Fused ring imidazole compounds

Abstract

Described herein, inter alia, are fused heterocyclic aromatic compounds useful as modulators of TNFα signaling and methods of use thereof.

Description

PATENTAttorney Docket No : 050935-527001 WOFUSED RING IMIDAZOLE COMPOUNDSCROSS-REFERENCES TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority of U.S. Provisional ApplicationNo. 63 / 691,945 filed on September 6, 2024 and U.S. Provisional Application No. 63 / 789,300 filed on April 15, 2025, which are incorporated herein by reference in their entirety and for all purposes.BACKGROUND

[0002] TNFa is the prototypical member of the Tumor Necrosis Factor (TNF) superfamily of proteins that share a primary function of regulating cell survival and cell death. One structural feature common to all known members of the TNF superfamily is the formation of complexes that bind to, and activate, specific TNF superfamily receptors. By way of example, TNFa exists in soluble and transmembrane forms and signals through two receptors, known as TNF1 and TNFR2, with distinct functional endpoints.

[0003] Various products capable of modulating TNFa activity are already commercially available. All are approved for the treatment of inflammatory and autoimmune disorders such as rheumatoid arthritis and Crohn’s disease. All currently approved products are macromolecular and act by inhibiting the binding of human TNFa to its receptor. Typical macromolecular TNFa inhibitors include anti-TNFa antibodies; and soluble TNFa receptor fusion proteins. Examples of commercially available anti-TNFa antibodies include fully human antibodies such as adalimumab (Humira®) and golimumab (Simponi®), chimeric antibodies such as infliximab (Remicade®), and pegylated Fab’ fragments such as certolizumab pegol (Cimzia®). An example of a commercially available soluble TNFa receptor fusion protein is etanercept (Enbrel®).

[0004] TNF superfamily members, including TNFa itself, are implicated in a variety of physiological and pathological functions that are believed to play a part in a range of conditions of significant medical importance (see, for example, M.G. Tansey & D.E. Szymkowski, Drug Discovery Today, 2009, 14, 1082-1088; and F.S. Carneiro et al, J. Sexual Medicine, 2010, 7, 3823-3834). The compounds in accordance with the present disclosure, being potent modulators of human TNFa activity, are therefore beneficial in the treatment and / or prevention of variousPATENTAttorney Docket No. : 050935-527001 WO human ailments. These include autoimmune and inflammatory disorders; neurological and neurodegenerative disorders; pain and nociceptive disorders; cardiovascular disorders; metabolic disorders; ocular disorders; and oncological disorders.

[0005] Compounds said to modulate TNFa activity are disclosed in PCT Publications De Haro Garcia et al., W02016 / 050975; Deligny et al., WO2017 / 167994; De Haro Garcia et al., WO2017 / 167995; Brookings et al., WO2018 / 197503; Johnson et al., W02020 / 084008; Kanouni et al., WO2024 / 112796; Kanouni et al., WO2024 / 129763; and Kanouni et al., WO2024 / 148191.

[0006] There is a need for novel and effective TNFa modulating agents that can be useful in the treatment of various disorders. This invention solves this and other related problems.BRIEF SUMMARY

[0007] In an aspect is provided a compound, or a pharmaceutically acceptable salt thereof,shared by Ring D and Ring E(Ib) are carbon atoms. The two atoms shared by Ring D and Ring E(Ic) are carbon atoms. The two atoms shared by Ring D and Ring E(Id) are carbon atoms.

[0009] The dotted bond - between two atoms shared by Ring D and Ring E(Ia) are carbon atoms. The dotted bond - between two atoms shared by Ring D and Ring E(Ib) arePATENTAttorney Docket No. : 050935-527001 WO carbon atoms. The dotted bond - between two atoms shared by Ring D and Ring E(Ic) are carbon atoms. The dotted bond - between two atoms shared by Ring D and Ring E(Id) are carbon atoms.

[0010] k is a single bond or a double bond.

[0011] Ring E(Ia) is a 6-membered heteroaryl, pyrrolidonyl, imidazolidinonyl, oxazolidinonyl, pyrrolyl, isoxazolidinyl, pyrazolyl, oxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, isoxazolyl or dioxolanyl.

[0012] Ring E(Ib), E(Ic) and E(Id) are independently heteroaryl or heterocycloalkyl.

[0013] Ring F is a phenyl or a 5- or 6-membered heteroaryl.

[0014] X is O or S.

[0015] The symbol n is an integer from 0 to 3.

[0016] The symbol n’ is an integer from 0 to 13.

[0017] The symbol m is an integer from 0 to 4.

[0018] The symbol p is an integer from 0 to 4.

[0019] The symbol q is an integer from 0 to 3.

[0020] R2is hydrogen, halogen, -CX23, -CHX22, -CH2X2, -OCX23, -OCHX22, -OCH2X2, - CN, -N3, -SR2A,-SOn2R2A, -SOv2NR2BR2C, -S(O)(R2B)NR2C, -NHNR2BR2C, -ONR2BR2C, -NHC(O)NHNR2BR2C, -NHC(O)NR2BR2C, -N(O)m2, -NR2BR2C, -C(O)R2D, -C(O)OR2D, -C(O)NR2BR2C, -OR2A, -NR2BSO2R2A, -NR2BC(O)R2D, -NR2BC(O)OR2D, -NR2BOR2D, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or

[0021] Li is a bond or substituted or unsubstituted alkylene.

[0022] R2A, R2B, R2Cand R2Dare independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted orPATENTAttorney Docket No. : 050935-527001 WO unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl R3is hydrogen, -OR5A, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or un substituted aryl or substituted or unsubstituted heteroaryl, or R3and R4can join together to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl, wherein R3and R4are not both hydrogen.

[0023] R4is hydrogen, -OR?B, 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, or R3and R4can join together to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl, wherein R3and R4are not both hydrogen.

[0024] R5Aand R3Bare independently hydrogen or substituted or unsubstituted alkyl.

[0025] R6and R7are independently hydrogen, 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, or R6and R7can join together to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

[0026] R8is hydrogen, halogen, -CX83, -CHX82, -CH2X8, -OCX83, -OCHX82, -OCH2X8, -CN, — N3, -SH, -NH2, -C(O)OH, -C(0)NH2, -OH, 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.

[0027] R9is independently halogen, -CX%, -CHX92, -CH2X9, -OCX93, -OCHX92, -OCH2X9, -CN, -N3, -SH, -NH2, -C(O)OH, -C(O)NH2, -OH, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or un substituted aryl, or substituted or unsubstituted heteroaryl.

[0028] R10is independently halogen, -CX103, -CHX102, -CH2X10, -OCX103, -OCHX102, -OCH2X10, -CN, -N3, -SH, -NH2, -C(O)OH, -C(O)NH2, -OH, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substitutedPATENTAttorney Docket No. : 050935-527001 WO or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0029] R11is hydrogen, halogen, -CXn3, -CHXn2, -CH2X11, -OCXn3, -OCHXU2,-OCH2X11, -CN, -N3, -SH, -NH2,-C(0)0H, -C(O)NH2, -OH, 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.

[0030] R12is hydrogen, halogen, -CX123, -CHX122, -CH2X12, -OCX123, -OCHX122,-OCH2X12, -CN, -N3, -SH, -NH2, -C(O)OH, -C(O)NH2, -OH, 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.

[0031] R13is hydrogen, halogen, CX133, CHX132, CH2X13, OCX133, OCHX132,-OCH2X13, -CN, -N3, -SR15A,-SOni3R15A, -SOvi3NR15BR15C, -NHNR15BR15C, -ONR15BR15C, -NHC(O)NHNR15BR15C, -NHC(O)NR15BR15C, -N(0)mi3, NR15BR15C, C(O)R15D, C(O)OR15D, -C(O)NR15BR15C, -OR15A, -NR15BSO2R15A, -NR15BC(O)R15D, -NR15BC(O)OR15D, -NR15BOR15D, 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.

[0032] R14is independently halogen, -CX143, -CHX142, -CH2X14, -OCX143, -OCHX142,-OCH2X14, -CN, -N3, -SR14A, — SOni4R14A, -SOV14NR14BR14C, -NHNR14BR14C, -ONR14BR14C, -NHC(O)NHNR14BR14C, -NHC(O)NR14BR14C, -N(0)mi4, -NR14BR14C, -C(O)R14D, -C(O)OR14D, -C(O)NR14BR14C, -OR14A, -NR14BSO2R14A, -NR14BC(O)R14D, -NR14BC(O)OR14D, -NR14BOR14D, =0, -NR16, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl.

[0033] R14A, R14B, R14C, and R14Dare independently hydrogen, halogen, -CX143,-CHX142, -CH2X14, -OCX143, -OCHX142, -OCH2X14, -CN, -N3, -SH, -NH2, -C(O)OH, -C(0)NH2, -OH, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl,PATENTAttorney Docket No. : 050935-527001 WO substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0034] R15A, R15B, R15C, and R15Dare independently hydrogen, halogen, -CX153,-CHX152, -CH2X15, -OCX153, -OCHX152, -OCH2X15, -CN, -N3, -SH, -NH2, -C(O)OH, -C(O)NH2, -OH, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0035] R16is hydrogen, 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.

[0036] R17is independently halogen, -CX173, -CHX172, -CH2X17, -OCX173, -OCHX17,-OCH2X17, -CN, -N3, -SH, -NH2, -C(O)OH, -C(0)NH2, -OH, 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.

[0037] R18is independently 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.

[0038] The symbols n2, nl3 and nl4 are independently an integer from 0 to 3.

[0039] The symbols m2, ml3 and ml4 are independently an integer from 0 to 4.

[0040] The symbols v2, vl3 and vl4 are independently an integer from 0 to 4.

[0041] Each X2, X8, X9, X10, X11, X12, X13, X14, X15and X17is independently halogen.

[0042] In an aspect is provided a compound, or a pharmaceutically acceptable salt thereof, having the formula (I):PATENTAttorney Docket No. : 050935-527001 WO

[0043] The two atoms shared by Ring D and Ring E are carbon atoms. The dotted bond - between two atoms shared by Ring D and Ring E are carbon atoms indicate the presence of a single bond or a double bond.

[0044] Ring E is a substituted or unsubstituted 6-membered heteroaryl, substituted or unsubstituted 5-membered heteroaryl, or a substituted or unsubstituted 5-membered heterocycloalkyl. In embodiments, Ring E is 2-pyrrolidone, pyrrole, pyrazole, oxazole, thiazole, isothiazole, oxadiazole, thiadiazole, triazole or isoxazole. In embodiments, Ring E is not substituted or unsubstituted imidazole. In embodiments, Ring E is not unsubstituted imidazole. In embodiments, Ring E is not substituted imidazole.

[0045] Ring F is a substituted or unsubstituted phenyl or a substituted or unsubstituted 5- or 6-membered heteroaryl having 1 to 2 nitrogen atoms.

[0046] The symbol n is an integer from 0 to 3.

[0047] The symbol m is an integer from 0 to 4.

[0048] R2is hydrogen, halogen, cyano, trifluoromethyl, trifluoromethoxy, -OR2A, -SR2A,SOR2A, -SO2R2A, -NR2BR2C, -NR2CCOR2D, -NR2CCO2R2D, -NHCONR2BR2C, -N2CSO2R2E, - COR2D, -CO2R2D, -CONR2BR2C, -SO2NR2BR2C, or -S(O)(NR2BR2E), 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 Li is a bond or substituted or unsubstituted alkylene.PATENTAttorney Docket No. : 050935-527001 WO

[0049] In embodiments, R2is hydrogen, halogen, cyano, trifluoromethyl, trifluoromethoxy, -OR2A, -SR2A, -SOR2A, -SO2R2A, -NR2BR2C, -NR2CCOR2D, -NR2CCO2R2D,-NHCONR2BR2C, -NR2CSO2R2E, -COR2D, -CO2R2D, -CONR2BR2C, -SO2NR2BR2C, or - S(O)(NR2BR2E), substituted or unsubstituted Ci.Ce alkyl, substituted or unsubstituted C3- C7 cycloalkyl, substituted or unsubstituted C4-C7 cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted aryl(Ci-C6)alkyl, substituted or unsubstituted 3 to 7 membered heterocycloalkyl, substituted or unsubstituted 3 to 7 membered heterocycloalkenyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaryl(Ci-C6)alkyl, substituted or unsubstituted 3 to 7 membered heterocycloalkyl(Ci-C6)alkyl-aryl, substituted or unsubstituted (C3-C7)cycloalkyl-heteroaryl, substituted or unsubstituted 3 to 7 membered heterocycloalkenyl-aryl, substituted or unsubstituted (C3-C7)cycloalkyl(Ci-6)alkyl-heteroaryl, substituted or unsubstituted (C4-C7) cycloalkenyl-heteroaryl, substituted or unsubstituted (C4-C9)bicycloalkyl-heteroaryl, substituted or unsubstituted 3 to 7 membered heterocycloalkyl-heteroaryl, substituted or unsubstituted 3 to 7 membered heterocycloalkyl (Ci-Ce)alkyl-heteroaryl, substituted or unsubstituted 3 to 7 membered heterocycloalkenyl-heteroaryl, substituted or unsubstituted 4 to 9 membered heterobicycloalkyl-heteroaryl, substituted or unsubstituted 4 to 9 membered spiroheterocy cl oal ky 1 -heteroaryl ,

[0050] R2Ais hydrogen, trifluoromethyl, 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. In embodiments, R2Ais a substituted or unsubstituted Ci.Ce alkyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted aryl(Ci-C6)alkyl, substituted or unsubstituted 3 to 7 membered heterocycloalkyl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heteroaryl(Ci-C6)alkyl.

[0051] R2Band R2Ceach independently hydrogen, trifluoromethyl, substituted or unsubstituted substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl,PATENTAttorney Docket No. : 050935-527001 WO substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl. In embodiments, R2Band R2Care each independently hydrogen, trifluoromethyl, substituted or unsubstituted Ci-Cg alkyl, substituted or un substituted C3-C7 cycloalkyl, substituted or unsubstituted C3-C7 cycloalkyl (Ci-Ce)alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aryl(Ci-C6)alkyl, substituted or unsubstituted 3 to 7 membered heterocycloalkyl, substituted or unsubstituted 3 to 7 membered heterocycloalkyl(Ci-C6)alkyl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heteroaryl(Ci-C6)alkyl, or R2Band R2C, when taken together with the nitrogen atom to which they are attached, is a heterocyclic moiety selected from substituted or unsubstituted azetidin-l-yl, substituted or unsubstituted pyrrolidin-l-yl, substituted or unsubstituted oxazolidin-3-yl, substituted or unsubstituted isoxazolidin-2-yl, substituted or unsubstituted thiazolidin-3-yl, substituted or unsubstituted isothiazolidin-2-yl, substituted or unsubstituted piperidin-l-yl, substituted or unsubstituted morpholin-4-yl, substituted or unsubstituted thiomorpholin-4-yl, substituted or unsubstituted piperazin4-yl, substituted or unsubstituted homopiperidin-l-yl, substituted or unsubstituted homomorpholin- 4-yl, substituted or unsubstituted homopiperazin-l-yl, substituted or unsubstituted (imino)(oxo)thiazinan-4-yl, substituted or unsubstituted (oxo)thiazinan-4-yl or substituted or unsubstituted (dioxo)-thiazinan-4-yl.

[0052] R2Dis hydrogen, substituted or unsubstituted 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. In embodiments, R2Dis hydrogen, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted 3 to 7 membered heterocycloalkyl or substituted or unsubstituted 5 to 7 membered heteroaryl.

[0053] R2Eis hydrogen, 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. In embodiments, R2Eis a substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.PATENTAttorney Docket No. : 050935-527001 WO

[0054] R3is hydrogen, -OR5A, 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, or R3and R4can join together to form a substituted or un substituted heterocycloalkyl or substituted or unsubstituted heteroaryl, wherein R3and R4are not both hydrogen.

[0055] R4is hydrogen, -OR5B, 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, or R3and R4can join together to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl, wherein R3and R4are not both hydrogen.

[0056] R5Aand R5Bare independently hydrogen or substituted or unsubstituted alkyl.

[0057] R6and R7are independently hydrogen, 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, or R6and R7can join together to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

[0058] R8is hydrogen or halogen.

[0059] R9is independently halogen or halogen-substituted or unsubstituted alkyl. In embodiments, R9is independently halogen or halogen-substituted or unsubstituted C1-C3 alkyl.

[0060] R11and R12are independently hydrogen or halogen-substituted alkyl. In embodiments, R11and R12are independently hydrogen or halogen-substituted methyl.

[0061] R13is hydrogen, halogen, hydroxy, cyano, -NH2, -SH, trifluoromethyl, difluoromethoxy, trifluoromethoxy, -OR15, substituted or unsubstituted alkyl sulphonyl or substituted or unsubstituted alkyl. In embodiments, R13is hydrogen, halogen, hydroxy, cyano, trifluoromethyl, difluoromethoxy, trifluoromethoxy, -OR15, substituted or unsubstituted Ci-Ce alkylsulphonyl or substituted or un substituted Ci-Ce alkyl.

[0062] R14is independently halogen, -OH, -NH2, -CF3, -CN, -SH, substituted or unsubstituted alkyl, substituted or membered heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted membered heterocycloalkyl, =0 or =NR16. In embodiments, R14is independently a substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted 2 to 6PATENTAttorney Docket No. : 050935-527001 WO membered heteroalkyl, substituted or unsubstituted Ci-Ce cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, =0 or =NR16.

[0063] R15is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or un substituted aryl, or substituted or unsubstituted heteroaryl. In embodiments, R15is a substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted 3 to 7 membered heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted aryl(Ci-C6)alkyl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heteroaryl ( C 1. Ce)alky 1.

[0064] R16is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl. In embodiments, R16is a substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, or substituted or unsubstituted 3 to 6 membered heterocycloalkyl.

[0065] In an aspect is provided a pharmaceutical composition including a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In embodiments, the pharmaceutical composition comprising the compound of formulae (I), (la), (lb), (Ic), (Id), (I-Ia), (I-Ib), (I-Ic), (I-Id) as described in the application, or a pharmaceutically acceptable salt thereof, further comprising an additional pharmaceutically active ingredient.

[0066] In an aspect is provided a compound of formulae (I), (la), (lb), (Ic), (Id), (I-Ia), (I-Ib), (I-Ic), (I-Id) as described in the application or a pharmaceutically acceptable salt thereof, for use in therapy.

[0067] In an aspect is provided a compound of formulae (I), (la), (lb), (Ic), (Id), (I-Ia), (I-Ib), (I-Ic), (I-Id) as described in the application, or a pharmaceutically acceptable salt thereof, for use in the treatment and / or prevention of disorders associated with modulation of the TNFa function. In embodiments, the compound of formulae (I), (la), (lb), (Ic), (Id), (I-Ia), (I-Ib), (I-Ic), (I-Id) as described in the application, or a pharmaceutically acceptable salt thereof, is for use in the treatment or prevention of inflammatory disease, autoimmune disease, neurological disease,PATENTAttorney Docket No. : 050935-527001 WO neurodegenerative disease, nociceptive disease, cardiovascular disease, metabolic disease, ocular disease, oncological disease, or pain.

[0068] In an aspect is provided the use of the compound of formulae (I), (la), (lb), (Ic), (Id), (I-Ia), (I-Ib), (Lie), (Lid) as described in the application, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of a disease or disorder associated with modulation of the TNFa function. In embodiments, the use of the compound of formulae (I), (la), (lb), (Ic), (Id), (Lla), (Lib), (Lie), (Lid) as described in the application, or a pharmaceutically acceptable salt thereof, is for the manufacture of a medicament for the treatment or prevention of inflammatory disease, autoimmune disease, neurological disease, neurodegenerative disease, nociceptive disease, cardiovascular disease, metabolic disease, ocular disease, oncological disease, or pain.

[0069] In an aspect is provided a method for treating a disease or disorder associated with the modulation of the TNFa function, said method comprising administering to a subject in need thereof a therapeutically effective amount of the compound of formulae (I), (la), (lb), (Ic), (Id), (Lla), (Lib), (Lie), (Lid) or a pharmaceutically acceptable salt thereof. In embodiments, said method is for the treatment or prevention of an inflammatory disease, autoimmune disease, neurological disease, neurodegenerative disease, nociceptive disease, cardiovascular disease, metabolic disease, ocular disease, oncological disease, or pain, said method comprising administering to a patient in need of such treatment a therapeutically effective amount of the compound of claim 1, or a pharmaceutically acceptable salt thereof.DETAILED DESCRIPTIONI. Definitions

[0070] The abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulae set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts.

[0071] Where substituent groups are specified by their conventional chemical formulae, written from left to right, they equally encompass the chemically identical substituents that would result from writing the structure from right to left, e.g., -CH2O- is equivalent to -OCH2-.

[0072] The term “alkyl,” by itself or as part of another substituent, means, unless otherwise stated, a straight (i.e., unbranched) or branched carbon chain (or carbon), or combination thereof,PATENTAttorney Docket No. : 050935-527001 WO which may be fully saturated, mono- or polyunsaturated and can include mono-, di-, and multivalent radicals. The alkyl may include a designated number of carbons (e.g., C1-C10 means one to ten carbons). In embodiments, the alkyl is fully saturated. In embodiments, the alkyl is monounsaturated. In embodiments, the alkyl is polyunsaturated. Alkyl is an uncyclized 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, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. An unsaturated alkyl group is one having one or more double bonds 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-(l,4-pentadienyl), ethynyl, 1- and 3-propynyl,3-butynyl, and the higher homologs and isomers. An alkoxy is an alkyl attached to the remainder of the molecule via an oxygen linker (-O-). An alkyl moiety may be an alkenyl moiety. An alkyl moiety may be an alkynyl moiety. An alkenyl includes one or more double bonds. An alkynyl includes one or more triple bonds.

[0073] The term “alkylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkyl, as exemplified, but not limited by, -CH2CH2CH2CH2-. Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those 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 eight 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. The term “alkynylene” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkyne. In embodiments, the alkylene is fully saturated. In embodiments, the alkylene is monounsaturated. In embodiments, the alkylene is polyunsaturated. An alkenylene includes one or more double bonds. An alkynylene includes one or more triple bonds.

[0074] The term “heteroalkyl,” by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or combinations thereof, including at least one carbon atom and at least one heteroatom (e.g., O, N, P, Si, and S), and wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quatemized. The heteroatom(s) (e.g., N, S, Si, or P) may be placed at any interior position of thePATENTAttorney Docket No. : 050935-527001 WO heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. Heteroalkyl is an uncyclized 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, -S-CH2-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. -0-CH3, -O-CH2-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. A heteroalkyl moiety may include one heteroatom (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include two optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include three optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include four optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include five optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include up to 8 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 including at least one double bond. A heteroalkenyl may optionally include more than one double bond and / or one or more triple bonds in addition to the one or more double bonds. The term “heteroalkynyl,” by itself or in combination with another term, means, unless otherwise stated, a heteroalkyl including at least one triple bond. A heteroalkynyl may optionally include more than one triple bond and / or one or more double bonds in addition to the one or more triple bonds. In embodiments, the heteroalkyl is fully saturated. In embodiments, the heteroalkyl is monounsaturated. In embodiments, the heteroalkyl is polyunsaturated.

[0075] Similarly, the term “heteroalkylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from heteroalkyl, as exemplified, but not limited by, -CH2-CH2-S-CH2-CH2- and -CH2-S-CH2-CH2-NH-CH2-. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). 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)2R’- represents both - C(O)2R’- and -R’C(O)2-. As described above, heteroalkyl groups, as used herein, include those groups that are attached to the remainder of the molecule through a heteroatom, such as -C(O)R’, recited, followed byPATENTAttorney Docket No. : 050935-527001 WO recitations of specific heteroalkyl groups, such as -NR’R” or the like, it will be understood that the terms heteroalkyl and -NR’R” are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity. Thus, the term “heteroalkyl” should not be interpreted herein as excluding specific heteroalkyl groups, such as -NR’R” or the like. 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, the heteroalkylene is fully saturated. In embodiments, the heteroalkylene is monounsaturated. In embodiments, the heteroalkylene is polyunsaturated. A heteroalkenyl ene includes one or more double bonds. A heteroalkynylene includes one or more triple bonds.

[0076] 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, l-(l,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, means a divalent radical derived from a cycloalkyl and 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 heterocycloalkyl is polyunsaturated.

[0077] In embodiments, the term “cycloalkyl” means a monocyclic, bicyclic, or a multicyclic cycloalkyl ring system. In embodiments, monocyclic ring systems are cyclic hydrocarbon groups containing from 3 to 8 carbon atoms, where such groups can be saturated or unsaturated,PATENTAttorney Docket No. : 050935-527001 WO but not aromatic. In embodiments, cycloalkyl groups are fully saturated. A bicyclic or multicyclic cycloalkyl ring system refers to multiple rings fused together wherein at least one of the fused rings is a cycloalkyl ring and wherein the multiple rings are attached to the parent molecular moiety through any carbon atom contained within a cycloalkyl ring of the multiple rings.

[0078] In embodiments, a cycloalkyl is a cycloalkenyl. The term “cycloalkenyl” is used in accordance with its plain ordinary meaning. In embodiments, a cycloalkenyl is a monocyclic, bicyclic, or a multicyclic cycloalkenyl ring system. A bicyclic or multicyclic cycloalkenyl ring system refers to multiple rings fused together wherein at least one of the fused rings is a cycloalkenyl ring and wherein the multiple rings are attached to the parent molecular moiety through any carbon atom contained within a cycloalkenyl ring of the multiple rings.

[0079] In embodiments, cycloalkyl is a bridged cycloalkyl.

[0080] In embodiments, cycloalkyl is a spirocycloalkyl.

[0081] In embodiments, the term “heterocycloalkyl” means a monocyclic, bicyclic, or a multicyclic heterocycloalkyl ring system. In embodiments, heterocycloalkyl groups are fully saturated. A bicyclic or multicyclic heterocycloalkyl ring system refers to multiple rings fused together wherein at least one of the fused rings is a heterocycloalkyl ring and wherein the multiple rings are attached to the parent molecular moiety through any atom contained within a heterocycloalkyl ring of the multiple rings.

[0082] In embodiments, heterocycloalkyl is a bridged heterocycloalkyl.

[0083] In embodiments, heterocycloalkyl is a spiroheterocycloalkyl.

[0084] 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(Ci-C4)alkyl” includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3 -bromopropyl, and the like.

[0085] The term “acyl” means, unless otherwise stated, -C(O)R where R is a 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.PATENTAttorney Docket No. : 050935-527001 WO

[0086] The term “aryl” means, unless otherwise stated, a polyunsaturated, aromatic, hydrocarbon substituent, which can be a single ring or multiple rings (preferably from 1 to 3 rings) that are fused together (i.e., a fused ring aryl) or linked covalently. A fused ring aryl refers to multiple rings fused together wherein at least one of the fused rings is an aryl ring and wherein the multiple rings are attached to the parent molecular moiety through any carbon atom contained within an aryl ring of the multiple rings. The term “heteroaryl” refers to aryl groups (or rings) that contain at least one heteroatom such as N, O, or S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. Thus, the term “heteroaryl” includes fused ring heteroaryl groups (i.e., multiple rings fused together wherein at least one of the fused rings is a heteroaromatic ring and wherein the multiple rings are attached to the parent molecular moiety through any atom contained within a heteroaromatic ring of the multiple rings). A 5,6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 5 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring. Likewise, a 6,6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring. And a 6,5-fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 5 members, and wherein at least one ring is a heteroaryl ring. A heteroaryl group can be attached to the remainder of the molecule through a carbon or 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, benzoxazoyl 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, 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,PATENTAttorney Docket No. : 050935-527001 WO mean a divalent radical derived from an aryl and heteroaryl, respectively. A heteroaryl group substituent may be -O- bonded to a ring heteroatom nitrogen.

[0087] The term "C3-C7 cycloalkyl" as used herein refers to monovalent groups of 3 to 7 carbon atoms derived from a saturated monocyclic hydrocarbon and may comprise benzo-fused analogues thereof. Suitable C3-C7 cycloalkyl groups include cyclopropyl, cyclobutyl, benzocyclobutenyl, cyclopentyl, indanyl, cyclohexyl and cycloheptyl.

[0088] The term "C4-C7 cycloalkenyl" as used herein refers to monovalent groups of 4 to 7 carbon atoms derived from a partially unsaturated monocyclic hydrocarbon. Suitable C4-C7 cycloalkenyl groups include cyclobutenyl, cyclopentenyl, cyclohexenyl and cycloheptenyl.

[0089] The term "C4-C9 bicycloalkyl" as used herein refers to monovalent groups of 4 to 9 carbon atoms derived from a saturated bicyclic hydrocarbon. Typical bicycloalkyl groups include bicyclo[3.1.0]hexanyl, bicyclo[4.1.0]heptanyl and bicyclo[2.2.2]octanyl.

[0090] The term "aryl" as used herein refers to monovalent carbocyclic aromatic groups derived from a single aromatic ring or multiple condensed aromatic rings. Suitable aryl groups include phenyl and naphthyl, preferably phenyl.

[0091] Suitable aryl(Ci-C6)alkyl groups include benzyl, phenylethyl, phenylpropyl and naphthylmethyl.

[0092] The term "C3-C7 heterocycloalkyl" as used herein refers to saturated monocyclic rings containing 3 to 7 carbon atoms and at least one heteroatom selected from oxygen, sulphur and nitrogen, and may comprise benzo-fused analogues thereof. Suitable heterocycloalkyl groups include oxetanyl, azetidinyl, tetrahydrofuranyl, dihydrobenzo-furanyl, dihydrobenzothienyl, pyrrolidinyl, indolinyl, isoindolinyl, oxazolidinyl, thiazolidinyl, isothiazolidinyl, imidazolidinyl, tetrahydropyranyl, chromanyl, dioxanyl, tetrahydrothiopyranyl, piperidinyl,1.2.3.4-tetrahydroquinolinyl, 1,2,3,4-tetrahydro-isoquinolinyl, piperazinyl,1.2.3.4-tetrahydroquinoxalinyl, hexahydro-[l,2,5]thiadiazolo-[2,3-a]pyrazinyl, homopiperazinyl, morpholinyl, benzoxazinyl, thiomorpholinyl, azepanyl, oxazepanyl, diazepanyl, thiadiazepanyl and azocanyl.

[0093] The term "C3-C7 heterocycloalkenyl" as used herein refers to monounsaturated or polyunsaturated monocyclic rings containing 3 to 7 carbon atoms and at least one heteroatom selected from oxygen, sulphur and nitrogen, and may comprise benzo-fused analogues thereof.PATENTAttorney Docket No. : 050935-527001 WOSuitable heterocycloalkenyl groups include thiazolinyl, imidazolinyl, dihydropyranyl, dihydrothiopyranyl and 1,2,3,6-tetrahydropyridinyl.

[0094] The term "C4-C9 heterobicycloalkyl" as used herein corresponds to C4-C9 bicycloalkyl wherein one or more of the carbon atoms have been replaced by one or more heteroatoms selected from oxygen, sulphur and nitrogen. Typical heterobicycloalkyl groups include 3-azabicyclo[3.1.0]hexanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 6-azabicyclo[3.2.0]heptanyl, 3-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[4.1.0]heptanyl,2-oxabicyclo[2.2.2]octanyl, quinuclidinyl, 2-oxa-5-azabicyclo[2.2.2]octanyl,3-azabicyclo[3.2.1]octanyl, 8-azabicyclo-[3.2.1]octanyl, 3-oxa-8-azabicyclo[3.2.1]octanyl,3.8-diazabicyclo[3.2.1]octanyl, 3,6-diazabicyclo[3.2.2]nonanyl, 3-oxa-7-azabicyclo[3.3.1 ]nonanyl, 3,7-dioxa-9-azabicyclo-[3.3.1 ]nonanyl and3.9-diazabicyclo[4.2.1]nonanyl.

[0095] The term "C4-C9 spiroheterocycloalkyl" as used herein refers to saturated bicyclic ring systems containing 4 to 9 carbon atoms and at least one heteroatom selected from oxygen, sulphur and nitrogen, in which the two rings are linked by a common atom. Suitable spiroheterocycloalkyl groups include 5-azaspiro[2.3]hexanyl, 5-azaspiro[2.4]-heptanyl, 2-azaspiro[3.3]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2-oxa-6-azaspiro[3.4]-octanyl, 2-oxa-6-azaspiro[3.5]nonanyl, 7-oxa-2-azaspiro[3.5]nonanyl, 2-oxa-7-azaspiro-[3.5]nonanyl and 2,4,8-triazaspiro[4.5]decanyl.

[0096] Spirocyclic rings are two or more rings wherein adjacent rings are attached through a single atom. The individual rings within spirocyclic rings may be identical or different. Individual rings in spirocyclic rings may be substituted or unsubstituted and may have different substituents from other individual rings within a set of spirocyclic rings. Possible substituents for individual rings within spirocyclic rings are the possible substituents for the same ring when not part of spirocyclic rings (e.g., substituents for cycloalkyl or heterocycloalkyl rings). Spirocylic rings may be substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heterocycloalkylene and individual rings within a spirocyclic ring group may be any of the immediately previous list, including having all rings of one type (e.g., all rings being substituted heterocycloalkylene wherein each ring may be the same or different substitutedPATENTAttorney Docket No. : 050935-527001 WO heterocycloalkylene). When referring to a spirocyclic ring system, heterocyclic spirocyclic rings means a spirocyclic rings wherein at least one ring is a heterocyclic ring and wherein each ring may be a different ring. When referring to a spirocyclic ring system, substituted spirocyclic rings means that at least one ring is substituted and each substituent may optionally be different.

[0097] The symbol ” denotes the point of attachment of a chemical moiety to the remainder of a molecule or chemical formula.

[0098] The term “oxo,” as used herein, means an oxygen that is double bonded to a carbon atom.

[0099] The term “alkylarylene” as an arylene moiety covalently bonded to an alkylene moiety (also referred to herein as an alkylene linker). In embodiments, the alkylarylene group has the formula:

[0100] An alkylarylene moiety may be substituted (e.g., with a substituent group) on the alkylene moiety or the arylene linker (e.g., at carbons 2, 3, 4, or 6) with halogen, oxo, -N3, -CF3, -CC13, -CBr3, -CI3, -CN, -CHO, -OH, -NH2, -COOH, -C0NH2, -NO2, -SH, -SO2CH3, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(0)NHNH2, substituted or unsubstituted C1-C5 alkyl or substituted or unsubstituted 2 to 5 membered heteroalkyl). In embodiments, the alkylarylene is unsubstituted.

[0101] 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.

[0102] Substituents for the alkyl and heteroalkyl radicals (including those groups often referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) can be one or more of a variety of groups selected from, but not limited to, -OR’, =0, =NR’, =N-0R’, -NR’R”, -SR’, halogen, -SiR’R”R’”, -OC(O)R’, -C(O)R’, -CO2R’, -CONR’R”, -0C(0)NR’R”, -NR”C(0)R’, -NR’C(0)NR”R’”, -NR”C(O)2R’, -NRC(NR’R”R’”)=NR””, -NRC(NR’R”)=NR’”, -S(O)R’, -S(O)2R’, -S(O)2NR’R”, -NRSO2R’, -NR’NR”R ”, -ONR’R”, -NR’C(O)NR”NR’”R””, -CN,PATENTAttorney Docket No. : 050935-527001 WO-N02, -NR’SO2R ”, -NR’C(O)R”, -NR’C(O)OR”, -NR’OR”, in a number ranging from zero to (2m’+l), where m’ is the total number of carbon atoms in such radical. R, R’, R”, R’”, and R”” each preferably independently refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or un substituted cycloalkyl, substituted or un substituted heterocycloalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1-3 halogens), substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, alkoxy, or thioalkoxy groups, or arylalkyl groups. When a compound described herein includes more than one R group, for example, each of the R groups is independently selected as are each R”, R”, R’”, and R”” group when more than one of these groups is present. When R’ and R” are attached to the same nitrogen atom, they can be combined 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 meant to include groups including carbon atoms bound to groups other than hydrogen groups, such as haloalkyl (e.g., -CF3and -CH2CF3) and acyl (e g., -C(O)CH3, -C(O)CF3, -C(O)CH2OCH3, and the like).

[0103] Similar to the substituents described for the alkyl radical, substituents for the aryl and heteroaryl groups are varied and are selected from, for example: -OR”, -NR’R”, -SR’, halogen, -SiR’R”R’”, -OC(O)R’, -C(O)R’, -CO2R’, -CONR’R”, -OC(O)NR’R”, -NR”C(O)R’, -NR’C(O)NR”R’”, -NR”C(O)2R’, -NR-C(NR’R”R’”)=NR””, -NR-C(NR’R”)=NR’”, -S(O)R’, -S(O)2R’, -S(O)2NR’R”, -NRSO2R’, -NR’NR”R’”, -ONR’R”, -NR’C(O)NR”NR’”R””, -CN, -NO2, -R’, -N3, -CH(Ph)2, fluoro(Ci-C4)alkoxy, and fluoro(Ci-C4)alkyl, -NR’SO2R”, -NR’C(O)R”, -NR’C(O)OR”, -NR’OR”, in a number ranging from zero to the total number of open valences on the aromatic ring system; and where 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. When a compound described herein includes more than one R group, for example, each of the R groups is independently selected as are each R’, R”, R’”, and R”” groups when more than one of these groups is present.

[0104] Substituents for rings (e.g., cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene) may be depicted as substituentsPATENTAttorney Docket No. : 050935-527001 WO on the ring rather than on a specific atom of a ring (commonly referred to as a floating substituent). In such a case, the substituent may be attached to any of the ring atoms (obeying the rules of chemical valency) and in the case of fused rings or spirocyclic rings, a substituent depicted as associated with one member of the fused rings or spirocyclic rings (a floating substituent on a single ring), may be a substituent on any of the fused rings or spirocyclic rings (a floating substituent on multiple rings). When a substituent is attached to a ring, but not a specific atom (a floating substituent), and a subscript for the substituent is an integer greater than one, the multiple substituents may be on the same atom, same ring, different atoms, different fused rings, different spirocyclic rings, and each substituent may optionally be different. Where a point of attachment of a ring to the remainder of a molecule is not limited to a single atom (a floating substituent), the attachment point may be any atom of the ring and in the case of a fused ring or spirocyclic ring, any atom of any of the fused rings or spirocyclic rings while obeying the rules of chemical valency. Where a ring, fused rings, or spirocyclic rings contain one or more ring heteroatoms and the ring, fused rings, or spirocyclic rings are shown with one more floating substituents (including, but not limited to, points of attachment to the remainder of the molecule), the floating substituents may be bonded to the heteroatoms. Where the ring heteroatoms are shown bound to one or more hydrogens (e.g., a ring nitrogen with two bonds to ring atoms and a third bond to a hydrogen) in the structure or formula with the floating substituent, when the heteroatom is bonded to the floating substituent, the substituent will be understood to replace the hydrogen, while obeying the rules of chemical valency.

[0105] Two or more substituents may optionally be joined to form aryl, heteroaryl, cycloalkyl, or heterocycloalkyl groups. Such so-called ring-forming substituents are typically, though 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 create 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 create a spirocyclic structure. In yet another embodiment, the ring-forming substituents are attached to non-adjacent members of the base structure.PATENTAttorney Docket No. : 050935-527001 WO

[0106] Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally form a ring of the formula -T-C(O)-(CRR’)q-U-, wherein T and U are independently -NR-, -O-, -CRR’-, or a single bond, and q is an integer of from 0 to 3. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A-(CH2)r-B-, wherein 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 of from 1 to 4. One of the single bonds of 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 of 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.

[0107] As used herein, the terms “heteroatom” or “ring heteroatom” are meant to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), selenium (Se), and silicon (Si). In embodiments, the terms “heteroatom” or “ring heteroatom” are meant to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).

[0108] A “substituent group,” as used herein, means a group selected from the following moi eties:(A) oxo, halogen, -CC13, -CBr3, -CF3, -CI3, -CHCI2, -CHBr2, -CHF2, -CHI2, -CH2C1, -CH2Br, -CH2F, -CH2I, -OCCI3, -OCF3, -OCBr3, -OCI3, -OCHCI2, -OCHBr2, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I, -OCH2F, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(0)NHNH2, -NHC(0)NH2, -NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(0)0H, -NHOH, -N3, -SF5, unsubstituted alkyl (e.g., Ci-Cg alkyl, Ci-Ce 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 Cs-Ce cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 memberedPATENTAttorney Docket No. : 050935-527001 WO heterocycloalkyl), unsubstituted aryl (e.g., C6-C10 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 / or(B) alkyl (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl), heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or Cs-Ce cycloalkyl), heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), aryl (e.g., Ce-Cio aryl, C10 aryl, or phenyl), heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), substituted with at least one substituent selected from:(i) oxo, halogen, -CCI3, -CBr3, -CF3, -CI3, -CHCh, -CHBr2, -CHF2, -CHI2, -CH2C1, -CH2Br, -CH2F, -CH2I, -OCCI3, -OCF3, -OCBr3, -OCI3, -OCHCI2, -OCHBr2, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I, -OCH2F, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -0NH2, -NHC(0)NHNH2, -NHC(0)NH2, -NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(0)0H, -NHOH, -N3, -SF5, unsubstituted alkyl (e g., Ci-Cs alkyl, Ci-Ce 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-Cs cycloalkyl, C3-Ce cycloalkyl, or Cs-Ce 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., Ce-Cio 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 / or(ii) alkyl (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl), heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or Cs-Ce cycloalkyl), heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), aryl (e.g., Ce-Cio aryl, C10 aryl, or phenyl), heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), substituted with at least one substituent selected from:PATENTAttorney Docket No. : 050935-527001 WO(a) oxo, halogen, -CCI3, -CBr3, -CF3, -CI3, -CHCh, -CHBr2, -CHF2, -CHI2, -CH2C1, -CH2Br, -CH2F, -CH2I, -OCCI3, -OCF3, -OCBr3, -OCI3, -OCHC12, -OCHBr2, -0CHI2, -OCHF2, -OCH2C1, -OCH2Br, -0CH2I, -OCH2F, -CN, -OH, -NH2, -COOH, -C0NH2, -N02, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -0NH2, -NHC(0)NHNH2, -NHC(0)NH2, -NHC(NH)NH2, -NHSO2H, -NHC(0)H, -NHC(0)0H, -NHOH, -N3, -SF5, unsubstituted alkyl (e.g., Ci-Cs alkyl, Ci-Ce 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., Ce-Cio 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 / or(b) alkyl (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl), heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or Cs-Ce cycloalkyl), heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), aryl (e.g., Ce-Cio aryl, C10 aryl, or phenyl), heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), substituted with at least one substituent selected from: oxo, halogen, -CCI3, -CBn, -CF3, -CI3, -CHC12, -CHBr2, -CHF2, -CHI2, -CH2C1, -CH2Br, -CH2F, -CH2I, -OCCI3, -OCF3, -OCBr3, -OCI3, -OCHC12, -OCHBr2, -OCHI2, -OCHF2, -OCH2C1, -OCH2Br, -0CH2I, -OCH2F, -CN, -OH, -NH2, -COOH, -C0NH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -0NH2, -NHC(0)NHNH2, -NHC(0)NH2, -NHC(NH)NH2, -NHS02H, -NHC(0)H, -NHC(0)0H, -NHOH, -N3, -SF5, unsubstituted alkyl (e.g., Ci-Cs alkyl, Ci-Ce 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-C cycloalkyl, C3-C6 cycloalkyl, or Cs-Ce cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 memberedPATENTAttorney Docket No. : 050935-527001 WO heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., Ce-Cio aryl, Cio aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0109] A “size-limited substituent” or “ size-limited substituent group,” as used herein, means a group selected from all of the substituents described above for a “substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C20 alkyl, 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 Cs-Cs cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 8 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted Ce-Cio aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 10 membered heteroaryl.

[0110] A “lower substituent” or “ lower substituent group,” as used herein, means a group selected from all of the substituents described above for a “substituent group,” wherein each substituted or un substituted alkyl is a substituted or unsubstituted Ci-Cs 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, each substituted or unsubstituted aryl is a substituted or unsubstituted phenyl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 6 membered heteroaryl.[0U1] In some embodiments, each substituted group described in the compounds herein is substituted with at least one substituent group. 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 are substituted with at least one substituent group. In other embodiments, at least one or all of these groups are substituted with at least one size-limited substituent group. In other embodiments, at least one or all of these groups are substituted with at least one lower substituent group.PATENTAttorney Docket No. : 050935-527001 WO

[0112] In other embodiments of the compounds herein, each substituted or unsubstituted alkyl may be a substituted or unsubstituted C1-C20 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or un substituted C3-C8 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 8 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted Ce-Cio aryl, and / or each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 10 membered heteroaryl. In some embodiments of the compounds herein, each substituted or unsubstituted alkylene is a substituted or unsubstituted C1-C20 alkylene, 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, each substituted or unsubstituted arylene is a substituted or unsubstituted Ce-Cio arylene, and / or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5 to 10 membered heteroarylene.

[0113] In some embodiments, each substituted or unsubstituted alkyl is a substituted or unsubstituted Ci-Cs 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, each substituted or unsubstituted aryl is a substituted or unsubstituted Ce-Cio aryl, and / or each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 9 membered heteroaryl. In some embodiments, each substituted or unsubstituted alkylene is a substituted or unsubstituted Ci-Cs alkylene, each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2 to 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 to 7 membered heterocycloalkylene, each substituted or unsubstituted arylene is a substituted or unsubstituted Ce-Cio arylene, and / or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5 to 9 membered heteroarylene. InPATENTAttorney Docket No. : 050935-527001 WO some embodiments, the compound is a chemical species set forth in the Examples section, figures, or tables below.

[0114] 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., is an 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., is 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, respectively).

[0115] 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 group, wherein if the substituted moiety is substituted with a plurality of substituent groups, each substituent group may optionally be different. In embodiments, if the substituted moiety is substituted with a plurality of substituent groups, each substituent group is different.PATENTAttorney Docket No. : 050935-527001 WO

[0116] 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-limited substituent group, wherein if the substituted moiety is substituted with a plurality of size-limited substituent groups, each size-limited substituent group may optionally be different. In embodiments, if the substituted moiety is substituted with a plurality of size-limited substituent groups, each size-limited substituent group is different.

[0117] 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 group, wherein if the substituted moiety is substituted with a plurality of lower substituent groups, each lower substituent group may optionally be different. In embodiments, if the substituted moiety is substituted with a plurality of lower substituent groups, each lower substituent group is different.

[0118] 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 group, size-limited substituent group, or lower substituent group; wherein if the substituted moiety is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, if the substituted moiety is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group is different.

[0119] In a recited claim or chemical formula description herein, each R substituent or L linker that is described as being “substituted” without reference as to the identity of any chemical moiety that composes the “substituted” group (also referred to herein as an “open substitution”PATENTAttorney Docket No. : 050935-527001 WO on an R substituent or L linker or an “openly substituted” R substituent or L linker), the recited R substituent or L linker may, in embodiments, be substituted with one or more first substituent groups as defined below.

[0120] The first substituent group is denoted with a corresponding first decimal point numbering system such that, for example, R1may be substituted with one or more first substituent groups denoted by R14, R2may be substituted with one or more first substituent groups denoted by R2 1, R3may be substituted with one or more first substituent groups denoted by R34, R4may be substituted with one or more first substituent groups denoted by R41, R5may be substituted with one or more first substituent groups denoted by R3 1, and the like up to or exceeding an R100that may be substituted with one or more first substituent groups denoted by R100 1. Asafurther example, R1Amay be substituted with one or more first substituent groups denoted by R1AA, R2Amay be substituted with one or more first substituent groups denoted by R2A 4, R3Amay be substituted with one or more first substituent groups denoted by R3A 1, R4Amay be substituted with one or more first substituent groups denoted by R4A4, R5 Amay be substituted with one or more first substituent groups denoted by R3A 1and the like up to or exceeding an R100Amay be substituted with one or more first substituent groups denoted by RIOOA I AS a further example, L1may be substituted with one or more first substituent groups denoted by RL1 1, L2may be substituted with one or more first substituent groups denoted by R1'2 J, L3may be substituted with one or more first substituent groups denoted by R1'3 1, L4may be substituted with one or more first substituent groups denoted by RL4 1, L5may be substituted with one or more first substituent groups denoted by RL5 1and the like up to or exceeding an L100which may be substituted with one or more first substituent groups denoted by RL10°A. Thus, each numbered R group or L group (alternatively referred to herein as Rwwor Lwwwherein“WW” represents the stated superscript number of the subject R group or L group) described herein may be substituted with one or more first substituent groups referred to herein generally as RWW 1or RLWW 1, respectively. In turn, each first substituent group (e.g., R1 1, R2 1, R3-1, R4 1, R5.1 RIOO.1 . R1A.1 R2A.1 R3A.1 R4A.1 R 5A.1 RIOOA.1. RLI.1 R L2.1 RL3.1 RL4.1 RL5.1 RLIOO.1) may be further substituted with one or more second substituent groups (e.g., R1 2, R22, R3 2, R42,R 5.2 J^100.2. J^1A.2 j^2A.2 j^3A.2 j^4A.2 R5A 2 RIOOA.2. RL1 2RL2.2 R L3.2 R L4.2 RL5.2 RL100.2 respectively). Thus, each first substituent group, which may alternatively be represented hereinPATENTAttorney Docket No. : 050935-527001 WO as Rww 1as described above, may be further substituted with one or more second substituent groups, which may alternatively be represented herein as RWW 2.

[0121] Finally, each second substituent group (e.g., R1 2, R2 2, R3 2, R42, R5 2. . . R100-2; R1-42, R2A'2,R3A.2R4A.2,R5A.2R100A.2.RL1.2,RL2.2RL3.2,RL42,RL5.2RL100.2)may befurthersubstituted with one or more third substituent groups (e.g., R1 3, R2 3, R3 3, R43, R5 3.. . R100 3; R14-3, R2A 3, R3 3, R4A3, R5A 3... R100A-3; RL1 3, RL2-3, RL3 3, RL43, RL5 3... RL100-3; respectively). Thus, each second substituent group, which may alternatively be represented herein as RWW2as described above, may be further substituted with one or more third substituent groups, which may alternatively be represented herein as RWW 3. Each of the first substituent groups may be optionally different. Each of the second substituent groups may be optionally different. Each of the third substituent groups may be optionally different.

[0122] Thus, as used herein, Rwwrepresents a substituent recited in a claim or chemical formula description herein which is openly substituted. “WW” represents the stated superscript number of the subject R group (1, 2, 3, 1 A, 2A, 3A, IB, 2B, 3B, etc.). Likewise, Lwwis a linker recited in a claim or chemical formula description herein which is openly substituted. Again, “WW” represents the stated superscript number of the subject L group (1, 2, 3, 1A, 2A, 3A, IB, 2B, 3B, etc.). As stated above, in embodiments, each Rwwmay be unsubstituted or independently substituted with one or more first substituent groups, referred to herein as RWW 1; each first substituent group, RWW 1, may be unsubstituted or independently substituted with one or more second substituent groups, referred to herein as RWW2; and each second substituent group may be unsubstituted or independently substituted with one or more third substituent groups, referred to herein as RW 3. Similarly, each Lwwlinker may be unsubstituted or independently substituted with one or more first substituent groups, referred to herein as RLWW 1; each first substituent group, RLWW1, may be unsubstituted or independently substituted with one or more second substituent groups, referred to herein as RLWW 2; and each second substituent group may be unsubstituted or independently substituted with one or more third substituent groups, referred to herein as RLWW 3Each first substituent group is optionally different. Each second substituent group is optionally different. Each third substituent group is optionally different. For example, if Rwwis phenyl, the said phenyl group is optionally substituted by one or more Rw w 1groups as defined herein below, e.g., when Rww 1is Rww^-substituted orPATENTAttorney Docket No. : 050935-527001 WO unsubstituted alkyl, examples of groups so formed include but are not limited to itself optionally substituted by 1 or more Rww'2, which RWW2is optionally substituted by one or more Rww-3. By way of example when the Rwwgroup is phenyl substituted by Rww\ which is methyl, the methyl group may be further substituted to form groups including but not limited to:

[0123] oxo, halogen, -H2XWW 1, -OCXWW 13, -OCH2XWW 1, -OCHXWW 12, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(0)NHNH2, -NHC(0)NH2, -NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, RWW2-substituted or unsubstituted alkyl (e.g., Ci-Cs, Ci-Ce, C1-C4, or Ci-C2), RWW2-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), RWW2-substituted or unsubstituted cycloalkyl (e.g., C3-Cs, C3-C6, C4-C6, or Cs-Ce), RWW2-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), RWW2-substituted or unsubstituted aryl (e g., Ce-Ci2, Ce-Cio, or phenyl), or RWW 2-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, RWW 1is independently oxo, halogen, -CXWW 13, -CHXWW 12, -CH2XWW 1, -OCXWW 13, -OCH2XWW 1, -OCHXWW 12, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -0NH2, -NHC(O)NHNH2, -NHC(0)NH2,PATENTAttorney Docket No. : 050935-527001 WO-NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, unsubstituted alkyl (e.g., Ci-Cs, Ci-Ce, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or Cs-Ce), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., Ce-Cn, Ce-Cio, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). Xww 1is independently -F, -Cl, -Br, or -I.

[0124] RWW2is independently oxo, halogen, -CXWW 23, -CHXWW 22, -CH2XWW2, -OCXWW 23, -OCH2XWW2, -OCHXWW 22, -CN, -OH, -NH2, -COOH, -C0NH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -0NH2, -NHC(0)NHNH2, -NHC(0)NH2, -NHC(NH)NH2, -NHSO2H, -NHC(0)H, -NHC(0)0H, -NHOH, -N3, Rww 3-substituted or unsubstituted alkyl (e.g., Ci-Cs, Ci-Ce, C1-C4, or C1-C2), RWW3-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), RWW3-substituted or unsubstituted cycloalkyl (e.g., C3-Cs, C3-Ce, C4-C6, or Cs-Ce), RWW3- substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), RWW3-substituted or unsubstituted aryl (e.g., Ce-Cn, Ce-Cio, or phenyl), or Rww 3-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, Rww-2is independently oxo, halogen, -CXWW\ -CHXWW22, -CH2XWW2, -OCXWW23, -OCH2XWW 2, -OCHXWW22, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(0)NHNH2, -NHC(0)NH2, -NHC(NH)NH2, -NHSO2H, -NHC(0)H, -NHC(O)OH, -NHOH, -N3, unsubstituted alkyl (e.g., Ci-Cs, Ci-Ce, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e g., C3-Cs, C3-Ce, C4-C6, or Cs-Ce), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., Ce-Cn, Ce-Cio, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). XWW2is independently -F, -Cl, -Br, or -I.

[0125] RWW3is independently oxo, halogen, -CXWW33, -CHXWW 32, -CH2XWW3,PATENTAttorney Docket No. : 050935-527001 WO-OSO3H, -SO2NH2, -NHNH2, -0NH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, unsubstituted alkyl (e.g., Ci-C8, Ci-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e g., C3-C8, C3-Ce, C4-C6, or Cs-Ce), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C12, Ce-Cio, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). XWW3is independently -F, -Cl, -Br, or -I.

[0126] Where two different Rwwsubstituents are joined together to form an openly substituted ring (e.g., substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl or substituted heteroaryl), in embodiments the openly substituted ring may be independently substituted with one or more first substituent groups, referred to herein as RWW 1; each first substituent group, Rww-', may be unsubstituted or independently substituted with one or more second substituent groups, referred to herein as Rww'2; and each second substituent group, RWW2, may be unsubstituted or independently substituted with one or more third substituent groups, referred to herein as Rww-3; and each third substituent group, RWW3, is unsubstituted. Each first substituent group is optionally different. Each second substituent group is optionally different. Each third substituent group is optionally different. In the context of two different Rwwsubstituents joined together to form an openly substituted ring, the “WW” symbol in the RWW1, RWW.2anj RWW.3refersthe designated number of one of the two different Rwwsubstituents. For example, in embodiments where R100Aand R100Bare optionally joined together to form an openly substituted ring, RWW 1is R100A-1, RWW2isR100A2,an(j ^ww,3R1OOA.3Alternatively, in embodiments where R100Aand R100Bare optionally joined together to form an openly substituted ring, RWW 1is R100B 1, RWW2is R100a2, and RWW3is R100B 3. RWW 1, RWW2and RWW3in this paragraph are as defined in the preceding paragraphs.

[0127] RLWW 1is independently oxo, halogen, -CXLWW 13, -CHXLWW\ -CH2XLWW 1, -OCXLWW 13, -OCH2XLWW 1, -OCHXLWW 12, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -0NH2, -NHC(0)NHNH2, -NHC(0)NH2, -NHC(NH)NH2, -NHSO2H, -NHC(0)H, -NHC(0)0H, -NHOH, -N3, RLWW 2-substituted or unsubstituted alkyl (e.g., Ci-C8, Ci-Ce, C1-C4, or C1-C2), RLWW2-substituted or unsubstitutedPATENTAttorney Docket No. : 050935-527001 WO heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to5 membered), RLWW 2-substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5- Cg), RLWW2- substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), RLWW 2-substituted or unsubstituted aryl (e.g., C6-C12, Cg-Cio, or phenyl), or RLWW 2-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, RLWW 1is independently oxo, halogen, -CXLWW 13, -CHXLWW 12, -CH2XLWW 1, -OCXLWW 13, -0CH2XLWW 1, -0CHXLWW 12, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -0NH2, -NHC(0)NHNH2, -NHC(0)NH2, -NHC(NH)NH2, -NHSO2H, -NHC(0)H, -NHC(0)0H, -NHOH, -N3, unsubstituted alkyl (e g., Ci-Cs, Ci-Cg, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or Cs-Cg), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-Ci2, Cg-Cio, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). XLWW 1is independently -F, -Cl, -Br, or -I.

[0128] RLWW2is independently oxo, halogen, -CXLWW 23, -CHXLWW 22, -CH2XLWW2, -OCXLWW 23, -OCH2XLWW2, -OCHXLWW 22, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -0NH2, -NHC(0)NHNH2, -NHC(0)NH2, -NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, RLWW 3-substituted or unsubstituted alkyl (e.g., Ci-Cs, Ci-Cg, C1-C4, or C1-C2), RLWW3-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), RWW 3-substituted or unsubstituted cycloalkyl (e.g., C3-C8, Cs-Cg, C4-C6, or Cs-Cg), RLWW 3-substitutedorunsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), RLWW 3-substituted or unsubstituted aryl (e.g., Cg-Ci2, Cg-Cio, or phenyl), or RLWW 3-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, RLWW2is independently oxo, halogen, -CXLWW23, -CHXLWW'22, -CH2XLWW 2, -OCXLWW'23, -OCH2XLWW 2, -OCHXLWW 22, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H,PATENTAttorney Docket No. : 050935-527001 WO-NHC(O)H, -NHC(O)OH, -NHOH, -N3, unsubstituted alkyl (e.g, Ci-Cs, Ci-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or Cs-Ce), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C12, Ce-Cio, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). XLWW'2is independently -F, -Cl, -Br, or -I.

[0129] RLWW3is independently oxo, halogen, -CXLWW 33, -CHXLWW 32, -CH2XLWW3, -OCXLWW 33, -OCH2XLWW3, -OCHXLWW32, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -0NH2, -NHC(0)NHNH2, -NHC(0)NH2, -NHC(NH)NH2, -NHSO2H, -NHC(0)H, -NHC(0)0H, -NHOH, -N3, unsubstituted alkyl (e.g, Ci-Cs, Ci-Ce, C1-C4, or Ci-C2), unsubstituted heteroalkyl (e.g, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g, C3-C8, C3-C6, C4-C6, or Cs-Ce), unsubstituted heterocycloalkyl (e.g, 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e g, C6-C12, Ce-Cio, or phenyl), or unsubstituted heteroaryl (e g, 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). XLWW'3is independently -F, -Cl, -Br, or -I.

[0130] In the event that any R group recited in a claim or chemical formula description set forth herein (Rwwsubstituent) is not specifically defined in this disclosure, then that R group (Rwwgroup) is hereby defined as independently oxo, halogen, -CXWW3, -CHXWW2, -CH2XWW, -OCXWW3, -0CH2XWW, -0CHXWW2, -CN, -OH, -NH2, -COOH, -C0NH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -0NH2, -NHC(0)NHNH2, -NHC(0)NH2, -NHC(NH)NH2, -NHSO2H, -NHC(0)H, -NHC(0)0H, -NHOH, -N3, RWW 1-substituted or unsubstituted alkyl (e.g, Ci-Cs, Ci-Ce, C1-C4, or C1-C2), RW W 1-substituted or unsubstituted heteroalkyl (e.g, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), RWW 1-substituted or unsubstituted cycloalkyl (e.g, C3-C8, C3-Ce, C4-C6, or Cs-Ce), RWW 1. substituted or unsubstituted heterocycloalkyl (e.g, 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), Rww^-substituted or unsubstituted aryl (e.g, C6-Ci2, Ce-Cio, or phenyl), or RWW 1-substituted or unsubstituted heteroaryl (e.g, 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). Xwwis independentlyPATENTAttorney Docket No. : 050935-527001 WO-F, -Cl, -Br, or -I. Again, “WW” represents the stated superscript number of the subject R group (e.g., 1, 2, 3, 1A, 2A, 3A, IB, 2B, 3B, etc.). RWW 15Rww-2, andRWW3are as defined above.

[0131] In the event that any L linker group recited in a claim or chemical formula description set forth herein (i.e., an Lwwsubstituent) is not explicitly defined, then that L group (Lwwgroup) is herein defined as independently a bond, -O-, -NH-, -C(O)-, -C(0)NH-, -NHC(O)-, -NHC(0)NH-, -NHC(NH)NH-, -C(O)O-, -OC(O)-, -S-, -SO2-, -SO2NH-, RLWW 1-substituted or unsubstituted alkylene (e.g., Ci-Cg, Ci-Ce, C1-C4, or C1-C2), RLWW 1- substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), RLWW 1- substituted or unsubstituted cycloalkylene (e.g., C3-C8, C3-C6, C4-C6, or Cs-Ce), RLWW 1- substituted or unsubstituted heterocycloalkylene (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), RLWW 1-substituted or unsubstituted arylene (e.g., C6-C12, Ce-Cio, or phenyl), or RLWW^-substituted or unsubstituted heteroarylene (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). Again, “WW” represents the stated superscript number of the subject L group (1, 2, 3, 1 A, 2A, 3A, IB, 2B, 3B, etc.). RLWW 15as well as RLWW 2andRLWW3are as defined above.

[0132] Certain compounds of the present disclosure possess asymmetric carbon atoms (optical or chiral centers) or double bonds; the enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisometric forms that may be defined, in terms of absolute stereochemistry, as (R)-or (S)- or, as (D)- or (L)- for amino acids, and individual isomers are encompassed within the scope of the present disclosure. The compounds of the present disclosure do not include those that are known in art to be too unstable to synthesize and / or isolate. The present disclosure is meant to include compounds in racemic and optically pure forms. 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, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers.

[0133] As used herein, the term “isomers” refers to compounds having the same number and kind of atoms, and hence the same molecular weight, but differing in respect to the structural arrangement or configuration of the atoms.PATENTAttorney Docket No. : 050935-527001 WO

[0134] The term “tautomer,” as used herein, refers to one of two or more structural isomers which exist in equilibrium and which are readily converted from one isomeric form to another.

[0135] It will be apparent to one skilled in the art that certain compounds of this disclosure may exist in tautomeric forms, all such tautomeric forms of the compounds being within the scope of the disclosure.

[0136] Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms of the structure; i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the disclosure.

[0137] Unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by13C- or14C-enriched carbon are within the scope of this disclosure.

[0138] 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 be radiolabeled with radioactive isotopes, such as for example tritium (3H), iodine-125 (125I), or carbon-14 (14C). All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure.

[0139] It should be noted that throughout the application that alternatives are written in Markush groups, for example, each amino acid position that contains more than one possible amino acid. It is specifically contemplated that each member of the Markush group should be considered separately, thereby comprising another embodiment, and the Markush group is not to be read as a single unit.

[0140] “Analog,” “analogue,” or “derivative” is used in accordance with its plain ordinary meaning within Chemistry and Biology and refers to a chemical compound that is structurally similar to another compound (i.e., a so-called “reference” compound) but differs in composition, e.g., in the replacement of one atom by an atom of a different element, or in the presence of a particular functional group, or the replacement of one functional group by another functionalPATENTAttorney Docket No. : 050935-527001 WO group, or the absolute stereochemistry of one or more chiral centers of the reference compound. Accordingly, an analog is a compound that is similar or comparable in function and appearance but not in structure or origin to a reference compound.

[0141] The terms “a” or “an”, as used in herein means one or more. In addition, the phrase “substituted with a[n]”, as used herein, means the specified group may be substituted with one or more of any or all of the named substituents. For example, where a group, such as an alkyl or heteroaryl group, is “substituted with an unsubstituted C1-C20 alkyl, or unsubstituted 2 to 20 membered heteroalkyl”, the group may contain one or more unsubstituted C1-C20 alkyls, and / or one or more unsubstituted 2 to 20 membered heteroalkyls.

[0142] Moreover, where a moiety is substituted with an R substituent, the group may be referred to as “R-substituted.” Where a moiety is R- substituted, the moiety is substituted with at least one R substituent and each R substituent is optionally different. Where a particular R group is present in the description of a chemical genus (such as Formula (I)), a Roman alphabetic symbol may be used to distinguish each appearance of that particular R group. For example, where multiple R13substituents are present, each R13substituent may be distinguished as R13A, R13B, R13C, R13D, etc., wherein each of R13A, R13B, R13C, R13D, etc. is defined within the scope of the definition of R13and optionally differently. Where an R moiety, group, or substituent as disclosed herein is attached through the representation of a single bond and the R moiety, group, or substituent is oxo, a person having ordinary skill in the art will immediately recognize that the oxo is attached through a double bond in accordance with the normal rules of chemical valency.

[0143] Descriptions of compounds of the present disclosure are limited by principles of chemical bonding known to those skilled in the art. Accordingly, where a group may be substituted by one or more of a number of substituents, such substitutions are selected so as to comply with principles of chemical bonding and to give compounds which are not inherently unstable and / or would be known to one of ordinary skill in the art as likely to be unstable under ambient conditions, such as aqueous, neutral, and several known physiological conditions. For example, a heterocycloalkyl or heteroaryl is attached to the remainder of the molecule via a ring heteroatom in compliance with principles of chemical bonding known to those skilled in the art thereby avoiding inherently unstable compounds.PATENTAttorney Docket No. : 050935-527001 WO

[0144] The term “pharmaceutically acceptable salts” is meant to include salts of the active compounds that are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the present disclosure contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When compounds of the present disclosure contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, oxalic, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (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. The salts of the compounds of formula (I) will be pharmaceutically acceptable salts. Other salts may, however, may be useful in the preparation of the compounds of formula (I) or of their pharmaceutically acceptable salts.Standard principles underlying the selection and preparation of pharmaceutically acceptable salts are described, for example, in Handbook of Pharmaceutical Salts: Properties, Selection and Use, ed. PH. Stahl & C.G. Wermuth, Wiley- VCH, 2002.

[0145] Thus, the compounds of the present disclosure may exist as salts, such as with pharmaceutically acceptable acids. The present disclosure includes such salts. Non-limiting examples of such salts include hydrochlorides, hydrobromides, phosphates, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, propri onates, tartrates (e.g.,PATENTAttorney Docket No. : 050935-527001 WO(+)-tartrates, (-)-tartrates, or mixtures thereof including racemic mixtures), succinates, benzoates, and salts with amino acids such as glutamic acid, and quaternary ammonium salts (e.g., methyl iodide, ethyl iodide, and the like). These salts may be prepared by methods known to those skilled in the art.

[0146] 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.

[0147] In addition to salt forms, the present disclosure provides compounds, which are in a prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present disclosure. Prodrugs of the compounds described herein may be converted in vivo after administration. Additionally, prodrugs can be converted to the compounds of the present disclosure by chemical or biochemical methods in an ex vivo environment, such as, for example, when contacted with a suitable enzyme or chemical reagent.

[0148] Certain compounds of the present disclosure can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed 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 uses contemplated by the present disclosure and are intended to be within the scope of the present disclosure.

[0149] The terms “treating” or “treatment” refers to any indicia of success in the treatment or amelioration of an injury, disease, pathology or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology or condition more tolerable to the patient; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; improving a patient’s physical or mental well-being. The treatment or amelioration of symptoms can be based on objective or subjective parameters; including the results of a physical examination, neuropsychiatric exams, and / or a psychiatric evaluation. The term “treating” and conjugations thereof, include prevention of an injury, pathology, condition, or disease. In embodiments, treating is preventing. InPATENTAttorney Docket No. : 050935-527001 WO embodiments, treating does not include preventing. In embodiments, the treating or treatment is no prophylactic treatment.

[0150] An “effective amount” is an amount sufficient for a compound to accomplish a stated purpose relative to the absence of the compound (e.g., achieve the effect for which it is administered, treat a disease, reduce enzyme activity, increase enzyme activity, reduce signaling pathway, reduce one or more symptoms of a disease or condition. An example of an “effective amount” is an amount sufficient to contribute to the treatment, prevention, or reduction of a symptom or symptoms of a disease, which could also be referred to as a “therapeutically effective amount” when referred to in this context. A “reduction” of a symptom or symptoms (and grammatical equivalents of this phrase) means decreasing of the severity or frequency of the symptom(s), or 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 prophylactic effect, e.g., preventing or delaying the onset (or reoccurrence) of an injury, disease, pathology or condition, or reducing the likelihood of the onset (or reoccurrence) of an injury, disease, pathology, or condition, or their symptoms. The full prophylactic effect does not necessarily occur by administration of one dose and may occur only after administration of a series of doses. Thus, a prophylactically effective amount may be administered in one or more administrations. An “activity decreasing amount,” as used herein, refers to an amount of antagonist required to decrease the activity of an enzyme relative to the absence of the antagonist. A “function disrupting amount,” as used herein, refers to the amount of antagonist required to disrupt the function of an enzyme or protein relative to the absence of the antagonist. An “activity increasing amount,” as used herein, refers to an amount of agonist required to increase the activity of an enzyme relative to the absence of the agonist. A “function increasing amount,” as used herein, refers to the amount of agonist required to increase the function of an enzyme or protein relative to the absence of the agonist. The exact amounts will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g., 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).PATENTAttorney Docket No. : 050935-527001 WO

[0151] Control” or “control experiment” is used in accordance with its plain ordinary meaning and refers to an experiment in which the subjects or reagents of the experiment are treated as in a parallel experiment except for omission of a procedure, reagent, or variable of the experiment. In some instances, the control is used as a standard of comparison in evaluating experimental effects. In some embodiments, a control is the measurement of the activity (e.g., signaling pathway) of a protein in the absence of a compound as described herein (including embodiments, examples, figures, or Tables).

[0152] “Contacting” is used in accordance with its plain ordinary meaning and refers to the process of allowing at least two distinct species (e.g., chemical compounds including biomolecules, or cells) to become sufficiently proximal to react, interact or physically touch. It should be appreciated; however, the resulting reaction product can be produced directly from a reaction between the added reagents or from an intermediate from one or more of the added reagents which can be produced in the reaction mixture.

[0153] The term “contacting” may include allowing two species to react, interact, or physically touch, wherein the two species may be a compound as described herein and a cellular component (e.g., protein, ion, lipid, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cellular compartment, microorganism, virus, lipid droplet, vesicle, small molecule, protein complex, protein aggregate, or macromolecule). In some embodiments contacting includes allowing a compound described herein to interact with a cellular component (e.g., protein, ion, lipid, nucleic acid, nucleotide, amino acid, protein, particle, virus, lipid droplet, organelle, cellular compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or macromolecule) that is involved in a signaling pathway.

[0154] As defined herein, the term “activation,” “activate,” “activating” and the like in reference to a protein refers to conversion of a protein into a biologically active derivative from an initial inactive or deactivated state. The terms reference activation, or activating, sensitizing, or up-regulating signal transduction or enzymatic activity or the amount of a protein decreased in a disease.

[0155] The terms “agonist,” “activator,” “upregulator,” etc. refer to a substance capable of detectably increasing the expression or activity of a given gene or protein. The agonist can increase expression or activity by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%,PATENTAttorney Docket No. : 050935-527001 WO95%, 96%, 97%, 98%, or 99% in comparison 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 higher than the expression or activity in the absence of the agonist.

[0156] As defined herein, the term “inhibition,” “inhibit,” “inhibiting” and the like in reference to a cellular component-inhibitor interaction means negatively affecting (e.g., decreasing) the activity or function of the cellular component (e.g., decreasing the signaling pathway stimulated by a cellular component (e.g., protein, ion, lipid, virus, lipid droplet, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cellular compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or macromolecule)), relative to the activity or function of the cellular component in the absence of the inhibitor. In embodiments inhibition means negatively affecting (e.g., decreasing) the concentration or levels of the cellular component relative to the concentration or level of the cellular component in the absence of the inhibitor. In some embodiments, inhibition refers to reduction of a disease or symptoms of disease. In some embodiments, inhibition refers to a reduction in the activity of a signal transduction pathway or signaling pathway (e.g., reduction of a pathway involving the cellular component). Thus, inhibition includes, at least in part, partially or totally blocking stimulation, decreasing, preventing, or delaying activation, or inactivating, desensitizing, or down-regulating the signaling pathway or enzymatic activity or the amount of a cellular component.

[0157] The terms “inhibitor,” “repressor,” “antagonist,” or “downregulator” interchangeably refer to a substance capable of detectably decreasing the expression or activity of a given gene or protein. The antagonist can decrease expression or activity by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% in comparison 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 lower than the expression or activity in the absence of the antagonist.

[0158] 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 the target of the molecule (e.g., a target may be a cellular component (e.g., protein, ion, lipid, virus, lipid droplet, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cellular compartment,PATENTAttorney Docket No. : 050935-527001 WO microorganism, vesicle, small molecule, protein complex, protein aggregate, or macromolecule)) relative to the absence of the composition.

[0159] The term “modulate” is used in accordance with its plain 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 effects of a modulator on a target protein, to modulate means to change by increasing or decreasing a property or function of the target molecule or the amount of the target molecule.

[0160] “Patient”, “patient in need thereof’, “subject”, or “subject in need thereof’ refers to a living organism suffering from or prone 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, bovines, rats, mice, dogs, monkeys, goat, sheep, cows, deer, and other non-mammalian animals. In some embodiments, a patient is human. In embodiments, a patient in need thereof is human. In embodiments, a subject is human. In embodiments, a subject in need thereof is human.

[0161] ‘Disease” or “condition” refer to a state of being or health status of a patient or subject capable of being treated with the compounds or methods provided herein. In some embodiments, the disease is a disease related to (e.g., caused by) a cellular component (e.g., protein, ion, lipid, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cellular compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or macromolecule). In embodiments, the disease is an autoimmune disease. In embodiments, the disease is an inflammatory disease.

[0162] As used herein, the term “autoimmune disease” refers to a disease or condition in which a subject’s immune system has an aberrant immune response against a substance that does not normally elicit an immune response in a healthy subject, and can be systemic autoimmune disorder, autoimmune endocrine disorder and organ-specific autoimmune disorder. Systemic autoimmune disorders include systemic lupus erythematosus (SLE), psoriasis, psoriatic arthropathy, vasculitis, inflammatory myopathy (including polymyositis, dermatomyositis and inclusion body myositis), scleroderma, multiple sclerosis, systemic sclerosis, ankylosing spondylitis, rheumatoid arthritis, non-specific inflammatory arthritis, juvenile inflammatory arthritis, juvenile idiopathic arthritis (including oligoarticular and polyarticular forms thereof),PATENTAttorney Docket No. : 050935-527001 WO anemia of chronic disease (ACD), Still’s disease (juvenile and / or adult onset), Behcet’s disease and Sjogren’s syndrome. Autoimmune endocrine disorders include thyroiditis. Organ-specific autoimmune disorders include Addison’s disease, hemolytic or pernicious anemia, acute kidney injury (AKI; including cisplatin- induced AKI), diabetic nephropathy (DN), obstructive uropathy (including cisplatin- induced obstructive uropathy), glomerulonephritis (including Goodpasture’s syndrome, immune complex-mediated glomerulonephritis and antineutrophil cytoplasmic antibodies (ANCA)-associated glomerulonephritis), lupus nephritis (LN), minimal change disease, Graves’ disease, idiopathic thrombocytopenic purpura, inflammatory bowel disease (including Crohn’s disease, ulcerative colitis, indeterminate colitis and pouchitis), pemphigus, atopic dermatitis, autoimmune hepatitis, primary biliary cirrhosis, autoimmune pneumonitis, autoimmune carditis, myasthenia gravis, spontaneous infertility, osteoporosis, osteopenia, erosive bone disease, chondritis, cartilage degeneration and / or destruction, fibrosing disorders (including various forms of hepatic and pulmonary fibrosis), asthma, rhinitis, chronic obstructive pulmonary disease (COPD), respiratory distress syndrome, sepsis, fever, muscular dystrophy (including Duchenne muscular dystrophy), organ transplant rejection (including kidney allograft rejection), scleritis (including giant cell arteritis scleritis), Takayasu arteritis, hidradenitis suppurativa, pyoderma gangrenosum, sarcoidosis, polymyalgia rheumatic and axial spondylarthritis.

[0163] As used herein, the term “inflammatory disease” refers to a disease or condition characterized by aberrant inflammation (e.g. an increased level of inflammation compared to a control such as a healthy person not suffering from a disease). Examples of inflammatory diseases include autoimmune diseases, arthritis, rheumatoid arthritis, psoriatic arthritisjuvenile idiopathic arthritis, multiple sclerosis, systemic lupus erythematosus (SLE), myasthenia gravis, juvenile onset diabetes, diabetes mellitus type 1, graft-versus-host disease (GvHD), Guillain-Barre syndrome, Hashimoto’s encephalitis, Hashimoto’s thyroiditis, ankylosing spondylitis, psoriasis, Sjogren’s syndrome, vasculitis, glomerulonephritis, auto-immune thyroiditis, Behcet’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, ischemia reperfusion injury, stroke,PATENTAttorney Docket No. : 050935-527001 WO sarcoidosis, transplant rejection, interstitial cystitis, atherosclerosis, scleroderma, and atopic dermatitis.

[0164] As used herein, the terms “neurological disorder” and “neurodegenerative disorder” refers to Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, ischemia, stroke, amyotrophic lateral sclerosis, spinal cord injury, head trauma, seizures and epilepsy.

[0165] As used herein, the term “cardiovascular disorder” refers to thrombosis, cardiac hypertrophy, hypertension, irregular contractility of the heart (e.g. during heart failure), and sexual disorders (including erectile dysfunction and female sexual dysfunction). Modulators of TNFa function may also be of use in the treatment and / or prevention of myocardial infarction (see J.J. Wu et al., MMA, 2013, 309, 2043-2044).

[0166] As used herein, the term “metabolic disorder” refers to diabetes (including insulindependent diabetes mellitus and juvenile diabetes), dyslipidemia and metabolic syndrome.

[0167] As used herein, the term “ocular disorder” refers to retinopathy (including diabetic retinopathy, proliferative retinopathy, non-proliferative retinopathy and retinopathy of prematurity), macular oedema (including diabetic macular oedema), age-related macular degeneration (ARMD), vascularization (including corneal vascularization and neovascularization), retinal vein occlusion, and various forms of uveitis (including iritis) and keratitis.

[0168] As used herein, the term “oncological disorder” refers to proliferative disorders, especially cancer, and cancer-associated complications (including skeletal complications, cachexia and anemia). Oncological disorder may be acute or chronic. Particular categories of cancer include hematological malignancy (including leukemia and lymphoma) and non- hematological malignancy (including solid tumor cancer, sarcoma, meningioma, glioblastoma multiforme, neuroblastoma, melanoma, gastric carcinoma and renal cell carcinoma).

[0169] Chronic leukemia may be myeloid or lymphoid. Varieties of leukemia include lymphoblastic T cell leukemia, chronic myelogenous leukemia (CML), chronic lymphocytic / lymphoid leukemia (CLL), hairy-cell leukemia, acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), myelodysplastic syndrome, chronic neutrophilic leukemia, acute lymphoblastic T cell leukemia, plasmacytoma, immunoblastic large cell leukemia, mantle cell leukemia, multiple myeloma, acute megakaryoblastic leukemia, acutePATENTAttorney Docket No. : 050935-527001 WO megakaryocytic leukemia, promyelocytic leukemia and erythroleukemia. Varieties of lymphoma include malignant lymphoma, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, lymphoblastic T cell lymphoma, Burkitt’s lymphoma, follicular lymphoma, MALT1 lymphoma and marginal zone lymphoma. Varieties of non-hematological malignancy include cancer of the prostate, lung, breast, rectum, colon, lymph node, bladder, kidney, pancreas, liver, ovary, uterus, cervix, brain, skin, bone, stomach and muscle. Modulators of TNFa function may also be used to increase the safety of the potent anticancer effect of TNF (see F.V Hauwermeiren et al., J. Clin. Invest., 2013, 123, 2590-2603).

[0170] “Pharmaceutically acceptable excipient” and “pharmaceutically acceptable carrier” refer to a substance that aids the administration of an active agent to and absorption by a subject and can be included in the compositions of the present invention without causing a significant adverse toxicological effect on the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline solutions, lactated Ringer’s, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer’s solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, and the like. Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and / or aromatic substances and the like that do not deleteriously react with the compounds of the invention. One of skill in the art will recognize that other pharmaceutical excipients are useful in the present invention.

[0171] The term “preparation” is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.

[0172] As used herein, the term “about” means a range of values including the specified value, which a person of ordinary skill in the art would consider reasonably similar to the specified value. In embodiments, about means within a standard deviation using measurementsPATENTAttorney Docket No. : 050935-527001 WO generally acceptable in the art. In embodiments, about means a range extending to + / - 10% of the specified value. In embodiments, about includes the specified value.

[0173] As used herein, the term “administering” is used in accordance with its plain and ordinary meaning and includes oral administration, administration as a suppository, topical contact, intravenous, intraperitoneal, intramuscular, intralesional, intrathecal, intranasal or subcutaneous administration, or the implantation of a slow-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, e.g., intravenous, intramuscular, intra-arteriole, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, etc. By “co-administer” it is meant that a composition described herein is administered at the same time, just prior to, or just after the administration of one or more additional therapies. The compounds of the invention can be administered alone or can be coadministered to the patient. Co-administration is meant to include simultaneous or sequential administration of the compounds individually or in combination (more than one compound). Thus, the preparations can also be combined, when desired, with other active substances (e.g., to reduce metabolic degradation). The compositions of the present invention can be delivered by transdermally, by a topical route, formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols.

[0174] The compounds described herein can be used in combination with one another, with other active agents known to be useful in treating a disease associated with cells expressing a disease associated cellular component, or with adjunctive agents that may not be effective alone, but may contribute to the efficacy of the active agent.

[0175] In some embodiments, co-administration includes administering one active agent within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of a second active agent. Co-administration includes administering two active agents simultaneously, approximately simultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each other), or sequentially in any order. In some embodiments, co-administration can be accomplished by co-formulation, i.e., preparing a single pharmaceutical composition including both active agents. In other embodiments, the activePATENTAttorney Docket No. : 050935-527001 WO agents can be formulated separately. In another embodiment, the active and / or adjunctive agents may be linked or conjugated to one another.

[0176] In therapeutic use for the treatment of a disease, compound utilized in the pharmaceutical compositions of the present invention may be administered at the initial dosage of about 0.001 mg / kg to about 1000 mg / kg daily. A daily dose range of about 0.01 mg / kg to about 500 mg / kg, or about 0.1 mg / kg to about 200 mg / kg, or about 1 mg / kg to about 100 mg / kg, or about 10 mg / kg to about 50 mg / kg, can be used. The dosages, however, may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound or drug being employed. For example, dosages can be empirically determined considering the type and stage of disease (e.g., inflammation or autoimmunity) diagnosed in a particular patient. The dose administered to a patient, in the context of the present invention, should be sufficient to affect 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 that accompany the administration of a compound in a particular patient. Determination of the proper dosage for a particular situation is within the skill of the practitioner. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day, if desired.

[0177] The term “associated” or “associated with” in the context of a substance or substance activity or function associated with a disease (e.g., a TNFa signaling) means that the disease (e.g., inflammation or autoimmunity) is caused by (in whole or in part), or a symptom of the disease is caused by (in whole or in part) the substance or substance activity or function or the disease or a symptom of the disease may be treated by modulating (e.g., inhibiting or activating) the substance (e.g., TNFa signaling). As used herein, what is described as being associated with a disease, if a causative agent, could be a target for treatment of the disease.

[0178] The term “Tumor necrosis factor alpha” (TNF alpha or TNFa) is used herein in its plane meaning and is a multifunctional cytokine that plays important roles in diverse cellular events such as cell survival, proliferation, differentiation, and death. As a pro-inflammatoryPATENTAttorney Docket No. : 050935-527001 WO cytokine, TNF is secreted by inflammatory cells, which may be involved in inflammation- associated carcinogenesis.

[0179] The term “disease or disorder associated with modulation of TNF a function” as used herein refers to an inflammatory disease, an autoimmune disease, a neurological disease, a neurodegenerative disease, a nociceptive disease, a cardiovascular disease, a metabolic disease, an ocular disease, an oncological disease, or pain.II. Compounds

[0180] In an aspect is provided a compound, or a pharmaceutically acceptable salt thereof, having the formulae (la), (lb), (Ic), or (Id):

[0181] The two atoms shared by Ring D and Ring E(Ia) are carbon atoms.

[0182] The two atoms shared by Ring D and Ring E(Ib) are carbon atoms.

[0183] The two atoms shared by Ring D and Ring E(Ic) are carbon atoms.

[0184] The two atoms shared by Ring D and Ring E(Id) are carbon atoms.

[0185] The symbol k is a single bond or a double bond.PATENTAttorney Docket No. : 050935-527001 WO

[0186] Ring E(Ia) is a 6-membered heteroaryl, pyrrolidonyl, imidazolidinonyl, oxazolidinonyl, pyrrolyl, isoxazolidinyl, pyrazolyl, oxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, isoxazolyl, or dioxolanyl.

[0187] Ring E(Ib), E(Ic) and E(Id) are independently heteroaryl or heterocycloalkyl.

[0188] Ring F is phenyl or 5- or 6-membered heteroaryl.

[0189] X is O or S.

[0190] R2is hydrogen, halogen, -CX23, -CHX22, -CH2X2, -OCX23, -OCHX22, -OCH2X2, -CN, -N3, -SR2A,-SOn2R2A, -SOV2NR2BR2C, -S(O)(R2B)NR2C, -NHNR2BR2C, -ONR2BR2C, -NHC(O)NHNR2BR2C, -NHC(O)NR2BR2C, -N(O)m2, -NR2BR2C, -C(O)R2D, -C(O)OR2D, -C(O)NR2BR2C, -OR2A, -NR2BSO2R2A, -NR2BC(O)R2D, -NR2BC(O)OR2D, -NR2BOR2D, substituted or un substituted alkyl (e.g., Ci-Cs, Ci-Ce, C1-C4, or Ci-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-Cs, C3-Ce, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., Ce-Cio or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered),

[0191] Li is a bond or substituted or unsubstituted alkylene (e.g., Ci-Cs, Ci-Ce, C1-C4, or Ci-C2).

[0192] R2A, R2B, R2Cand R2Dare independently hydrogen, substituted or unsubstituted alkyl (e.g., Ci-Cs, Ci-Ce, C1-C4, or Ci-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-Cs, C3-Ce, C4-C6, or Cs-Ce), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., Ce-Cio or phenyl), orPATENTAttorney Docket No. : 050935-527001 WO substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0193] R3is hydrogen, -OR5A, substituted or unsubstituted alkyl (e.g., Ci-Cs, Ci-Ce, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., Cs-Cs, C3-C6, C4-C6, or Cs-Ce), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., Ce-Cio or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); or R3and R4can join together to form a substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered) or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered), wherein R3and R4are not both hydrogen.

[0194] R4is hydrogen, -OR5B, substituted or unsubstituted alkyl (e.g., Ci-Cs, Ci-Ce, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or Cs-Ce), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., Ce-Cio or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); or R3and R4can join together to form a substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered) or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered), wherein R3and R4are not both hydrogen.

[0195] R?and R5Bare independently hydrogen or substituted or unsubstituted alkyl (e.g., Ci-C8, Ci-C6, C1-C4, or Ci-C2).

[0196] R6and R7are independently hydrogen, substituted or unsubstituted alkyl (e.g., Ci-C8, Ci-Ce, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or Cs-Ce), substituted or unsubstitutedPATENTAttorney Docket No. : 050935-527001 WO heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., Ce-Cio or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); or R6and R7can join together to form a substituted or un substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered) or a substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0197] R8is hydrogen, halogen, -CX83, -CHX82, -CH2X8, -OCX83, -OCHX82, -OCH2X8, -CN, — N3, -SH, -NH2, -C(O)OH, -C(0)NH2, -OH, substituted or unsubstituted alkyl (e.g., Ci-Cs, Ci-Ce, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-Cs, C3-Ce, C4-C6, or Cs-Ce), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., Ce-Cio or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0198] R9is independently halogen, -CX^, -CHX92, -CH2X9, -OCX93, -OCHX92, -OCH2X9, -CN, -N3, -SH, -NH2, -C(O)OH, -C(0)NH2, -OH, substituted or unsubstituted alkyl (e g., Ci-Cs, Ci-Ce, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-Cs, C3-Ce, C4-C6, or Cs-Ce), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., Ce-Cio or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0199] R10is independently halogen, -CX103, -CHX102, -CH2X10, -OCX103, -OCHX102, -OCH2X10, -CN, -N3, -SH, -NH2, -C(0)0H, -C(O)NH2, -OH, substituted or unsubstituted alkyl (e.g., Ci-Cs, Ci-Ce, C1-C4, or Ci-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-Cg, C3-Ce, C4-C6, or Cs-Ce), substituted orPATENTAttorney Docket No. : 050935-527001 WO unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., Ce-Cio or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0200] R11is hydrogen, halogen, -CXn3, -CHXn2, -CH2Xn, -OCXn3, -0CHXn2,-0CH2Xn, -CN, -N3, -SH, -NH2,-C(0)0H, -C(0)NH2, -OH, substituted or unsubstituted alkyl (e.g., Ci-Cs, Ci-Ce, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-Cs, C3-Ce, C4-C6, or Cs-Ce), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., Ce-Cio or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0201] R12is hydrogen, halogen, -CX123, -CHX122, -CH2X12, -OCX123, -OCHX122,-OCH2X12, -CN, -N3, -SH, -NH2, -C(O)OH, -C(0)NH2, -OH, substituted or unsubstituted alkyl (e.g., Ci-Cs, Ci-Ce, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-Cs, C3-Ce, C4-C6, or Cs-Ce), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., Ce-Cio or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0202] R13is hydrogen, halogen, -CX133, -CHX132, -CH2X13, -OCX133, -OCHX132,-OCH2X13, -CN, -N3, -SR15A,-SOni3R15A, -SOvi3NR15BR15C, -NHNR15BR15C, -ONR15BR15C, -NHC(O)NHNR15BR15C, -NHC(O)NR15BR15C, -N(O)mi3, -NR15BR15C, -C(O)R15D, -C(O)OR15D, -C(O)NR15BR15C, -OR15A, -NR15BSO2R15A, -NR15BC(O)R15D, -NR15BC(O)OR15D, -NR15BOR15D, substituted or unsubstituted alkyl (e.g., Ci-Cs, Ci-Ce, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-Cg, C3-Ce, C4-C6, or Cs-Ce), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6PATENTAttorney Docket No. : 050935-527001 WO membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., Ce-Cio or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0203] R14is independently halogen, -CX143, -CHX142, -CH2X14, -OCX143, -OCHX142,-OCH2X14, -CN, -N3, -SR14A,-SOni4R14A, -SOvi4NR14BR14C, -NHNR14BR14C, -ONR14BR14C, -NHC(O)NHNR14BR14C, -NHC(O)NR14BR14C, -N(O)mi4, -NR14BR14C, -C(O)R14D, -C(O)OR14D, -C(O)NR14BR14C, -OR14A, -NR14BSO2R14A, -NR14BC(O)R14D, -NR14BC(O)OR14D, -NR14BOR14D, =0, -NR16, substituted or unsubstituted alkyl (e.g., Ci-Cs, Ci-Ce, C1-C4, or Ci-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-Ce, C4-C6, or Cs-Ce), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., Ce-Cio or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0204] R14A, R14B, R14C, and R14Dare independently hydrogen, halogen, -CX143,-CHX142, -CH2X14, -OCX143, -OCHX142, -OCH2X14, -CN, -N3, -SH, -NH2, -C(O)OH, -C(0)NH2, -OH, substituted or un substituted alkyl (e.g., Ci-Cs, Ci-Ce, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-Ce, C4-C6, or Cs-Ce), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., Ce-Cio or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0205] R15A, R15B, R15C, and R15Dare independently hydrogen, halogen, -CX153,-CHX152, -CH2X15, -OCX153, -OCHX152, -OCH2X15, -CN, -N3, -SH, -NH2, -C(O)OH, -C(0)NH2, -OH, substituted or unsubstituted alkyl (e.g., Ci-C8, Ci-Ce, C1-C4, or Ci-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-Ce, C4-C6, or Cs-Ce), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),PATENTAttorney Docket No. : 050935-527001 WO substituted or unsubstituted aryl (e.g., Cg-Cio or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0206] R16is hydrogen, substituted or unsubstituted alkyl (e g., Ci-Cs, Ci-Ce, C1-C4, or Ci-C2), substituted or unsubstituted heteroalkyl (e g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or Cs-Ce), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., Cg-Cio or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0207] R17is independently halogen, -CX173, -CHX172, -CH2X17, -OCX173, -OCHX172, -OCH2X17, -CN, -N3, -SH, -NH2, -C(O)OH, -C(O)NH2, -OH, substituted or unsubstituted alkyl (e.g., Ci-Cs, Ci-Ce, C1-C4, or Ci-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or Cs-Ce), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., Ce-Cio or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0208] R18is independently substituted or unsubstituted alkyl (e.g., Ci-Cs, Ci-Ce, C1-C4, orCi-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or Cs-Cg), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., Cg-Cio or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0209] The symbols n2, nl3 and nl4 are independently an integer from 0 to 3.

[0210] The symbols m2, ml3 and ml4 are independently an integer from 0 to 4.

[0211] The symbols v2, v!3 and v!4 are independently an integer from 0 to 4.

[0212] Each X2, X8, X9, X10, X11, X12, X13, X14, X15and X17is independently -F, -Cl, -Br, or-I.PATENTAttorney Docket No. : 050935-527001 WO

[0213] In embodiments, the two atoms shared Ring D and Ring E(Ia) are carbon atoms. In embodiments, the two atoms shared Ring D and Ring E(Ib) are carbon atoms. In embodiments, the two atoms shared Ring D and Ring E(Ic) are carbon atoms. In embodiments, the two atoms shared Ring D and Ring E(Id) are carbon atoms. In embodiments, the dotted bond - between two carbon atoms shared by Ring D and Ring E(Ia), Ring E(Ib), Ring E(Ic) or Ring E(Id) indicates the presence of a single bond or a double bond. In embodiments, k is a double bond. In embodiments, k is a single bond.

[0214] In embodiments, a substituted Ring E(Ia) (e.g. substituted 6-membered heteroaryl, substituted pyrrolidonyl, substituted imidazolidinonyl, substituted oxazolidinonyl, substituted pyrrolyl, substituted isoxazolidinyl, substituted pyrazolyl, substituted oxazolyl, substituted thiazolyl, substituted isothiazolyl, substituted oxadiazolyl, substituted thiadiazolyl, substituted triazolyl, er substituted isoxazolyl, or substituted dioxolanyl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted Ring E(Ia) is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, sizelimited substituent group, and / or lower substituent group may optionally be different. In embodiments, when Ring E(Ia) is substituted, it is substituted with at least one substituent group. In embodiments, when Ring E(Ia) is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when Ring E(Ia) is substituted, it is substituted with at least one lower substituent group.

[0215] In embodiments, Ring E(Ia) is substituted or unsubstituted 6-membered heteroaryl, substituted or unsubstituted pyrrolidonyl, substituted or unsubstituted imidazolidinonyl, substituted or unsubstituted oxazolidinonyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted isoxazolidinyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted isothiazolyl, substituted or un substituted oxadiazolyl, substituted or unsubstituted thiadiazolyl, substituted or unsubstituted triazolyl, er substituted or unsubstituted isoxazolyl, or substituted or unsubstituted dioxolanyl.

[0216] In embodiments, Ring E(Ia) is substituted or unsubstituted 6-membered heteroaryl. In embodiments, Ring E(Ia) is substituted or unsubstituted pyridinyl, pyrazinyl, pyrimidinyl,PATENTAttorney Docket No. : 050935-527001 WO pyridazinyl, or triazenyl. In embodiments, Ring E(Ia) is substituted or unsubstituted pyridinyl. In embodiments, Ring E(Ia) is substituted or unsubstituted pyrazinyl. In embodiments, Ring E(Ia) is substituted or unsubstituted pyrimidinyl. In embodiments, Ring E(Ia) is substituted or unsubstituted pyridazinyl. In embodiments, Ring E(Ia) is substituted or un substituted triazenyl.

[0217] In embodiments, Ring E(Ia) is pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, or triazenyl. In embodiments, Ring E(Ia) is pyridinyl. In embodiments, Ring E(Ia) is pyrazinyl. In embodiments, Ring E(Ia) is pyrimidinyl. In embodiments, Ring E(Ia) is pyridazinyl. In embodiments, Ring E(Ia) is triazenyl.

[0218] In embodiments, Ring E(Ia) is substituted or unsubstituted pyrrolidonyl, substituted or unsubstituted imidazolidinonyl, substituted or unsubstituted oxazolidinonyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted isoxazolidinyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted isothiazolyl, substituted or unsubstituted oxadiazolyl, substituted or unsubstituted thiadiazolyl, substituted or unsubstituted triazolyl, OF substituted or unsubstituted isoxazolyl, or substituted or unsubstituted dioxolanyl. In embodiments, Ring E(Ia) is substituted or unsubstituted pyrrolidonyl. In embodiments, Ring E(Ia) is substituted or unsubstituted imidazolidinonyl. In embodiments, Ring E(Ia) is substituted or unsubstituted oxazolidinonyl. In embodiments, Ring E(Ia) is substituted or unsubstituted pyrrolyl. In embodiments, Ring E(Ia) is substituted or unsubstituted isoxazolidinyl. In embodiments, Ring E(Ia) is substituted or unsubstituted pyrazolyl. In embodiments, Ring E(la) is substituted or unsubstituted oxazolyl. In embodiments, Ring E(Ia) is substituted or unsubstituted thiazolyl. In embodiments, Ring E(Ia) is substituted or unsubstituted isothiazolyl. In embodiments, Ring E(Ia) is substituted or unsubstituted oxadiazolyl. In embodiments, Ring E(Ia) is substituted or unsubstituted thiadiazolyl. In embodiments, Ring E(Ia) is substituted or unsubstituted triazolyl. In embodiments, Ring E(Ia) is substituted or unsubstituted isoxazolyl. In embodiments, Ring E(Ia) is substituted or unsubstituted dioxolanyl.

[0219] In embodiments, Ring E(Ia) is pyrrolidonyl, imidazolidinonyl, oxazolidinonyl, pyrrolyl, isoxazolidinyl, pyrazolyl, oxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, er isoxazolyl, or dioxolanyl. In embodiments, Ring E(Ia) is pyrrolidonyl. In embodiments, Ring E(Ia) is imidazolidinonyl. In embodiments, Ring E(Ia) is oxazolidinonyl. InPATENTAttorney Docket No. : 050935-527001 WO embodiments, Ring E(Ia) is pyrrolyl. In embodiments, Ring E(Ia) is isoxazolidinyl. In embodiments, Ring E(Ia) is pyrazolyl. In embodiments, Ring E(Ia) is oxazolyl. In embodiments, Ring E(Ia) is thiazolyl. In embodiments, Ring E(Ia) is isothiazolyl. In embodiments, Ring E(Ia) is oxadiazolyl. In embodiments, Ring E(Ia) is thiadiazolyl. In embodiments, Ring E(Ia) is triazolyl. In embodiments, Ring E(Ia) is isoxazolyl. In embodiments, Ring E(Ia) is dioxolanyl.

[0220] In embodiments, a substituted Ring E(Ib) (e.g. substituted heterocycloalkyl or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted Ring E(Ib) is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when Ring E(Ib) is substituted, it is substituted with at least one substituent group. In embodiments, when Ring E(Ib)is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when Ring E(Ib) is substituted, it is substituted with at least one lower substituent group.

[0221] In embodiments, Ring E(Ib) is substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted 6-membered heteroaryl.

[0222] In embodiments, Ring E(Ib) is substituted or unsubstituted heterocycloalkyl. In embodiments, Ring E(Ib) is substituted or unsubstituted pyrrolidinonyl, substituted or unsubstituted oxazolidinonyl, substituted or unsubstituted imidazolidinonyl, substituted or unsubstituted dihydrofuranonyl, or substituted or unsubstituted imidazolidinethionyl. In embodiments, Ring E(Ib) is substituted or unsubstituted pyrrolidinonyl. In embodiments, Ring E(Ib) is substituted or unsubstituted oxazolidinonyl. In embodiments, Ring E(Ib) is substituted or unsubstituted imidazolidinonyl. In embodiments, Ring E(Ib) is substituted or unsubstituted dihydrofuranonyl. In embodiments, Ring E(Ib) is substituted or unsubstituted imidazolidinethionyl.

[0223] In embodiments, Ring E(Ib) is pyrrolidinonyl, oxazolidinonyl, imidazolidinonyl, dihydrofuranonyl, or imidazolidinethionyl. In embodiments, Ring E(Ib) is pyrrolidinonyl. In embodiments, Ring E(Ib) is oxazolidinonyl. In embodiments, Ring E(Ib) is imidazolidinonyl. In embodiments, Ring E(Ib) is dihydrofuranonyl. In embodiments, Ring E(Ib) is imidazolidinethionyl.PATENTAttorney Docket No. : 050935-527001 WO

[0224] In embodiments, Ring E(Ib) is substituted or unsubstituted pyrrolidine-2-onyl, substituted or unsubstituted oxazolidine-2-onyl, substituted or unsubstituted imidazolidine-2-onyl, substituted or unsubstituted dihydrofuran-2-onyl, or substituted or unsubstituted imidazolidine-2-thionyl. In embodiments, Ring E(Ib) is substituted or unsubstituted pyrrolidine-2-onyl. In embodiments, Ring E(Ib) is substituted or unsubstituted oxazolidine-2-onyl. In embodiments, Ring E(Ib) is substituted or unsubstituted imidazolidine-2-onyl. In embodiments, Ring E(Ib) is substituted or unsubstituted dihydrofuran- 2-onyl. In embodiments, Ring E(Ib) is substituted or unsubstituted imidazolidine-2-thionyl.

[0225] In embodiments, Ring E(Ib) is pyrrolidine-2-onyl, oxazolidine-2-onyl, imidazolidine- 2-onyl, dihydrofuran-2-onyl, or imidazolidine-2-thionyl. In embodiments, Ring E(Ib) is pyrrolidine-2-onyl. In embodiments, Ring E(Ib) is oxazolidine-2-onyl. In embodiments, Ring E(Ib) is imidazolidine-2-onyl. In embodiments, Ring E(Ib) is dihydrofuran-2-onyl. In embodiments, Ring E(Ib) is imidazolidine-2-thionyl.

[0226] In embodiments, Ring E(Ib) is substituted or unsubstituted 6-membered heteroaryl. In embodiments, Ring E(Ib) is substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyridazinyl, and substituted or unsubstituted triazenyl. In embodiments, Ring E(Ib) is substituted or unsubstituted pyridinyl. In embodiments, Ring E(Ib) is substituted or unsubstituted pyrazinyl. In embodiments, Ring E(Ib) is substituted or unsubstituted pyrimidinyl. In embodiments, Ring E(Ib) is substituted or unsubstituted pyridazinyl. In embodiments, Ring E(Ib) is substituted or unsubstituted tri azenyl.

[0227] In embodiments, Ring E(Ib) is pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, and triazenyl. In embodiments, Ring E(Ib) is pyridinyl. In embodiments, Ring E(Ib) is pyrazinyl. In embodiments, Ring E(Ib) is pyrimidinyl. In embodiments, Ring E(Ib) is pyridazinyl. In embodiments, Ring E(Ib) is triazenyl.

[0228] In embodiments, a substituted Ring E(Ic) (e.g. substituted heterocycloalkyl or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted Ring E(Ic) is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lowerPATENTAttorney Docket No. : 050935-527001 WO substituent group may optionally be different. In embodiments, when Ring E(Ic) is substituted, it is substituted with at least one substituent group. In embodiments, when Ring E(Ic) is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when Ring E(Ic) is substituted, it is substituted with at least one lower substituent group.

[0229] In embodiments, Ring E(Ic) is substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted 6-membered heteroaryl.

[0230] In embodiments, Ring E(Ic) is substituted or unsubstituted heterocycloalkyl. In embodiments, Ring E(Ic) is substituted or unsubstituted 2-pyrrolidonyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted isoxazolidinyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted isothiazolyl, substituted or unsubstituted oxadiazolyl, substituted or unsubstituted thiadiazolyl, substituted or unsubstituted triazolyl or substituted or unsubstituted isoxazolyl. In embodiments, Ring E(Ic) is substituted or unsubstituted 2-pyrrolidonyl. In embodiments, Ring E(Ic) is substituted or unsubstituted pyrrolyl. In embodiments, Ring E(Ic) is substituted or unsubstituted isoxazolidinyl. In embodiments, Ring E(Ic) is substituted or unsubstituted pyrazolyl. In embodiments, Ring E(Ic) is substituted or unsubstituted oxazolyl. In embodiments, Ring E(Ic) is substituted or unsubstituted thiazolyl. In embodiments, Ring E(Ic) is substituted or unsubstituted isothiazolyl. In embodiments, Ring E(Ic) is substituted or unsubstituted oxadiazolyl. In embodiments, Ring E(Ic) is substituted or unsubstituted thiadiazolyl. In embodiments, Ring E(Ic) is substituted or unsubstituted triazolyl. In embodiments, Ring E(Ic) is substituted or unsubstituted isoxazolyl. In embodiments, Ring E(Ic) is substituted or unsubstituted dioxolanyl.

[0231] In embodiments, Ring E(Ic) is 2-pyrrolidonyl, pyrrolyl, isoxazolidinyl, pyrazolyl, oxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl or isoxazolyl. In embodiments, Ring E(Ic) is 2-pyrrolidonyl. In embodiments, Ring E(Ic) is pyrrolyl. In embodiments, Ring E(Ic) is isoxazolidinyl. In embodiments, Ring E(Ic) is pyrazolyl. In embodiments, Ring E(Ic) is oxazolyl. In embodiments, Ring E(Ic) is thiazolyl. In embodiments, Ring E(Ic) is isothiazolyl. In embodiments, Ring E(Ic) is oxadiazolyl. In embodiments, Ring E(Ic) is thiadiazolyl. In embodiments, Ring E(Ic) is triazolyl. In embodiments, Ring E(Ic) is isoxazolyl. In embodiments, Ring E(Ic) is dioxolanyl.PATENTAttorney Docket No. : 050935-527001 WO

[0232] In embodiments, Ring E(Ic) is substituted or unsubstituted 6-membered heteroaryl. In embodiments, Ring E(Ic) is substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrazinyl, substituted or un substituted pyrimidinyl, substituted or unsubstituted pyridazinyl, and substituted or unsubstituted triazenyl. In embodiments, Ring E(Ic) is substituted or unsubstituted pyridinyl. In embodiments, Ring E(Ic) is substituted or unsubstituted pyrazinyl. In embodiments, Ring E(Ic) is substituted or unsubstituted pyrimidinyl. In embodiments, Ring E(Ic) is substituted or unsubstituted pyridazinyl. In embodiments, Ring E(Ic) is substituted or unsubstituted triazenyl. In embodiments, Ring E(Ic) is substituted or unsubstituted dioxolanyl.

[0233] In embodiments, Ring E(Ic) is pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, and triazenyl. In embodiments, Ring E(Ic) is pyridinyl. In embodiments, Ring E(Ic) is pyrazinyl. In embodiments, Ring E(Ic) is pyrimidinyl. In embodiments, Ring E(Ic) is pyridazinyl. In embodiments, Ring E(Ic) is triazenyl. In embodiments, Ring E(Ic) is dioxolanyl.

[0234] In embodiments, a substituted Ring E(Id) (e.g. substituted heterocycloalkyl or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted Ring E(Id) is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when Ring E(Id) is substituted, it is substituted with at least one substituent group. In embodiments, when Ring E(Id)is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when Ring E(Id) is substituted, it is substituted with at least one lower substituent group.

[0235] In embodiments, Ring E(Id) is substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted 6-membered heteroaryl.

[0236] In embodiments, Ring E(Id) is substituted or unsubstituted heterocycloalkyl. In embodiments, Ring E(Id) is substituted or unsubstituted pyrrolidinonyl, substituted or unsubstituted oxazolidinonyl, substituted or unsubstituted imidazolidinonyl, substituted or unsubstituted dihydrofuranonyl, or substituted or unsubstituted imidazolidinethionyl. In embodiments, Ring E(Id) is substituted or unsubstituted pyrrolidinonyl. In embodiments, Ring E(Id) is substituted or unsubstituted oxazolidinonyl. In embodiments, Ring E(Id) is substituted orPATENTAttorney Docket No. : 050935-527001 WO unsubstituted imidazolidinonyl. In embodiments, Ring E(Id) is substituted or unsubstituted dihydrofuranonyl. In embodiments, Ring E(Id) is substituted or unsubstituted imidazolidinethionyl.

[0237] In embodiments, Ring E(Id) is pyrrolidinonyl, oxazolidinonyl, imidazolidinonyl, dihydrofuranonyl, or imidazolidinethionyl. In embodiments, Ring E(Id) is pyrrolidinonyl. In embodiments, Ring E(Id) is oxazolidinonyl. In embodiments, Ring E(Id) is imidazolidinonyl. In embodiments, Ring E(Id) is dihydrofuranonyl. In embodiments, Ring E(Id) imidazolidinethionyl.

[0238] In embodiments, Ring E(Id) is substituted or unsubstituted pyrrolidine-2-onyl, substituted or unsubstituted oxazolidine-2-onyl, substituted or unsubstituted imidazolidine-2-onyl, substituted or unsubstituted dihydrofuran-2-onyl, or substituted or unsubstituted imidazolidine-2-thionyl. In embodiments, Ring E(Id) is substituted or unsubstituted pyrrolidine-2-onyl. In embodiments, Ring E(Id) is substituted or unsubstituted oxazolidine-2-onyl. In embodiments, Ring E(Id) is substituted or unsubstituted imidazolidine-2-onyl. In embodiments, Ring E(Id) is substituted or unsubstituted dihydrofuran-2-onyl. In embodiments, Ring E(Id) is substituted or un substituted imidazolidine-2-thionyl.

[0239] In embodiments, Ring E(Id) is pyrrolidine-2-onyl, oxazolidine-2-onyl, substituted or unsubstituted imidazolidine-2-onyl, dihydrofuran-2-onyl, or imidazolidine-2-thionyl. In embodiments, Ring E(Id) is pyrrolidine-2-onyl. In embodiments, Ring E(Id) is oxazolidine-2-onyl. In embodiments, Ring E(Id) is imidazolidine-2-onyl. In embodiments, Ring E(Id) is dihydrofuran-2-onyl. In embodiments, Ring E(Id) is imidazolidine-2-thionyl.

[0240] In embodiments, Ring E(Id) is substituted or unsubstituted 6-membered heteroaryl. In embodiments, Ring E(Id) is substituted or unsubstituted pyridinyl, substituted or un substituted pyrazinyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyridazinyl, and substituted or unsubstituted triazenyl. In embodiments, Ring E(Id) is substituted or unsubstituted pyridinyl. In embodiments, Ring E(Id) is substituted or unsubstituted pyrazinyl. In embodiments, Ring E(Id) is substituted or unsubstituted pyrimidinyl. In embodiments, Ring E(Id) is substituted or unsubstituted pyridazinyl. In embodiments, Ring E(Id) is substituted or unsubstituted tri azenyl.PATENTAttorney Docket No. : 050935-527001 WO

[0241] In embodiments, Ring E(Id) is pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, and triazenyl. In embodiments, Ring E(Id) is pyridinyl. In embodiments, Ring E(Id) is pyrazinyl. In embodiments, Ring E(Id) is pyrimidinyl. In embodiments, Ring E(Id) is pyridazinyl. In embodiments, Ring E(Id) is triazenyl.

[0242] In embodiments, a substituted ring F (e.g., substituted phenyl, substituted pyridyl, substituted pyrimidinyl, or substituted pyrazolyl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted ring F is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when ring F is substituted, it is substituted with at least one substituent group. In embodiments, when ring F is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when ring F is substituted, it is substituted with at least one lower substituent group.

[0243] In embodiments, Ring F is a substituted or unsubstituted phenyl or a substituted or unsubstituted 5- or 6-membered heteroaryl having 1 to 2 nitrogen atoms. In embodiments, Ring F is substituted or unsubstituted phenyl. In embodiments, Ring F is substituted phenyl. In embodiments, Ring F is unsubstituted phenyl.

[0244] In embodiments, Ring F is a substituted or unsubstituted 5- or 6-membered heteroaryl having 1 to 2 nitrogen atoms. In embodiments, Ring F is a substituted or unsubstituted pyridyl, substituted or un substituted pyrimidinyl or substituted or unsubstituted pyrazolyl. In embodiments, Ring F is a substituted or unsubstituted pyridyl. In embodiments, Ring F is a substituted or unsubstituted pyrimidinyl. In embodiments, Ring F is a substituted or unsubstituted pyrazolyl.

[0245] In embodiments, Ring F is phenyl or 5- or 6-membered heteroaryl having 1 to 2 nitrogen atoms. In embodiments, Ring F is phenyl. In embodiments, Ring F is 5- or 6-membered heteroaryl. In embodiments, Ring F is 5- or 6-membered heteroaryl having 1 to 2 nitrogen atoms. In embodiments, Ring F is pyridyl, pyrimidinyl or pyrazolyl. In embodiments, Ring F is pyridyl. In embodiments, Ring F is pyrimidinyl. In embodiments, Ring F is pyrazolyl.

[0246] In embodiments, a substituted R2(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloakyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl) isPATENTAttorney Docket No. : 050935-527001 WO substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R2is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R2is substituted, it is substituted with at least one substituent group. In embodiments, when R2is substituted, it is substituted with at least one sizelimited substituent group. In embodiments, when R2is substituted, it is substituted with at least one lower substituent group.

[0247] In embodiments, X is O or S. In embodiments, X is O. In embodiments, X is S.

[0248] In embodiments, R2is hydrogen, halogen, -CX23, -CHX22, -CH2X2, -OCX23,-OCHX22, -OCH2X2, -CN, -N3, -SR2A,-SOn2R2A, -SOv2NR2BR2C, -S(O)(R2B)NR2C, -NHNR2BR2C, -ONR2BR2C, -NHC(O)NHNR2BR2C, -NHC(O)NR2BR2C, -N(O)m2, -NR2BR2C, -C(O)R2D, -C(O)OR2D, -C(O)NR2BR2C, -OR2A, -NR2BSO2R2A, -NR2BC(O)R2D, -NR2BC(O)OR2D, -NR2BOR2D, substituted or unsubstituted alkyl (e.g., Ci-Cs, Ci-Ce, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C7, C4-C6, or Cs-Ce), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 7 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., Ce-Cio or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered),

[0249] In embodiments, Li is a bond or substituted or unsubstituted alkylene (e.g., Ci-Cs, Ci- C6, C1-C4, or Ci-C2).

[0250] In embodiments, R2is halogen, cyano, trifluoromethyl, trifluoromethoxy, -OR2A, -SR2A, -SOR2A, -SO2R2A, -NR2BR2C, -NR2BCOR2D, -NR2BCO2R2D, -NHCONR2BR2C, -NR2BSO2R2A, -COR2D, -CO2R2D, -CONR2BR2C, -SO2NR2BR2C, -S(O)(NR2BR2C), substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted C4-C7 cycloalkenyl, substituted or unsubstituted aryl, substituted or un substitutedPATENTAttorney Docket No. : 050935-527001 WO aryl(Ci-C6)alkyl, substituted or unsubstituted 3 to 7 membered heterocycloalkyl, substituted or unsubstituted 3 to 7 membered heterocycloalkenyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaryl(Ci-C6)alkyl, substituted or unsubstituted 3 to 7 membered heterocycloalkyl(Ci.C6)alkyl-aryl, substituted or unsubstituted (C3-C7)cycloalkyl-heteroaryl, substituted or unsubstituted 3 to 7 membered heterocycloalkenyl-aryl, substituted or unsubstituted (C3-C7)cycloalkyl(Ci-6)alkyl-heteroaryl, substituted or unsubstituted (C4-C7) cycloalkenyl-heteroaryl, substituted or unsubstituted (C4-C9)bicycloalkyl-heteroaryl-, substituted or unsubstituted 3 to 7 membered heterocycloalkyl-heteroaryl, substituted or unsubstituted 3 to 7 membered heterocycloalkyl(Ci-C6)alkyl-heteroaryl, substituted or unsubstituted 3 to 7 membered heterocycloalkenyl-heteroaryl, substituted or unsubstituted 3 to 7 membered heterobicycloalkyl-heteroaryl, substituted or unsubstituted 3 to 7 membered spiroheterocycloalkyl-heteroaryl,

[0251] In embodiments, R2is hydrogen, halogen, cyano, trifluoromethyl, trifluoromethoxy, -OH, -SH, -SCH3, -SO2H, -SO2CH3, -NH2, -NHC(0)H, -NHC(0)0H, NHC(0)NH2, -NHSO2H, -C(O)H, -C(O)CH3, -COOH, -COOCH3, -CONH2, -SO2NH2, or -S(O)NHCH3.

[0252] In embodiments, R2is hydrogen. In embodiments, R2is halogen. In embodiments, R2is -F. In embodiments, R2is -Cl. In embodiments, R2is -Br. In embodiments, R2is -I. In embodiments, R2is cyano. In embodiments, R2is trifluoromethyl. In embodiments, R2is trifluoromethoxy. In embodiments, R2is -OH. In embodiments, R2is -OCH3. In embodiments, R2is -SH. In embodiments, R2is -SCH3. In embodiments, R2is -SOH. In embodiments, R2is -SCH3. In embodiments, R2is -SO2H. In embodiments, R2is -SO2CH3. In embodiments, R2is -NH2. In embodiments, R2is -NHCH3. In embodiments, R2is -N(CH3)2. In embodiments, R2is -NHC(O)H. In embodiments, R2is -NHC(O)CH3. In embodiments, R2is -NHC(0)0H. In embodiments, R2is -NHC(O)OCH3. In embodiments, R2is -NHC(0)NH2. In embodiments, R2is -NHC(O)NHCH3. In embodiments, R2is -NHSO2H. In embodiments, R2is -NHSO2CH3. In embodiments, R2is -C(O)H. In embodiments, R2is -C(O)CH3. In embodiments, R2is -COOH.PATENTAttorney Docket No. : 050935-527001 WOIn embodiments, R2is -COOCH3. In embodiments, R2is -C(O)CHB. In embodiments, R2is -C(O)NH2. In embodiments, R2is -C(O)NHCHB. In embodiments, R2is -SO2NH2. In embodiments, R2is -SO2NHCH3. In embodiments, R2is -S(O)NH2. In embodiments, R2is -S(O)NH2. In embodiments, R2is a substituted or un substituted Ci-Ce alkyl. In embodiments, R2is substituted or unsubstituted methyl. In embodiments, R2is substituted or unsubstituted ethyl. In embodiments, R2is substituted or unsubstituted propyl. In embodiments, R2is substituted or unsubstituted butyl. In embodiments, R2is substituted or unsubstituted pentyl. In embodiments, R2is substituted or unsubstituted hexyl. In embodiments, R2is a substituted or unsubstituted C3-C7 cycloalkyl. In embodiments, R2is a substituted or unsubstituted cyclopropyl. In embodiments, R2is a substituted or unsubstituted cyclobutyl. In embodiments, R2is a substituted or unsubstituted cyclopentyl. In embodiments, R2is a substituted or unsubstituted cyclohexyl. In embodiments, R2is a substituted or unsubstituted cycloheptyl. In embodiments, R2is a substituted or unsubstituted C4-C7 cycloalkenyl. In embodiments, R2is a substituted or unsubstituted Ce-Cio aryl. In embodiments, R2is a substituted or unsubstituted phenyl. In embodiments, R2is a substituted or unsubstituted aryl(Ci-C6)alkyl. In embodiments, R2is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl. In embodiments, R2is a substituted or unsubstituted 3 to 7 membered heterocycloalkenyl. In embodiments, R2is a substituted or unsubstituted 5 to 10 membered heteroaryl. In embodiments, R2is a substituted or unsubstituted heteroaryl(Ci-Ce)alkyl. In embodiments, R2is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl(Ci-C6)alkylaryl. In embodiments, R2is a substituted or unsubstituted (C3-C7)cycloalkylheteroaryl. In embodiments, R2is a substituted or unsubstituted 3 to 7 membered heterocycloalkenylaryl. In embodiments, R2is a substituted or unsubstituted (C3-C7) cycloalkyl(Ci-6)alkylheteroaryl. In embodiments, R2is a substituted or unsubstituted (C4-C7) cycloalkenylheteroaryl. In embodiments, R2is a substituted or unsubstituted (C4-C9) bicycloalkylheteroaryl. In embodiments, R2is a substituted or unsubstituted 3 to 7 membered heterocycloalkyheteroaryl. In embodiments, R2is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl(Ci-C6)alkylheteroaryl. In embodiments, R2is a substituted or unsubstituted 3 to 7 membered heterocycloalkenylheteroaryl. In embodiments, R2is a substituted or unsubstituted 4 to 9 membered heterobicycloalkylheteroaryl. In embodiments, R2is a substituted or unsubstituted 4 to 9 membered spiroheterocycloalkylheteroaryl.PATENTAttorney Docket No. : 050935-527001 WO

[0253] In embodiments, R2is substituted or unsubstituted bridged cycloalkyl or substituted or unsubstituted bridged heterocycloalkyl. In embodiments, R2is substituted or unsubstituted bridged cycloalkyl. In embodiments, R2is substituted or unsubstituted bridged heterocycloalkyl.In embodiments, R2is. In embodiments, R2isIn embodiments,,

[0254] In embodiments, R2is substituted or unsubstituted spirocycloalkyl or substituted or unsubstituted spiroheterocycloalkyl. In embodiments, R2is substituted or unsubstituted spirocycloalkyl. In embodiments, R2is substituted or unsubstituted spiroheterocycloalkyl.In embodiments, R2isO. In embodiments, R2is. In embodiments, R2isPATENTAttorney Docket No. : 050935-527001 WO

[0255] In embodiments,, embodiments, R2. In embodiments,embodiments, R2is, In embodiments, R2. InIn embodiments,

[0257] In embodiments, a substituted R2A(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lowerPATENTAttorney Docket No. : 050935-527001 WO substituent group; wherein if the substituted R2Ais substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R2Ais substituted, it is substituted with at least one substituent group. In embodiments, when R2Ais substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R2Ais substituted, it is substituted with at least one lower substituent group.

[0258] In embodiments, R2Ais hydrogen, substituted or unsubstituted alkyl (e.g., Ci-Cs, Ci- Ce, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C7, C4-C6, or Cs-Ce), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 7 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., Ce-Cio or phenyl), substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered), substituted or unsubstituted aryl(Ci-C6)alkyl, or substituted or unsubstituted heteroaryl(Ci-C6)alkyl.

[0259] In embodiments, R2Ais hydrogen. In embodiments, R2Ais a substituted or unsubstituted Ci-Ce alkyl. In embodiments, R2Ais substituted or unsubstituted methyl. In embodiments, R2Ais trifluoromethyl. In embodiments, R2Ais substituted or unsubstituted ethyl. In embodiments, R2Ais substituted or unsubstituted propyl. In embodiments, R2Ais substituted or unsubstituted butyl. In embodiments, R2Ais substituted or unsubstituted pentyl. In embodiments, R2Ais substituted or unsubstituted hexyl. In embodiments, R2Ais substituted or unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R2Ais a substituted or unsubstituted C3-C7 cycloalkyl. In embodiments, R2Ais a substituted or unsubstituted cyclopropyl. In embodiments, R2Ais a substituted or unsubstituted cyclobutyl. In embodiments, R2Ais a substituted or unsubstituted cyclopentyl. In embodiments, R2Ais a substituted or unsubstituted cyclohexyl. In embodiments, R2Ais a substituted or unsubstituted cycloheptyl. In embodiments, R2Ais a substituted or unsubstituted 3 to 7 membered heterocycloalkyl. In embodiments, R2Ais a substituted or unsubstituted Ce-Cio aryl. In embodiments, R2Ais a substituted or unsubstituted phenyl. In embodiments, R2Ais a substituted or unsubstituted 5 to 9 membered heteroaryl. InPATENTAttorney Docket No. : 050935-527001 WO embodiments, R2Ais a substituted or unsubstituted aryl(Ci-C6)alkyl. In embodiments, R2Ais a substituted or unsubstituted heteroaryl(Ci-C6)alkyl.

[0260] In embodiments, a substituted R2B(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R2Bis substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R2Bis substituted, it is substituted with at least one substituent group. In embodiments, when R2Bis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R2Bis substituted, it is substituted with at least one lower substituent group.

[0261] In embodiments, a substituted R2C(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R2Cis substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R2Cis substituted, it is substituted with at least one substituent group. In embodiments, when R2Cis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R2Cis substituted, it is substituted with at least one lower substituent group.

[0262] In embodiments, R2Band R2Care each independently hydrogen, substituted or unsubstituted alkyl (e.g., Ci-Cs, Ci-Ce, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl, (e.g., C3-C8, C3-C7, C4-C6, or Cs-Ce), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 7 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., Ce-Cio or phenyl), substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered), substituted or unsubstituted aryl(Ci-C6)alkyl, substituted or unsubstitutedPATENTAttorney Docket No. : 050935-527001 WOC3-C7 cycloalkyl(Ci-C6)alkyl, or substituted or unsubstituted heteroaryl(Ci-C6)alkyl, substituted or un substituted C3-C7 cj7c-loalkyl(Ci-6)alkyl, substituted or unsubstituted aryl(Cj-6)aikyl, substituted or unsubstituted C3.7 heteroc\7cloaikyl(Ci-6)alkyl, substituted or unsubstituted heteroaryl (Ci-c, )alkyl, or R2Band R2C, when taken together with the nitrogen atom to which they are attached, is a heterocyclic moiety selected from substituted or unsubstituted azetidin-l-yl, substituted or unsubstituted pyrrolidin-l-yl, substituted or unsubstituted oxazolidin-3-yl, substituted or unsubstituted isoxazolidin-2-yl, substituted or unsubstituted thiazolidin-3-yl, substituted or unsubstituted isothiazolidin-2-yl, substituted or unsubstituted piperidin-l-yl, substituted or unsubstituted morpholin-4-yl, substituted or unsubstituted thiomorpholin-4-yl, substituted or un substituted piperazin-l-yl, substituted or unsubstituted homopiperidin-l-yl, substituted or unsubstituted homomorpholin- 4-yl, substituted or unsubstituted homopiperazin-l-yl, substituted or unsubstituted (imino)(oxo)thiazinan-4-yl, substituted or unsubstituted (oxo)thiazinan-4-yl or substituted or unsubstituted (dioxo)-thiazinan-4-yl.

[0263] In embodiments, R2Band R2Care each independently hydrogen. In embodiments, R2Band R2Care each independently substituted or unsubstituted Ci-Ce alkyl. In embodiments, R2Band R2Care each independently substituted or unsubstituted methyl. In embodiments, R2Band R2Care each independently trifluoromethyl. In embodiments, R2Band R2Care each independently substituted or unsubstituted ethyl. In embodiments, R2Band R2Care each independently substituted or unsubstituted propyl. In embodiments, R2Band R2Care each independently substituted or unsubstituted butyl. In embodiments, R2Band R2Care each independently substituted or unsubstituted pentyl. In embodiments, R2Band R2Care each independently substituted or unsubstituted hexyl. In embodiments, R2Band R2Care each independently substituted or unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R2Band R2Care each independently substituted or unsubstituted C3-C7 cycloalkyl. In embodiments, R2Band R2Care each independently substituted or unsubstituted cyclopropyl. In embodiments, R2Band R2Care each independently substituted or unsubstituted cyclobutyl. In embodiments, R2Band R2Care each independently substituted or unsubstituted cyclopentyl. In embodiments, R2Band R2Care each independently substituted or unsubstituted cyclohexyl. In embodiments, R2Band R2Care each independently substituted or unsubstituted cycloheptyl. In embodiments, R2Band R2Care each independently substituted or unsubstituted 3 to 7 memberedPATENTAttorney Docket No. : 050935-527001 WO heterocycloalkyl. In embodiments, R2Band R2Care each independently substituted or unsubstituted Ce-Cio aryl. In embodiments, R2Band R2Care each independently substituted or unsubstituted phenyl. In embodiments, R2Band R2Care each independently substituted or unsubstituted 5 to 9 membered heteroaryl. In embodiments, R2Band R2Care each independently substituted or unsubstituted aryl(Ci-C6)alkyl. In embodiments, R2Band R2Care each independently substituted or unsubstituted C3-C7 cycloalkyl(Ci-C6)alkyl. In embodiments, R2Band R2Care each independently substituted or unsubstituted heteroaryl(Ci-C6)alkyl. In embodiments, R2Band R2Care each independently substituted or un ubstituted C3-C7 cycloalkyl(C: .f. jalkyl. In embodiments, R2Dand R2Care each independently substituted or on substituted aryl(Ci-6)alkyl. In embodiments, R2Band R2Care each independently substituted or unsubstituted C -7 heteroc cloalkyl(CI k 1. In embodiments, R2Band R2Care each independently substituted or unsubstituted heteroaryl(Ci-6)alkyl.

[0264] In embodiments, a substituted ring formed when R2Band R2Care taken together with the nitrogen atom to which they are attached (e.g., substituted heterocycloalkyl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein a substituted ring formed when R2Band R2Care taken together with the nitrogen atom to which they are attached, is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when the substituted ring formed when R2Band R2Care taken together with the nitrogen atom to which they are attached is substituted, it is substituted with at least one substituent group. In embodiments, when the substituted ring formed when R2Band R2Care taken together with the nitrogen atom to which they are attached is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when the substituted ring formed when R2Band R2Care taken together with the nitrogen atom to which they are attached is substituted, it is substituted with at least one lower substituent group.

[0265] In embodiments, a substituted ring formed when R2Band R2Care taken together with the nitrogen atom to which they are attached (e.g., substituted azetidin-l-yl, substituted pyrrolidin-l-yl, substituted oxazolidin-3-yl, substituted isoxazolidin-2-yl, substituted thiazolidin-3-yl, substituted isothiazolidin-2-yl, substituted piperidin-l-yl, substitutedPATENTAttorney Docket No. : 050935-527001 WO morpholin-4-yl, substituted thiomorpholin-4-yl, substituted piperazin-l-yl, substituted homopiperidin-l-yl, substituted homomorpholin- 4-yl, substituted homopiperazin-l-yl, substituted (imino)(oxo)thiazinan-4-yl, substituted (oxo)thiazinan-4-yl or substituted (dioxo)-thiazinan-4-yl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein a substituted ring formed when R2Band R2Care taken together with the nitrogen atom to which they are attached, is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when the substituted ring formed when R2Dand R2Care taken together with the nitrogen atom to which they are attached is substituted, it is substituted with at least one substituent group. In embodiments, when the substituted ring formed when R2Band R2Care taken together with the nitrogen atom to which they are attached is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when the substituted ring formed when R2Band R2Care taken together with the nitrogen atom to which they are attached is substituted, it is substituted with at least one lower substituent group.

[0266] In embodiments, R2Band R2C, when taken together with the nitrogen atom to which they are attached, is a heterocyclic moiety selected from substituted or unsubstituted azetidin-1- yl, substituted or unsubstituted pyrrolidin-l-yl, substituted or unsubstituted oxazolidin-3-yl, substituted or unsubstituted isoxazolidin-2-yl, substituted or unsubstituted thiazolidin-3-yl, substituted or unsubstituted isothiazolidin-2-yl, substituted or unsubstituted piperidin-l-yl, substituted or unsubstituted morpholin-4-yl, substituted or unsubstituted thiomorpholin-4-yl, substituted or unsubstituted piperazin-l-yl, substituted or unsubstituted homopiperidin-l-yl, substituted or unsubstituted homomorpholin- 4-yl, substituted or unsubstituted homopiperazin-l-yl, substituted or unsubstituted (imino)(oxo)thiazinan-4-yl, substituted or unsubstituted (oxo)thiazinan-4-yl or substituted or unsubstituted (dioxo)-thiazinan-4-yl.

[0267] In embodiments, R2Band R2C, when taken together with the nitrogen atom to which they are attached, is substituted or unsubstituted azetidin-l-yl. In embodiments, R2Dand R2C, when taken together with the nitrogen atom to which they are attached, is substituted or unsubstituted pyrrolidin-l-yl. In embodiments, R2Band R2C, when taken together with thePATENTAttorney Docket No. : 050935-527001 WO nitrogen atom to which they are attached, is substituted or unsubstituted oxazolidin-3-yl. In embodiments, R2Band R2C, when taken together with the nitrogen atom to which they are attached, is substituted or unsubstituted isoxazolidin-2-yl. In embodiments, R2Band R2C, when taken together with the nitrogen atom to which they are attached, is substituted or unsubstituted thiazolidin-3-yl. In embodiments, R2Band R2C, when taken together with the nitrogen atom to which they are attached, is substituted or unsubstituted isothiazolidin-2-yl. In embodiments, R2Band R2C, when taken together with the nitrogen atom to which they are attached, is substituted or unsubstituted piperi din-1 -yl. In embodiments, R2Band R2C, when taken together with the nitrogen atom to which they are attached, is substituted or unsubstituted morpholin-4-yl. In embodiments, R2Band R2C, when taken together with the nitrogen atom to which they are attached, is substituted or unsubstituted thiomorpholin-4-yl. In embodiments, R2Band R2C, when taken together with the nitrogen atom to which they are attached, is substituted or unsubstituted piperazin-l-yl. In embodiments, R2Band R2C, when taken together with the nitrogen atom to which they are attached, is substituted or unsubstituted homopiperi din-1 -yl. In embodiments, R2Band R2C, when taken together with the nitrogen atom to which they are attached, is substituted or unsubstituted homomorpholin- 4-yl. In embodiments, R2Band R2C, when taken together with the nitrogen atom to which they are attached, is substituted or unsubstituted homopiperazin-l-yl. In embodiments, R2Band R2C, when taken together with the nitrogen atom to which they are attached, is substituted or unsubstituted (imino)(oxo)thiazinan-4-yl. In embodiments, R2Band R2C, when taken together with the nitrogen atom to which they are attached, is substituted or unsubstituted (oxo)thiazinan-4-yl. In embodiments, R2Band R2C, when taken together with the nitrogen atom to which they are attached, is or substituted or unsubstituted (diox o)-thiazinan -4-yl.

[0268] In embodiments, a substituted R2D(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R2Dis substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R2Dis substituted, it is substituted with at least onePATENTAttorney Docket No. : 050935-527001 WO substituent group. In embodiments, when R2Dis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R2Ais substituted, it is substituted with at least one lower substituent group.

[0269] In embodiments, R2Dis hydrogen, substituted or unsubstituted alkyl (e.g., Ci-Cg, Ci- Ce, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C7, C4-C6, or Cs-Ce), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 7 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., Ce-Cio or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0270] In embodiments, R2Dis hydrogen. In embodiments, R2Dis substituted or unsubstituted Ci-Ce alkyl. In embodiments, R2Dis substituted or unsubstituted methyl. In embodiments, R2Dis substituted or unsubstituted ethyl. In embodiments, R2Dis substituted or unsubstituted propyl. In embodiments, R2Dis substituted or unsubstituted butyl. In embodiments, R2Dis substituted or unsubstituted pentyl. In embodiments, R2Dis substituted or unsubstituted hexyl. In embodiments, R2Dis substituted or unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R2Dis a substituted or unsubstituted C3-C7 cycloalkyl. In embodiments, R2Dis a substituted or unsubstituted cyclopropyl. In embodiments, R2Dis a substituted or unsubstituted cyclobutyl. In embodiments, R2Dis a substituted or unsubstituted cyclopentyl. In embodiments, R2Dis a substituted or unsubstituted cyclohexyl. In embodiments, R2Dis a substituted or unsubstituted cycloheptyl. In embodiments, R2Dis a substituted or unsubstituted 3 to 7 membered heterocycloalkyl. In embodiments, R2Dis a substituted or unsubstituted Ce-Cio aryl. In embodiments, R2Dis a substituted or unsubstituted phenyl. In embodiments, R2Dis a substituted or unsubstituted 5 to 9 membered heteroaryl.

[0271] In embodiments, a substituted R3(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R3is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionallyPATENTAttorney Docket No. : 050935-527001 WO be different. In embodiments, when R3is substituted, it is substituted with at least one substituent group. In embodiments, when R3is substituted, it is substituted with at least one sizelimited substituent group. In embodiments, when R3is substituted, it is substituted with at least one lower substituent group.

[0272] In embodiments, R3is hydrogen, -OR5A, substituted or unsubstituted alkyl (e.g., Ci- Cs, Ci-Ce, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., Cs-Cs, C3-C7, C4-C6, or Cs-Ce), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 7 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered), or R3and R4can join together to form a substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 7 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered) or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered), wherein R3and R4are not both hydrogen.

[0273] In embodiments, R3is hydrogen. In embodiments, R3is -OR5A. In embodiments, R3is -OH. In embodiments, R3is -OCH3. In embodiments, R3is substituted or unsubstituted Ci-Ce alkyl. In embodiments, R3is substituted or unsubstituted methyl. In embodiments, R3is substituted or unsubstituted ethyl. In embodiments, R3is substituted or unsubstituted propyl. In embodiments, R3is substituted or unsubstituted butyl. In embodiments, R3is substituted or unsubstituted pentyl. In embodiments, R3is substituted or unsubstituted hexyl. In embodiments, R3is substituted or unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R3is a substituted or un substituted C3-C7 cycloalkyl. In embodiments, R3is substituted or unsubstituted cyclopropyl. In embodiments, R3is a substituted or unsubstituted cyclobutyl. In embodiments, R3is a substituted or unsubstituted cyclopentyl. In embodiments, R3is a substituted or unsubstituted cyclohexyl. In embodiments, R3is a substituted or unsubstituted cycloheptyl. In embodiments, R3is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl. In embodiments, R3is substituted or unsubstituted Ce-Cio aryl. In embodiments, R3is substituted or unsubstituted phenyl. In embodiments, R3is substituted or unsubstituted 5 to 9 memberedPATENTAttorney Docket No. : 050935-527001 WO heteroaryl. In embodiments, R3and R4can join together to form a substituted or unsubstituted C3-C7 heterocycloalkyl, wherein R3and R4are not both hydrogen.

[0274] In embodiments, R3is methyl.

[0275] In embodiments, a substituted ring formed when R3and R4substituents are joined (e.g., substituted heterocycloalkyl or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted ring formed when R3and R4substituents are joined is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when the substituted ring formed when R3and R4substituents are joined is substituted, it is substituted with at least one substituent group. In embodiments, when the substituted ring formed when R3and R4substituents are joined is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when the substituted ring formed when R3and R4substituents are joined is substituted, it is substituted with at least one lower substituent group.

[0276] In embodiments, R3and R4can join together to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl. In embodiments, R3and R4can join together to form a substituted or unsubstituted 3 to 7 membered heterocycloalkyl. In embodiments, R3and R4can join together to form a substituted or unsubstituted 5 to 9 membered heteroaryl. In embodiments, R3and R4can join together to formembodiments, R3and R4can join together to form. In embodiments, R3and R4can join together t

[0277] In embodiments, a substituted R4(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lowerPATENTAttorney Docket No. : 050935-527001 WO substituent group; wherein if the substituted R4is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R4is substituted, it is substituted with at least one substituent group. In embodiments, when R4is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R4is substituted, it is substituted with at least one lower substituent group.

[0278] In embodiments, R4is hydrogen, -OR5B, substituted or unsubstituted alkyl (e.g., Ci- Cs, Ci-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C7, C4-C6, or Cs-Ce), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 7 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., Ce-Cio or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered), or R3and R4can join together to form a substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 7 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered) or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered), wherein R3and R4are not both hydrogen.

[0279] In embodiments, R4is hydrogen. In embodiments, R4is -OR5B. In embodiments, R4is -OH. In embodiments, R4is -OCH3. In embodiments, R4is substituted or unsubstituted Ci-Ce alkyl. In embodiments, R4is substituted or unsubstituted methyl. In embodiments, R4is substituted or unsubstituted ethyl. In embodiments, R4is substituted or unsubstituted propyl. In embodiments, R4is substituted or unsubstituted butyl. In embodiments, R4is substituted or unsubstituted pentyl. In embodiments, R4is substituted or unsubstituted hexyl. In embodiments, R4is substituted or unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R4is a substituted or un substituted C3-C7 cycloalkyl. In embodiments, R4is substituted or unsubstituted cyclopropyl. In embodiments, R4is a substituted or unsubstituted cyclobutyl. In embodiments, R4is a substituted or unsubstituted cyclopentyl. In embodiments, R4is a substituted or unsubstituted cyclohexyl. In embodiments, R4is a substituted or unsubstituted cycloheptyl. In embodiments, R4is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl. InPATENTAttorney Docket No. : 050935-527001 WO embodiments, R4is substituted or unsubstituted Ce-Cio aryl. In embodiments, R4is substituted or unsubstituted phenyl. In embodiments, R4is substituted or unsubstituted 5 to 9 membered heteroaryl. In embodiments, R3and R4can join together to form a substituted or unsubstituted C3-C7 heterocycloalkyl, wherein R3and R4are not both hydrogen.

[0280] In embodiments, R4is methyl.

[0281] In embodiments, a substituted R5A(e.g., substituted alkyl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R5Ais substituted with a plurality of groups selected from substituent groups, sizelimited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R5Ais substituted, it is substituted with at least one substituent group. In embodiments, when R5Ais substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R5Ais substituted, it is substituted with at least one lower substituent group.

[0282] In embodiments, a substituted R5B(e.g., substituted alkyl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R5Bis substituted with a plurality of groups selected from substituent groups, sizelimited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R5Bis substituted, it is substituted with at least one substituent group. In embodiments, when R5Bis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R5Bis substituted, it is substituted with at least one lower substituent group.

[0283] In embodiments, R5Aand R5Bare independently hydrogen. In embodiments, R5Aand RISare independently substituted or unsubstituted Ci-Ce alkyl. In embodiments, R5Aand R3Bare independently substituted or unsubstituted methyl. In embodiments, R5Aand R5Bare independently substituted or unsubstituted ethyl. In embodiments, R5Aand R5Bare independently substituted or unsubstituted propyl. In embodiments, R5Aand R5Bare independently substituted or unsubstituted butyl. In embodiments, R5Aand R5Bare independently substituted or unsubstituted pentyl. In embodiments, R5Aand R?liare independently substituted or unsubstituted hexyl.PATENTAttorney Docket No. : 050935-527001 WO

[0284] In embodiments, a substituted R6(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R6is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R6is substituted, it is substituted with at least one substituent group. In embodiments, when R6is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R6is substituted, it is substituted with at least one lower substituent group.

[0285] In embodiments, a substituted R7(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R7is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R7is substituted, it is substituted with at least one substituent group. In embodiments, when R7is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R7is substituted, it is substituted with at least one lower substituent group.

[0286] In embodiments, R6and R7are independently hydrogen, substituted or unsubstituted alkyl (e.g., Ci-Cs, Ci-Ce, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C7, C4-C6, or Cs-Ce), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 7 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., Ce-Cio or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered), or R6and R7can join together to form a substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 7 membered, 4 to 6 membered, 4 to 5 membered,PATENTAttorney Docket No. : 050935-527001 WO or 5 to 6 membered) or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0287] In embodiments, R6and R7are independently hydrogen. In embodiments, R6and R7are independently substituted or unsubstituted Ci-Ce alkyl. In embodiments, R6and R7are independently substituted or unsubstituted methyl. In embodiments, R6and R7are independently substituted or unsubstituted ethyl. In embodiments, R6and R7are independently substituted or unsubstituted propyl. In embodiments, R6and R7are independently substituted or unsubstituted butyl. In embodiments, R6and R7are independently substituted or unsubstituted pentyl. In embodiments, R6and R7are independently substituted or unsubstituted hexyl. In embodiments, R6and R7are independently substituted or unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R6and R7are independently substituted or unsubstituted C3-C7 cycloalkyl. In embodiments, R6and R7are independently substituted or unsubstituted cyclopropyl. In embodiments, R6and R7are independently substituted or unsubstituted cyclobutyl. In embodiments, R6and R7are independently substituted or unsubstituted cyclopentyl. In embodiments, R6and R7are independently substituted or unsubstituted cyclohexyl. In embodiments, R6and R7are independently substituted or unsubstituted cycloheptyl. In embodiments, R6and R7are independently substituted or unsubstituted 3 to 7 membered heterocycloalkyl. In embodiments, R6and R7are independently substituted or unsubstituted Ce-Cio aryl. In embodiments, R6and R7are independently substituted or unsubstituted phenyl. In embodiments, R6and R7are independently substituted or unsubstituted 5 to 9 membered heteroaryl. In embodiments, R6and R7can join together to form a substituted or unsubstituted C3-C7 heterocycloalkyl.

[0288] In embodiments, a substituted ring formed when R6and R7substituents are joined (e.g., substituted heterocycloalkyl or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted ring formed when R6and R7substituents are joined is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when the substituted ring formed when R6and R7substituents are joined is substituted, it is substituted with at least one substituent group. InPATENTAttorney Docket No. : 050935-527001 WO embodiments, when the substituted ring formed when R6and R7substituents are joined is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when the substituted ring formed when R6and R7substituents are joined is substituted, it is substituted with at least one lower substituent group.

[0289] In embodiments, R6and R7can join together to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl. In embodiments, R6and R7can join together to form a substituted or unsubstituted 3 to 7 membered heterocycloalkyl. In embodiments, R6and R7can join together to form a substituted or unsubstituted 5 to 9 membered heteroaryl.

[0290] In embodiments, a substituted R8(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R8is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R8is substituted, it is substituted with at least one substituent group. In embodiments, when R8is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R8is substituted, it is substituted with at least one lower substituent group.

[0291] In embodiments, R8is hydrogen, halogen, -CCI3, -CBn, -CF3, -CI3, -CH2CI, -CH2Br, -CH2F, -CH2I, -CHC12, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -SH, -OCCI3, -OCBr3, -OCF3, -OCI3, -OCH2C1, -OCH2Br, -OCH2F, -OCH2I, -OCHCh, -OCHBr2, -OCHF2, -OCHI2, -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.

[0292] In embodiments, R8is hydrogen or halogen. In embodiments, R8is hydrogen. In embodiments, R8is -F. In embodiments, R8is -Cl. In embodiments, R8is -Br. In embodiments, R8is -I. In embodiments, R8is -CCI3. In embodiments, R8is -CBr?. In embodiments, R8is -CF3. In embodiments, R8is -CI3. In embodiments, R8is -CH2CI. In embodiments, R8is -CH2Br. In embodiments, R8is -CH2F. In embodiments, R8is -CH2I. InPATENTAttorney Docket No. : 050935-527001 WO embodiments, R8is -CHCI2. In embodiments, R8is -CHE . In embodiments, R8is -CHF2. In embodiments, R8is -CHI2. In embodiments, R8is -CN. In embodiments, R8is -COOH. In embodiments, R8is -CONH2. In embodiments, R8is -OCCI3. In embodiments, R8is -OCBra. In embodiments, R8is -OCF3. In embodiments, R8is -OCI3. In embodiments, R8is -OCH2CI. In embodiments, R8is -OCFbBr. In embodiments, R8is -OCH2F. In embodiments, R8is -OCH2I. In embodiments, R8is -OCHCh. In embodiments, R8is -OCHBn. In embodiments, R8is -OCHF2. In embodiments, R8is -OCHI2. In embodiments, R8is -N3.

[0293] In embodiments, a substituted R9(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R9is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R9is substituted, it is substituted with at least one substituent group. In embodiments, when R9is substituted, it is substituted with at least one sizelimited substituent group. In embodiments, when R9is substituted, it is substituted with at least one lower substituent group.

[0294] In embodiments, R9is independently halogen, -CCI3, -CBo, -CF3, -CI3, -CH2CI, -CH2Br, -CH2F, -CH2I, -CHCI2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -SH, -OCCI3, -OCBr3, -OCF3, -OCI3, -OCH2CI, -OCH2Br, -OCH2F, -OCH2I, -OCHCh, -OCHBr2, -OCHF2, -OCHI2, -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.

[0295] In embodiments, R9is halogen or halogen-substituted or unsubstituted alkyl (e.g., Ci- C8, Ci-C6, C1-C4, or Ci-C2).

[0296] In embodiments, R9is independently -F. In embodiments, R9is independently -Cl. In embodiments, R9is independently -Br. In embodiments, R9is independently -I. In embodiments, R9is -CCI3. In embodiments, R9is -CBr3. In embodiments, R9is -CF3. In embodiments, R9is -CI3. In embodiments, R9is -CH2CI. In embodiments, R9is -CH2Br. In embodiments, R9is -CH2F. In embodiments, R9is -CH2I. In embodiments, R9is -CHCh. InPATENTAttorney Docket No. : 050935-527001 WO embodiments, R9is -CHBrz. In embodiments, R9is -CHF2. In embodiments, R9is -CHE. In embodiments, R9is -CN. In embodiments, R9is -COOH. In embodiments, R9is -CONH2. In embodiments, R9is -OCCI3. In embodiments, R9is -OCBrs. In embodiments, R9is -OCF3. In embodiments, R9is -OCI3. In embodiments, R9is -OCH2CI. In embodiments, R9is -OCFkBr. In embodiments, R9is -OCH2F. In embodiments, R9is -OCH2I. In embodiments, R9is -OCHCh. In embodiments, R9is -OCHBr2. In embodiments, R9is -OCHF2. In embodiments, R9is -OCHI2. In embodiments, R9is -N3. In embodiments, R9is halogen or halogen-substituted or unsubstituted C1-C3 alkyl. In embodiments, R9is independently halogen-substituted or unsubstituted methyl. In embodiments, R9is independently unsubstituted methyl. In embodiments, R9is independently halogen- substituted or unsubstituted ethyl. In embodiments, R9is independently halogen- substituted or unsubstituted propyl.

[0297] In embodiments, a substituted R10(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R10is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R10is substituted, it is substituted with at least one substituent group. In embodiments, when R10is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R10is substituted, it is substituted with at least one lower substituent group.

[0298] In embodiments, R10is independently halogen, -CCI3, -CB13, -CF3, -CI3, -CH2CI, -CH2Br, -CH2F, -CH2I, -CHCI2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -SH, -OCCI3, -OCBr3, -OCF3, -OCI3, -OCH2CI, -OCH2Br, -OCH2F, -OCH2I, -OCHCh, -OCHBr2, -OCHF2, -OCHI2, -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.

[0299] In embodiments, R10is independently halogen. In embodiments, R10is independently -F. In embodiments, R10is independently -Cl. In embodiments, R10is independently -Br. In embodiments, R10is independently -I. In embodiments, R10is -CCI3. In embodiments, R10PATENTAttorney Docket No. : 050935-527001 WO is -CBri. In embodiments, R10is -CF3. In embodiments, R10is -Ch. In embodiments, R10is -CH2CI. In embodiments, R10is -CFbBr. In embodiments, R10is -CH2F. In embodiments, R10is -CH2I. In embodiments, R10is -CHCh. In embodiments, R10is -CHBr2. In embodiments, R10is -CHF2. In embodiments, R10is -CHI2. In embodiments, R10is -CN. In embodiments, R10is -COOH. In embodiments, R10is -CONH2. In embodiments, R10is -OCCI3. In embodiments, R10is -OCBrs. In embodiments, R10is -OCF3. In embodiments, R10is -OCI3. In embodiments, R10is -OCH2CI. In embodiments, R10is -OC BBr. In embodiments, R10is -OCH2F. In embodiments, R10is -OCH2I. In embodiments, R10is -OCHCh. In embodiments, R10is -OCHBF2. In embodiments, R10is -OCHF2. In embodiments, R10is -OCHI2. In embodiments, R10is -N3. In embodiments, R10is independently unsubstituted C1-C3 alkyl. In embodiments, R10is independently unsubstituted methyl. In embodiments, R10is independently unsubstituted ethyl. In embodiments, R10is independently unsubstituted propyl. In embodiments, R10is independently unsubstituted n-propyl. In embodiments, R10is independently unsubstituted isopropyl.

[0300] In embodiments, a substituted R11(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R11is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R11is substituted, it is substituted with at least one substituent group. In embodiments, when R11is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R11is substituted, it is substituted with at least one lower substituent group.

[0301] In embodiments, R11is hydrogen, halogen, -CCI3, -CBrs, -CF3, -CI3, -CH2CI, -CH2Br, -CH2F, -CH2I, -CHCh, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -SH, -OCCI3, -OCBr3, -OCF3, -OCI3, -OCH2CI, -OCH2Br, -OCH2F, -OCH2I, -OCHCh, -OCHBr2, -OCHF2, -OCHI2, -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.PATENTAttorney Docket No. : 050935-527001 WO

[0302] In embodiments, R11is hydrogen, halogen, halogen-substituted C1-C3 alkyl, or C1-C3 alkoxy.

[0303] In embodiments, R11is hydrogen. In embodiments, R11is halogen. In embodiments, R11is -F. In embodiments, R11is -Cl. In embodiments, R11is -Br. In embodiments, R11is -I. In embodiments, R11is halogen-substituted methyl. In embodiments, R11is -CF3, -CHF2,

[0304] -CH2F, -CCI3, -CHCh, or -CH2CI. In embodiments, R11is -CCI3. In embodiments, R11is -CBn. In embodiments, R11is -CF3. In embodiments, R11is -CI3. In embodiments, R11is -CH2CI. In embodiments, R11is -CFBBr. In embodiments, R11is -CH2F. In embodiments, R11is -CH2I. In embodiments, R11is -CHCh. In embodiments, R11is -CHBr2. In embodiments, R11is -CHF2. In embodiments, R11is -CHI2. In embodiments, R11is -CN. In embodiments, R11is -COOH. In embodiments, R11is -CONH2. In embodiments, R11is -OCCI3. In embodiments, R11is -OCBr3. In embodiments, R11is -OCF3. In embodiments, R11is -OCI3. In embodiments, R11is -OCH2CI. In embodiments, R11is -OCFBBr. In embodiments, R11is -OCH2F. In embodiments, R11is -OCH2I. In embodiments, R11is -OCHCh. In embodiments, R11is -OCHBr2. In embodiments, R11is -OCHF2. In embodiments, R11is -OCHI2. In embodiments, R11is -N3. In embodiments, R11is C1-C3 alkoxy. In embodiments, R11is -OCH3. In embodiments, R11is -OCH2CH3. In embodiments, R11is -OCH2CH2CH3.

[0305] In embodiments, a substituted R12(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R12is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R12is substituted, it is substituted with at least one substituent group. In embodiments, when R12is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R12is substituted, it is substituted with at least one lower substituent group.

[0306] In embodiments, R12is hydrogen, halogen, -CCI3, -CBrs, -CF3, -CI3, -CH2CI, -CH2Br, -CH2F, -CH2I, -CHCh, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2,PATENTAttorney Docket No. : 050935-527001 WO-0CHBr2, -OCHF2, -OCHI2, -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.

[0307] In embodiments, R12is hydrogen, halogen, halogen-substituted C1-C3 alkyl, or C1-C3 alkoxy.

[0308] In embodiments, R12is hydrogen. In embodiments, R12is halogen. In embodiments, R12is -F. In embodiments, R12is -Cl. In embodiments, R12is -Br. In embodiments, R12is -I. In embodiments, R12is halogen-substituted methyl. In embodiments, R12is -CF3, -CHF2, - CH2F, -CCI3, -CHCh, or-CFbCL In embodiments, R12is -CCI3. In embodiments, R12is -CBrs. In embodiments, R12is -CF3. In embodiments, R12is -CI3. In embodiments, R12is -CH2CI. In embodiments, R12is -CIBBr. In embodiments, R12is -CH2F. In embodiments, R12is -CH2I. In embodiments, R12is -CHCh. In embodiments, R12is -CHBr2. In embodiments, R12is -CHF2. In embodiments, R12is -CHh. In embodiments, R12is -CN. In embodiments, R12is -COOH. In embodiments, R12is -CONH2. In embodiments, R12is -OCCI3. In embodiments, R12is -OCBrs. In embodiments, R12is -OCF3. In embodiments, R12is -OCI3. In embodiments, R12is -OCH2CI. In embodiments, R12is -OCftBr. In embodiments, R12is -OCH2F. In embodiments, R12is -OCH2I. In embodiments, R12is -OCHCh. In embodiments, R12is -OCHBr2. In embodiments, R12is -OCHF2. In embodiments, R12is -OCHh. In embodiments, R12is -N3. In embodiments, R12is C1-C3 alkoxy. In embodiments, R12is -OCH3. In embodiments, R12is - OCH2CH3. In embodiments, R12is -OCH2CH2CH3.

[0309] In embodiments, a substituted R13(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R13is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R13is substituted, it is substituted with at least one substituent group. In embodiments, when R13is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R13is substituted, it is substituted with at least one lower substituent group.PATENTAttorney Docket No. : 050935-527001 WO

[0310] In embodiments, R13is hydrogen, halogen, hydroxy, cyano, trifluoromethyl, difluoromethoxy, trifluoromethoxy, -OR15, substituted or unsubstituted Ci-6 alkyl sulphonyl (e.g., Ci-Cs, Ci-Ce, C1-C4, or C1-C2) or substituted or unsubstituted C1-6 alkyl (e.g., Ci-Cs, Ci-Ce, C1-C4, or Ci-C2).

[0311] In embodiments, R13is hydrogen, halogen, -CCI3, -CBr?, -CF3, -CI3, -CH2CI, -CH2Br, -CH2F, -CH2I, -CHCI2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI3, -OCBr3, -OCF3, -OCI3, -OCH2C1, -OCH2Br, -OCH2F, -OCH2I, -OCHCI2, -OCHBr2, -OCHF2, -OCHI2, -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.

[0312] In embodiments, R13is halogen, -CCI3, -CBr3, -CF3, -CI3, -CH2C1, -CH2Br, -CH2F, -CH2I, -CHCI2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO2NH2, -NHNH2, -0NH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI3, -OCBr3, -OCF3, -OCI3, -OCH2C1, -OCH2Br, -OCH2F, -OCH2I, -OCHC12, -OCHBr2, -OCHF2, -OCHI2, -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.

[0313] In embodiments, R13is hydrogen. In embodiments, R13is halogen. In embodiments, R13is -F. In embodiments, R13is -Cl. In embodiments, R13is -Br. In embodiments, R13is -I. In embodiments, R13is hydroxy. In embodiments, R13is cyano. In embodiments, R13is trifluoromethyl. In embodiments, R13is difluoromethoxy. In embodiments, R13is trifluoromethoxy. In embodiments, R13is -CCI3. In embodiments, R13is -CBr3. In embodiments, R13is -CF3. In embodiments, R13is -CI3. In embodiments, R13is -CH2CI. In embodiments, R13is -CH2Br. In embodiments, R13is -CH2F. In embodiments, R13is -CH2I. In embodiments, R13is -CHCh. In embodiments, R13is -CHBr2. In embodiments, R13is -CHF2. In embodiments, R13is -CHI2. In embodiments, R13is -CN. In embodiments, R13is -COOH. In embodiments, R13is -CONH2. In embodiments, R13is -NO2. In embodiments, R13is -SO3H. In embodiments, R13is -SO2NH2. In embodiments, R13is -NHNH2. In embodiments, R13isPATENTAttorney Docket No. : 050935-527001 WO-ONH2. In embodiments, R13is -NHC(0)NH2. In embodiments, R13is -NHSO2H. In embodiments, R13is -NHC(O)H. In embodiments, R13is -NHC(O)OH. In embodiments, R13is -NHOH. In embodiments, R13is -OCCI3. In embodiments, R13is -OCBrs. In embodiments, R13is -OCF3. In embodiments, R13is -OCI3. In embodiments, R13is -OCH2CI. In embodiments, R13is -OCH2BE In embodiments, R13is -OCH2F. In embodiments, R13is -OCH2I. In embodiments, R13is -OCHCh. In embodiments, R13is -OCHBn. In embodiments, R13is -OCHF2. In embodiments, R13is -OCHI2. In embodiments, R13is -N3. In embodiments, R13is substituted or unsubstituted Ci-Ce alkylsulphonyl. In embodiments, R13is substituted or unsubstituted methyl sulphonyl. In embodiments, R13is substituted or unsubstituted ethyl sulphonyl. In embodiments, R13is substituted or unsubstituted propylsulphonyl. In embodiments, R13is substituted or unsubstituted butyl sulphonyl. In embodiments, R13is substituted or unsubstituted pentylsulphonyl. In embodiments, R13is substituted or unsubstituted hexyl sulphonyl. In embodiments, R13is substituted or unsubstituted Ci-Ce alkyl. In embodiments, R13is substituted or unsubstituted methyl. In embodiments, R13is substituted or unsubstituted ethyl. In embodiments, R13is substituted or unsubstituted propyl. In embodiments, R13is substituted or unsubstituted butyl. In embodiments, R13is substituted or unsubstituted pentyl. In embodiments, R13is substituted or unsubstituted hexyl. In embodiments, R13is -OR13. In embodiments, R15is substituted or unsubstituted Ci-Ce alkyl. In embodiments, R15is substituted or unsubstituted C3-C7 cycloalkyl. In embodiments, R15is substituted or unsubstituted 3 to 7 membered heterocycloalkyl. In embodiments, R15is substituted or unsubstituted Ce-Cio aryl. In embodiments, R15is substituted or unsubstituted 5 to 9 membered heteroaryl. In embodiments, R15is aryl(Ci-6)alkyl. In embodiments, R15is heteroaryl(Ci-6)alkyl.

[0314] In embodiments, a substituted R14(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R14is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R14is substituted, it is substituted with at least one substituent group. In embodiments, when R14is substituted, it is substituted with at least onePATENTAttorney Docket No. : 050935-527001 WO size-limited substituent group. In embodiments, when R14is substituted, it is substituted with at least one lower substituent group.

[0315] In embodiments, R14is substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, O or =NR16.

[0316] In embodiments, R14is substituted or unsubstituted Ci-Cs alkyl. In embodiments, R14is substituted or unsubstituted methyl. In embodiments, R14is substituted or unsubstituted ethyl. In embodiments, R14is substituted or unsubstituted propyl. In embodiments, R14is substituted or unsubstituted butyl. In embodiments, R14is substituted or unsubstituted pentyl. In embodiments, R14is substituted or unsubstituted hexyl. In embodiments, R14is substituted or unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R14is substituted or unsubstituted C3-C6 cycloalkyl. In embodiments, R14is substituted or unsubstituted 3 to 6 membered heterocycloalkyl. In embodiments, R14is =0. In embodiments, R14is =NR16. In embodiments, R16is a substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted 3 to 6 cycloalkyl, or substituted or unsubstituted 3 to 6 membered heterocycloalkyl. In embodiments, R16is substituted or unsubstituted Ci-Ce alkyl. In embodiments, R16is substituted or unsubstituted methyl. In embodiments, R16is substituted or unsubstituted ethyl. In embodiments, R16is substituted or unsubstituted propyl. In embodiments, R16is substituted or unsubstituted butyl. In embodiments, R16is substituted or unsubstituted pentyl. In embodiments, R16is substituted or unsubstituted hexyl. In embodiments, R16is substituted or unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R16is substituted or unsubstituted C3-C6 cycloalkyl. In embodiments, R16is substituted or unsubstituted 3 to 6 membered heterocycloalkyl.

[0317] In embodiments, a substituted R14A(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R14Ais substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R14Ais substituted, it is substituted with at leastPATENTAttorney Docket No. : 050935-527001 WO one substituent group. In embodiments, when R14Ais substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R14Ais substituted, it is substituted with at least one lower substituent group.

[0318] In embodiments, R14Ais hydrogen, halogen, -CCI3, -CBr3, -CF3, -CI3, -CH2CI, -CH2Br, -CH2F, -CH2I, -CHCI2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -SH, -OCCI3, -OCBr3, -OCF3, -OCI3, -OCH2CI, -OCH2Br, -OCH2F, -OCH2I, -OCHCh, -OCHBr2, -OCHF2, -OCHI2, -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.

[0319] In embodiments, R14Ais hydrogen. In embodiments, R14Ais halogen. In embodiments, R14Ais -F. In embodiments, R14Ais -Cl. In embodiments, R14Ais -Br. In embodiments, R14Ais -I. In embodiments, R14Ais halogen-substituted methyl. In embodiments, R14Ais CF3, CHF2,

[0320] -CH2F, -CCI3, -CHCh, or -CH2C1. In embodiments, R14Ais -CCI3. In embodiments, R14Ais -CBr3. In embodiments, R14Ais -CF3. In embodiments, R14Ais -CI3. In embodiments, R14Ais -CH2CI. In embodiments, R14Ais -CICBr In embodiments, R14Ais -CH2F. In embodiments, R14Ais -CH2I. In embodiments, R14Ais -CHCh. In embodiments, R14Ais -CHBr2. In embodiments, R14Ais -CHF2. In embodiments, R14Ais -CHI2. In embodiments, R14Ais -CN. In embodiments, R14Ais -COOH. In embodiments, RI4Ais -CONH2. In embodiments, R14Ais -OH. In embodiments, R14Ais -NH2. In embodiments, R14Ais -SH. In embodiments, R14Ais -OCC13. In embodiments, R14Ais -OCBr3. In embodiments, R14Ais -OCF3. In embodiments, R14Ais -OCI3. In embodiments, R14Ais -OCH2CI. In embodiments, R14Ais -OCH2Br. In embodiments, R14Ais -OCH2F. In embodiments, R14Ais -OCH2I. In embodiments, R14Ais -OCHCh. In embodiments, R14Ais -OCHBr2. In embodiments, R14Ais -OCHF2. In embodiments, R14Ais -OCHI2. In embodiments, R14Ais -N3. In embodiments, R14Ais Ci-C3alkoxy. In embodiments, R14Ais -OCH3. In embodiments, R14Ais -OCH2CH3. In embodiments, R14Ais -OCH2CH2CH3.

[0321] In embodiments, a substituted R14D(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lowerPATENTAttorney Docket No. : 050935-527001 WO substituent group; wherein if the substituted R14Bis substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R14Bis substituted, it is substituted with at least one substituent group. In embodiments, when R14Bis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R14Bis substituted, it is substituted with at least one lower substituent group.

[0322] In embodiments, R14Bis hydrogen, halogen, -CCI3, -CBr3, -CF3, -CI3, -CH2CI, -CH2Br, -CH2F, -CH2I, -CHC12, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -SH, -OCCI3, -OCBr3, -OCF3, -OCI3, -OCH2CI, -OCH2Br, -OCH2F, -OCH2I, -OCHCh, -OCHBr2, -OCHF2, -OCHI2, -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.

[0323] In embodiments, R14Bis hydrogen. In embodiments, R14Bis halogen. In embodiments, R14Bis -F. In embodiments, R14Bis -Cl. In embodiments, R14Bis -Br. In embodiments, R14Bis -I. In embodiments, R14Bis halogen- substituted methyl. In embodiments, R14Bis -CF3, -CHF2, -CH2F, -CCI3, -CHC12, or -CH2C1. In embodiments, R14Bis -CCI3. In embodiments, R14Bis -CBrs. In embodiments, R14Bis -CF3. In embodiments, R14Bis -CI3. In embodiments, R14Bis -CH2C1. In embodiments, R14Bis -CH2Br. In embodiments, R14Bis -CH2F. In embodiments, R14Bis -CH21. In embodiments, R14Bis -CHCh. In embodiments, R14Bis -CHBr2. In embodiments, R14Bis -CHF2. In embodiments, R14Bis -CHI2. In embodiments, R14Bis -CN. In embodiments, R14Bis -COOH. In embodiments, R14Bis -CONH2. In embodiments, R14Bis -OH. In embodiments, R14Bis -NH2. In embodiments, R14Bis -SH. In embodiments, R14Bis -OCCI3. In embodiments, R14Bis -OCBr?. In embodiments, R14Bis -OCF3. In embodiments, R14Bis -OCI3. In embodiments, R14Bis -OCH2C1. In embodiments, R14Bis -OCH2Br. In embodiments, R14Bis -OCH2F. In embodiments, R14Bis -OCH2I. In embodiments, R14Bis -OCHC12. In embodiments, R14Bis -OCHBr2. In embodiments, R14Bis -OCHF2. In embodiments, R14Bis -OCHI2. In embodiments, R14Bis -N3. In embodiments, R14Bis C1-C3 alkoxy. In embodiments, R14Bis -OCH3. In embodiments, R14Bis -OCH2CH . In embodiments, R14Bis -OCH2CH2CH3.PATENTAttorney Docket No. : 050935-527001 WO

[0324] In embodiments, a substituted R14C(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R14Cis substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R14Cis substituted, it is substituted with at least one substituent group. In embodiments, when R14Cis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R14Cis substituted, it is substituted with at least one lower substituent group.

[0325] In embodiments, R14Cis hydrogen, halogen, -CCI3, -CBrs, -CF3, -CI3, -CH2CI, -CH2Br, -CH2F, -CH2I, -CHCI2, -CHBr2, -CHF2, -CHE, -CN, -OH, -NH2, -COOH, -CONH2, -SH, -OCCI3, -OCBr3, -OCF3, -OCI3, -OCH2CI, -OCH2Br, -OCH2F, -OCH2I, -OCHCh, -OCHBr2, -OCHF2, -OCHI2, -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.

[0326] In embodiments, R14Cis hydrogen. In embodiments, R14Cis halogen. In embodiments, R14Cis -F. In embodiments, R14Cis -Cl. In embodiments, R14Cis -Br. In embodiments, R14Cis -I. In embodiments, R14Cis halogen- substituted methyl. In embodiments, R14Cis -CF3, -CHF2, -CH2F, -CCI3, -CHCh, or -CH2CI. In embodiments, R14Cis -CCI3. In embodiments, R14Cis -CBrs. In embodiments, R14Cis -CF3. In embodiments, R14Cis -CI3. In embodiments, R14Cis -CH2CI. In embodiments, R14Cis -CH2Br. In embodiments, R14Cis -CH2F. In embodiments, R14Cis -CH2I. In embodiments, R14Cis -CHCh. In embodiments, R14Cis -CHBr2. In embodiments, R14Cis -CHF2. In embodiments, R14Cis -CHI2. In embodiments, R14Cis -CN. In embodiments, R14Cis -COOH. In embodiments, R14Cis -CONH2. In embodiments, R14Cis -OH. In embodiments, R14Cis -NH2. In embodiments, R14Cis -SH. In embodiments, R14Cis -OCCI3. In embodiments, R14Cis -OCBr3. In embodiments, R14Cis -OCF3. In embodiments, R14Cis -OCI3. In embodiments, R14Cis -OCH2CI. In embodiments, R14Cis -OCH2Br. In embodiments, R14Cis -OCH2F. In embodiments, R14Cis -OCH2I. In embodiments, R14Cis -OCHCh. In embodiments, R14Cis -OCHBr2. In embodiments, R14CPATENTAttorney Docket No. : 050935-527001 WO is -OCHF2. In embodiments, R14Cis -OCHI2. In embodiments, R14Cis -N3. In embodiments, R14Cis C1-C3 alkoxy. In embodiments, R14Cis -OCH3. In embodiments, R14Cis -OCH2CH3. In embodiments, R14Cis -OCH2CH2CH3.

[0327] In embodiments, a substituted R14D(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R14Dis substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R14Dis substituted, it is substituted with at least one substituent group. In embodiments, when R14Dis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R14Dis substituted, it is substituted with at least one lower substituent group.

[0328] In embodiments, R14Dis hydrogen, halogen, -CCI3, -CBrs, -CF3, -CI3, -CH2CI, -CH2Br, -CH2F, -CH2I, -CHCI2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -SH, -OCCI3, -OCBr3, -OCF3, -OCI3, -OCH2CI, -OCH2Br, -OCH2F, -OCH2I, -OCHCh, -OCHBr2, -OCHF2, -OCHI2, -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.

[0329] In embodiments, R14Dis hydrogen. In embodiments, R14Dis halogen. In embodiments, R14Dis -F. In embodiments, R14Dis -Cl. In embodiments, R14Dis -Br. In embodiments, R14Dis -I. In embodiments, R14Dis halogen-substituted methyl. In embodiments, R14Dis -CF3, -CHF2, -CH2F, -CCI3, -CHCh, or -CH2CI. In embodiments, R14Dis -CCI3. In embodiments, R14Dis -CBr3. In embodiments, R14Dis -CF3. In embodiments, R14Dis -CI3. In embodiments, R14Dis -CH2CI. In embodiments, R14Dis -CH2Br. In embodiments, R14Dis -CH2F. In embodiments, R14Dis -CH2I. In embodiments, R14Dis -CHCh. In embodiments, R14Dis -CHBr2. In embodiments, R14Dis -CHF2. In embodiments, R14Dis -CHI2. In embodiments, R14Dis -CN. In embodiments, R14Dis -COOH. In embodiments, R14Dis -CONH2. In embodiments, R14Dis -OH. In embodiments, R14Dis -NH2. In embodiments, R14Dis -SH. In embodiments, R14Dis -OCCI3. In embodiments, R14Dis -OCBrs. In embodiments, R14DPATENTAttorney Docket No. : 050935-527001 WO is -OCF3. In embodiments, R14Dis -OCR. In embodiments, R14Dis -OCH2CL In embodiments, R14Dis -OCFfcBr. In embodiments, R14Dis -OCH2F. In embodiments, R14Dis -OCH2I. In embodiments, R14Dis -OCHCh. In embodiments, R14Dis -OCHE . In embodiments, R14Dis -OCHF2. In embodiments, R14Dis -OCHI2. In embodiments, R14Dis -N3. In embodiments, R14Dis C1-C3 alkoxy. In embodiments, R14Dis -OCH3. In embodiments, R14Dis -OCH2CH3. In embodiments, R14Dis -OCH2CH2CH3.

[0330] In embodiments, a substituted R1?A(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R15Ais substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R15Ais substituted, it is substituted with at least one substituent group. In embodiments, when RI ?is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R15Ais substituted, it is substituted with at least one lower substituent group.

[0331] In embodiments, R13Ais hydrogen, halogen, -CCI3, -CBo, -CF3, -CI3, -CH2CI, -CH2Br, -CH2F, -CH2I, -CHCI2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -SH, -OCCI3, -OCBr3, -OCF3, -OCI3, -OCH2CI, -OCH2Br, -OCH2F, -OCH2I, -OCHCh, -OCHBr2, -OCHF2, -OCHI2, -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.

[0332] In embodiments, RAis hydrogen. In embodiments, R13Ais halogen. In embodiments, R15Ais -F. In embodiments, R15Ais -Cl. In embodiments, R13Ais -Br. In embodiments, R15Ais -I. In embodiments, R15Ais halogen-substituted methyl. In embodiments, R15Ais -CF3, -CHF2, -CH2F, -CCI3, -CHCh, or -CH2C1. In embodiments, R15Ais -CCI3. In embodiments, R15Ais -CBr . In embodiments, R15Ais -CF3. In embodiments, R15Ais -CI3. In embodiments, R15Ais -CH2CI. In embodiments, R15Ais -CH2Br. In embodiments, R13Ais -CH2F. In embodiments, R15Ais -CH2I. In embodiments, R15Ais -CHCh. In embodiments, R15Ais -CHBr2. In embodiments, R15Ais -CHF2. In embodiments, R15Ais -CHh. InPATENTAttorney Docket No. : 050935-527001 WO embodiments, R15Ais -CN. In embodiments, R15Ais -COOH. In embodiments, R15Ais -CONH2. In embodiments, R15Ais -OH. In embodiments, R15Ais -NH2. In embodiments, R15Ais -SH. In embodiments, R15Ais -OCCI3. In embodiments, R15Ais -OCBrs. In embodiments, R15Ais -OCF3. In embodiments, R15Ais -OCI3. In embodiments, R15Ais -OCH2CI. In embodiments, R15Ais -OCH2Br. In embodiments, R13Ais -OCH2F. In embodiments, R15Ais -OCH2I. In embodiments, R15Ais -OCHCh. In embodiments, R15Ais -OCHB . In embodiments, R13Ais -OCHF2. In embodiments, R15Ais -OCHI2. In embodiments, R15Ais -N3. In embodiments, R15Ais C1-C3 alkoxy. In embodiments, R15Ais -OCH3. In embodiments, R15Ais -OCH2CH3. In embodiments, R15Ais -OCH2CH2CH3.

[0333] In embodiments, a substituted R1?B(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R15Bis substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R15Bis substituted, it is substituted with at least one substituent group. In embodiments, when R15Bis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R15Bis substituted, it is substituted with at least one lower substituent group.

[0334] In embodiments, R13Bis hydrogen, halogen, -CCI3, -CBn, -CF3, -CI3, -CH2CI, -CH2Br, -CH2F, -CH2I, -CHCI2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -SH, -OCCI3, -OCBr3, -OCF3, -OCI3, -OCH2CI, -OCH2Br, -OCH2F, -OCH2I, -OCHCh, -OCHBr2, -OCHF2, -OCHh, -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.

[0335] In embodiments, R15Bis hydrogen. In embodiments, R15Bis halogen. In embodiments, R15Bis -F. In embodiments, R15Bis -Cl. In embodiments, R15Bis -Br. In embodiments, R15Dis -I. In embodiments, R15Bis halogen- substituted methyl. In embodiments, R15Bis -CF3, -CHF2, -CH2F, -CCI3, -CHCh, or -CH2C1. In embodiments, R15Bis -CCI3. In embodiments, R15Bis -CBn. In embodiments, R15Bis -CF3. In embodiments, R15Bis -CI3. InPATENTAttorney Docket No. : 050935-527001 WO embodiments, R15Bis -CH2CI. In embodiments, R15Bis -CHzBr. In embodiments, R13Bis -CH2F. In embodiments, R15Bis -CH2I. In embodiments, R15Bis -CHCh. In embodiments, R15Bis -CHBF2. In embodiments, R15Bis -CHF2. In embodiments, R15Bis -CHI2. In embodiments, R1?Bis -CN. In embodiments, R1?Bis -COOH. In embodiments, R1?Bis -CONH2. In embodiments, R15Bis -OH. In embodiments, R15Bis -NH2. In embodiments, R15Bis -SH. In embodiments, R15Bis -OCCI3. In embodiments, R15Bis -OCBrs. In embodiments, R13Bis -OCF3. In embodiments, R15Bis -OCI3. In embodiments, R15Bis -OCH2CI. In embodiments, R15Bis -OCH2Br. In embodiments, R15Bis -OCH2F. In embodiments, R15Bis -OCH2I. In embodiments, R15Bis -OCHCh. In embodiments, R15Bis -OCHBr2. In embodiments, R1:,Bis -OCHF2. In embodiments, R15Bis -OCHI2. In embodiments, R15Bis -N3. In embodiments, R15Bis C1-C3 alkoxy. In embodiments, R15Bis -OCH3. In embodiments, R15Bis -OCH2CH3. In embodiments, R15Bis -OCH2CH2CH3.

[0336] In embodiments, a substituted R15C(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R15Cis substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R, scis substituted, it is substituted with at least one substituent group. In embodiments, when R15Cis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R15Cis substituted, it is substituted with at least one lower substituent group.

[0337] In embodiments, Rcis hydrogen, halogen, -CCI3, -CBr?, -CF3, -CI3, -CH2CI, -CH2Br, -CH2F, -CH2I, -CHCh, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -SH, -OCCI3, -OCBr3, -OCF3, -OCI3, -OCH2CI, -OCH2Br, -OCH2F, -OCH2I, -OCHCh, -OCHBr2, -OCHF2, -OCHI2, -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.

[0338] In embodiments, R15Cis hydrogen. In embodiments, R15Cis halogen. In embodiments, R15Cis -F. In embodiments, R15Cis -Cl. In embodiments, R15Cis -Br. InPATENTAttorney Docket No. : 050935-527001 WO embodiments, R15Cis -I. In embodiments, R15Cis halogen- substituted methyl. In embodiments, R15Cis -CF3, -CHF2, -CH2F, -CCI3, -CHC12, or -CH2C1. In embodiments, R15Cis -CCI3. In embodiments, R15Cis -CBr3. In embodiments, R15Cis -CF3. In embodiments, R15Cis -CI3. In embodiments, R1?cis -CH2C1. In embodiments, R15Cis -CH2Br. In embodiments, R15Cis -CH2F. In embodiments, R15Cis -CH2I. In embodiments, R15Cis -CHC12. In embodiments, R15Cis -CHBr2. In embodiments, R15Cis -CHF2. In embodiments, R15Cis -CHI2. In embodiments, R1?cis -CN. In embodiments, R1?cis -COOH. In embodiments, R1?cis -CONH2. In embodiments, R15Cis -OH. In embodiments, R15Cis -NH2. In embodiments, R15Cis -SH. In embodiments, R15Cis -OCCI3. In embodiments, R15Cis -OCBr3. In embodiments, R13Cis -OCF3. In embodiments, R15Cis -OCI3. In embodiments, R15Cis -OCH2C1. In embodiments, R15Cis -OCH2Br. In embodiments, R15Cis -OCH2F. In embodiments, R15Cis -OCH2I. In embodiments, R15Cis -OCHC12. In embodiments, R15Cis -OCHBr2. In embodiments, R13Cis -OCHF2. In embodiments, R15Cis -OCHI2. In embodiments, R15Cis -N3. In embodiments, R15Cis C1-C3 alkoxy. In embodiments, R15Cis -OCH3. In embodiments, R15Cis -OCH2CH3. In embodiments, R1?cis -OCH2CH2CH3.

[0339] In embodiments, a substituted R15D(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R15Dis substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R15Dis substituted, it is substituted with at least one substituent group. In embodiments, when RDis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R15Dis substituted, it is substituted with at least one lower substituent group.

[0340] In embodiments, R15Dis hydrogen, halogen, -CCI3, -CBn, -CF3, -CI3, -CH2C1, -CH2Br, -CH2F, -CH2I, -CHC12, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -SH, -OCC13, -OCBr3, -OCF3, -OCI3, -OCH2C1, -OCH2Br, -OCH2F, -OCH2I, -OCHCh, -OCHBr2, -OCHF2, -OCHI2, -N3, substituted or unsubstituted alkyl, substituted or unsubstitutedPATENTAttorney Docket No. : 050935-527001 WO heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0341] In embodiments, R13Dis hydrogen. In embodiments, R15Dis halogen. In embodiments, R1?Dis -F. In embodiments, R1?Dis -Cl. In embodiments, R13Dis -Br. In embodiments, R15Dis -I. In embodiments, R15Dis halogen-substituted methyl. In embodiments, R15Dis -CF3, -CHF2, -CH2F, -CCI3, -CHC12, or -CH2C1. In embodiments, R15Dis -CCI3. In embodiments, R13Dis -CBr3. In embodiments, R1?Dis -CF3. In embodiments, R15Dis -CI3. In embodiments, R15Dis -CH2C1. In embodiments, R15Dis -CH2Br. In embodiments, R15Dis -CH2F. In embodiments, R15Dis -CH2I. In embodiments, R15Dis -CHC12. In embodiments, R15Dis -CHBr2. In embodiments, R13Dis -CHF2. In embodiments, R15Dis -CHI2. In embodiments, R15Dis -CN. In embodiments, R15Dis -COOH. In embodiments, R15Dis -CONH2. In embodiments, R13Dis -OH. In embodiments, R15Dis -NH2. In embodiments, R1:>Dis -SH. In embodiments, R15Dis -OCCI3. In embodiments, R13Dis -OCBr3. In embodiments, R13Dis -OCF3. In embodiments, R15Dis -OCI3. In embodiments, R15Dis -OCH2C1. In embodiments, R1?Dis -OCH2Br. In embodiments, R13Dis -OCH2F. In embodiments, R1?Dis -OCH2I. In embodiments, R15Dis -OCHC12. In embodiments, R15Dis -OCHBr2. In embodiments, R15Dis -OCHF2. In embodiments, R15Dis -OCHI2. In embodiments, R15Dis -N3. In embodiments, R1?Dis C1-C3 alkoxy. In embodiments, R15Dis -OCH3. In embodiments, R15Dis -OCH2CH3. In embodiments, R15Dis -OCH2CH2CH3.

[0342] In embodiments, a substituted R16(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R16is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R16is substituted, it is substituted with at least one substituent group. In embodiments, when R16is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R16is substituted, it is substituted with at least one lower substituent group.PATENTAttorney Docket No. : 050935-527001 WO

[0343] In embodiments, R16is substituted or unsubstituted Ci-Cs 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 C5- C10 aryl or substituted or unsubstituted 5 to 9 membered heteroaryl. In embodiments, R16is substituted or unsubstituted Ci-Ce alkyl. In embodiments, R16is substituted or unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R16is substituted or unsubstituted C3-C6 cycloalkyl. In embodiments, R16is substituted or unsubstituted 3 to 6 membered heterocycloalkyl. In embodiments, R16is substituted or unsubstituted C5-C10 aryl. In embodiments, R16is substituted or unsubstituted 5 to 9 membered heteroaryl.

[0344] In embodiments, R16is unsubstituted C1-C3 alkyl. In embodiments, R16is unsubstituted methyl. In embodiments, R16is unsubstituted ethyl. In embodiments, R16is unsubstituted propyl. In embodiments, R16is unsubstituted n-propyl. In embodiments, R16is unsubstituted isopropyl.

[0345] In embodiments, a substituted R17(e.g., substituted alkyl, substituted heteroalkyl, or substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R17is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R17is substituted, it is substituted with at least one substituent group. In embodiments, when R17is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R17is substituted, it is substituted with at least one lower substituent group.

[0346] In embodiments, R17is independently halogen, -CCI3, -CBrs, -CF3, -CI3, -CH2CI, -CH2Br, -CH2F, -CH2I, -CHC12, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -SH, -OCCI3, -OCBr3, -OCF3, -OCI3, -OCH2CI, -OCH2Br, -OCH2F, -OCH2I, -OCHCh, -OCHBr2, -OCHF2, -OCHI2, -N3, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted 3 to 7 membered heterocycloalkyl, substituted or unsubstituted C& aryl or substituted or unsubstituted 5 to 9 membered heteroaryl.PATENTAttorney Docket No. : 050935-527001 WO

[0347] In embodiments, R17is independently halogen. In embodiments, R17is independently -F. In embodiments, R17is independently -Cl. In embodiments, R17is independently -Br. In embodiments, R17is independently -I. In embodiments, R17is -CCI3. In embodiments, R17is -CBD. In embodiments, R17is -CF3. In embodiments, R17is -CI3. In embodiments, R17is -CH2CI. In embodiments, R17is -CFBBr. In embodiments, R17is -CH2F. In embodiments, R17is -CH2I. In embodiments, R17is -CHCI2. In embodiments, R17is -CHBr2. In embodiments, R17is -CHF2. In embodiments, R17is -CHI2. In embodiments, R17is -CN. In embodiments, R17is -COOH. In embodiments, R17is -CONH2. In embodiments, R17is -OCCI3. In embodiments, R17is -OCBrs. In embodiments, R17is -OCF3. In embodiments, R17is -OCI3. In embodiments, R17is -OCH2CI. In embodiments, R17is -OCFBBr. In embodiments, R17is -OCH2F. In embodiments, R17is -OCH2L In embodiments, R17is -OCHCh. In embodiments, R17is -OCHBn. In embodiments, R17is -OCHF2. In embodiments, R17is -OCHI2. In embodiments, R17is -N3. In embodiments, R17is independently unsubstituted C1-C3 alkyl. In embodiments, R17is independently unsubstituted methyl. In embodiments, R17is independently unsubstituted ethyl. In embodiments, R17is independently unsubstituted propyl. In embodiments, R17is independently unsubstituted n-propyl. In embodiments, R17is independently unsubstituted isopropyl.

[0348] In embodiments, a substituted R18(e.g., substituted alkyl, substituted heteroalkyl, or substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R18is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R18is substituted, it is substituted with at least one substituent group. In embodiments, when R18is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R18is substituted, it is substituted with at least one lower substituent group.

[0349] In embodiments, R18is independently substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C3-C7PATENTAttorney Docket No. : 050935-527001 WO cycloalkyl, substituted or unsubstituted 3 to 7 membered heterocycloalkyl, substituted or unsubstituted Ce aryl or substituted or unsubstituted 5 to 9 membered heteroaryl.

[0350] In embodiments, R18is unsubstituted C1-C3 alkyl. In embodiments, R18is unsubstituted methyl. In embodiments, R18is unsubstituted ethyl. In embodiments, R18is unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R18is unsubstituted C3-C6 cycloalkyl. In embodiments, R18is unsubstituted cyclopropyl. In embodiments, R18is unsubstituted cyclobutyl. In embodiments, R18is unsubstituted cyclopentyl. In embodiments, R18is unsubstituted cyclohexyl.

[0351] In embodiments, R18is unsubstituted 3 to 6 membered heterocycloalkyl. In embodiments, R18is unsubstituted Ce aryl. In embodiments, R18is unsubstituted phenyl. In embodiments, R18is unsubstituted 5 to 6 membered heteroaryl.

[0352] In embodiments, n is an integer from 0 to 3. In embodiments, n is 0. In embodiments, n is 1. In embodiments, n is 2. In embodiments, n is 3.

[0353] In embodiments, n’ is an integer from 0 to 13. In embodiments, n’ is 0. In embodiments, n’ is 1. In embodiments, n’ is 2. In embodiments, n’ is 3. In embodiments, n’ is 4. In embodiments, n’ is 5. In embodiments, n’ is 6. In embodiments, n’ is 7. In embodiments, n’ is 8. In embodiments, n’ is 9. In embodiments, n’ is 10. In embodiments, n’ is 11. In embodiments, n’ is 12. In embodiments, n’ is 13.

[0354] In embodiments, m is an integer from 0 to 4. In embodiments, m is 0. In embodiments, m is 1. In embodiments, m is 2. In embodiments, m is 3. In embodiments, m is 4.

[0355] In embodiments, p is an integer from 0 to 4. In embodiments, p is 0. In embodiments, p is 1. In embodiments, p is 2. In embodiments, p is 3. In embodiments, p is 4.

[0356] In embodiments, q is an integer from 0 to 3. In embodiments, q is 0. In embodiments, q is 1. In embodiments, q is 2. In embodiments, q is 3.

[0357] In embodiments, n2 is an integer from 0 to 3. In embodiments, n2 is 0. In embodiments, n2 is 1. In embodiments, n2 is 2. In embodiments, n2 is 3.

[0358] In embodiments, nl3 is an integer from 0 to 3. In embodiments, nl3 is 0. In embodiments, n!3 is 1. In embodiments, nl3 is 2. In embodiments, n!3 is 3.

[0359] In embodiments, nl4 is an integer from 0 to 3. In embodiments, nl4 is 0. In embodiments, nl4 is 1. In embodiments, nl4 is 2. In embodiments, nl4 is 3.PATENTAttorney Docket No. : 050935-527001 WO

[0360] In embodiments, m2 is an integer from 0 to 4. In embodiments, m2 is 0. In embodiments, m2 is 1. In embodiments, m2 is 2. In embodiments, m2 is 3. In embodiments, m2 is 4.

[0361] In embodiments, ml 3 is an integer from 0 to 4. In embodiments, ml3 is 0. In embodiments, m!3 is 1. In embodiments, ml 3 is 2. In embodiments, ml3 is 3. In embodiments, ml3 is 4.

[0362] In embodiments, ml4 is an integer from 0 to 4. In embodiments, ml4 is 0. In embodiments, m 14 is 1. In embodiments, m 14 is 2. In embodiments, m 14 is 3. In embodiments, ml4 is 4.

[0363] In embodiments, v2 is an integer from 0 to 4. In embodiments, v2 is 0. In embodiments, v2 is 1. In embodiments, v2 is 2. In embodiments, v2 is 3. In embodiments, v2 is 4.

[0364] In embodiments, vl3 is an integer from 0 to 4. In embodiments, vl3 is 0. In embodiments, vl3 is 1. In embodiments, vl3 is 2. In embodiments, vl3 is 3. In embodiments, vl3 is 4.

[0365] In embodiments, vl4 is an integer from 0 to 4. In embodiments, vl4 is 0. In embodiments, vl4 is 1. In embodiments, vl4 is 2. In embodiments, vl4 is 3. In embodiments, vl4 is 4.

[0366] In embodiments, X2is -F, -Cl, -Br, or -I. In embodiments, X2is -F. In embodiments, X2is -Cl. In embodiments, X2is -Br. In embodiments, X2is -I.

[0367] In embodiments, X8is -F, -Cl, -Br, or -I. In embodiments, X8is -F. In embodiments, X8is -Cl. In embodiments, X8is -Br. In embodiments, X8is -I.

[0368] In embodiments, X9is -F, -Cl, -Br, or -I. In embodiments, X9is -F. In embodiments, X9is -Cl. In embodiments, X9is -Br. In embodiments, X9is -I.

[0369] In embodiments, X10is -F, -Cl, -Br, or -I. In embodiments, X10is -F. In embodiments, X10is -Cl. In embodiments, X10is -Br. In embodiments, X10is -I.

[0370] In embodiments, X11is -F, -Cl, -Br, or -I. In embodiments, X11is -F. In embodiments, X11is -Cl. In embodiments, X11is -Br. In embodiments, X11is -I.

[0371] In embodiments, X12is -F, -Cl, -Br, or -I. In embodiments, X12is -F. In embodiments, X12is -Cl. In embodiments, X12is -Br. In embodiments, X12is -I.PATENTAttorney Docket No. : 050935-527001 WO

[0372] In embodiments, X13is -F, -Cl, -Br, or -I. In embodiments, X13is -F. In embodiments, X13is -Cl. In embodiments, X13is -Br. In embodiments, X13is -I.

[0373] In embodiments, X14is -F, -Cl, -Br, or -I. In embodiments, X14is -F. In embodiments, X14is -Cl. In embodiments, X14is -Br. In embodiments, X14is -I.

[0374] In embodiments, X15is -F, -Cl, -Br, or -I. In embodiments, X15is -F. In embodiments, X15is -Cl. In embodiments, X15is -Br. In embodiments, X15is -I.

[0375] In embodiments, X17is -F, -Cl, -Br, or -I. In embodiments, X17is -F. In embodiments, X17is -Cl. In embodiments, X17is -Br. In embodiments, X17is -I.

[0376] In embodiments, the compound, or a pharmaceutically acceptable salt thereof, having the formulae (I-Ia), (I-Ib), (I-Ic), or (I-Id):variables are as defined above, including embodiments.

[0377] In an aspect is provided a compound of formula (I):PATENTAttorney Docket No. : 050935-527001 WOpharmaceutically acceptable salt thereof.

[0378] The two atoms shared by Ring D and Ring E are carbon atoms. The dotted bond - between two atoms shared by Ring D and Ring E are carbon atoms indicate the presence of a single bond or a double bond.

[0379] Ring E is a substituted or unsubstituted 6-membered heteroaryl, substituted or unsubstituted 5-membered heteroaryl, or a substituted or unsubstituted 5-membered heterocycloalkyl. In embodiments, Ring E is 2-pyrrolidone, pyrrole, pyrazole, oxazole, thiazole, isothiazole, oxadiazole, thiadiazole, triazole or isoxazole. In embodiments, Ring E is not substituted or unsubstituted imidazole. In embodiments, Ring E is not unsubstituted imidazole. In embodiments, Ring E is not substituted imidazole.

[0380] Ring F is a substituted or unsubstituted phenyl or a substituted or unsubstituted 5- or 6-membered heteroaryl having 1 to 2 nitrogen atoms.

[0381] The symbol n is an integer from 0 to 3.

[0382] The symbol m is an integer from 0 to 4.

[0383] R2is hydrogen, halogen, cyano, trifluoromethyl, trifluoromethoxy, -OR2A, -SR2A,-SOR2A, -SO2R2A, -NR2BR2C, -NR2CCOR2D, -NR2CCO2R2D, -NHCONR2BR2C, -NR2CSO2R2E, -COR2D, -CO2R2D, -CONR2BR2C, -SO2NR2BR2C, or -S(O)(N-R2BR2E), substituted or unsubstituted alkyl (e.g., Ci-Cs, Ci-Ce, C1-C4, or C1-C2), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C7, C4-C6, or Cs-Ce), substituted or unsubstituted cycloalkenyl (e.g., C3-C8, C3-C7, C4-C6, or Cs-Ce), substituted or unsubstituted heterocycloalkyl (e g., 3 to 8 membered, 3 to 7 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted heterocycloalkenyl (e.g., 3 to 8 membered, 3 to 7 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., Ce-Cio or phenyl), substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6PATENTAttorney Docket No. : 050935-527001 WO membered), substituted or unsubstituted aryl(Ci.C6)alkyl, substituted or unsubstituted heteroaryl(Ci-C6)alkyl, substituted or unsubstituted 3 to 7 membered heterocycloalkyl(Ci-C6)alkyl-aryl, substituted or unsubstituted (C3-C7)cycloalkyl-heteroaryl, substituted or un substituted 3 to 7 membered heterocycloalkenyl-aryl, substituted or unsubstituted (C3-C7)cycloalkyl(Ci-6)alkyl-heteroaryl, substituted or unsubstituted (C4-C7) cycloalkenyl-heteroaryl, substituted or unsubstituted (C4-C9)bicycloalkyl-heteroaryl, substituted or unsubstituted 3 to 7 membered heterocycloalkyl-heteroaryl, substituted or unsubstituted 3 to 7 membered heterocycloalkyl(Ci-C6)alkyl-heteroaryl, substituted or unsubstituted 3 to 7 membered heterocycloalkenyl-heteroaryl, substituted or unsubstituted 4 to 9 membered heterobicycloalkyl-heteroaryl, substituted or unsubstituted 4 to 9 membered spiroheterocycloalkyl-heteroaryl,

[0384] R2Ais a substituted or unsubstituted alkyl (e.g., Ci-Cs, Ci-Ce, C1-C4, or C1-C2), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C7, C4-C6, or Cs-Ce), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 7 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., Ce-Cio or phenyl), substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered), substituted or unsubstituted aryl(Ci-C6)alkyl, or substituted or unsubstituted heteroaryl(Ci-C6)alkyl.

[0385] R2Band R2Ceach independently hydrogen, trifluoromethyl, substituted or unsubstituted alkyl (e.g., Ci-Cs, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted cycloalkyl, (e.g., C3-C8, C3-C7, C4-C6, or Cs-Ce), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 7 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., Ce-Cio or phenyl), substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered), substituted or unsubstituted aryl(Ci-Cs)alkyl, substituted or unsubstituted C3-C7 cycloalkyl(Ci-Ce)alkyl, or substituted or unsubstituted heteroaryl(Ci-C6)alkyl, or R2Band R2C, when taken together with the nitrogen atom to which they are attached, is a heterocyclic moiety selected from substituted or unsubstitutedPATENTAttorney Docket No. : 050935-527001 WO azetidin-l-yl, substituted or unsubstituted pyrrolidin-l-yl, substituted or unsubstituted oxazolidin-3-yl, substituted or unsubstituted isoxazolidin-2-yl, substituted or unsubstituted thiazolidin-3-yl, substituted or unsubstituted isothiazolidin-2-yl, substituted or unsubstituted piperidin-l-yl, substituted or un substituted morpholin-4-yl, substituted or un substituted thiomorpholin-4-yl, substituted or unsubstituted piperazin4-yl, substituted or unsubstituted homopiperidin-l-yl, substituted or unsubstituted homomorpholin- 4-yl, substituted or unsubstituted homopiperazin-l-yl, substituted or unsubstituted (imino)(oxo)thiazinan-4-yl, substituted or unsubstituted (oxo)thiazinan-4-yl or substituted or unsubstituted (dioxo)-thiazinan-4-yl.

[0386] R2Dis hydrogen, substituted or unsubstituted alkyl (e.g., Ci-Cs, Ci-Ce, C1-C4, or Ci- C2), substituted or unsubstituted cycloalkyl (e g., C3-C8, C3-C7, C4-C6, or Cs-Ce), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 7 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., Ce-Cio or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0387] R2Eis a substituted or unsubstituted alkyl (e.g., Ci-Cs, Ci-Ce, C1-C4, or C1-C2), substituted or unsubstituted aryl (e.g., Ce-Cio or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0388] R3is hydrogen, -OR54, substituted or unsubstituted alkyl (e.g., Ci-Cs, Ci-Ce, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C7, C4-C6, or Cs-Ce), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 7 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., Ce-Cio or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered), or R3and R4can join together to form a substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 7 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered) or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered), wherein R3and R4are not both hydrogen.PATENTAttorney Docket No. : 050935-527001 WO

[0389] R4is hydrogen, -OR5B, substituted or unsubstituted alkyl (e.g., Ci-Cs, Ci-Ce, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C7, C4-C6, or Cs-Ce), substituted or un substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 7 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., Ce-Cio or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered), or R3and R4can join together to form a substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 7 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered) or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered), wherein R3and R4are not both hydrogen.

[0390] R5Aand R3Bare independently hydrogen or substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or Ci-C2).

[0391] R6and R7are independently hydrogen, substituted or unsubstituted alkyl (e.g., Ci-Cs, Ci-Ce, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C7, C4-C6, or Cs-Ce), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 7 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., Ce-Cio or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered), or R6and R7can join together to form a substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 7 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered) or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0392] R8is hydrogen or halogen.

[0393] R9is independently halogen or halogen-substituted or unsubstituted C1-C3 alkyl.

[0394] R11and R12are independently hydrogen or halogen-substituted methyl.

[0395] R13is hydrogen, halogen, hydroxy, cyano, trifluoromethyl, difluoromethoxy, trifluoromethoxy, -OR15, substituted or unsubstituted Ci-Ce alkylsulphonyl or substituted or unsubstituted Ci-Ce alkyl.PATENTAttorney Docket No. : 050935-527001 WO

[0396] R14is independently a 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, =0 or =NR16.

[0397] R15is a substituted or un substituted Ci.Ce alkyl, substituted or un substituted C3-C7 cycloalkyl, substituted or unsubstituted 3 to 7 membered heterocycloalkyl, substituted or unsubstituted aryl (e.g., Cs-Cio or phenyl), substituted or unsubstituted aryl(Ci-C6)alkyl, substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered) or substituted or unsubstituted heteroaryl(Ci-C6)alkyl.

[0398] R16is a substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, or substituted or unsubstituted 3 to 6 membered heterocycloalkyl.

[0399] In embodiments, Ring E is a substituted or unsubstituted 6-membered heteroaryl or a substituted or unsubstituted 5-membered heteroaryl selected from 2-pyrrolidone, pyrrole, pyrazole, oxazole, thiazole, isothiazole, oxadiazole, thiadiazole, triazole or isoxazole.

[0400] In embodiments, Ring E is a substituted or unsubstituted 6-membered heteroaryl. In embodiments, Ring E is pyridine, pyridazine, pyrimidine, pyrazine, 1,2,4-triazine, 1,3,5-triazine, 277-thiopyran, 4 / / -th iopyran, 477-1,2-oxazine, 2 / / -l,2-oxazine, 4Z / -l,4-thiazine, 2 / / -l,2-thiazine, 6 / / -l,2-thiazine, 2 / 7-1,4-thiazine, cytozine, thymine, uracil, 2,3-dihydro-l / f-indene, indene, indolene, 3 / 7-indole, l / / -indole, 2 / / -isoindole, indolizine, 177-indazole, benzimidazole, 7-azaindazole, pyrazolo[l,5-a] pyrimidine, purine, benzofuran, isobenzofuran, benzo[c]thiophene, benzo[ / >]thiophene, benzo[d]isoxazole, benzo[c]isoxazole, benzo[t / ]isothiazole, benzo[c] isothiazole, benzofc / ] oxazole, benzo[t / ]thiazole, benzo[c][l,2,5]thiadiazole, l,2-benzisothiazole-3(2H)-one, adenine, guanine, quiniline, phenazine, phenoxazine, or 1 -azaadamantane. In embodiments, Ring E is pyridine. In embodiments, Ring E is pyridazine. In embodiments, Ring E is pyrimidine. In embodiments, Ring E is pyrazine. In embodiments, Ring E is 1,2,4-triazine. In embodiments, Ring E is 1,3,5- triazine. In embodiments, Ring E is2 / / -thiopyran. In embodiments, Ring E is 4 / / -thiopyran. In embodiments, Ring E is 4 / / -l,2-oxazine. In embodiments, Ring E is 2 / 7-1,2-oxazine. In embodiments, Ring E is 4 / / -l,4-thiazine. In embodiments, Ring E is 2 / 7-1,2-thiazine. In embodiments, Ring E isPATENTAttorney Docket No. : 050935-527001 WO6 / / -l,2-thiazine. In embodiments, Ring E is 2 / 7-1, 4-thiazine. In embodiments, Ring E is cytozine. In embodiments, Ring E is thymine. In embodiments, Ring E is uracil. In embodiments, Ring E is 2,3-dihydro-l / 7-indene. In embodiments, Ring E is indene. In embodiments, Ring E is indolene. In embodiments, Ring E is 3 / 7-indole. In embodiments, Ring E is 1 / f-indole. In embodiments, Ring E is 2 / 7-isoindole. In embodiments, Ring E is indolizine. In embodiments, Ring E is 1 / 7-indazole. In embodiments, Ring E is benzimidazole. In embodiments, Ring E is 7-azaindazole. In embodiments, Ring E is pyrazolo[l,5-a] pyrimidine. In embodiments, Ring E is purine. In embodiments, Ring E is benzofuran. In embodiments, Ring E is isobenzofuran. In embodiments, Ring E is benzo[c]thiophene. In embodiments, Ring E is benzo[Z>]thiophene. In embodiments, Ring E is benzo[ ]isoxazole. In embodiments, Ring E is benzo[c]isoxazole. In embodiments, Ring E is benzo[<7]isothiazole. In embodiments, Ring E is benzo[c]isothiazole. In embodiments, Ring E is benzo[t / ]oxazole. In embodiments, Ring E is benzo[ ]thiazole. In embodiments, Ring E is benzofc] [1, 2, 5]thiadiazole. In embodiments, Ring E is l,2-benzisothiazole-3(2H)-one. In embodiments, Ring E is adenine. In embodiments, Ring E is guanine. In embodiments, Ring E is quiniline. In embodiments, Ring E is phenazine. In embodiments, Ring E is phenoxazine. In embodiments, Ring E is 1 -azaadamantane.

[0401] In embodiments, Ring E is a substituted or unsubstituted 5-membered heteroaryl. In embodiments, Ring E is pyrrole, pyrazole, oxazole, thiazole, isothiazole, oxadiazole, thiadiazole, triazole or isoxazole. In embodiments, Ring E is pyrrole. In embodiments, Ring E is pyrazole. In embodiments, Ring E is oxazole. In embodiments, Ring E is thiazole. In embodiments, Ring E is isothiazole. In embodiments, Ring E is oxadiazole. In embodiments, Ring E is thiadiazole. In embodiments, Ring E is triazole. In embodiments, Ring E is isoxazole.

[0402] In embodiments, Ring F is a substituted or unsubstituted phenyl or a substituted or unsubstituted 5- or 6-membered heteroaryl having 1 to 2 nitrogen atoms.

[0403] In embodiments, Ring F is phenyl.

[0404] In embodiments, Ring F is a substituted or unsubstituted 5- or 6-membered heteroaryl having 1 to 2 nitrogen atoms. In embodiments, Ring F is pyrrolyl, imidazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, or pyridazinyl. In embodiments, Ring F is pyrrolyl. In embodiments, Ring F is imidazolyl. In embodiments, Ring F is pyrazolyl. In embodiments, RingPATENTAttorney Docket No. : 050935-527001 WOF is pyridinyl. In embodiments, Ring F is pyrazinyl. In embodiments, Ring F is pyrimidinyl. In embodiments, Ring F is pyridazinyl.

[0405] In embodiments, R2is a substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted C3-C7 cycloalkenyl, substituted or unsubstituted 3 to 7 membered heterocycloalkyl, substituted or unsubstituted 3 to 7 membered heterocycloalkenyl, substituted or unsubstituted Ce-Cio aryl, substituted or unsubstituted 5 to 9 membered heteroaryl, substituted or unsubstituted Ce-Cio aryl(Ci-Ce)alkyl, substituted or unsubstituted 5 to 9 membered heteroaryl(Ci-C6)alkyl, substituted or unsubstituted 3 to 7 membered heterocycloalkyl(Ci-C6)alkyl-C6-Cio aryl, substituted or unsubstituted (C3-C7) cycloalkyl-5 to 9 membered heteroaryl, substituted or unsubstituted 3 to 7 membered heterocycloalkenyl-Ce-Cio aryl, substituted or unsubstituted (C3-C7)cycloalkyl(Ci-6)alkyl-5 to 9 membered heteroaryl, substituted or unsubstituted (C4-C7) cycloalkenyl-5 to 9 membered heteroaryl, substituted or unsubstituted (C4-C9)bicycloalkyl-5 to 9 membered heteroaryl, substituted or unsubstituted 3 to 7 membered heterocycloalkyl-5 to 9 membered heteroaryl, substituted or unsubstituted 3 to 7 membered heterocycloalkyl(Ci-C6)alkyl-5 to 9 membered heteroaryl, substituted or unsubstituted 3 to 7 membered heterocycloalkenyl-5 to 9 membered heteroaryl, substituted or unsubstituted (C4-C9) heterobicycloalkyl-5 to 9 membered heteroaryl, substituted or unsubstituted (C4-C9)spiroheterocycloalkyl-5 to 9 membered heteroaryl.

[0406] In embodiments, R2is a substituted or unsubstituted Ci-Ce alkyl. In embodiments, R2is a substituted or unsubstituted C3-C7 cycloalkyl. In embodiments, R2is a substituted or unsubstituted C3-C7 cycloalkenyl. In embodiments, R2is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl. In embodiments, R2is a substituted or unsubstituted 3 to 7 membered heterocycloalkenyl. In embodiments, R2is a substituted or unsubstituted Ce-Cio aryl. In embodiments, R2is a substituted or unsubstituted 5 to 9 membered heteroaryl. In embodiments, R2is a substituted or unsubstituted Ce-Cio aryl(Ci-C6)alkyl. In embodiments, R2is a substituted or unsubstituted 5 to 9 membered heteroaryl(Ci-C6)alkyl. In embodiments, R2is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl(Ci-C6)alkyl-C6-Cio aryl. In embodiments, R2is a substituted or unsubstituted (C3-C7) cycloalkyl-5 to 9 membered heteroaryl. In embodiments, R2is a substituted or unsubstituted 3 to 7 membered heterocycloalkenyl-Ce-Cio aryl. In embodiments, R2is a substituted or unsubstituted (C3-C7)cycloalkyl(Ci-6)alkyl-5 to 9PATENTAttorney Docket No. : 050935-527001 WO membered heteroaryl. In embodiments, R2is a substituted or unsubstituted (C4-C7) cycloalkenyl-5 to 9 membered heteroaryl. In embodiments, R2is a substituted or unsubstituted (C4-C9) bicycloalkyl-5 to 9 membered heteroaryl. In embodiments, R2is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl-5 to 9 membered heteroaryl. In embodiments, R2is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl(Ci-C6)alkyl-5 to 9 membered heteroaryl. In embodiments, R2is a substituted or unsubstituted 3 to 7 membered heterocycloalkenyl-5 to 9 membered heteroaryl. In embodiments, R2is a substituted or unsubstituted (C4-C9) heterobicycloalkyl-5 to 9 membered heteroaryl. In embodiments, R2is a substituted or unsubstituted (C4-C9)spiroheterocycloalkyl-5 to 9 membered heteroaryl.

[0407] In embodiments, R2is hydrogen, halogen, cyano, trifluoromethyl, trifluoromethoxy, -OH, -SH, -SCH3, -SO2H, -SO2CH3, -NH2, -NHC(0)H, -NHC(0)0H, NHC(0)NH2, -NHSO2H, -C(O)H, -C(O)CH3, -COOH, -COOCH3, -CONH2, -SO2NH2, or -S(O)NHCH3. In embodiments, R2is hydrogen. In embodiments, R2is -F. In embodiments, R2is -Cl. In embodiments, R2is -Br. In embodiments, R2is -I. In embodiments, R2is cyano. In embodiments, R2is trifluoromethyl. In embodiments, R2is trifluoromethoxy. In embodiments, R2is -OH. In embodiments, R2is -SH. In embodiments, R2is -SCH3. In embodiments, R2is -SO2H. In embodiments, R2is -SO2CH3. In embodiments, R2is -NH2. In embodiments, R2is -NHC(O)H. In embodiments, R2is -NHC(O)OH. In embodiments, R2is NHC(O)NH2. In embodiments, R2is -NHSO2H. In embodiments, R2is -C(O)H. In embodiments, R2is -C(O)CH3. In embodiments, R2is -COOH. In embodiments, R2is -COOCH3. In embodiments, R2is -CONH2. In embodiments, R2is -SO2NH2. In embodiments, R2is -S(O)NHCH .

[0408] In embodiments,In embodiments, R2is. In embodiments, R2is. In embodiments,PATENTAttorney Docket No. : 050935-527001 WO

[0409] In embodiments, R3is hydrogen, -OR3A, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted Ca-Cs cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted Ce-Cio aryl, or substituted or unsubstituted 5 to 9 membered heteroaryl.

[0410] In embodiments, R3is hydrogen or -OR5A. In embodiments, R3is hydrogen. In embodiments, R3is -OR5A. In embodiments, R? xis hydrogen or substituted or unsubstituted alkyl. In embodiments, R5Ais hydrogen. In embodiments, R5Ais substituted or unsubstituted Ci-C4alkyl.

[0411] In embodiments, R3is substituted or unsubstituted Ci-Ce alkyl. In embodiments, R3is substituted or unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R3is substituted or unsubstituted C3-C8 cycloalkyl. In embodiments, R3is substituted or unsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, R3is substituted or unsubstituted phenyl. In embodiments, R3is substituted or unsubstituted 5 to 9 membered heteroaryl.

[0412] In embodiments, R3is methyl.

[0413] In embodiments, R3and R4are not both hydrogen.

[0414] In embodiments, R3and R4can join together to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl. In embodiments, R3and R4can join together to form a substituted or unsubstituted 3 to 7 membered heterocycloalkyl. In embodiments, R3and R4can join together to form a substituted or unsubstituted 5 to 9 membered heteroaryl.

[0415] In embodiments, R4is hydrogen, -OR5B, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted Ce-Cio aryl, or substituted or unsubstituted 5 to 9 membered heteroaryl.

[0416] In embodiments, R4is hydrogen or -OR?I!In embodiments, R4is hydrogen. In embodiments, R4is -OR?B. In embodiments, R5Bis hydrogen or substituted or unsubstituted C1-C4 alkyl. In embodiments, R5Bis hydrogen. In embodiments, R5Bis substituted or unsubstituted C1-C4 alkyl.

[0417] In embodiments, R4is substituted or unsubstituted Ci-Ce alkyl. In embodiments, R4is substituted or unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R4is substituted orPATENTAttorney Docket No. : 050935-527001 WO unsubstituted Cs-Cs cycloalkyl. In embodiments, R4is substituted or unsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, R4is substituted or unsubstituted Ce-Cio aryl. In embodiments, R4is substituted or unsubstituted 5 to 9 membered heteroaryl.

[0418] In embodiments, R4is methyl.

[0419] In embodiments, R6is hydrogen.

[0420] In embodiments, R6is substituted or unsubstituted Ci-Ce alkyl. In embodiments, R6is substituted or unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R6is substituted or unsubstituted Cs-Cs cycloalkyl. In embodiments, R6is substituted or unsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, R6is substituted or unsubstituted Ce-Cio aryl. In embodiments, R6is substituted or unsubstituted 5 to 9 membered heteroaryl.

[0421] In embodiments, R6and R7can join together to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl. In embodiments, R6and R7can join together to form a substituted or unsubstituted 3 to 7 membered heterocycloalkyl. In embodiments, R6and R7can join together to form a substituted or unsubstituted 5 to 9 membered heteroaryl.

[0422] In embodiments, R7is hydrogen.

[0423] In embodiments, R7is substituted or unsubstituted Ci-Ce alkyl. In embodiments, R7is substituted or unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R7is substituted or unsubstituted C3-C8 cycloalkyl. In embodiments, R7is substituted or unsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, R7is substituted or unsubstituted Ce-Cio. In embodiments, R7is substituted or unsubstituted 5 to 9 membered heteroaryl.

[0424] In embodiments, R8is hydrogen or halogen. In embodiments, R8is hydrogen. In embodiments, R8is -F. In embodiments, R8is -Cl. In embodiments, R8is -Br. In embodiments, R8is -I.

[0425] In embodiments, R9is hydrogen or halogen-substituted or unsubstituted C1-C3 alkyl. In embodiments, R9is hydrogen. In embodiments, R9is halogen-substituted or unsubstituted Ci- C3 alkyl. In embodiments, R9is unsubstituted methyl. In embodiments, R9is -CHF2. In embodiments, R9is -CF3.

[0426] In embodiments, R11is hydrogen or halogen-substituted methyl. In embodiments, R11is hydrogen. In embodiments, R11is -CF3, -CHF2, -CH2F, -CCI3, -CHQ2, -CH2CI, -CBn,PATENTAttorney Docket No. : 050935-527001 WO-CHBr2, -CFBBr, -CI3, -CHI2, or -CH2I. In embodiments, R11is -CF3. In embodiments, R11is -CHF2. In embodiments, R11is - CH2F. In embodiments, R11is -CCI3. In embodiments, R11is -CHCh. In embodiments, R11is -CH2CI. In embodiments, R11is -CBrs. In embodiments, R11is -CHBr2 In embodiments, R11is -CFhBr In embodiments, R11is -CI3. In embodiments, R11is -CHI2. In embodiments, R11is -CH2I.

[0427] In embodiments, R12is hydrogen or halogen-substituted methyl. In embodiments, R12is hydrogen. In embodiments, R12is -CF3, -CHF2, -CH2F, -CCI3, -CHCh, -CH2CI, -CBn, -CHBr2, -Cl kBr. -CI3, -CHI2, or -CH2I. In embodiments, R12is -CF3. In embodiments, R12is -CHF2. In embodiments, R12is - CH2F. In embodiments, R12is -CCI3. In embodiments, R13is -CHCI2. In embodiments, R12is -CH2CI. In embodiments, R12is -CBr3. In embodiments, R12is -CHBr2 In embodiments, R12is -CFhBr. In embodiments, R12is -CI3. In embodiments, R12is -CHI2 In embodiments, R12is -CH2I.

[0428] In embodiments, R13is hydrogen, halogen, hydroxy, cyano, trifluoromethyl, difluoromethoxy, trifluoromethoxy, -OR15, substituted or unsubstituted C1-6 alkylsulphonyl, substituted or un substituted C1-6 alkyl. In embodiments, R13is hydrogen. In embodiments, R13is -F. In embodiments, R13is -Cl. In embodiments, R13is -Br. In embodiments, R13is -I. In embodiments, R13is hydroxy. In embodiments, R13is cyano. In embodiments, R13is trifluoromethyl. In embodiments, R13is difluoromethoxy. In embodiments, R13is trifluoromethoxy.

[0429] In embodiments, R13is substituted or unsubstituted C1-6 alkylsulphonyl. In embodiments, R13is methyl sulphonyl. In embodiments, R13is substituted or unsubstituted ethyl sulphonyl. In embodiments, R13is substituted or unsubstituted propylsulphonyl. In embodiments, R13is substituted or unsubstituted butyl sulphonyl. In embodiments, R13is substituted or unsubstituted pentyl sulphonyl. In embodiments, R13is substituted or unsubstituted hexyl sulphonyl.

[0430] In embodiments, R13is substituted or unsubstituted C1-6 alkyl. In embodiments, R13is substituted or unsubstituted methyl. In embodiments, R13is substituted or unsubstituted ethyl. In embodiments, R13is substituted or unsubstituted propyl. In embodiments, R13is substituted or unsubstituted butyl. In embodiments, R13is substituted or unsubstituted pentyl. In embodiments, R13is substituted or unsubstituted hexyl.PATENTAttorney Docket No. : 050935-527001 WO

[0431] In embodiments, R13is -OR13. In embodiments, R13is substituted or unsubstituted Ci- Ce alkyl. In embodiments, R15is substituted or unsubstituted C3-C7 cycloalkyl. In embodiments, R15is substituted or unsubstituted 3 to 7 membered heterocycloalkyl. In embodiments, R15is substituted or unsubstituted Ce-Cio aryl. In embodiments, R15is substituted or unsubstituted 5 to 9 membered heteroaryl. In embodiments, R15is aryl(Ci-6)alkyl. In embodiments, R15is heteroary 1(C 1 -e) al ky 1.

[0432] In embodiments, R14is substituted or unsubstituted Ci-Cs alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, =0 or =NR16.

[0433] In embodiments, R14is substituted or unsubstituted Ci-Ce alkyl. In embodiments, R14is substituted or unsubstituted methyl. In embodiments, R14is substituted or unsubstituted ethyl. In embodiments, R14is substituted or unsubstituted propyl. In embodiments, R14is substituted or unsubstituted butyl. In embodiments, R14is substituted or unsubstituted pentyl. In embodiments, R14is substituted or unsubstituted hexyl. In embodiments, R14is substituted or unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R14is substituted or unsubstituted C3 C6 cycloalkyl. In embodiments, R14is substituted or unsubstituted 3 to 6 membered heterocycloalkyl. In embodiments, R14is =0. In embodiments, R14is =NR16.

[0434] In embodiments, R16is a substituted or unsubstituted Ci-Cs alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted 3 to 6 cycloalkyl, or substituted or unsubstituted 3 to 6 membered heterocycloalkyl.

[0435] In embodiments, R16is substituted or unsubstituted Ci-Ce alkyl. In embodiments, R16is substituted or unsubstituted methyl. In embodiments, R16is substituted or unsubstituted ethyl. In embodiments, R16is substituted or unsubstituted propyl. In embodiments, R16is substituted or unsubstituted butyl. In embodiments, R16is substituted or unsubstituted pentyl. In embodiments, R16is substituted or unsubstituted hexyl. In embodiments, R16is substituted or unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R16is substituted or un substituted C3-C6 cycloalkyl. In embodiments, R16is substituted or unsubstituted 3 to 6 membered heterocycloalkyl.

[0436] In embodiments, n is an integer from 0 to 3. In embodiments, n is 0. In embodiments, n is 1. In embodiments, n is 2. In embodiments, n is 3.PATENTAttorney Docket No. : 050935-527001 WO

[0437] In embodiments, m is an integer from 0 to 4. In embodiments, m is 0. In embodiments, m is 1. In embodiments, m is 2. In embodiments, m is 3. In embodiments, m is 4.

[0438] In embodiments, the compound is:PATENTAttorney Docket No.: 050935-527001 WOPATENTAttorney Docket No. : 050935-527001 WO, pharmaceutically acceptable salt thereof.

[0440] pharmaceutically acceptable salt thereof.

[0441] In embodiments, the compound ipharmaceutically acceptable salt thereof.

[0442] In embodiments, the compoundpharmaceutically acceptable salt thereof.PATENTAttorney Docket No. : 050935-527001 WO

[0443] In embodiments, the compoundpharmaceutically acceptable salt thereof.

[0444] In embodiments, the compoundpharmaceutically acceptable salt thereof.

[0445] In embodiments, the compoundpharmaceutically acceptable salt thereof.

[0446] In embodiments, the compoundpharmaceutically acceptable salt thereof.

[0447] In embodiments, the compoundpharmaceutically acceptable salt thereof.PATENTAttorney Docket No. : 050935-527001 WO

[0448] In embodiments, the compoundpharmaceutically acceptable salt thereof.

[0449] In embodiments, the compoundpharmaceutically acceptable salt thereof.

[0450] In embodiments, the compoundpharmaceutically acceptable salt thereof.

[0451] In embodiments, the compoundpharmaceutically acceptable salt thereof.

[0452] In embodiments, the compoundpharmaceutically acceptable salt thereof.PATENTAttorney Docket No. : 050935-527001 WO

[0453] In embodiments, the compoundpharmaceutically acceptable salt thereof.

[0454] In embodiments, the compoundpharmaceutically acceptable salt thereof.

[0455] In embodiments, the compoundpharmaceutically acceptable salt thereof.

[0456] In embodiments, the compoundpharmaceutically acceptable salt thereof.

[0457] In embodiments, the compoundpharmaceutically acceptable salt thereof.PATENTAttorney Docket No. : 050935-527001 WO

[0458] In embodiments, the compoundpharmaceutically acceptable salt thereof.

[0459] In embodiments, the compoundpharmaceutically acceptable salt thereof.

[0460] In embodiments, the compoundpharmaceutically acceptable salt thereof.

[0461] pharmaceutically acceptable salt thereof.

[0462] In embodiments, the compound isPATENTAttorney Docket No.: 050935-527001 WOPATENTAttorney Docket No.: 050935-527001 WOPATENTAttorney Docket No. : 050935-527001 WOpharmaceutically acceptable salt thereof.

[0465] In embodiments, the compound ipharmaceutically acceptable salt thereof.

[0466] In embodiments, the compound ipharmaceutically acceptable salt thereof.

[0467] In embodiments, the compound ipharmaceutically acceptable salt thereof.PATENTAttorney Docket No. : 050935-527001 WO

[0468] In embodiments, the compound ipharmaceutically acceptable salt thereof.

[0469] In embodiments, the compound ipharmaceutically acceptable salt thereof.

[0470] In embodiments, the compound ipharmaceutically acceptable salt thereof.

[0471] In embodiments, the compound ipharmaceutically acceptable salt thereof.

[0472] In embodiments, the compound ipharmaceutically acceptable salt thereof.PATENTAttorney Docket No. : 050935-527001 WO

[0473] In embodiments, the compound ipharmaceutically acceptable salt thereof.

[0474] In embodiments, the compoundpharmaceutically acceptable salt thereof.

[0475] In embodiments, the compoundpharmaceutically acceptable salt thereof.

[0476] In embodiments, the compoundpharmaceutically acceptable salt thereof.

[0477] In embodiments, the compound ipharmaceutically acceptable salt thereof.PATENTAttorney Docket No. : 050935-527001 WO

[0478] In embodiments, the compound ipharmaceutically acceptable salt thereof.

[0479] In embodiments, the compoundpharmaceutically acceptable salt thereof.pharmaceutically acceptable salt thereof.PATENTAttorney Docket No. : 050935-527001 WOpharmaceutically acceptable salt thereof.

[0485] pharmaceutically acceptable salt thereof.

[0486] In embodiments, the compound is:Attorney Docket No PATENT 050935-527001 WOPATENTAttorney Docket No. : 050935-527001 WOpharmaceutically acceptable salt thereof.

[0487] In embodiments, the compound ior a pharmaceutically acceptable salt thereof.

[0488] In embodiments, the compound ior a pharmaceutically acceptable salt thereof.

[0489] In embodiments, the compound ior a pharmaceutically acceptable salt thereof.

[0490] In embodiments, the compound ipharmaceutically acceptable salt thereof.PATENTAttorney Docket No. : 050935-527001 WO

[0491] In embodiments, the compound ipharmaceutically acceptable salt thereof.

[0492] In embodiments, the compound ipharmaceutically acceptable salt thereof.

[0493] In embodiments, the compoundpharmaceutically acceptable salt thereof.

[0494] In embodiments, the compoundpharmaceutically acceptable salt thereof.

[0495] In embodiments, the compoundpharmaceutically acceptable salt thereof.PATENTAttorney Docket No. : 050935-527001 WO

[0496] In embodiments, the compound ipharmaceutically acceptable salt thereof.

[0497] In embodiments, the compound ipharmaceutically acceptable salt thereof.

[0498] In embodiments, the compound ipharmaceutically acceptable salt thereof.

[0499] In embodiments, the compound ipharmaceutically acceptable salt thereof.

[0500] In embodiments, the compound ipharmaceutically acceptable salt thereof.PATENTAttorney Docket No. : 050935-527001 WO

[0501] In embodiments, the compound ipharmaceutically acceptable salt thereof.

[0502] In embodiments, the compound ipharmaceutically acceptable salt thereof.

[0503] In embodiments, the compound ipharmaceutically acceptable salt thereof.

[0504] In embodiments, the compound isPATENTAttorney Docket No.: 050935-527001 WOPATENTAttorney Docket No. : 050935-527001 WO

[0505] In embodiments, the compound ipharmaceutically acceptable salt thereof.

[0506] In embodiments, the compound ipharmaceutically acceptable salt thereof.

[0507] In embodiments, the compound ipharmaceutically acceptable salt thereof.

[0508] In embodiments, the compound ipharmaceutically acceptable salt thereof.

[0509] In embodiments, the compoundpharmaceutically acceptable salt thereof.PATENTAttorney Docket No. : 050935-527001 WO

[0510] In embodiments, the compound ipharmaceutically acceptable salt thereof.

[0511] In embodiments, the compound ipharmaceutically acceptable salt thereof.

[0512] In embodiments, the compound ipharmaceutically acceptable salt thereof.

[0513] In embodiments, the compoundpharmaceutically acceptable salt thereof.

[0514] In embodiments, the compoundpharmaceutically acceptable salt thereof.PATENTAttorney Docket No. : 050935-527001 WO

[0515] In embodiments, the compound ipharmaceutically acceptable salt thereof.

[0516] In embodiments, the compound ipharmaceutically acceptable salt thereof.

[0517] In embodiments, the compoundpharmaceutically acceptable salt thereof.

[0518] In embodiments, the compound ipharmaceutically acceptable salt thereof.

[0519] In embodiments, the compoundpharmaceutically acceptable salt thereof.PATENTAttorney Docket No. : 050935-527001 WO

[0520] In embodiments, the compound ipharmaceutically acceptable salt thereof.

[0521] In embodiments, the compound ior a pharmaceutically acceptable salt thereof.

[0522] In embodiments, the compound ispharmaceutically acceptable salt thereof.

[0523] In embodiments, the compound is a compound of Example 25 through Example 297.In embodiments, the compound is a compound of Example 299.

[0524] In embodiments, the compound is useful as a comparator compound. In embodiments, the comparator compound can be used to assess the activity of a test compound as set forth in an assay described herein (e.g., in the examples section, figures, or tables).

[0525] In embodiments, the compound is a compound as described herein, including in embodiments. In embodiments the compound is a compound described herein, including the embodiments.Pharmaceutical compositions

[0526] In an aspect is provided a pharmaceutical composition including a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.PATENTAttorney Docket No. : 050935-527001 WO

[0527] In embodiments, the pharmaceutical composition includes an effective amount of the compound. In embodiments, the pharmaceutical composition includes a therapeutically effective amount of the compound.

[0528] In embodiments, the compound is a compound of formulae (I), (la), (lb), (Ic), (Id), (I- la), (Lib), (Lie), (Lid) or a pharmaceutically acceptable salt thereof, including all embodiments thereof.

[0529] The compounds (the compounds of formulae (I), (la), (lb), (Ic), (Id), (Lla), (Lib), (I- Ic), (Lid)) of the present disclosure may be in the form of compositions suitable for administration to a subject. In embodiments, the pharmaceutical compositions comprise a compound (e.g., the compound of formulae (I), (la), (lb), (Ic), (Id), (Lla), (Lib), (Lie), (Lid)) and one or more pharmaceutically acceptable or physiologically acceptable diluents, carriers or excipients. In certain embodiments, the compound (e.g., the compound of formulae (I), (la), (lb), (Ic), (Id), (Lla), (Lib), (Lie), (Lid)) is present in a therapeutically effective amount. The pharmaceutical compositions can be administered ex vivo or in vivo to a subject in order to practice the therapeutic and prophylactic methods and uses described herein.

[0530] The pharmaceutical compositions of the present disclosure can be formulated to be compatible with the intended method or route of administration; exemplary routes of administration are set forth herein.

[0531] The pharmaceutical compositions containing the active ingredient (e.g., the compound of formulae (1), (la), (lb), (Ic), (Id), (Lla), (Lib), (Lie), (Lid)) may be in a form suitable for oral use, for example, as tablets, capsules, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups, solutions, microbeads or elixirs. Pharmaceutical compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents such as, for example, sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets, capsules and the like contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture thereof. These excipients may be, for example, diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate;PATENTAttorney Docket No. : 050935-52...

Claims

1. PATENTAttorney Docket No. : 050935-527001 WOWHAT IS CLAIMED IS:

1. A compound of formula (la), (lb), (Ic) or (Id), or a pharmaceutically acceptable salt thereof:wherein: the two atoms shared by Ring D and Ring E(Ia) are carbon atoms; the two atoms shared by Ring D and Ring E(Ib) are carbon atoms; the two atoms shared by Ring D and Ring E(Ic) are carbon atoms; the two atoms shared by Ring D and Ring E(Id) are carbon atoms; k is a double bond or single bond;Ring E(Ia) is a 6-membered heteroaryl, pyrrolidonyl, imidazolidinonyl, oxazolidinonyl, pyrrolyl, isoxazolidinyl, pyrazolyl, oxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, isoxazolyl, or dioxolanyl;Ring E(Ib), E(Ic) and E(Id) are independently heteroaryl or heterocycloalkyl;Ring F is a phenyl or a 5- or 6-membered heteroaryl;PATENTAttorney Docket No. : 050935-527001 WO n is an integer from 0 to 3; n’ is an integer from 0 to 13; m is an integer from 0 to 4; p is an integer from 0 to 4; q is an integer from 0 to 3;X is O or S;R2is hydrogen, halogen, -CX23, -CHX22, -CH2X2, -OCX23, -OCHX22, -OCH2X2, -CN, -N3, -SR2A,-SOn2R2A, -SOv2NR2BR2C, -S(O)(R2B)NR2C, -NHNR2BR2C, -ONR2BR2C, -NHC(O)NHNR2BR2C, -NHC(O)NR2BR2C, -N(O)m2, -NR2BR2C, -C(O)R2D, -C(O)OR2D,-C(O)NR2BR2C, -OR2A,-NR2BSO2R2A, -NR2BC(O)R2D, -NR2BC(O)OR2D, -NR2BOR2D, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl,Li is a bond or substituted or unsubstituted alkylene.R2A, R2B, R2Cand R2Dare independently hydrogen, 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;R3is hydrogen, -OR5A, 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, or R3and R4can join together to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl, wherein R3and R4are not both hydrogen;R4is hydrogen, -OR?B, 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, orPATENTAttorney Docket No. : 050935-527001 WOR3and R4can join together to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl, wherein R3and R4are not both hydrogen;R5Aand R5Bare independently hydrogen or substituted or unsubstituted alkyl;R6and R7are independently hydrogen, 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, or R6and R7can join together to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl;R8is hydrogen, halogen, -CX83, -CHX82, -CH2X8, -OCX83, -OCHX82,-OCH2X8, -CN, -N3, -SH, -NH2, -C(O)OH, -C(O)NH2, -OH, 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;R9is independently halogen, -CX93, -CHX92, -CH2X9, -OCX93, -OCHX92, -OCH2X9, -CN, -N3, -SH, -NH2, -C(O)OH, -C(O)NH2, -OH, 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;R10is independently halogen, -CX103, -CHX102, -CH2X10, -OCX103, -OCHX102,-OCH2X10, -CN, -N3, -SH, -NH2, -C(O)OH, -C(O)NH2, -OH, 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;R11is hydrogen, halogen, -CXn3, -CHXn2, -CH2X11, -OCXn3, -OCHXn2, -OCH2X11, -CN, -N3, -SH, -NH2,-C(O)OH, -C(O)NH2, -OH, 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;R12is hydrogen, halogen, -CX123, -CHX122, -CH2X12, -OCX123, -OCHX122, -OCH2X12,PATENTAttorney Docket No. : 050935-527001 WO-CN, — N3, -SH, -NH2, -C(O)OH, -C(O)NH2, -OH, 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;R13is hydrogen, halogen, -CX133, -CHX132, -CH2X13, -OCX133, -OCHX132, - OCH2X13, -CN, -N3, -SR15A,-SOni3R15A, -SOVI3NR15DR15C, -NHNR15DR15C, -ONR15BR15C, NHC(O)NHNR15BR15C, NHC(O)NR15BR15C, -N(0)mi3, -NR15BR15C, -C(O)R15D, -C(O)OR15D, -C(O)NR15BR15C, -OR15A, -NR15BSO2R15A, -NR15BC(O)R15D, -NR15BC(O)OR15D,-NR15BOR15D, 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;R14is independently halogen, -CX143, -CHX142, -CH2X14, -OCX143, -OCHX142,-OCH2X14, -CN, -N3, -SR14A,-SOni4R14A-SOvi4NR14BR14C, -NHNR14BR14C, -ONR14BR14C, -NHC(O)NHNR14BR14C, -NHC(O)NR14BR14C, -N(O)mi4, -NR14BR14C, - C(O)R14D, -C(O)OR14D, -C(O)NR14BR14C, -OR14A, -NR14BSO2R14A, -NR14BC(O)R14D, - NR14BC(O)OR14D,-NR14BOR14D, =0, -NR16, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;R14A, R14B, R14C, and R14Dare independently hydrogen, halogen, -CX143, -CHX142, -CH2X14, -OCX143, -OCHX142, -OCH2X14, -CN, -N3, -SH, -NH2, -C(0)0H, - C(0)NH2, -OH, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R15A, R15B, R15C, and R13Dare independently hydrogen, halogen, -CX153, -CHX152, -CH2X15, -OCX153, -OCHX152, -OCH2X15, -CN, -N3, -SH, -NH2, -C(0)0H, - C(0)NH2, -OH, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;PATENTAttorney Docket No. : 050935-527001 WOR16is hydrogen, 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;R17is independently halogen, -CX173, -CHX172, -CH2X17, -OCX173, -OCHX172, -OCH2X17, -CN, -N3, -SH, -NH2, -C(O)OH, -C(O)NH2, -OH, 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; n2, nl3 and n!4 are independently an integer from 0 to 3; m2, ml3 and m 14 are independently an integer from 0 to 4; v2, vl3 and vl4 are independently an integer from 0 to 4; and each X2, X8, X9, X10, X11, X12, X13, X14, X15and X17is independently halogen.

2. The compound of claim 1, wherein ring E(Ib) and E(Id) are independently pyrrolidinonyl, oxazolidinonyl, imidazolidinonyl, dihydrofuranonyl, or imidazolidinethionyl.

3. The compound of claim 1, wherein ring E(Ib) and E(Id) are independently pyrrolidine-2-onyl, oxazolidine-2-onyl, imidazolidine-2-onyl, dihydrofuran-2-onyl, or imidazolidine-2-thionyl.

4. The compound of claim 1, wherein ring E(Tc) is 2-pyrrolidonyl, pyrrolyl, isoxazolidinyl, pyrazolyl, oxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl or isoxazolyl.

5. The compound of claim 1, wherein k is a single bond.

6. The compound of claim 1, wherein k is a double bond.

7. The compound of claim 1, wherein the compound has formula (I-Ia), (I-Ib),(I-Ic), or (I-Id):PATENTAttorney Docket No. : 050935-527001 WOor a pharmaceutically acceptable salt thereof, wherein: k is a double bond or single bond;R2is hydrogen, halogen, -CX23, -CHX22, -CH2X2, -OCX23, -OCHX22, -OCH2X2, -CN, -N3, -SR2A,-SO112R2A, -SOV2NR2BR2C, -S(O)(R2B)NR2C, -NHNR2BR2C, -ONR2BR2C, -NHC(O)NHNR2BR2C,-NHC(O)NR2BR2C, -N(O)m2, -NR2BR2C, -C(O)R2D, -C(O)OR2D, -C(O)NR2BR2C, -OR2A, -NR2BSO2R2A, -NR2BC(O)R2D, -NR2BC(O)OR2D, -NR2BOR2D, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl,R2Ais a substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted orPATENTAttorney Docket No. : 050935-527001 WO unsubstituted arylalkyl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heteroarylalkyl;R2Band R2Care each independently substituted or unsubstituted alkyl, substituted or un substituted cycloalkyl, substituted or un substituted cycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heteroaryl alkyl, or R2Band R2C, when taken together with the nitrogen atom to which they are attached, is a heterocyclic moiety;R2Dis substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;R8is hydrogen or halogen;R9is independently halogen or halogen-substituted or unsubstituted alkyl;R11is hydrogen or halogen- substituted alkyl;R12is hydrogen or halogen-substituted alkyl;R13is hydrogen, halogen, hydroxy, cyano, trifluoromethyl, difluoromethoxy, trifluoromethoxy, -OR15A, substituted or unsubstituted alkylsulphonyl or substituted or unsubstituted alkyl;R14is independently a substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, =0 or =NR16;R15Ais a substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heteroaryl alkyl; andR16is a substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl.

8. The compound of any one of claim 1, wherein:PATENTAttorney Docket No. : 050935-527001 WOR2is substituted or unsubstituted Ci-Cs alkyl, substituted or unsubstituted C3- C7 cycloalkyl, substituted or unsubstituted C4-C7 cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted aryl(Ci-C6)alkyl, substituted or unsubstituted 3 to 7 membered heterocycloalkyl, substituted or un substituted 3 to 7 membered heterocycloalkenyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaryl(Ci-C6)alkyl, substituted or unsubstituted 3 to 7 membered heterocycloalkyl(Ci-C6)alkyl-aryl, substituted or unsubstituted (C3-C7)cycloalkyl-heteroaryl, substituted or unsubstituted 3 to 7 membered heterocycloalkenylaryl, substituted or unsubstituted (C3-C7)cycloalkyl(Ci-6)alkyl-heteroaryl, substituted or unsubstituted (C4-C7) cycloalkenyl-heteroaryl, substituted or unsubstituted (C4-C9)bicycloalkyl- heteroaryl-, substituted or unsubstituted 3 to 7 membered heterocycloalkyl-heteroaryl, substituted or unsubstituted 3 to 7 membered heterocycloalkyl(Ci-C6)alkyl-heteroaryl, substituted or unsubstituted 3 to 7 membered heterocycloalkenyl-heteroaryl, substituted or unsubstituted 3 to 7 membered heterobicycloalkyl-heteroaryl, substituted or unsubstituted 3 to 7 memb ered spi roheterocy cl oal ky 1 -heteroaryl ,R2Ais a substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted aryl(Ci-C6)alkyl, substituted or unsubstituted 3 to 7 membered heterocycloalkyl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heteroaryl(Ci.C6)alkyl;R2Band R2Care each independently hydrogen, trifluoromethyl, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted C3 C7 cycloalkyl(Ci-C6)alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aryl(Ci-C6)alkyl, substituted or unsubstituted 3 to 7 membered heterocycloalkyl, substituted or unsubstituted 3 to 7 membered heterocycloalkyl(Ci-Ce)alkyl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heteroaryl(Ci-C6)alkyl, or R2Band R2C, when taken together with the nitrogen atom to which they are attached, is a heterocyclic moiety selected from substituted or unsubstituted azetidin-l-yl, substituted or unsubstituted pyrrolidin-1-PATENTAttorney Docket No. : 050935-527001 WO yl, substituted or unsubstituted oxazolidin-3-yl, substituted or unsubstituted isoxazolidin-2-yl, substituted or unsubstituted thiazolidin-3-yl, substituted or unsubstituted isothiazolidin-2-yl, substituted or unsubstituted piperidin-l-yl, substituted or unsubstituted morpholin-4-yl, substituted or un substituted thiomorpholin-4-yl, substituted or un substituted piperazin-l-yl, substituted or unsubstituted homopiperidin-l-yl, substituted or unsubstituted homomorpholin- 4- yl, substituted or unsubstituted homopiperazin-l-yl, substituted or unsubstituted (imino)(oxo)thiazinan-4-yl, substituted or unsubstituted (oxo)thiazinan-4-yl or substituted or unsubstituted (dioxo)-thiazinan-4-yl;R2Dis substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted 3 to 7 membered heterocycloalkyl or substituted or unsubstituted 5 to 7 membered heteroaryl;R9is independently halogen or halogen-substituted or unsubstituted C1-C3 alkyl;R10is independently halogen, -CF3, -CN, SH, -NH2, -C(O)OH, -C(O)NH2, -OH, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, or substituted or unsubstituted C3-C7 cycloalkyl;R11is hydrogen or halogen-substituted methyl;R12is hydrogen or halogen-substituted methyl;R13is hydrogen, halogen, hydroxy, cyano, trifluoromethyl, difluoromethoxy, trifluoromethoxy, -OR15A, substituted or unsubstituted Ci-Ce alkyl sulphonyl or substituted or unsubstituted Ci-Ce alkyl;R14is independently a substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted Ci-Ce cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, =0 or =NR16;R15Ais a substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted 3 to 7 membered heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted aryl(Ci-Ce)alkyl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heteroaryl(Ci-C6)alkyl;R16is a substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstitutedPATENTAttorney Docket No. : 050935-527001 WO3 to 6 membered heterocycloalkyl; substituted or unsubstituted C5-C10 aryl or substituted or unsubstituted 5 to 9 membered heteroaryl; andR17is independently halogen, -CF3, -CN, -SH, -NH2, -C(O)OH, -C(O)NH2, -OH, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, or substituted or unsubstituted C3-C7 cycloalkyl.

9. The compound of claim 1, wherein Ring E(Ia), Ring E(Ib), Ring E(Ic), or Ring E(Id) is a 6-membered heteroaryl.

10. The compound of claim 1, wherein Ring E(Ia), Ring E(Ib), Ring E(Ic), or Ring E(Id) is selected from pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, and triazenyl.

11. The compound of claim 1, wherein Ring E(Ib) or E(Id) is a substituted heterocycloalkyl, wherein the substituted heterocycloalkyl is substituted with an oxo group.

12. The compound of claim 1, wherein R2is13. The compound of claim 1, wherein R2is14. The compound of claim 1, wherein R2is15. The compound of claim 1, wherein R2isPATENTAttorney Docket No. : 050935-527001 WO16. The compound of claim 1, wherein Ring F is a 5- or 6-membered heteroaryl having 1 to 2 nitrogen atoms.

17. The compound of claim 1, wherein Ring F is pyridyl, pyrimidinyl or pyrazolyl.

18. The compound of claim 1, wherein R8is hydrogen.

19. The compound of claim 1, wherein m is an integer from 0 to 2.

20. The compound of claim 1, wherein R9is independently halogen or methyl.

21. The compound of claim 1, wherein R11is hydrogen.

22. The compound of claim 1, wherein R12is hydrogen.

23. The compound of claim 1, wherein n is 0 or 1.

24. The compound of claim 1, wherein R14is independently methyl or =0.

25. The compound of claim 1, wherein the compound is:PATENTAttorney Docket No.: 050935-527001 WOPATENTAttorney Docket No.: 050935-527001 WOPATENTAttorney Docket No.: 050935-527001 WOPATENTAttorney Docket No. : 050935-527001 WOr a pharmaceutically acceptable salt thereof.

26. The compound of claim 1, wherein the compound is:PATENTAttorney Docket No.: 050935-527001 WOPATENTAttorney Docket No.: 050935-527001 WOPATENTAttorney Docket No.: 050935-527001 WOPATENTAttorney Docket No. : 050935-527001 WOpharmaceutically acceptable salt thereof.

27. The compound of claim 1, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of a disease or disorder associated with modulation of the TNFa function.

28. The compound of claim 1, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of an inflammatory disease, an autoimmune disease, a neurological disease, a neurodegenerative disease, a nociceptive disease, a cardiovascular disease, a metabolic disease, an ocular disease, an oncological disease, or pain.

29. A pharmaceutical composition comprising the compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

30. The pharmaceutical composition of claim 29, further comprising an additional pharmaceutically active ingredient.

31. Use of the compound of claim 1, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of a disease or disorder associated with modulation of TNFa function.

32. Use of the compound of claim 1, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of an inflammatory disease, an autoimmune disease, a neurological disease, a neurodegenerative disease, a nociceptive disease, a cardiovascular disease, a metabolic disease, an ocular disease, an oncological disease, or pain.

33. A method for the treatment or prevention of a disease or disorder associated with modulation of TNFa function, said method comprising administering to a patient in need of suchPATENTAttorney Docket No. : 050935-527001 WO treatment a therapeutically effective amount of the compound of claim 1, or a pharmaceutically acceptable salt thereof.

34. A method for the treatment or prevention of an inflammatory disease, an autoimmune disease, a neurological disease, a neurodegenerative disease, a nociceptive disease, a cardiovascular disease, a metabolic disease, an ocular disease, an oncological disease, or pain, the method comprising administering to a patient in need of such treatment a therapeutically effective amount of the compound of claim 1, or a pharmaceutically acceptable salt thereof.

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