C , -C(O)-OR 1C , -C(O)NR 1A R 1B , -OR 1D , -NR 1A SO2R 1D , -NR 1A C(O)R 1C , -NR 1A C(O)OR 1C , -NR 1A OR 1C , -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted heteroaryl, and two adjacent R on adjacent carbons 1 The substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted phenyl, or a substituted or unsubstituted heteroaryl, or two R 1 The substituents may optionally be combined to form a substituted or unsubstituted alkyl or a substituted or unsubstituted heterocycloalkyl.

[0286] In embodiments, R 1 are independently halogen, -CX 1 3. -CHX 1 2. -CH2X 1, -OCX 1 3. -OCH2X 1 , -OCHX 1 2, -CN, -OH, -NH2, -COOH, -CONH2, -C(O)N(CH3)2, -NO2, -SH, -SO3H, -SO4H, -SON2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -SF5, -N3, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 2- to 6-membered heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted C6-C 10 aryl, or substituted or unsubstituted 5- to 10-membered heteroaryl, and two adjacent R 1 The substituents may optionally be joined to form a substituted or unsubstituted C3-C6 cycloalkyl, a substituted or unsubstituted 3- to 6-membered heterocycloalkyl, a substituted or unsubstituted phenyl, or a substituted or unsubstituted 5- to 6-membered heteroaryl, or two R 1 The substituents may optionally be joined to form a substituted or unsubstituted C3-C6 cycloalkyl or a substituted or unsubstituted 3- to 6-membered heterocycloalkyl.

[0287] In embodiments, R 1 are independently halogen, —CCl3, —CBr3, —CF3, —CI3, —CN, —OH, —NH2, —COOH, —CONH2, —OCCl3, —OCF3, —OCBr3, —OCI3, —N3, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted 2-4 membered heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5-6 membered heteroaryl. 1are independently halogen, —CCl3, —CBr3, —CF3, —CI3, —CN, —OH, —NH2, —COOH, —CONH2, —OCCl3, —OCF3, —OCBr3, —OCI3, —N3, substituted or unsubstituted C1-C3 alkyl, or substituted or unsubstituted 2-4 membered heteroalkyl. 1 are independently halogen. In embodiments, R 1 is independently -F. In an embodiment, R 1 is independently -Cl. In an embodiment, R 1 is independently -Br. In an embodiment, R 1 is independently -I. In an embodiment, R 1 is independently —CCl. In embodiments, R 1 is independently —CBr. In embodiments, R 1 is independently —CF. In an embodiment, R 1 is independently -CI. In an embodiment, R 1 is independently —CN. In embodiments, R 1 is independently —OH. In embodiments, R 1 is independently —NH. In an embodiment, R 1 is independently —COOH. In embodiments, R 1 is independently -CONH. In an embodiment, R 1 is independently —OCCl. In embodiments, R 1 is independently -OCF. In an embodiment, R 1 is independently —OCBr. In embodiments, R 1 is independently -OCI. In embodiments, R 1 is independently -N3. In an embodiment, R 1 is independently substituted or unsubstituted C1-C3 alkyl. In embodiments, R 1 is independently unsubstituted methyl. In embodiments, R 1 is independently unsubstituted ethyl. In embodiments, R 1 is independently unsubstituted propyl. In embodiments, R 1is independently a substituted or unsubstituted 2-4 membered heteroalkyl. In embodiments, R 1 is independently an unsubstituted 2-4 membered heteroalkyl. In embodiments, R 1 is independently substituted or unsubstituted C-C cycloalkyl. In embodiments, R 1 is independently a substituted or unsubstituted 3- to 6-membered heterocycloalkyl. 1 is independently substituted or unsubstituted phenyl. In embodiments, R 1 is independently a substituted or unsubstituted 5-6 membered heteroaryl. 1 is independently or substituted 5-6 membered heteroaryl. In embodiments, R 1 is independently an unsubstituted 5-6 membered heteroaryl. In embodiments, R 1 is independently an unsubstituted 5-membered heteroaryl. In embodiments, R 1 is independently an unsubstituted 6-membered heteroaryl.

[0288] In embodiments, two R on adjacent carbons 1 The substituents may be joined to form a substituted or unsubstituted phenyl, or a substituted or unsubstituted 5- to 6-membered heteroaryl. In embodiments, two R 1 The substituents are joined to form a substituted or unsubstituted phenyl. In embodiments, two R on adjacent carbons 1 The substituents are bonded together to form R 11 In embodiments, two R on adjacent carbons form a substituted phenyl. 1 The substituents are joined to form an unsubstituted phenyl. In embodiments, two R on adjacent carbons 1 The substituents are joined to form a substituted or unsubstituted 5- to 6-membered heteroaryl.

[0289] In embodiments, R 2 are independently oxo, halogen, -CX 2 3. -CHX 2 2. -CH2X 2 , -OCX 2 3. -OCH2X 2 , -OCHX2 2, -CN, -SO n2 R 2D , -SO v2 NR 2A R 2B , -NR 2C NR 2A R 2B , -ONR 2A R 2B , -NHC(O)NR 2C NR 2A R 2B , -NHC(O)NR 2A R 2B , -N(O) m2 , -NR 2A R 2B , -C(O)R 2C , -C(O)-OR 2C , -C(O)NR 2A R 2B , -OR 2D , -NR 2A SO2R 2D , -NR 2A C(O)R 2C , -NR 2A C(O)OR 2C , -NR 2A OR 2C , -SF5, -N3, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 2- to 6-membered heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted C6-C 10 aryl, or substituted or unsubstituted 5- to 10-membered heteroaryl, and two adjacent R 2 The substituents may optionally be combined to form a substituted or unsubstituted C3-C6 cycloalkyl, a substituted or unsubstituted 3- to 6-membered heterocycloalkyl, a substituted or unsubstituted phenyl, or a substituted or unsubstituted 5- to 6-membered heteroaryl.

[0290] In embodiments, R 2 are independently halogen, —OCCl3, —OCF3, —OCBr3, —OCI3, or substituted or unsubstituted 5-6 membered heteroaryl. 2 are independently halogen. In embodiments, R2 is independently -F. In an embodiment, R 2 is independently -Cl. In an embodiment, R 2 is independently -Br. In an embodiment, R 2 is independently -I. In an embodiment, R 2 is independently —OCCl. In embodiments, R 2 is independently -OCF. In an embodiment, R 2 is independently —OCBr. In embodiments, R 2 is independently -OCI. In embodiments, R 2 is an unsubstituted 5-6 membered heteroaryl. In embodiments, R 2 is an unsubstituted 5-membered heteroaryl. In embodiments, R 2 is an unsubstituted 6-membered heteroaryl. In embodiments, R 2 is unsubstituted pyrrolyl, pyrazolyl, pyridazinyl, triazinyl, pyrimidinyl, imidazolyl, pyrazinyl, oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzofuran, isobenzofuranyl, indolyl, or isoindolyl. 2 is unsubstituted phenyl, benzimidazolyl, or indolyl. 2 is unsubstituted pyrrolyl. In embodiments, R 2 is unsubstituted pyrazolyl. In embodiments, R 2 is unsubstituted pyridazinyl. In embodiments, R 2 is unsubstituted triazinyl. In embodiments, R 2 is unsubstituted pyrimidinyl. In embodiments, R 2 is unsubstituted imidazolyl. In embodiments, R 2 is unsubstituted pyrazinyl. In embodiments, R 2 is unsubstituted oxazolyl. In embodiments, R 2 is unsubstituted isoxazolyl. In embodiments, R 2 is unsubstituted thiazolyl. In embodiments, R 2is unsubstituted furyl. In embodiments, R 2 is unsubstituted thienyl. In embodiments, R 2 is unsubstituted pyridyl. In embodiments, R 2 is unsubstituted pyrimidyl. In embodiments, R 2 is unsubstituted benzothiazolyl. In embodiments, R 2 is unsubstituted benzoxazolyl. In embodiments, R 2 is unsubstituted benzimidazolyl. In embodiments, R 2 is an unsubstituted benzofuran. In embodiments, R 2 is unsubstituted isobenzofuranyl. In embodiments, R 2 is an unsubstituted indolyl. In embodiments, R 2 is unsubstituted isoindolyl. In embodiments, R 2 are independently -F or -OCF3.

[0291] In embodiments, R 2 are independently halogen, —OCCl3, —OCF3, —OCBr3, —OCI3, or substituted 5-6 membered heteroaryl. 2 are independently halogen. In embodiments, R 2 is independently -F. In an embodiment, R 2 is independently -Cl. In an embodiment, R 2 is independently -Br. In an embodiment, R 2 is independently -I. In an embodiment, R 2 is independently —OCCl. In embodiments, R 2 is independently -OCF. In an embodiment, R 2 is independently —OCBr. In embodiments, R 2 is independently -OCI. In embodiments, R 2 is a substituted 5-6 membered heteroaryl. In embodiments, R 2 is a substituted 5-membered heteroaryl. In embodiments, R 2 is a substituted 6-membered heteroaryl. In embodiments, R 2is a substituted pyrrolyl, pyrazolyl, pyridazinyl, triazinyl, pyrimidinyl, imidazolyl, pyrazinyl, oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzofuran, isobenzofuranyl, indolyl, or isoindolyl. 2 is a substituted phenyl, benzimidazolyl, or indolyl. 2 is a substituted pyrrolyl. In embodiments, R 2 is a substituted pyrazolyl. In embodiments, R 2 is a substituted pyridazinyl. In embodiments, R 2 is a substituted triazinyl. In embodiments, R 2 is a substituted pyrimidinyl. In embodiments, R 2 is a substituted imidazolyl. In embodiments, R 2 is a substituted pyrazinyl. In embodiments, R 2 is a substituted oxazolyl. In embodiments, R 2 is a substituted isoxazolyl. In embodiments, R 2 is a substituted thiazolyl. In embodiments, R 2 is a substituted furyl. In embodiments, R 2 is substituted thienyl. In embodiments, R 2 is a substituted pyridyl. In embodiments, R 2 is substituted pyrimidyl. In embodiments, R 2 is a substituted benzothiazolyl. In embodiments, R 2 is a substituted benzoxazolyl. In embodiments, R 2 is a substituted benzimidazolyl. In embodiments, R 2 is a substituted benzofuran. In embodiments, R 2 is substituted isobenzofuranyl. In embodiments, R 2 is a substituted indolyl. In embodiments, R 2 is a substituted isoindolyl. In embodiments, R 2 are independently -F or -OCF3.

[0292] In an embodiment, L 3 is a bond, -S(O)2-, -NR 3 -, -NH-, -O-, -S-, -C(O)-, -C(O)NR 3 -, -NR 3 C(O)-, -N(R 3 )CH2-, -NR 3 C(O)NH-, -NHC(O)NR 3 -, -C(O)O-, -OC(O)-, substituted or unsubstituted C1-C6 alkylene, or substituted or unsubstituted 2- to 6-membered heteroalkylene.

[0293] In an embodiment, L 3 -C(O)-, -CH2-, -C(O)NR 3 -, -CH2CH2NR 3 -, -C(O)CH2NR 3 - or -CH2C(O)NR 3 In an embodiment, L 3 is —C(O)—. In embodiments, L 3 is -CH-. In embodiments, L 3 is -C(O)NR 3 In an embodiment, L 3 is -CH2CH2NR 3 In an embodiment, L 3 is -C(O)CH2NR 3 In an embodiment, L 3 is -CH2C(O)NR 3 In an embodiment, L 3 is —C(O)—, —CH—, —C(O)NH—, —CHCHNH—, —C(O)CHNH—, or —CHC(O)NH. 3 is —CH— or —C(O)NH—. In embodiments, L 3 is —C(O)NH—. In embodiments, L 3 is —CH2CH2NH—. In embodiments, L 3 is —C(O)CHNH—. In embodiments, L 3 is —CHC(O)NH. In embodiments, L3 is a bond, substituted or unsubstituted C1-C6 alkylene, or substituted or unsubstituted 2- to 6-membered heteroalkylene. 2 is a bond. In embodiments, L 3 is a substituted or unsubstituted C1-C6 alkylene. 3 is a substituted or unsubstituted 2- to 6-membered heteroalkylene.

[0294] In an embodiment, L 4 is -NH-.

[0295] In an embodiment, L 4 is -CH2-.

[0296] In an embodiment, L 4 is -N(CH3)-.

[0297] In an embodiment, L 6 is -N(R 6 )-L 3 In an embodiment, L 6 is -N(R 6 )-L 3 -It is. L 3 is -CH2- and R 6 is as described herein, including the embodiments.

[0298] In an embodiment, L 6 is -N(R 6 )-L 3 -It is. L 3 is -CH2- and R 6 is -CF3, -COCH3, or cyclopropyl.

[0299] In an embodiment, L 6 is —C(O)NH—.

[0300] In an embodiment, W 5 is CH. In an embodiment, W 5 is N.

[0301] In embodiments, R 3 , R 4 , and R 6 are independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CO(C1-C6 alkyl), -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, unsubstituted C1-C6 alkyl, unsubstituted 2- to 6-membered heteroalkyl, unsubstituted C3-C6 cycloalkyl, or unsubstituted 3- to 6-membered heterocycloalkyl.

[0302] In embodiments, R 3 , R 4 , and R 6 are independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, unsubstituted C1-C6 alkyl, or unsubstituted 2- to 6-membered heteroalkyl.

[0303] In embodiments, R 3 are independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -COCH3, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, unsubstituted C1-C6 alkyl, unsubstituted 2- to 6-membered heteroalkyl, unsubstituted C3-C6 cycloalkylene, or unsubstituted 3- to 6-membered heterocycloalkylene.

[0304] In embodiments, R 3 are independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, unsubstituted C1-C6 alkyl, or unsubstituted 2- to 6-membered heteroalkyl.

[0305] In embodiments, R 4 are independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -COCH3, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, unsubstituted C1-C6 alkyl, unsubstituted 2- to 6-membered heteroalkyl, unsubstituted C3-C6 cycloalkylene, or unsubstituted 3- to 6-membered heterocycloalkylene.

[0306] In embodiments, R 4 are independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, unsubstituted C1-C6 alkyl, or unsubstituted 2- to 6-membered heteroalkyl.

[0307] In embodiments, R 6are independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -COCH3, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, unsubstituted C1-C6 alkyl, unsubstituted 2- to 6-membered heteroalkyl, unsubstituted C3-C6 cycloalkylene, or unsubstituted 3- to 6-membered heterocycloalkylene.

[0308] In embodiments, R 6 are independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, unsubstituted C1-C6 alkyl, or unsubstituted 2- to 6-membered heteroalkyl.

[0309] In embodiments, R 3 are independently hydrogen. In embodiments, R 3 is independently —CCl. In embodiments, R 3 is independently —CBr. In embodiments, R 3 is independently —CF. In an embodiment, R 3 is independently -CI. In an embodiment, R 3 is independently CHCl. ​​In embodiments, R 3 is independently —CHBr. In embodiments, R 3 is independently -CHF. In an embodiment, R 3 is independently -CHI. In embodiments, R 3 is independently —C(O)CH. In embodiments, R 3is independently —CH2Cl. In embodiments, R 3 is independently —CHBr. In embodiments, R 3 is independently -CHF. In an embodiment, R 3 is independently -CH2I. In embodiments, R 3 is independently unsubstituted C1-C6 alkyl. In embodiments, R 3 is independently unsubstituted C1-C2 alkyl. In embodiments, R 3 is independently unsubstituted methyl. In embodiments, R 3 is independently an unsubstituted 2-6 membered heteroalkyl. In embodiments, R 3 is independently unsubstituted C-C cycloalkyl. In embodiments, R 3 is independently unsubstituted cyclopropyl. In embodiments, R 3 is independently unsubstituted cyclobutyl. In embodiments, R 3 is independently unsubstituted cyclopentyl. In embodiments, R 3 is independently unsubstituted cyclohexyl. In embodiments, R 3 is independently an unsubstituted 3- to 6-membered heterocycloalkyl.

[0310] In embodiments, R 4 are independently hydrogen. In embodiments, R 4 is independently —CCl. In embodiments, R 4 is independently —CBr. In embodiments, R 4 is independently —CF. In an embodiment, R 4 is independently -CI. In an embodiment, R 4 is independently CHCl. ​​In embodiments, R 4 is independently —CHBr. In embodiments, R 4 is independently -CHF. In an embodiment, R 4 is independently -CHI. In embodiments, R 4 is independently —CH2Cl. In embodiments, R 4 is independently —CHBr. In embodiments, R4 is independently -CHF. In an embodiment, R 4 is independently -CH2I. In embodiments, R 4 is independently —C(O)CH. In embodiments, R 4 is independently unsubstituted C1-C6 alkyl. In embodiments, R 4 is independently unsubstituted C1-C2 alkyl. In embodiments, R 4 is independently unsubstituted methyl. In embodiments, R 4 is independently an unsubstituted 2-6 membered heteroalkyl. In embodiments, R 4 is independently unsubstituted C-C cycloalkyl. In embodiments, R 4 is independently unsubstituted cyclopropyl. In embodiments, R 4 is independently unsubstituted cyclobutyl. In embodiments, R 4 is independently unsubstituted cyclopentyl. In embodiments, R 4 is independently unsubstituted cyclohexyl. In embodiments, R 4 is independently an unsubstituted 3- to 6-membered heterocycloalkyl.

[0311] In embodiments, R 6 are independently hydrogen. In embodiments, R 6 is independently —CCl. In embodiments, R 6 is independently —CBr. In embodiments, R 6 is independently —CF. In an embodiment, R 6 is independently -CI. In an embodiment, R 6 is independently CHCl. ​​In embodiments, R 6 is independently —CHBr. In embodiments, R 6 is independently -CHF. In an embodiment, R 6 is independently -CHI. In embodiments, R 6 is independently —CH2Cl. In embodiments, R 6 is independently —CHBr. In embodiments, R 6is independently -CHF. In an embodiment, R 6 is independently -CH2I. In embodiments, R 6 is independently —C(O)CH. In embodiments, R 6 is independently unsubstituted C1-C6 alkyl. In embodiments, R 6 is independently unsubstituted C1-C2 alkyl. In embodiments, R 6 is independently unsubstituted methyl. In embodiments, R 6 is independently an unsubstituted 2-6 membered heteroalkyl. In embodiments, R 6 is unsubstituted C-C cycloalkyl. In embodiments, R 6 is independently unsubstituted cyclopropyl. In embodiments, R 6 is independently unsubstituted cyclobutyl. In embodiments, R 6 is independently unsubstituted cyclopentyl. In embodiments, R 6 is independently unsubstituted cyclohexyl. In embodiments, R 6 is independently an unsubstituted 3- to 6-membered heterocycloalkyl.

[0312] In embodiments, R 7 are independently hydrogen or substituted or unsubstituted C-C 10 In embodiments, R 7 are independently hydrogen or unsubstituted C1-C6 alkyl. In embodiments, R 7 are independently hydrogen or unsubstituted C1-C4 alkyl. In embodiments, R 7 are independently hydrogen or unsubstituted methyl. In embodiments, R 7 are independently hydrogen or unsubstituted ethyl. In embodiments, R 7 are independently hydrogen. In embodiments, R 7 is independently unsubstituted methyl. In embodiments, R 7 is independently unsubstituted ethyl.

[0313] In embodiments, R 8 are independently hydrogen or substituted or unsubstituted C-C 10In embodiments, R 8 are independently hydrogen or unsubstituted C1-C6 alkyl. In embodiments, R 8 are independently hydrogen or unsubstituted C1-C4 alkyl. In embodiments, R 8 are independently hydrogen or unsubstituted methyl. In embodiments, R 8 are independently hydrogen or unsubstituted ethyl. In embodiments, R 8 are independently hydrogen. In embodiments, R 8 is independently unsubstituted methyl. In embodiments, R 8 is independently unsubstituted ethyl.

[0314] In embodiments, R 9 are independently hydrogen or substituted or unsubstituted C-C 10 In embodiments, R 9 are independently hydrogen or unsubstituted C1-C6 alkyl. In embodiments, R 9 are independently hydrogen or unsubstituted C1-C4 alkyl. In embodiments, R 9 are independently hydrogen or unsubstituted methyl. In embodiments, R 9 are independently hydrogen or unsubstituted ethyl. In embodiments, R 9 are independently hydrogen. In embodiments, R 9 is independently unsubstituted methyl. In embodiments, R 9 is independently unsubstituted ethyl.

[0315] In embodiments, R 10 are independently hydrogen or substituted or unsubstituted C-C 10 In embodiments, R 10 are independently hydrogen or unsubstituted C1-C6 alkyl. In embodiments, R 10 are independently hydrogen or unsubstituted C1-C4 alkyl. In embodiments, R 10 are independently hydrogen or unsubstituted methyl. In embodiments, R 10 are independently hydrogen or unsubstituted ethyl. In embodiments, R 10are independently hydrogen. In embodiments, R 10 is independently unsubstituted methyl. In embodiments, R 10 is independently unsubstituted ethyl.

[0316] In embodiments, R 7 and R 8 is hydrogen. In embodiments, R 7 and R 8 is unsubstituted C1-C6 alkyl. In embodiments, R 7 and R 8 is unsubstituted methyl. In embodiments, R 9 and R 10 is hydrogen. In embodiments, R 9 and R 10 is unsubstituted C1-C6 alkyl. In embodiments, R 9 and R 10 is unsubstituted methyl. In embodiments, R 7 and R 8 is hydrogen and R 9 and R 10 is unsubstituted C1-C6 alkyl. In embodiments, R 7 and R 8 is hydrogen and R 9 and R 10 is unsubstituted methyl. In embodiments, R 9 and R 10 is hydrogen and R 7 and R 8 is unsubstituted C1-C6 alkyl. In embodiments, R 9 and R 10 is hydrogen and R 7 and R 8 is unsubstituted methyl.

[0317] In embodiments, Ring B is aryl. In embodiments, Ring B is C-C 10 In embodiments, Ring B is aryl. In embodiments, Ring B is phenyl. In embodiments, Ring B is C aryl. In embodiments, Ring B is C 10In embodiments, Ring B is aryl. In embodiments, Ring B is heteroaryl. In embodiments, Ring B is 5-10 membered heteroaryl. In embodiments, Ring B is 5-6 membered heteroaryl. In embodiments, Ring B is 9-10 membered heteroaryl. In embodiments, Ring B is 5-membered heteroaryl. In embodiments, Ring B is 6-membered heteroaryl. In embodiments, Ring B is pyrrolyl, pyrazolyl, pyridazinyl, triazinyl, pyrimidinyl, imidazolyl, pyrazinyl, oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzofuran, isobenzofuranyl, indolyl, or isoindolyl. In embodiments, Ring B is phenyl, benzimidazolyl, or indolyl. In embodiments, Ring B is pyrrolyl. In embodiments, Ring B is pyrazolyl. In embodiments, Ring B is pyridazinyl. In embodiments, Ring B is triazinyl. In embodiments, Ring B is pyrimidinyl. In embodiments, Ring B is imidazolyl. In embodiments, Ring B is pyrazinyl. In embodiments, Ring B is oxazolyl. In embodiments, Ring B is isoxazolyl. In embodiments, Ring B is thiazolyl. In embodiments, Ring B is furyl. In embodiments, Ring B is thienyl. In embodiments, Ring B is pyridyl. In embodiments, Ring B is pyrimidyl. In embodiments, Ring B is benzothiazolyl. In embodiments, Ring B is benzoxazolyl. In embodiments, Ring B is benzimidazolyl. In embodiments, Ring B is benzofuran. In embodiments, Ring B is isobenzofuranyl. In embodiments, Ring B is indolyl. In embodiments, Ring B is isoindolyl.

[0318] In embodiments, -(Ring B)-(R 2 ) z2 C is R 2 Substituted or unsubstituted (C6-C 10 ) aryl. In embodiments, ring B is R 2 In an embodiment, ring B is R 2In an embodiment, ring B is R 2 Substituted or unsubstituted C 10 In embodiments, ring B is R 2 In an embodiment, ring B is a substituted or unsubstituted 5-10 membered heteroaryl. 2 In an embodiment, ring B is a substituted or unsubstituted 5-6 membered heteroaryl. 2 In an embodiment, ring B is a substituted or unsubstituted 9-10 membered heteroaryl. 2 In an embodiment, ring B is a substituted or unsubstituted 5-membered heteroaryl. 2 In an embodiment, ring B is a substituted or unsubstituted 6-membered heteroaryl. 2 In an embodiment, Ring B is substituted or unsubstituted pyrrolyl, pyrazolyl, pyridazinyl, triazinyl, pyrimidinyl, imidazolyl, pyrazinyl, oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzofuran, isobenzofuranyl, indolyl, or isoindolyl. 2 In an embodiment, ring B is R 2 In an embodiment, ring B is R 2 In an embodiment, ring B is R 2 In an embodiment, ring B is R 2 In an embodiment, ring B is R 2 In an embodiment, ring B is R 2 In an embodiment, ring B is R 2 In an embodiment, ring B is R 2 In an embodiment, ring B is R 2 In an embodiment, ring B is R 2 In an embodiment, ring B is R2 In an embodiment, ring B is substituted or unsubstituted furyl. 2 In an embodiment, ring B is R 2 In an embodiment, ring B is R 2 In an embodiment, ring B is R 2 In an embodiment, ring B is R 2 In an embodiment, ring B is R 2 In an embodiment, ring B is R 2 In an embodiment, ring B is a substituted or unsubstituted benzofuran. 2 In an embodiment, ring B is R 2 In embodiments, ring B is R 2 It is a substituted or unsubstituted isoindolyl.

[0319] In embodiments, ring B has the formula: [ka] R 2.1 and R 2.2 is as described herein, including the embodiments.

[0320] In embodiments, ring B has the formula: [ka] R 2.1 is as described herein, including embodiments. In embodiments, ring B is of the formula: [ka] R 2.1 and R 2.2 is as described herein, including embodiments. In embodiments, ring B is of the formula: [ka] R 2.1 is as described herein, including embodiments. In embodiments, ring B is of the formula: [ka] R 2.1 and R 2.2 is as described herein, including embodiments. In embodiments, ring B is of the formula: [ka] R 2.1 is as described herein, including embodiments. In embodiments, ring B is of the formula: [ka] R 2.1 and R 2.2 is as described herein, including the embodiments.

[0321] In embodiments, ring B has the formula: [ka] R 2 , z2, W 1 , W 2 , and W 3 is as described herein, including the embodiments.

[0322] In embodiments, R 5 is independent, [ka] R 16 , R 17 , and R 18 is as described herein, including embodiments. In embodiments, R 5 is independent, [ka] R 17 is as described herein, including embodiments. In embodiments, R 5 is independent, [ka] R 17 is as described herein, including embodiments. In embodiments, R 5 is independent, [ka] R 17 is as described herein, including embodiments. In embodiments, R 5 is independent, [ka] R 17 is as described herein, including embodiments. In embodiments, R 5 is independent, [ka] R 16 , R 17 , and R 18 is as described herein, including embodiments. In embodiments, R 5 is independent, [ka] R 16 , R 17 , and R 18 is as described herein, including embodiments. In embodiments, R 5 is independent, [ka] R 16 , R 17 , and R 18 is as described herein, including embodiments. In embodiments, R 5is independent, [ka] R 16 , R 17 , R 18 , and R 19 is as described herein, including embodiments. In embodiments, R 5 is independent, [ka] R 16 , R 17 , R 18 , R 19 , and R 20 is as described herein, including embodiments. In embodiments, R 5 is independent, [ka] R 15 , R 16 , R 17 , and R 18 is as described herein, including embodiments. In embodiments, R 5 is independent, [ka] R 14 , R 16 , R 17 , and R 18 is as described herein, including embodiments. In embodiments, R 5 is independent, [ka] R 16 , R 17 , and R 18 is as described herein, including embodiments. In embodiments, R 5 is independent, [ka] R 14 , R 15 , R 16 , R 17 , and R 18 is as described herein, including the embodiments.

[0323] In embodiments, R 5 is independent, [ka] R 17 is substituted or unsubstituted alkyl. In embodiments, R 17 is unsubstituted alkyl. In embodiments, R 17 is unsubstituted methyl. In embodiments, R 17 is unsubstituted ethyl. In embodiments, R 17 is unsubstituted propyl.

[0324] In embodiments, R 5 is independent, [ka] R 16 , R 17 , and R 18 is as described herein, including embodiments. 19 is hydrogen, —CF, —CN, or unsubstituted methyl. In embodiments, R 19 is hydrogen. In embodiments, R 19 is —CF. In embodiments, R 19 is -CN. In embodiments, R 19 is unsubstituted methyl. In embodiments, R 16 , R 17 , and R 18 is hydrogen.

[0325] In embodiments, R 5 is independent, [ka] R16 , R 17 , and R 18 is as described herein, including embodiments. 19 and R 20 are independently hydrogen, —CF, —CN, or unsubstituted methyl. In embodiments, R 19 is hydrogen. In embodiments, R 19 is —CF. In embodiments, R 19 is -CN. In embodiments, R 19 is unsubstituted methyl. In embodiments, R 20 is hydrogen. In embodiments, R 20 is —CF. In embodiments, R 20 is -CN. In embodiments, R 20 is unsubstituted methyl. In embodiments, R 16 , R 17 , and R 18 is hydrogen.

[0326] In embodiments, R 5 is independent, [ka] R 15 , R 16 , R 17 , and R 18 is as described herein, including embodiments. In embodiments, R 17 is substituted or unsubstituted phenyl. In embodiments, R 5 is independent, [ka] R 14 , R 16 , R 17 , and R 18 is as described herein, including embodiments. In embodiments, R 17 is substituted or unsubstituted phenyl. In embodiments, R 5 is independent, [ka] R 16 , R 17 , and R 18 is as described herein, including embodiments. In embodiments, R 17 is substituted or unsubstituted phenyl. In embodiments, R 5 is independent, [ka] R 14 , R 15 , R 16 , R 17 , and R 18 is as described herein, including embodiments. In embodiments, R 17 is substituted or unsubstituted phenyl.

[0327] In embodiments, R 14 are independently =O. In embodiments, R 14 are independent, =NR 19 is.

[0328] In embodiments, R 15 are independently =O. In embodiments, R 15 are independent, =NR 20 is.

[0329] In embodiments, R 5 is independent, [ka] R 16 and R 17 is as described herein, including the embodiments.

[0330] In embodiments, R 5 is independent, [ka] R 17 is as described herein, including the embodiments.

[0331] In embodiments, R 5 is independent, [ka] R 17 is as described herein, including embodiments. In embodiments, R 17 is substituted or unsubstituted heteroaryl. In embodiments, R 17 is a substituted or unsubstituted 5-6 membered heteroaryl. 17 is a substituted or unsubstituted pyrrolyl, pyrazolyl, pyridazinyl, triazinyl, pyrimidinyl, imidazolyl, pyrazinyl, oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, or pyrimidyl. 17 is a substituted or unsubstituted triazinyl. In embodiments, R 17 is unsubstituted triazinyl. In embodiments, R 17 is a substituted or unsubstituted benzothiazolyl, benzoxazolyl, benzimidazolyl, benzofuran, isobenzofuranyl, indolyl, isoindolyl, benzothiophenyl, isoquinolyl, quinoxalinyl, or quinolyl.

[0332] In embodiments, R 5 is independent, [ka] R 16 is as described herein, including embodiments. In embodiments, R 16 is substituted or unsubstituted heteroaryl. In embodiments, R 16 is a substituted or unsubstituted 5-6 membered heteroaryl. 16 is a substituted or unsubstituted pyrrolyl, pyrazolyl, pyridazinyl, triazinyl, pyrimidinyl, imidazolyl, pyrazinyl, oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, or pyrimidyl. 16is a substituted or unsubstituted triazinyl. In embodiments, R 16 is unsubstituted triazinyl. In embodiments, R 16 is a substituted or unsubstituted benzothiazolyl, benzoxazolyl, benzimidazolyl, benzofuran, isobenzofuranyl, indolyl, isoindolyl, benzothiophenyl, isoquinolyl, quinoxalinyl, or quinolyl.

[0333] In embodiments, R 5 is independent, [ka] R 17 is as described herein, including embodiments. In embodiments, R 5 is independent, [ka] R 17 is as described herein, including embodiments. In embodiments, R 5 is independent, [ka] R 17 is as described herein, including embodiments. In embodiments, R 5 is independent, [ka] R 17 is as described herein, including embodiments. In embodiments, R 5 is independent, [ka] R 17 is as described herein, including embodiments. In embodiments, R 5 is independent, [ka] R 17 is as described herein, including embodiments. In embodiments, R 5 is independent, [ka] R 17 is as described herein, including embodiments. In embodiments, R 5 is independent, [ka] R 17 is as described herein, including the embodiments.

[0334] In embodiments, R 5 is independent, [ka] In an embodiment, R 17 is substituted or unsubstituted aryl. In embodiments, R 17 is substituted or unsubstituted phenyl. In embodiments, R 17 is unsubstituted phenyl. In embodiments, R 5 is independent, [ka] In an embodiment, R 17 is substituted or unsubstituted aryl. In embodiments, R 17 is substituted or unsubstituted phenyl. In embodiments, R 17 is unsubstituted phenyl. In embodiments, R 5 is independent, [ka] In an embodiment, R 17 is substituted or unsubstituted aryl. In embodiments, R 17 is substituted or unsubstituted phenyl. In embodiments, R 17is unsubstituted phenyl. In embodiments, R 5 is independent, [ka] In an embodiment, R 17 is substituted or unsubstituted aryl. In embodiments, R 17 is substituted or unsubstituted phenyl. In embodiments, R 17 is unsubstituted phenyl. In embodiments, R 5 is independent, [ka] In an embodiment, R 17 is substituted or unsubstituted aryl. In embodiments, R 17 is substituted or unsubstituted phenyl. In embodiments, R 17 is unsubstituted phenyl. In embodiments, R 5 is independent, [ka] In an embodiment, R 17 is substituted or unsubstituted aryl. In embodiments, R 17 is substituted or unsubstituted phenyl. In embodiments, R 17 is unsubstituted phenyl. In embodiments, R 5 is independent, [ka] In an embodiment, R 17 is substituted or unsubstituted aryl. In embodiments, R 17 is substituted or unsubstituted phenyl. In embodiments, R 17 is unsubstituted phenyl. In embodiments, R 5 is independent, [ka] In an embodiment, R 17is substituted or unsubstituted aryl. In embodiments, R 17 is substituted or unsubstituted phenyl. In embodiments, R 17 is unsubstituted phenyl.

[0335] In embodiments, R 5 is independent, [ka] is.

[0336] In embodiments, R 5 is independent, [ka] In an embodiment, R 5 is independent, [ka] In an embodiment, R 5 is independent, [ka] In an embodiment, R 5 is independent, [ka] In an embodiment, R 5 is independent, [ka] In an embodiment, R 5 is independent, [ka] In an embodiment, R 5 is independent, [ka] In an embodiment, R 5 is independent, [ka] In an embodiment, R 5 is independent, [ka] In an embodiment, R 5 is independent, [ka] In an embodiment, R 5 is independent, [ka] In an embodiment, R 5 is independent, [ka] In an embodiment, R 5 is independent, [ka] In an embodiment, R 5 is independent, [ka] In an embodiment, R 5 is independent, [ka] In an embodiment, R 5 is independent, [ka] In an embodiment, R 5 is independent, [ka] In an embodiment, R 5 is independent, [ka] is.

[0337] In an embodiment, L 4 -R 5 is independent, [ka] R 16 , R 17 , R 18 , and R 19 is as described herein, including embodiments. 16 , R 17 , and R 18 is as described herein, including embodiments. 19 is hydrogen, —CF, —CN, or unsubstituted methyl. In embodiments, R 19 is hydrogen. In embodiments, R 19 is —CF. In embodiments, R 19 is -CN. In embodiments, R 19 is unsubstituted methyl. In embodiments, R 16 , R 17 , and R 18 is hydrogen.

[0338] In an embodiment, L 4 -R 5 is independent, [ka] R 16 , R 17 , R 18 , and R 19 is as described herein, including embodiments. 16 , R 17 , and R 18 is as described herein, including embodiments. 19 is hydrogen, —CF, —CN, or unsubstituted methyl. In embodiments, R 19 is hydrogen. In embodiments, R 19is —CF. In embodiments, R 19 is -CN. In embodiments, R 19 is unsubstituted methyl. In embodiments, R 16 , R 17 , and R 18 is hydrogen.

[0339] In an embodiment, L 4 -R 5 is independent, [ka] R 16 , R 17 , and R 18 is as described herein, including embodiments. 19 and R 20 are independently hydrogen, —CF, —CN, or unsubstituted methyl. In embodiments, R 19 and R 20 are independently hydrogen or unsubstituted methyl. In embodiments, R 19 is hydrogen. In embodiments, R 19 is unsubstituted methyl. In embodiments, R 20 is hydrogen. In embodiments, R 20 is unsubstituted methyl. In embodiments, R 16 , R 17 , and R 18 is hydrogen.

[0340] In an embodiment, L 4 -R 5 is independent, [ka] R 15 , R 16 , R 17 , and R 18 is as described herein, including embodiments. In embodiments, R 17 is substituted or unsubstituted phenyl. In embodiments, L 4 -R 5 is independent, [ka] R 14 , R 16 , R 17 , and R 18 is as described herein, including embodiments. In embodiments, R 17 is substituted or unsubstituted phenyl. In embodiments, L 4 -R 5 is independent, [ka] R 16 , R 17 , and R 18 is as described herein, including embodiments. In embodiments, R 17 is substituted or unsubstituted phenyl. In embodiments, L 4 -R 5 is independent, [ka] R 14 , R 15 , R 16 , R 17 , and R 18 is as described herein, including embodiments. In embodiments, R 17 is substituted or unsubstituted phenyl.

[0341] In an embodiment, L 4 -R 5 is independent, [ka] R 15 is as described herein, including embodiments, and R 17 is a substituted or unsubstituted phenyl, and R 16 and R 18 is hydrogen. In embodiments, L 4 -R 5 is independent, [ka] R 15 is as described herein, including embodiments, and R 17 is a substituted or unsubstituted phenyl, and R 16 and R 18 is hydrogen. In embodiments, L 4 -R 5 is independent, [ka] R 15 is as described herein, including embodiments, and R 17 is a substituted or unsubstituted phenyl, and R 16 and R 18 is hydrogen. In embodiments, L 4 -R 5 is independent, [ka] R 15 is as described herein, including embodiments, and R 17 is a substituted or unsubstituted phenyl, and R 16 and R 18 is hydrogen.

[0342] In an embodiment, L 4 -R 5 is independent, [ka] In an embodiment, L 4 -R 5 is independent, [ka] In an embodiment, L 4 -R 5 is independent, [ka] In an embodiment, L 4-R 5 is independent, [ka] In an embodiment, L 4 -R 5 is independent, [ka] In an embodiment, L 4 -R 5 is independent, [ka] In an embodiment, L 4 -R 5 is independent, [ka] In an embodiment, L 4 -R 5 is independent, [ka] In an embodiment, L 4 -R 5 is independent, [ka] is.

[0343] In embodiments, R 16 , R 17 , and R 18are independently hydrogen, oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -C(O)N(CH3)2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC( O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 2-6 membered heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted C6-C 12 It is aryl, or substituted or unsubstituted 5- to 12-membered heteroaryl.

[0344] In embodiments, R 16 , R 17 , and R 18 are independently hydrogen, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted 2-6 membered heteroalkyl. 16 , R 17 , and R 18 are independently hydrogen. In embodiments, R 16 , R 17 , and R 18 is independently substituted or unsubstituted C1-C6 alkyl. In embodiments, R 16 , R 17 , and R 18 is independently a substituted or unsubstituted 2-6 membered heteroalkyl. In embodiments, R 16 , R 17 , and R 18 is independently a substituted or unsubstituted 2-3 membered heteroalkyl. In embodiments, R 16 , R 17 , and R 18is independently hydrogen or —C(O)N(CH). In embodiments, R 16 , R 17 , and R 18 are independently hydrogen or substituted or unsubstituted C1-C6 alkyl. In embodiments, R 16 , R 17 , and R 18 are independently hydrogen or substituted or unsubstituted C1-C4 alkyl. In embodiments, R 16 , R 17 , and R 18 are independently hydrogen or substituted or unsubstituted C1-C2 alkyl. In embodiments, R 16 , R 17 , and R 18 are independently hydrogen or unsubstituted methyl. In embodiments, R 16 and R 17 is hydrogen and R 18 is unsubstituted methyl. In embodiments, R 16 and R 18 is hydrogen and R 17 is —C(O)N(CH) In embodiments, R 16 , R 17 , and R 18 is hydrogen. In embodiments, R 17 is hydrogen or substituted or unsubstituted C1-C4 alkyl. In embodiments, R 17 is hydrogen. In embodiments, R 17 is unsubstituted methyl. In embodiments, R 17 is ethyl. In embodiments, R 17 is propyl. In embodiments, R 17 is isopropyl. In embodiments, R 17 is n-propyl.

[0345] In embodiments, R 16 and R 18 is hydrogen and R 17 is substituted or unsubstituted aryl. In embodiments, R 16 and R 18 is hydrogen and R 17 is unsubstituted C6-C12 In embodiments, R 16 and R 18 is hydrogen and R 17 is substituted or unsubstituted phenyl. In embodiments, R 16 and R 18 is hydrogen and R 17 is unsubstituted phenyl.

[0346] In embodiments, R 16 and R 18 is hydrogen and R 17 is a substituted or unsubstituted 5-6 membered heteroaryl. 16 and R 18 is hydrogen and R 17 is an unsubstituted 5-6 membered heteroaryl. In embodiments, R 16 and R 18 is hydrogen and R 17 is substituted or unsubstituted pyrrolyl. In embodiments, R 16 and R 18 is hydrogen and R 17 is substituted or unsubstituted pyrazolyl. In embodiments, R 16 and R 18 is hydrogen and R 17 is substituted or unsubstituted pyridazinyl. In embodiments, R 16 and R 18 is hydrogen and R 17 is a substituted or unsubstituted triazinyl. In embodiments, R 16 and R 18 is hydrogen and R 17 is substituted or unsubstituted pyrimidinyl. In embodiments, R 16 and R 18 is hydrogen and R 17 is substituted or unsubstituted imidazolyl. In embodiments, R 16 and R 18 is hydrogen and R 17 is substituted or unsubstituted pyrazinyl. In embodiments, R 16 and R 18 is hydrogen and R 17is substituted or unsubstituted oxazolyl. In embodiments, R 16 and R 18 is hydrogen and R 17 is substituted or unsubstituted isoxazolyl. In embodiments, R 16 and R 18 is hydrogen and R 17 is substituted or unsubstituted thiazolyl. In embodiments, R 16 and R 18 is hydrogen and R 17 is substituted or unsubstituted furyl. In embodiments, R 16 and R 18 is hydrogen and R 17 is substituted or unsubstituted thienyl. In embodiments, R 16 and R 18 is hydrogen and R 17 is substituted or unsubstituted pyridyl. In embodiments, R 16 and R 18 is hydrogen and R 17 is substituted or unsubstituted pyrimidyl. In embodiments, R 16 and R 18 is hydrogen and R 17 is unsubstituted pyrrolyl. In embodiments, R 16 and R 18 is hydrogen and R 17 is unsubstituted pyrazolyl. In embodiments, R 16 and R 18 is hydrogen and R 17 is unsubstituted pyridazinyl. In embodiments, R 16 and R 18 is hydrogen and R 17 is unsubstituted triazinyl. In embodiments, R 16 and R 18 is hydrogen and R 17 is unsubstituted pyrimidinyl. In embodiments, R 16 and R 18 is hydrogen and R 17 is unsubstituted imidazolyl. In embodiments, R 16 and R 18 is hydrogen and R 17is unsubstituted pyrazinyl. In embodiments, R 16 and R 18 is hydrogen and R 17 is unsubstituted oxazolyl. In embodiments, R 16 and R 18 is hydrogen and R 17 is unsubstituted isoxazolyl. In embodiments, R 16 and R 18 is hydrogen and R 17 is unsubstituted thiazolyl. In embodiments, R 16 and R 18 is hydrogen and R 17 is unsubstituted furyl. In embodiments, R 16 and R 18 is hydrogen and R 17 is unsubstituted thienyl. In embodiments, R 16 and R 18 is hydrogen and R 17 is unsubstituted pyridyl. In embodiments, R 16 and R 18 is hydrogen and R 17 is unsubstituted pyrimidyl.

[0347] In embodiments, R 16are independently hydrogen, oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -C(O)N(CH3)2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC( O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 2-6 membered heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted C6-C 12 It is aryl, or substituted or unsubstituted 5- to 12-membered heteroaryl.

[0348] In embodiments, R 17 are independently hydrogen, oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -C(O)N(CH3)2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC( O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 2-6 membered heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted C6-C 12 It is aryl, or substituted or unsubstituted 5- to 12-membered heteroaryl.

[0349] In embodiments, R 18 are independently hydrogen, oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -C(O)N(CH3)2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC( O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 2-6 membered heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted C6-C 12 It is aryl, or substituted or unsubstituted 5- to 12-membered heteroaryl.

[0350] In embodiments, R 16 are independently hydrogen, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted 2-6 membered heteroalkyl. 16 are independently hydrogen. In embodiments, R 16 is independently substituted or unsubstituted C1-C6 alkyl. In embodiments, R 16 is a substituted methyl. In embodiments, R 16 is a substituted ethyl. In embodiments, R 16 is a substituted propyl. In embodiments, R 16 is substituted isopropyl. In embodiments, R 16 is substituted n-propyl. In embodiments, R 16 is unsubstituted methyl. In embodiments, R 16 is unsubstituted ethyl. In embodiments, R 16 is unsubstituted propyl. In embodiments, R 16is unsubstituted isopropyl. In embodiments, R 16 is unsubstituted n-propyl. In embodiments, R 16 is independently a substituted or unsubstituted 2-6 membered heteroalkyl. In embodiments, R 16 is independently a substituted or unsubstituted 2-3 membered heteroalkyl. In embodiments, R 16 is independently hydrogen or —C(O)N(CH). In embodiments, R 16 is independently —C(O)N(CH). In embodiments, R 16 are independently hydrogen or substituted or unsubstituted C1-C6 alkyl. In embodiments, R 16 are independently hydrogen or substituted or unsubstituted C1-C4 alkyl. In embodiments, R 16 are independently hydrogen or substituted or unsubstituted C1-C2 alkyl. In embodiments, R 16 are independently hydrogen or unsubstituted methyl.

[0351] In embodiments, R 17 are independently hydrogen, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted 2-6 membered heteroalkyl. 17 are independently hydrogen. In embodiments, R 17 is independently substituted or unsubstituted C1-C6 alkyl. In embodiments, R 17 is a substituted methyl. In embodiments, R 17 is a substituted ethyl. In embodiments, R 17 is a substituted propyl. In embodiments, R 17 is substituted isopropyl. In embodiments, R 17 is substituted n-propyl. In embodiments, R 17 is unsubstituted methyl. In embodiments, R 17 is unsubstituted ethyl. In embodiments, R 17 is unsubstituted propyl. In embodiments, R 17 is unsubstituted isopropyl. In embodiments, R 17 is unsubstituted n-propyl. In embodiments, R 17is independently a substituted or unsubstituted 2-6 membered heteroalkyl. In embodiments, R 17 is independently a substituted or unsubstituted 2-3 membered heteroalkyl. In embodiments, R 17 is independently hydrogen or —C(O)N(CH). In embodiments, R 17 is independently —C(O)N(CH). In embodiments, R 17 are independently hydrogen or substituted or unsubstituted C1-C6 alkyl. In embodiments, R 17 are independently hydrogen or substituted or unsubstituted C1-C4 alkyl. In embodiments, R 17 are independently hydrogen or substituted or unsubstituted C1-C2 alkyl. In embodiments, R 17 are independently hydrogen or unsubstituted methyl.

[0352] In embodiments, R 17 is substituted or unsubstituted aryl. In embodiments, R 17 is a substituted or unsubstituted C6-C 12 In embodiments, R 17 is substituted or unsubstituted phenyl. In embodiments, R 17 is unsubstituted phenyl.

[0353] In embodiments, R 17 is substituted or unsubstituted heteroaryl. In embodiments, R 17 is a substituted or unsubstituted 5-6 membered heteroaryl. 17 is substituted or unsubstituted pyrrolyl. In embodiments, R 17 is substituted or unsubstituted pyrazolyl. In embodiments, R 17 is substituted or unsubstituted pyridazinyl. In embodiments, R 17 is a substituted or unsubstituted triazinyl. In embodiments, R 17 is substituted or unsubstituted pyrimidinyl. In embodiments, R 17 is substituted or unsubstituted imidazolyl. In embodiments, R 17 is substituted or unsubstituted pyrazinyl. In embodiments, R17 is substituted or unsubstituted oxazolyl. In embodiments, R 17 is substituted or unsubstituted isoxazolyl. In embodiments, R 17 is substituted or unsubstituted thiazolyl. In embodiments, R 17 is substituted or unsubstituted furyl. In embodiments, R 17 is substituted or unsubstituted thienyl. In embodiments, R 17 is substituted or unsubstituted pyridyl. In embodiments, R 17 is substituted or unsubstituted pyrimidyl. In embodiments, R 17 is substituted or unsubstituted benzothiazolyl. In embodiments, R 17 is a substituted or unsubstituted benzoxazolyl. In embodiments, R 17 is substituted or unsubstituted benzimidazolyl. In embodiments, R 17 is a substituted or unsubstituted benzofuran. In embodiments, R 17 is substituted or unsubstituted isobenzofuranyl. In embodiments, R 17 is a substituted or unsubstituted indolyl. In embodiments, R 17 is a substituted or unsubstituted isoindolyl. In embodiments, R 17 is substituted or unsubstituted benzothiophenyl. In embodiments, R 17 is substituted or unsubstituted isoquinolyl. In embodiments, R 17 is a substituted or unsubstituted quinoxalinyl. In embodiments, R 17 is a substituted or unsubstituted quinolyl.

[0354] In embodiments, R 18 are independently hydrogen, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted 2-6 membered heteroalkyl. 18 are independently hydrogen. In embodiments, R 18 is independently substituted or unsubstituted C1-C6 alkyl. In embodiments, R 18 is a substituted methyl. In embodiments, R 18 is a substituted ethyl. In embodiments, R18 is a substituted propyl. In embodiments, R 18 is substituted isopropyl. In embodiments, R 18 is substituted n-propyl. In embodiments, R 18 is unsubstituted methyl. In embodiments, R 18 is unsubstituted ethyl. In embodiments, R 18 is unsubstituted propyl. In embodiments, R 18 is unsubstituted isopropyl. In embodiments, R 18 is unsubstituted n-propyl. In embodiments, R 18 is independently a substituted or unsubstituted 2-6 membered heteroalkyl. In embodiments, R 18 is independently a substituted or unsubstituted 2-3 membered heteroalkyl. In embodiments, R 18 is independently hydrogen or —C(O)N(CH). In embodiments, R 18 is independently —C(O)N(CH). In embodiments, R 18 are independently hydrogen or substituted or unsubstituted C1-C6 alkyl. In embodiments, R 18 are independently hydrogen or substituted or unsubstituted C1-C4 alkyl. In embodiments, R 18 are independently hydrogen or substituted or unsubstituted C1-C2 alkyl. In embodiments, R 18 are independently hydrogen or unsubstituted methyl.

[0355] In embodiments, R 19 and R 20 are independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -COOH, -CONH2, -C(O)N(CH3)2, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 2- to 6-membered heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted C6-C 12 It is aryl, or substituted or unsubstituted 5- to 12-membered heteroaryl.

[0356] In embodiments, R 19 are independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -COOH, -CONH2, -C(O)N(CH3)2, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 2- to 6-membered heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted C6-C 12 It is aryl, or substituted or unsubstituted 5- to 12-membered heteroaryl.

[0357] In embodiments, R 20 are independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -COOH, -CONH2, -C(O)N(CH3)2, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 2- to 6-membered heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted C6-C 12 It is aryl, or substituted or unsubstituted 5- to 12-membered heteroaryl.

[0358] In embodiments, R 19 are independently hydrogen, —CCl, —CBr, —CF, —CI, CHCl, —CHBr, —CHF, —CHI, —CHCl, —CHBr, —CHF, —CHI, —CN, substituted or unsubstituted C-C alkyl, or substituted or unsubstituted 2-6 membered heteroalkyl. 19 are independently hydrogen. In embodiments, R 19 is independently —CCl. In embodiments, R 19 is independently —CBr. In embodiments, R 19 is independently —CF. In an embodiment, R 19is independently -CI. In an embodiment, R 19 is independently CHCl. ​​In embodiments, R 19 is independently —CHBr. In embodiments, R 19 is independently -CHF. In an embodiment, R 19 is independently -CHI. In embodiments, R 19 is independently —CH2Cl. In embodiments, R 19 is independently —CHBr. In embodiments, R 19 is independently -CHF. In an embodiment, R 19 is independently -CH2I. In embodiments, R 19 is independently —CN. In embodiments, R 19 are independent, R 4 In embodiments, R is a substituted or unsubstituted C1-C6 alkyl. 19 is a substituted methyl. In embodiments, R 19 is a substituted ethyl. In embodiments, R 19 is a substituted propyl. In embodiments, R 19 is substituted isopropyl. In embodiments, R 19 is substituted n-propyl. In embodiments, R 19 is unsubstituted methyl. In embodiments, R 19 is unsubstituted ethyl. In embodiments, R 19 is unsubstituted propyl. In embodiments, R 19 is unsubstituted isopropyl. In embodiments, R 19 is unsubstituted n-propyl. In embodiments, R 19 is independently a substituted or unsubstituted 2-6 membered heteroalkyl. In embodiments, R 19 is independently a substituted or unsubstituted 2-3 membered heteroalkyl. In embodiments, R 19 is independently hydrogen or —C(O)N(CH). In embodiments, R 19 is independently —C(O)N(CH). In embodiments, R 19 are independently hydrogen or substituted or unsubstituted C1-C6 alkyl. In embodiments, R19 are independently hydrogen or substituted or unsubstituted C1-C4 alkyl. In embodiments, R 19 are independently hydrogen or substituted or unsubstituted C1-C2 alkyl. In embodiments, R 19 are independently hydrogen or unsubstituted methyl. In embodiments, R 19 are independently hydrogen, —CF 3 , —CN, or unsubstituted methyl.

[0359] In embodiments, R 19 are independently hydrogen, —CF, —CN, or substituted or unsubstituted C-C alkyl. 19 are independently hydrogen, —CF, —CN, or unsubstituted C-C alkyl. In embodiments, R 19 are independently hydrogen, —CF, —CN, or unsubstituted methyl. In embodiments, R 19 are independently hydrogen or unsubstituted methyl. In embodiments, R 19 are independently hydrogen or unsubstituted ethyl. In embodiments, R 19 is independently hydrogen or unsubstituted propyl.

[0360] In embodiments, R 20 are independently hydrogen, —CCl, —CBr, —CF, —CI, CHCl, —CHBr, —CHF, —CHI, —CHCl, —CHBr, —CHF, —CHI, —CN, substituted or unsubstituted C-C alkyl, or substituted or unsubstituted 2-6 membered heteroalkyl. 20 are independently hydrogen. In embodiments, R 20 is independently —CCl. In embodiments, R 20 is independently —CBr. In embodiments, R 20 is independently —CF. In an embodiment, R 20 is independently -CI. In an embodiment, R 20 is independently CHCl. ​​In embodiments, R 20 is independently —CHBr. In embodiments, R 20is independently -CHF. In an embodiment, R 20 is independently -CHI. In embodiments, R 20 is independently —CH2Cl. In embodiments, R 20 is independently —CHBr. In embodiments, R 20 is independently -CHF. In an embodiment, R 20 is independently -CH2I. In embodiments, R 20 is independently —CN. In embodiments, R 20 is independently substituted or unsubstituted C1-C6 alkyl. In embodiments, R 20 is a substituted methyl. In embodiments, R 20 is a substituted ethyl. In embodiments, R 20 is a substituted propyl. In embodiments, R 20 is substituted isopropyl. In embodiments, R 20 is substituted n-propyl. In embodiments, R 20 is unsubstituted methyl. In embodiments, R 20 is unsubstituted ethyl. In embodiments, R 20 is unsubstituted propyl. In embodiments, R 20 is unsubstituted isopropyl. In embodiments, R 20 is unsubstituted n-propyl. In embodiments, R 20 is independently a substituted or unsubstituted 2-6 membered heteroalkyl. In embodiments, R 20 is independently a substituted or unsubstituted 2-3 membered heteroalkyl. In embodiments, R 20 is independently hydrogen or —C(O)N(CH). In embodiments, R 20 is independently —C(O)N(CH). In embodiments, R 20 are independently hydrogen or substituted or unsubstituted C1-C6 alkyl. In embodiments, R 20 are independently hydrogen or substituted or unsubstituted C1-C4 alkyl. In embodiments, R 20 are independently hydrogen or substituted or unsubstituted C1-C2 alkyl. In embodiments, R 20are independently hydrogen or unsubstituted methyl. In embodiments, R 20 are independently hydrogen, —CF 3 , —CN, or unsubstituted methyl.

[0361] In embodiments, R 20 are independently hydrogen, —CF, —CN, or substituted or unsubstituted C-C alkyl. 20 are independently hydrogen, —CF, —CN, or unsubstituted C-C alkyl. In embodiments, R 20 are independently hydrogen, —CF, —CN, or unsubstituted methyl. In embodiments, R 20 are independently hydrogen or unsubstituted methyl. In embodiments, R 20 are independently hydrogen or unsubstituted ethyl. In embodiments, R 20 is independently hydrogen or unsubstituted propyl.

[0362] In embodiments, R 1A are independently hydrogen, —CCl3, —CBr3, —CF3, —CI3, CHCl2, —CHBr2, —CHF2, —CHI2, —CH2Cl, —CH2Br, —CH2F, —CH2I, —CN, —OH, —NH2, —COOH, —CONH2, —OCCl3, —OCF3, —OCBr3, —OCI3, —OCHCl2, —OCHBr2, —OCHI2, —OCHF2, —OCH2Cl, —OCH2Br, —OCHI, —OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0363] In embodiments, R 1Aare independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 2- to 6-membered heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted C6-C 12 It is aryl, or substituted or unsubstituted 5- to 12-membered heteroaryl.

[0364] In embodiments, R 1A are independently hydrogen, —CCl, —CBr, —CF, —CI, CHCl, —CHBr, —CHF, —CHI, —CHCl, —CHBr, —CHF, —CHI, substituted or unsubstituted C-C alkyl, or substituted or unsubstituted 2-4 membered heteroalkyl. 1A are independently hydrogen, substituted or unsubstituted C1-C4 alkyl, or substituted or unsubstituted 2-4 membered heteroalkyl. 1A are independently hydrogen. In embodiments, R 1A is independently substituted or unsubstituted C1-C4 alkyl. In embodiments, R 1A is independently a substituted or unsubstituted 2-4 membered heteroalkyl. In embodiments, R 1A is independently unsubstituted methyl.

[0365] In embodiments, R 1Bare independently hydrogen, —CCl3, —CBr3, —CF3, —CI3, CHCl2, —CHBr2, —CHF2, —CHI2, —CH2Cl, —CH2Br, —CH2F, —CH2I, —CN, —OH, —NH2, —COOH, —CONH2, —OCCl3, —OCF3, —OCBr3, —OCI3, —OCHCl2, —OCHBr2, —OCHI2, —OCHF2, —OCH2Cl, —OCH2Br, —OCHI, —OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0366] In embodiments, R 1B are independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 2- to 6-membered heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted C6-C 12 It is aryl, or substituted or unsubstituted 5- to 12-membered heteroaryl.

[0367] In embodiments, R 1B are independently hydrogen, —CCl, —CBr, —CF, —CI, CHCl, —CHBr, —CHF, —CHI, —CHCl, —CHBr, —CHF, —CHI, substituted or unsubstituted C-C alkyl, or substituted or unsubstituted 2-4 membered heteroalkyl. 1B are independently hydrogen, substituted or unsubstituted C1-C4 alkyl, or substituted or unsubstituted 2-4 membered heteroalkyl. 1Bare independently hydrogen. In embodiments, R 1B is independently substituted or unsubstituted C1-C4 alkyl. In embodiments, R 1B is independently a substituted or unsubstituted 2-4 membered heteroalkyl. In embodiments, R 1B is independently unsubstituted methyl.

[0368] In embodiments, R 1A and R 1B The substituents may optionally be combined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

[0369] In embodiments, R 1A and R 1B The substituents may optionally be combined to form a substituted or unsubstituted 3- to 6-membered heterocycloalkyl or a substituted or unsubstituted 5- to 12-membered heteroaryl.

[0370] In embodiments, R 1C are independently hydrogen, —CCl3, —CBr3, —CF3, —CI3, CHCl2, —CHBr2, —CHF2, —CHI2, —CH2Cl, —CH2Br, —CH2F, —CH2I, —CN, —OH, —NH2, —COOH, —CONH2, —OCCl3, —OCF3, —OCBr3, —OCI3, —OCHCl2, —OCHBr2, —OCHI2, —OCHF2, —OCH2Cl, —OCH2Br, —OCHI, —OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0371] In embodiments, R 1Care independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 2- to 6-membered heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted C6-C 12 It is aryl, or substituted or unsubstituted 5- to 12-membered heteroaryl.

[0372] In embodiments, R 1C are independently hydrogen, —CCl, —CBr, —CF, —CI, CHCl, —CHBr, —CHF, —CHI, —CHCl, —CHBr, —CHF, —CHI, substituted or unsubstituted C-C alkyl, or substituted or unsubstituted 2-4 membered heteroalkyl. 1C are independently hydrogen, substituted or unsubstituted C1-C4 alkyl, or substituted or unsubstituted 2-4 membered heteroalkyl. 1C are independently hydrogen. In embodiments, R 1C is independently substituted or unsubstituted C1-C4 alkyl. In embodiments, R 1C is independently a substituted or unsubstituted 2-4 membered heteroalkyl. In embodiments, R 1C is independently unsubstituted methyl.

[0373] In embodiments, R 1Dare independently hydrogen, —CCl3, —CBr3, —CF3, —CI3, CHCl2, —CHBr2, —CHF2, —CHI2, —CH2Cl, —CH2Br, —CH2F, —CH2I, —CN, —OH, —NH2, —COOH, —CONH2, —OCCl3, —OCF3, —OCBr3, —OCI3, —OCHCl2, —OCHBr2, —OCHI2, —OCHF2, —OCH2Cl, —OCH2Br, —OCHI, —OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0374] In embodiments, R 1D are independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 2- to 6-membered heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted C6-C 12 It is aryl, or substituted or unsubstituted 5- to 12-membered heteroaryl.

[0375] In embodiments, R 1D are independently hydrogen, —CCl, —CBr, —CF, —CI, CHCl, —CHBr, —CHF, —CHI, —CHCl, —CHBr, —CHF, —CHI, substituted or unsubstituted C-C alkyl, or substituted or unsubstituted 2-4 membered heteroalkyl. 1D are independently hydrogen, substituted or unsubstituted C1-C4 alkyl, or substituted or unsubstituted 2-4 membered heteroalkyl. 1Dare independently hydrogen. In embodiments, R 1D is independently substituted or unsubstituted C1-C4 alkyl. In embodiments, R 1D is independently a substituted or unsubstituted 2-4 membered heteroalkyl. In embodiments, R 1D is independently unsubstituted methyl.

[0376] In embodiments, R 2A are independently hydrogen, —CCl3, —CBr3, —CF3, —CI3, CHCl2, —CHBr2, —CHF2, —CHI2, —CH2Cl, —CH2Br, —CH2F, —CH2I, —CN, —OH, —NH2, —COOH, —CONH2, —OCCl3, —OCF3, —OCBr3, —OCI3, —OCHCl2, —OCHBr2, —OCHI2, —OCHF2, —OCH2Cl, —OCH2Br, —OCHI, —OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0377] In embodiments, R 2A are independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 2- to 6-membered heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted C6-C 12 It is aryl, or substituted or unsubstituted 5- to 12-membered heteroaryl.

[0378] In embodiments, R 2Aare independently hydrogen, —CCl, —CBr, —CF, —CI, CHCl, —CHBr, —CHF, —CHI, —CHCl, —CHBr, —CHF, —CHI, substituted or unsubstituted C-C alkyl, or substituted or unsubstituted 2-4 membered heteroalkyl. 2A are independently hydrogen, substituted or unsubstituted C1-C4 alkyl, or substituted or unsubstituted 2-4 membered heteroalkyl. 2A are independently hydrogen. In embodiments, R 2A is independently substituted or unsubstituted C1-C4 alkyl. In embodiments, R 2A is independently a substituted or unsubstituted 2-4 membered heteroalkyl. In embodiments, R 2A is independently unsubstituted methyl.

[0379] In embodiments, R 2B are independently hydrogen, —CCl3, —CBr3, —CF3, —CI3, CHCl2, —CHBr2, —CHF2, —CHI2, —CH2Cl, —CH2Br, —CH2F, —CH2I, —CN, —OH, —NH2, —COOH, —CONH2, —OCCl3, —OCF3, —OCBr3, —OCI3, —OCHCl2, —OCHBr2, —OCHI2, —OCHF2, —OCH2Cl, —OCH2Br, —OCHI, —OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0380] In embodiments, R 2Bare independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 2- to 6-membered heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted C6-C 12 It is aryl, or substituted or unsubstituted 5- to 12-membered heteroaryl.

[0381] In embodiments, R 2B are independently hydrogen, —CCl, —CBr, —CF, —CI, CHCl, —CHBr, —CHF, —CHI, —CHCl, —CHBr, —CHF, —CHI, substituted or unsubstituted C-C alkyl, or substituted or unsubstituted 2-4 membered heteroalkyl. 2B are independently hydrogen, substituted or unsubstituted C1-C4 alkyl, or substituted or unsubstituted 2-4 membered heteroalkyl. 2B are independently hydrogen. In embodiments, R 2B is independently substituted or unsubstituted C1-C4 alkyl. In embodiments, R 2B is independently a substituted or unsubstituted 2-4 membered heteroalkyl. In embodiments, R 2B is independently unsubstituted methyl.

[0382] In embodiments, R 2A and R 2B The substituents may optionally be combined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

[0383] In embodiments, R 2A and R2B The substituents may optionally be combined to form a substituted or unsubstituted 3- to 6-membered heterocycloalkyl or a substituted or unsubstituted 5- to 12-membered heteroaryl.

[0384] In embodiments, R 2C are independently hydrogen, —CCl3, —CBr3, —CF3, —CI3, CHCl2, —CHBr2, —CHF2, —CHI2, —CH2Cl, —CH2Br, —CH2F, —CH2I, —CN, —OH, —NH2, —COOH, —CONH2, —OCCl3, —OCF3, —OCBr3, —OCI3, —OCHCl2, —OCHBr2, —OCHI2, —OCHF2, —OCH2Cl, —OCH2Br, —OCHI, —OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0385] In embodiments, R 2C are independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 2- to 6-membered heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted C6-C 12 It is aryl, or substituted or unsubstituted 5- to 12-membered heteroaryl.

[0386] In embodiments, R 2Care independently hydrogen, —CCl, —CBr, —CF, —CI, CHCl, —CHBr, —CHF, —CHI, —CHCl, —CHBr, —CHF, —CHI, substituted or unsubstituted C-C alkyl, or substituted or unsubstituted 2-4 membered heteroalkyl. 2C are independently hydrogen, substituted or unsubstituted C1-C4 alkyl, or substituted or unsubstituted 2-4 membered heteroalkyl. 2C are independently hydrogen. In embodiments, R 2C is independently substituted or unsubstituted C1-C4 alkyl. In embodiments, R 2C is independently a substituted or unsubstituted 2-4 membered heteroalkyl. In embodiments, R 2C is independently unsubstituted methyl.

[0387] In embodiments, R 2D are independently hydrogen, —CCl3, —CBr3, —CF3, —CI3, CHCl2, —CHBr2, —CHF2, —CHI2, —CH2Cl, —CH2Br, —CH2F, —CH2I, —CN, —OH, —NH2, —COOH, —CONH2, —OCCl3, —OCF3, —OCBr3, —OCI3, —OCHCl2, —OCHBr2, —OCHI2, —OCHF2, —OCH2Cl, —OCH2Br, —OCHI, —OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0388] In embodiments, R 2Dare independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 2- to 6-membered heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted C6-C 12 It is aryl, or substituted or unsubstituted 5- to 12-membered heteroaryl.

[0389] In embodiments, R 2D are independently hydrogen, —CCl, —CBr, —CF, —CI, CHCl, —CHBr, —CHF, —CHI, —CHCl, —CHBr, —CHF, —CHI, substituted or unsubstituted C-C alkyl, or substituted or unsubstituted 2-4 membered heteroalkyl. 2D are independently hydrogen, substituted or unsubstituted C1-C4 alkyl, or substituted or unsubstituted 2-4 membered heteroalkyl. 2D are independently hydrogen. In embodiments, R 2D is independently substituted or unsubstituted C1-C4 alkyl. In embodiments, R 2D is independently a substituted or unsubstituted 2-4 membered heteroalkyl. In embodiments, R 2D is independently unsubstituted methyl.

[0390] In embodiments, R 1.2 are independently hydrogen, halogen, —CCl3, —CBr3, —CF3, —CI3, —CN, —OH, —NH2, —COOH, —CONH2, —OCCl3, —OCF3, —OCBr3, —OCI3, —N3, substituted or unsubstituted C1-C3 alkyl, or substituted or unsubstituted 2-4 membered heteroalkyl. 1.2are independently hydrogen. In embodiments, R 1.2 are independently halogen. In embodiments, R 1.2 is independently -F. In an embodiment, R 1.2 is independently -Cl. In an embodiment, R 1.2 is independently -Br. In an embodiment, R 1.2 is independently -I. In an embodiment, R 1.2 is independently —CCl. In embodiments, R 1.2 is independently —CBr. In embodiments, R 1.2 is independently —CF. In an embodiment, R 1.2 is independently -CI. In an embodiment, R 1.2 is independently —CN. In embodiments, R 1.2 is independently —OH. In embodiments, R 1.2 is independently —NH. In an embodiment, R 1.2 is independently —COOH. In embodiments, R 1.2 is independently -CONH. In an embodiment, R 1.2 is independently —OCCl. In embodiments, R 1.2 is independently -OCF. In an embodiment, R 1.2 is independently —OCBr. In embodiments, R 1.2 is independently -OCI. In embodiments, R 1.2 is independently -N3. In an embodiment, R 1.2 is independently substituted or unsubstituted C1-C3 alkyl. In embodiments, R 1.2 is independently unsubstituted methyl. In embodiments, R 1.2 is independently unsubstituted ethyl. In embodiments, R 1.2 is independently unsubstituted propyl. In embodiments, R 1.2 is independently a substituted or unsubstituted 2-4 membered heteroalkyl. In embodiments, R 1.2 is independently unsubstituted 2-4 membered heteroalkyl.

[0391] In embodiments, R 1.3are independently hydrogen, halogen, —CCl3, —CBr3, —CF3, —CI3, —CN, —OH, —NH2, —COOH, —CONH2, —OCCl3, —OCF3, —OCBr3, —OCI3, —N3, substituted or unsubstituted C1-C3 alkyl, or substituted or unsubstituted 2-4 membered heteroalkyl. 1.3 are independently halogen. In embodiments, R 1.3 is independently -F. In an embodiment, R 1.3 is independently -Cl. In an embodiment, R 1.3 is independently -Br. In an embodiment, R 1.3 is independently -I. In an embodiment, R 1.3 is independently —CCl. In embodiments, R 1.3 is independently —CBr. In embodiments, R 1.3 is independently —CF. In an embodiment, R 1.3 is independently -CI. In an embodiment, R 1.3 is independently —CN. In embodiments, R 1.3 is independently —OH. In embodiments, R 1.3 is independently —NH. In an embodiment, R 1.3 is independently —COOH. In embodiments, R 1.3 is independently -CONH. In an embodiment, R 1.3 is independently —OCCl. In embodiments, R 1.3 is independently -OCF. In an embodiment, R 1.3 is independently —OCBr. In embodiments, R 1.3 is independently -OCI. In embodiments, R 1.3 is independently -N3. In an embodiment, R 1.3 is independently substituted or unsubstituted C1-C3 alkyl. In embodiments, R 1.3 is independently unsubstituted methyl. In embodiments, R 1.3 is independently unsubstituted ethyl. In embodiments, R 1.3 is independently unsubstituted propyl. In embodiments, R 1.3is independently a substituted or unsubstituted 2-4 membered heteroalkyl. In embodiments, R 1.3 is independently unsubstituted 2-4 membered heteroalkyl.

[0392] In embodiments, R on adjacent carbons 1.2 and R 1.3 The substituents may be joined to form a substituted or unsubstituted phenyl, or a substituted or unsubstituted 5- to 6-membered heteroaryl. In embodiments, R 1.2 and R 1.3 The substituents are joined to form a substituted or unsubstituted phenyl. In embodiments, R on adjacent carbons 1.2 and R 1.3 The substituents are bonded together to form R 11 In embodiments, R on adjacent carbons forms a substituted phenyl. 1.2 and R 1.3 The substituents are joined to form an unsubstituted phenyl. In embodiments, R on adjacent carbons 1.2 and R 1.3 The substituents combine to form a substituted or unsubstituted 5-6 membered heteroaryl. In embodiments, R on adjacent carbons 1.2 and R 1.3 The substituents are bonded together to form R 11 In one embodiment, R on adjacent carbons forms a substituted or unsubstituted 5- to 6-membered heteroaryl. 1.2 and R 1.3 The substituents are joined to form an unsubstituted 5- to 6-membered heteroaryl.

[0393] In embodiments, R 1.4 are independently hydrogen, halogen, —CCl3, —CBr3, —CF3, —CI3, —CN, —OH, —NH2, —COOH, —CONH2, —OCCl3, —OCF3, —OCBr3, —OCI3, —N3, substituted or unsubstituted C1-C3 alkyl, or substituted or unsubstituted 2-4 membered heteroalkyl. 1.4 are independently halogen. In embodiments, R 1.4 is independently -F. In an embodiment, R 1.4 is independently -Cl. In an embodiment, R 1.4is independently -Br. In an embodiment, R 1.4 is independently -I. In an embodiment, R 1.4 is independently —CCl. In embodiments, R 1.4 is independently —CBr. In embodiments, R 1.4 is independently —CF. In an embodiment, R 1.4 is independently -CI. In an embodiment, R 1.4 is independently —CN. In embodiments, R 1.4 is independently —OH. In embodiments, R 1.4 is independently —NH. In an embodiment, R 1.4 is independently —COOH. In embodiments, R 1.4 is independently -CONH. In an embodiment, R 1.4 is independently —OCCl. In embodiments, R 1.4 is independently -OCF. In an embodiment, R 1.4 is independently —OCBr. In embodiments, R 1.4 is independently -OCI. In embodiments, R 1.4 is independently -N3. In an embodiment, R 1.4 is independently substituted or unsubstituted C1-C3 alkyl. In embodiments, R 1.4 is independently unsubstituted methyl. In embodiments, R 1.4 is independently unsubstituted ethyl. In embodiments, R 1.4 is independently unsubstituted propyl. In embodiments, R 1.4 is independently a substituted or unsubstituted 2-4 membered heteroalkyl. In embodiments, R 1.4 is independently unsubstituted 2-4 membered heteroalkyl.

[0394] In embodiments, R 1.5are independently hydrogen, halogen, —CCl3, —CBr3, —CF3, —CI3, —CN, —OH, —NH2, —COOH, —CONH2, —OCCl3, —OCF3, —OCBr3, —OCI3, —N3, substituted or unsubstituted C1-C3 alkyl, or substituted or unsubstituted 2-4 membered heteroalkyl. 1.5 are independently halogen. In embodiments, R 1.5 is independently -F. In an embodiment, R 1.5 is independently -Cl. In an embodiment, R 1.5 is independently -Br. In an embodiment, R 1.5 is independently -I. In an embodiment, R 1.5 is independently —CCl. In embodiments, R 1.5 is independently —CBr. In embodiments, R 1.5 is independently —CF. In an embodiment, R 1.5 is independently -CI. In an embodiment, R 1.5 is independently —CN. In embodiments, R 1.5 is independently —OH. In embodiments, R 1.5 is independently —NH. In an embodiment, R 1.5 is independently —COOH. In embodiments, R 1.5 is independently -CONH. In an embodiment, R 1.5 is independently —OCCl. In embodiments, R 1.5 is independently -OCF. In an embodiment, R 1.5 is independently —OCBr. In embodiments, R 1.5 is independently -OCI. In embodiments, R 1.5 is independently -N3. In an embodiment, R 1.5 is independently substituted or unsubstituted C1-C3 alkyl. In embodiments, R 1.5 is independently unsubstituted methyl. In embodiments, R 1.5 is independently unsubstituted ethyl. In embodiments, R 1.5 is independently unsubstituted propyl. In embodiments, R 1.5is independently a substituted or unsubstituted 2-4 membered heteroalkyl. In embodiments, R 1.5 is independently unsubstituted 2-4 membered heteroalkyl.

[0395] In embodiments, R 1.4 is hydrogen and R 1.5 is -F. In an embodiment, R 1.4 is -F and R 1.5 is hydrogen. In embodiments, R 1.4 and R 1.5 is -F. In an embodiment, R 1.4 and R 1.5 is hydrogen.

[0396] In an embodiment, W 1 is independently —O—. In embodiments, W 1 is independently —NH—. In an embodiment, W 1 are independently, -NR 2 In an embodiment, W 2 are independently =N-. In embodiments, W 2 are independently =CH-. In embodiments, W 2 is independent, =CR 2 In an embodiment, W 3 are independently =N-. In embodiments, W 3 are independently =CH-. In embodiments, W 3 is independent, =CR 2 -It is.

[0397] In embodiments, R 2are independently oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -C(O)N(CH3)2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O )H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 2- to 6-membered heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted C6-C 12 It is aryl, or substituted or unsubstituted 5- to 12-membered heteroaryl.

[0398] In embodiments, R 11 are independently oxo, halogen, -CX 11 3. -CHX 11 2. -CH2X 11 , -OCX 11 3. -OCH2X 11 , -OCHX 11 2, -CN, -OH, -NH2, -COOH, -CONH2, -C(O)N(CH3)2, -NO2, -SH, -SO3H, -SO4H, -SON2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 2- to 6-membered heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted C6-C 12 It is aryl, or substituted or unsubstituted 5- to 12-membered heteroaryl.

[0399] In embodiments, R 11are independently oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -C(O)N(CH3)2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O )H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 2- to 6-membered heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted C6-C 12 It is aryl, or substituted or unsubstituted 5- to 12-membered heteroaryl.

[0400] In embodiments, R 21 are independently oxo, halogen, -CX 21 3. -CHX 21 2. -CH2X 21 , -OCX 21 3. -OCH2X 21 , -OCHX 21 2, -CN, -OH, -NH2, -COOH, -CONH2, -C(O)N(CH3)2, -NO2, -SH, -SO3H, -SO4H, -SON2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 2- to 6-membered heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted C6-C 12 It is aryl, or substituted or unsubstituted 5- to 12-membered heteroaryl.

[0401] In embodiments, R 21are independently oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -C(O)N(CH3)2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O )H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 2- to 6-membered heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted C6-C 12 It is aryl, or substituted or unsubstituted 5- to 12-membered heteroaryl.

[0402] In embodiments, R 2 are independently halogen, -OCX 2 3. -OCH2X 2 , -OCHX 2 2, unsubstituted C1-C3 alkyl, or unsubstituted 5-6 membered heteroaryl. 11 are independently halogen, -OCX 11 3. -OCH2X 11 , -OCHX 11 2, unsubstituted C1-C3 alkyl, or unsubstituted 5-6 membered heteroaryl. 21 are independently halogen, -OCX 21 3. -OCH2X 21 , -OCHX 21 2. Unsubstituted C1-C3 alkyl, or unsubstituted 5- to 6-membered heteroaryl.

[0403] In embodiments, R 11are independently halogen, —OCCl3, —OCF3, —OCBr3, —OCI3, —OCHCl2, —OCHBr2, —OCHI2, —OCHF2, —OCH2Cl, —OCH2Br, —OCH2I, —OCH2F, unsubstituted C1-C3 alkyl, or unsubstituted 5-6 membered heteroaryl. 11 are independently halogen. In embodiments, R 11 is independently -F. In an embodiment, R 11 is independently -Cl. In an embodiment, R 11 is independently -Br. In an embodiment, R 11 is independently -I. In an embodiment, R 11 is independently —OCCl. In embodiments, R 11 is independently -OCF. In an embodiment, R 11 is independently —OCBr. In embodiments, R 11 is independently -OCI. In embodiments, R 11 is independently —OCHCl. ​​In an embodiment, R 11 is independently —OCHBr. In embodiments, R 11 is independently -OCHI. In embodiments, R 11 is independently -OCHF. In an embodiment, R 11 is independently —OCH2Cl. In embodiments, R 11 is independently —OCHBr. In embodiments, R 11 is independently -OCH2I. In embodiments, R 11 is independently -OCHF. In an embodiment, R 11 is independently unsubstituted methyl. In embodiments, R 11 is independently unsubstituted ethyl. In embodiments, R 11 is independently unsubstituted propyl. In embodiments, R 11 is independently an unsubstituted 5-6 membered heteroaryl. In embodiments, R 11 is independently an unsubstituted 5-membered heteroaryl. In embodiments, R 11 is independently an unsubstituted 6-membered heteroaryl.

[0404] In embodiments, R 11.1 are independently oxo, halogen, -CX 11 3. -CHX 11 2. -CH2X 11 , -OCX 11 3. -OCH2X 11 , -OCHX 11 2, -CN, -OH, -NH2, -COOH, -CONH2, -C(O)N(CH3)2, -NO2, -SH, -SO3H, -SO4H, -SON2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 2- to 6-membered heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted C6-C 12 It is aryl, or substituted or unsubstituted 5- to 12-membered heteroaryl.

[0405] In embodiments, R 11.1 are independently oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -C(O)N(CH3)2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O )H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 2- to 6-membered heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted C6-C 12 It is aryl, or substituted or unsubstituted 5- to 12-membered heteroaryl.

[0406] In embodiments, R 11.1 are independently halogen, —OCCl3, —OCF3, —OCBr3, —OCI3, —OCHCl2, —OCHBr2, —OCHI2, —OCHF2, —OCH2Cl, —OCH2Br, —OCH2I, —OCH2F, unsubstituted C1-C3 alkyl, or unsubstituted 5-6 membered heteroaryl. 11.1 are independently halogen. In embodiments, R 11.1 is independently -F. In an embodiment, R 11.1 is independently -Cl. In an embodiment, R 11.1 is independently -Br. In an embodiment, R 11.1 is independently -I. In an embodiment, R 11.1 is independently —OCCl. In embodiments, R 11.1 is independently -OCF. In an embodiment, R 11.1 is independently —OCBr. In embodiments, R 11.1 is independently -OCI. In embodiments, R 11.1 is independently —OCHCl. ​​In an embodiment, R 11.1 is independently —OCHBr. In embodiments, R 11.1 is independently -OCHI. In embodiments, R 11.1 is independently -OCHF. In an embodiment, R 11.1 is independently —OCH2Cl. In embodiments, R 11.1 is independently —OCHBr. In embodiments, R 11.1 is independently -OCH2I. In embodiments, R 11.1 is independently -OC...

Claims

1. Formula (I) or (III): 【Chemistry 1】 A compound having the formula: R 1 is independently halogen; z1 is an integer from 0 to 9, R2 is independently halogen, -CX23, -CHX22, -CH2X2, -OCX23, -OCH2X2, -OCHX22, -CN, -SOn2R2D, -SOv2NR2A R2B, -NR 2C NR 2A R 2B , -ONR 2A R 2B , -NHC(O)NR 2C NR 2A R 2B , -NHC(O)NR 2A R 2B , -N(O) m2 , -NR 2A R 2B , -C(O)R 2C , -C(O)-OR 2C , -C(O)NR 2A R 2B , —OR 2D , —NR 2A SO 2 R 2D , —NR 2A C(O)R 2C , —NR 2A C(O)OR 2C , —NR 2A OR 2C , —SF 5 , —N 3 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; z2 is an integer from 0 to 6, L 3 is —C(O)—, —CH 2 —, —C(O)NH—, —CH 2 CH 2 NH—, —C(O)CH 2 NH—, or —CH 2 C(O)NH—; L 4 is —NH— or —NR 4 —; L 6 is —N(R 6 )-L 3 — or —C(O)NH—; W 5 is CH or N; z6 is 1, R 4 and R 6 are independently hydrogen or unsubstituted alkyl; R 7 , R 8 , R 9 and R 10 are independently hydrogen or unsubstituted alkyl; Ring B is aryl or heteroaryl; R 5 is 【Chemistry 2】 wherein: R 16 , R 17 and R 18 are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -C(O)N(CH 3 ) 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl 3 , —OCF 3 , —OCBr 3 , —OCI 3 , —OCHCl 2 , —OCHBr 2 , —OCHI 2 , —OCHF 2 , —OCH 2 Cl, —OCH 2 Br, —OCH 2 I, —OCH 2 F, —N 3 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2A , R 2B , R 2C , and R 2D are independently hydrogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, wherein the R 2A and R 2B substituents attached to the same nitrogen atom may optionally join to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; X 2 is independently —F, —Cl, —Br, or —I; n2 is an integer from 0 to 4, A compound wherein m2 and v2 are independently 1 or 2.

2. The following formula: 【Transformation 3】 2. The compound of claim 1 having the formula:

3. The following formula: 【Chemistry 4】 2. The compound of claim 1 having the formula:

4. The following formula: 【Transformation 5】 wherein W 1 is —O, —NH—, or —NR 2 —; W 2 and W 3 are independently ═N, ═CH—, or ═CR 2 —; R 2 and R 21 are independently halogen, —OCX 2 O 3 , —OCH 2 X 2 , —OCHX 2 O 2 , unsubstituted C 1 -C 3 alkyl, or unsubstituted 5-6 membered heteroaryl; z2 is an integer from 0 to 4, z21 is an integer of 0 to 5, L 3 is —C(O)— or —CH 2 —; R 5 is 【Transformation 6】 and 4. The compound of claim 3, wherein R 16 , R 17 , and R 18 are independently hydrogen, —C(O)N(CH 3 ) 2 , or unsubstituted C 1 -C 3 alkyl.

5. The following formula: 【Transformation 7】 and During the ceremony, R 2.1 is hydrogen, —OCX 2 3 , or unsubstituted 5-6 membered heteroaryl; 5. The compound of claim 4, wherein R2.2 is hydrogen or halogen.

6. (Ring B)-(R 2 ) z2 is 【Transformation 8】 2. The compound of claim 1, wherein:

7. The compound according to claim 1, wherein L 4 is —NH—.

8. The compound according to claim 1, wherein L 4 is —N(CH 3 )—.

9. R 5 is 【Chemistry 9】 The compound according to any one of claims 1 to 8, wherein 10. The compound according to claim 1, wherein L 3 is —CH 2 — or —C(O)NH—.

11. The compound of claim 1, wherein R 2 is independently —F or —OCF 3 .

12. The following formula: 【Chemistry 10】 2. The compound of claim 1 having the formula:

13. A pharmaceutical composition comprising a compound according to any one of claims 1 to 12 and a pharmaceutically acceptable excipient.

14. A pharmaceutical composition as described in claim 13 for use in a method for inhibiting the activity of human caspase-6 protein, the method comprising contacting the human caspase-6 protein with a compound as described in any one of claims 1 to 12.

15. The pharmaceutical composition described in claim 14, wherein the compound covalently binds to C264 of the human caspase-6 protein.

16. The pharmaceutical composition described in claim 14, wherein the compound inhibits the activity of the human caspase 6 protein more than other human caspase proteins.

17. The pharmaceutical composition described in claim 14, wherein the compound inhibits the activity of human caspase-6 protein more than human caspase-2 and human caspase-3.

18. A pharmaceutical composition as described in claim 13 for use in a method for treating a neurodegenerative disease in a subject in need of such treatment, the method comprising administering the pharmaceutical composition to the subject.

19. The pharmaceutical composition described in claim 18, wherein the neurodegenerative disease is a tauopathy.

20. The pharmaceutical composition of claim 18, wherein the neurodegenerative disease is Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, Lewy body disease, progressive supranuclear palsy, or Parkinson's disease.

21. The pharmaceutical composition described in claim 18, wherein the neurodegenerative disease is Alzheimer's disease.

22. A pharmaceutical composition as described in claim 13 for use in a method for treating memory loss in a subject in need of such treatment, the method comprising administering the pharmaceutical composition to the subject.

23. A pharmaceutical composition as described in claim 13 for use in a method for treating axonal degeneration in a subject in need of such treatment, the method comprising administering the pharmaceutical composition to the subject.

24. A pharmaceutical composition as described in claim 13 for use in a method for treating neuroinflammation in a subject in need of such treatment, the method comprising administering the pharmaceutical composition to the subject.

25. A pharmaceutical composition as described in claim 13 for use in a method for treating liver disease in a subject in need of such treatment, the method comprising administering the pharmaceutical composition to the subject.

26. A pharmaceutical composition as described in claim 13 for use in a method for treating non-alcoholic steatohepatitis or non-alcoholic fatty liver disease in a subject in need of treatment thereof, the method comprising administering the pharmaceutical composition to the subject.

27. Use of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12 for the manufacture of a medicament for use in a method for treating a neurodegenerative disease in a subject in need thereof, said method comprising administering an effective amount of said compound to said subject.

28. The use described in claim 27, wherein the neurodegenerative disease is a tauopathy.

29. The use described in claim 27, wherein the neurodegenerative disease is Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, Lewy body disease, progressive supranuclear palsy, or Parkinson's disease.

30. The use described in claim 27, wherein the neurodegenerative disease is Alzheimer's disease.

31. Use of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12 for the manufacture of a medicament for use in a method for treating memory loss in a subject in need thereof, said method comprising administering to said subject an effective amount of said compound.

32. Use of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12 for the manufacture of a medicament for use in a method for treating axonal degeneration in a subject in need thereof, said method comprising administering an effective amount of said compound to said subject.

33. Use of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12 for the manufacture of a medicament for use in a method for treating neuroinflammation in a subject in need thereof, said method comprising administering an effective amount of said compound to said subject.

34. Use of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12 for the manufacture of a medicament for use in a method of treating liver disease in a subject in need thereof, said method comprising administering an effective amount of said compound to said subject.

35. Use of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12 for the manufacture of a medicament for use in a method for treating non-alcoholic steatohepatitis or non-alcoholic fatty liver disease in a subject in need thereof, said method comprising administering an effective amount of said compound to said subject.

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