Compositions and methods for treating cancer and reducing WNT mediated effects

Abstract

Disclosed herein, inter alia, are compounds, pharmaceutical compositions, and methods of reducing Wnt-mediated effects and treating cancer.

Description

COMPOSITIONS AND METHODS FOR TREATING CANCER AND REDUCING WNT MEDIATED EFFECTSCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 549,370 filed February' 2, 2024, which is incorporated herein by reference in its entirety and for all purposes.BACKGROUND

[0002] The Wnt pathway is an evolutionarily conserved growth pathway in multicellular organisms that regulates animal development and plays critical roles in human disease. Signaling through the Wnt pathway is regulated by secreted Wnt proteins, which act as morphogens to mediate 1) cell fate determination and differentiation required for establishing the body plan, neural patterning, and organogenesis, 2) cell motility' and polarity, 3) cell proliferation and apoptosis, and 4) stem cell maintenance.

[0003] In Wnt signaling, the transcriptional coactivator, beta-catenin. is constitutively degraded in the absence of a Wnt signal thereby allowing a cell to maintain low cytoplasmic levels of beta-catenin and keeping the Wnt pathway' in the “off’ position. Degradation of beta-catenin requires its recruitment into a complex consisting primarily of Glycogen synthase kinase (Gsk3), Casein Kinase 1 (CK1), Protein phosphatase 2A (PP2A), Axin, and the tumor suppressor adenomatous polyposis coli (APC). Within this complex, beta-catenin is phosphorylated by CK1, which primes it for further phosphorylation by Gsk3.Phosphorylated beta-catenin is recognized by the SCF (Skipl, Cullen, F-box) ubiquitin ligase complex, of which the specificity' F-box determinant is beta-TRCP, and targeted for polyubiquitination and subsequent degradation by the proteasome. The Wnt pathway is turned “on” upon binding of Wnt ligands to the Frizzled family of receptors and the coreceptor family members LDL receptor-related protein 5 or 6 (LRP5 / 6), which results in translocation of the beta-catenin destruction complex to the membrane through interaction of Axin with LRP5 / 6. The interaction between Axin and LRP5 / 6 is promoted by the phosphorylation of LRP5 / 6 by CK1 and Gsk3, and Axin-LRP5 / 6 interaction results in inhibition of beta-catenin phosphory lation and degradation. Because beta-catenin is continually synthesized in cells, its cytoplasmic concentration increases, and it enters thenucleus and forms a complex with the TCF / LEF1 family of transcriptional factors (as well as the nuclear proteins BCL9 and Pygopus) to regulate a Wnt-specific transcriptional program.

[0004] Our bodies are composed of numerous cell types specialized to perform specific functions. These specialized or differentiated cells are derived from a small group of stem and progenitor cells that have the capacity to divide asymmetrically, allowing them to regenerate themselves, and also giving rise to a daughter cell that can differentiate into cell types characteristic of various organs in our bodies. It is recognized that diseases like diabetes, Parkinson’s disease, and heart disease are caused by death or dysfunction of differentiated cells in tissues where stem cells are limiting. These diseases may be caused by loss of stem cell activity and / or misregulation of critical signaling pathways in stem cells residing in tissues such as the pancreas, brain, and heart. The Wnt pathway is a key regulator of stem cell behavior and viability, and modulation of this pathway presents a method of treating diseases associated with dysfunctional stem cell activity. For example, activation of the Wnt pathway has been associated with heart failure, and inhibition of Wnt signaling has been shown to improve recovery after a heart attack in animal models. Thus. Wnt inhibitors could have broad applications in regenerative (stem cell) medicine for the treatment of major human diseases such as heart disease.

[0005] Cancer has been shown to be stem cell related disease, resulting from failure of cells to respond to normal cues to stop proliferating. Wnt signaling is also a critical pathway that drives the uncontrolled proliferation of many solid tumors in cancer stem cells (CSCs). Thus, therapies that down-regulate the activity of Wnt signaling, a fundamental pathway in CSCs, would be effective in the treatment of cancer. Such inhibitors would result in a long-term therapeutic benefit because the cells capable of repopulating the tumor would be killed. Most notably, there is clear evidence that colorectal cancer arises from mutations in the stem cell compartment, and it has been demonstrated that all major solid cancers in humans (e.g., melanoma, hepatocellular carcinoma, and breast cancer) have abnormal Wnt signaling. Thus, Wnt inhibitors may be useful in the treatment of most of the major solid cancers in humans.

[0006] Disclosed herein, inter alia, are solutions to these and other problems known in the art.BRIEF SUMMARY

[0007] In an aspect is provided a compound, or a pharmaceutically acceptable salt or tautomer thereof, having the formula:

[0008] Ring A is cycloalkyl, heterocycloalkyl, ary l, or heteroaryl.

[0009] L1is a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene.

[0010] R1is independently halogen, -CX'3. -CHX^, -CH2X1, -OCX1., -OCH2X1, -OCHX^, -CN, -SOniR1D, -SOviNR1AR1B, -NR1CNR1AR1B, -ONR1AR1B, -NR1CC(O)NR1AR1B. -N(0)mi. -NR1AR1B, -C(O)R1C, -C(O)OR1C. -C(O)NR1AR1B, -OR1D, -NR1ASO2R1D, -NR1AC(O)R1C, -NR1AC(O)OR1C, -NR1AOR1C, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted ary l, or substituted or unsubstituted heteroaryl; two R1substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0011] The symbol zl is an integer from 0 to 4.

[0012] R2is hydrogen, halogen, -CCI3, -CBr3, -CF3, -CI3, -CHC12, -CHBr2, -CHF2, -CHI2, -CH2CI, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCC13, -OCF3, -OCBr3, -OCI3, -OCHCI2, -OCHBr2, -OCHI2, -OCHF2, -OCH2C1, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted ary l, or substituted or unsubstituted heteroary l.

[0013] R3is independently halogen, -CX33, -CHX32, -CH2X3, -OCX33, -OCH2X3, -OCHX32, -CN, -SOn3R3D. -SOV3NR3AR3B, -NR3CNR3AR3B. -ONR3AR3B.-NR3CC(O)NR3AR3B-N(O)m3, -NR3AR3B, -C(O)R3C, -C(O)OR3C, -C(O)NR3AR3B, -OR3D, -NR3ASO2R3D, -NR3AC(O)R3C, -NR3AC(O)OR3C, -NR3AOR3C, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two R3substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted and, or substituted or unsubstituted heteroaryl.

[0014] The symbol z3 is an integer from 0 to 2.

[0015] R4is independently oxo, halogen, -CX43, -CHX42, -CH2X4, -OCX43, -OCH2X4, -OCHX42, -CN, -SOn4R4D, -SOV4NR4AR4B, -NR4CNR4AR4B, -ONR4AR4B, -NR4CC(O)NR4AR4B, -N(0)m4, -NR4AR4B, -C(O)R4C, -C(O)OR4C, -C(O)NR4AR4B, -OR4D, -NR4ASO2R4D, -NR4AC(O)R4C, -NR4AC(O)OR4C, -NR4AOR4C, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted and, or substituted or unsubstituted heteroaryl; two R4substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyd, substituted or unsubstituted and. or substituted or unsubstituted heteroaryl.

[0016] The symbol z4 is an integer from 0 to 11.

[0017] R5is hydrogen, halogen, -CC13, -CBr3. -CF3. -CI3. -CH2C1, -CH2Br. -CH2F. -CH2I. -CHC12, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, NHNH2, 0NH2, NHC(0)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCC13, -OCBr3, -OCF3, -OCI3, -OCH2C1. -OCH2Br, -OCH2F, -OCH2I. -OCHC12, -OCHBr2, -OCHF2, -OCH12. -SF5. -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0018] R1A, R1B, R1C, R1D, R3A, R3B, R3C, R3D, R4A, R4B, R4C, and R4Dare independently hydrogen, halogen. -CC13, -CBr3, -CF3, -CI3, -CHC12, -CHBr2, -CHF2, -CHI2. -CH2C1, -CH2Br, -CH2F, -CH21, -CN. -OH. -NH2, -COOH. -CONH2, -OCC13. -OCF3. -OCBr3, -OCI3, -OCHC12, -OCHBr2, -OCHI2, -OCHF2, -OCH2C1, -OCH2Br, -OCH2I, -OCH2F, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryk R1Aand R1Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R3Aand R3Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R4Aand R4Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.

[0019] Each X1, X3, and X4is independently -F, -Cl, -Br, or -I. The symbols nl, n3, and n4 are independently an integer from 0 to 4. The symbols ml, m3, m4. vl. v3, and v4 are independently 1 or 2.

[0020] In embodiments, when Ring A is phenyl and z4 is 0, then R3is not unsubstituted isopropyl, unsubstituted cyclopropyl, unsubstituted furanyl, or unsubstituted thienyl.

[0021] In an aspect is provided a pharmaceutical composition including a compound described herein, or a pharmaceutically acceptable salt or tautomer thereof, and a pharmaceutically acceptable excipient.

[0022] In an aspect is provided a method of treating a cancer in a subject in need thereof, the method including administering to the subject in need thereof a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt or tautomer thereof.

[0023] In an aspect is provided a method of reducing a Wnt-mediated effect on a cell, the method including contacting the cell with an effective amount of a compound as described herein, or a pharmaceutically acceptable salt or tautomer thereof.DETAILED DESCRIPTIONI. Definitions

[0024] 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.

[0025] Where substituent groups are specified by their conventional chemical formulae, written from left to right, they equally encompass the chemically identical substituents thatwould result from writing the structure from right to left, e.g., -CH2O- is equivalent to -OCH2-.

[0026] 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, 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-buty l, methy l, 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.

[0027] 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 alkyd” or “lower alkylene” is a shorter chain alkyd 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 alky lene is monounsaturated. In embodiments, the alkylene is polyunsaturated. An alkenylene includes one or more double bonds. An alkynylene includes one or more triple bonds.

[0028] 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 atleast 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 the 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, -O-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 otherw ise 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 additional 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 additional 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.

[0029] 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 w hich 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', -C(O)NR', -NR'R", -OR', -SR', and / or -SO2R'. Where "heteroalkyl" is recited, followed by recitations of specific heteroalkyl groups, such as -NR'R" or the like, it will be understood that the terms heteroalkyd 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 hke. 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 heteroalky dene is polyunsaturated. A heteroalkenylene includes one or more double bonds. A heteroalkynylene includes one or more triple bonds.

[0030] The terms “cycloalkyl” and “heterocycloalkyl,” by themselves or in combination with other terms, mean, unless otherwise stated, cyclic versions of “alkyl” and “heteroalkyl,” respectively. Cycloalkyl and heterocycloalkyl are not aromatic. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1 -cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkyl include, but are not limited to, 1- (1,2,5,6-tetrahydropyridyl), 1-piperidinyL 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3- morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1 -piperazinyl, 2-piperazinyl, and the hke. 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.

[0031] 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, but not aromatic. In embodiments, cycloalkyl groups are fully saturated. Abicyclic or multi cyclic 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.

[0032] 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.

[0033] 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.

[0034] 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, fluoromethy l, difluoromethyl, trifluoromethyl, 2, 2.2 -trifluoroethyl, 4-chlorobutyl. 3-bromopropyl, and the like.

[0035] 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 ary l, or substituted or unsubstituted heteroaryl.

[0036] 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 ary l) or linked covalently. A fused ring aryl refers to multiple rings fused together wherein at least one of the fused rings is an ary l 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” refersto ary l 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 quatemized. 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 moiety7through 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 ary l and heteroary l 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, mean a divalent radical derived from an aryl and heteroaryl, respectively. A heteroary l group substituent may be -O- bonded to a ring heteroatom nitrogen.

[0037] 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 thesame ring when not part of spirocyclic rings (e.g., substituents for cycloalkyl or heterocycloalkyl rings). Spirocylic rings may be substituted or unsubstituted cycloalkyd, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heterocycloalky dene 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 substituted 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.

[0038] Idle symbol •” denotes the point of attachment of a chemical moiety to the remainder of a molecule or chemical formula.

[0039] The term “oxo,” as used herein, means an oxygen that is double bonded to a carbon atom.

[0040] The term “alkylarylene” as an ary lene moiety covalently bonded to an alkylene moiety (also referred to herein as an alkylene linker). In embodiments, the alkylarylene group has the formula:

[0041] 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, -CCh, -CBr3, -CI3, -CN, -CHO, -OH, -NH2, -COOH, -CONH2, -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.

[0042] Each of the above terms (e.g., “alkyl,” “heteroalkyl.” “cycloalkyl.” “heterocycloalkyd,” “aryl,” and “heteroaryl”) includes both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided below.

[0043] 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(0)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. -NO2, -NR'SO2R", -NR'C(0)R", -NR'C(0)0R", -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 unsubstituted cycloalkyl, substituted or unsubstituted 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., -CF3 and -CH2CF3) and acyl (e g., -C(O)CH3, -C(O)CF3, -C(O)CH2OCH3, and the like).

[0044] 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(0)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(C i-C4)alkyl. -NR'SO2R", -NR'C(0)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 unsubstitutedheteroaryl. 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.

[0045] Substituents for rings (e g., cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene) may be depicted as substituents 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.

[0046] 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, tw o 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.

[0047] 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.

[0048] As used herein, the terms “heteroatom” or “ring heteroatom” are meant to include oxygen (O), nitrogen (N), sulfur (S). phosphorus (P), and silicon (Si).

[0049] A “substituent group,” as used herein, means a group selected from the following moieties:(A) oxo, halogen, -CCh, -CBr3, -CF3, -CI3, -CHCh, -CHBr2, -CHF2, -CHI2, -CH2CI, -CH2Br, -CH2F, -CH2I, -OCC13, -OCF3, -OCBr3, -OCI3, -OCHC12, -OCHBr2, -OCHI2, -OCHF2, -OCH2C1, -OCH2Br, -OCH2I, -OCH2F, -CN, -OH. -NH2, -COOH, -C0NH2, -NO2, -SH. -SO3H. -OSO3H, -SO2NH2, -NHNH2, -0NH2, -NHC(O)NHNH2, -NHC(0)NH2, -NHC(NH)NH2, -NHSO2H, -NHC(0)H, -NHC(0)0H, -NHOH, -N3, -SF5, unsubstituted alkyl (e.g., Ci-C§ alky l, 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 heteroalkyd), unsubstituted cycloalkyl (e.g., C3-Cs cycloalkyl, C3-Ce cycloalky 1, or Cs-Ce cycloalkyl), unsubstituted heterocycloalkyl (e g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalky 1, or 5 to 6 memberedheterocycloalkyl), unsubstituted aryl (e.g., Cg-Cio aryl, Cio ary l, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl. 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), and(B) alkyl (e.g., Ci-Cs alkyl, Ci-Ce alkyl, or C1-C4 alkyl), heteroalkyl (e.g., 2 to 8 membered heteroalkyd, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), cycloalkyl (e.g., C3-C8 cy cloalkyl, C3-C6 cycloalky 1, or C5-C6 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, Cio aryl, or phenyl), heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), substituted wi th at least one substituent selected from:(i) oxo, halogen, -CCI3, -CBr3, -CF3. -CI3, -CHCh, -CHBr2, -CHF2. -CHI2, -CH2C1, -CH2Br, -CH2F, -CH2I, -OCCh, -OCF3, -OCBn. -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(O)OH, -NHOH, -Ns, -SF5, unsubstituted alky l (e.g., Ci-Cs alkyl, Ci-Cg alkyl, or C1-C4 alky l), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyd, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl. C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyd (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyd, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., Cg- C10 aryl, Cio ary l, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), and(ii) alkyl (e.g., Ci-Cs alkyl. Ci-Cg alkyl, or C1-C4 alkyl), heteroalkyl (e.g.. 2 to 8 membered heteroalkyd, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), cycloalky l (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or Cs-Cg cycloalkyl), heterocycloalkyl (e.g.. 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), aryl (e.g., Cg- C10 aryl, Cio 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:(a) oxo, halogen, -CC13, -CBr3, -CF3, -CI3, -CHCh, -CHBr2, -CHF2. -CHI2, -CH2C1, -CH2Br, -CH2F, -CH2I, -OCCh. -OCF3. -OCBr3, -OCI3, -OCHCh. -OCHBr2, -OCHb, -OCHF2, -OCH2C1, -OCH2Br, -OCH2I, -OCH2F, -CN, -OH, -NH2, -COOH, -CONH2, -N02, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -0NH2, -NHC(0)NHNH2, -NHC(0)NH2, -NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -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., Cs-Cs 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(b) alkyl (e.g., Ci-Cs alkyl. Ci-Cs alkyl, or C1-C4 alkyl), heteroalkyl (e.g.. 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyd), cycloalkyl (e.g., C3-C8 cycloalky l, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), aryl (e.g., Ce- C10 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, -CBr3, -CF3, -CI3, -CHC12, -CHBr2, -CHF2, -CHI2. -CH2C1, -CH2Br, -CH2F, -CH2I, -OCCh, -OCF3, -OCBr3. -OCI3, -OCHCh, -OCHBr2, -0CHI2, -OCHF2, -OCH2C1, -OCH2Br, -0CH2I, -OCH2F, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSOsH, -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 heteroalky 1 (e.g., 2 to 8 membered heteroalky 1, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalky 1), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyd (e.g., 3 to 8 membered heterocycloalkyd, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyd), unsubstituted aryl (e.g., Ce-Cio aryl, C10 aryl, or phenyl), orunsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl. 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0050] A "‘size-limited substituent7’ 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 alky l 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 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 each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 10 membered heteroaryl.

[0051] 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 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 phenyl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 6 membered heteroaryl.

[0052] 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 ary l, substituted heteroaryl, substituted alky lene, 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.

[0053] 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 heteroalkyd, each substituted orunsubstituted cycloalkyl is a substituted or unsubstituted 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.

[0054] 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 ary l 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. In some embodiments, the compound is a chemical species set forth in the Examples section, figures, or tables below.

[0055] 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 heteroaiyl, substituted or unsubstituted alkylene, substituted orunsubstituted 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 cycloalkyd, unsubstituted heterocycloalkyl, unsubstituted ary l, unsubstituted heteroaryl, unsubstituted alkylene, unsubstituted heteroalky lene, 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 cycloalkyd, substituted or unsubstituted heterocycloalkyd, substituted or unsubstituted aryl, substituted or unsubstituted heteroaiy 1, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkydene, 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 alkyd, substituted heteroalkyd, substituted cycloalkyd, substituted heterocycloalkyd, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene, respectively).

[0056] In embodiments, a substituted moiety7(e.g., substituted alkyl, substituted heteroalkyd, substituted cycloalkyd, substituted heterocycloalkyl, substituted ary 1, 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 plurality7of 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.

[0057] 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 substitutedwith a plurality of size-limited substituent groups, each size-limited substituent group is different.

[0058] 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 plurality7of lower substituent groups, each lower substituent group is different.

[0059] In embodiments, a substituted moiety7(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 moiety7is 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.

[0060] 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 identity7of any chemical moiety that composes the “substituted” group (also referred to herein as an “open substitution” on an R substituent or L linker or an “openly7substituted” 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.

[0061] 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 R1 1, R2may be substituted with one or more first substituent groups denoted by R2 1, R3may be substituted with one or more first substituent groupsdenoted by R3\ R4may be substituted with one or more first substituent groups denoted by R4R5may be substituted with one or more first substituent groups denoted by R / 1. and the like up to or exceeding an R100that may be substituted with one or more first substituent groups denoted by R100 1. As a further example, R1Amay be substituted with one or more first substituent groups denoted by R1A 1, R2Amay be substituted with one or more first substituent groups denoted by R2A I. R3Amay be substituted with one or more first substituent groups denoted by R3A\ R4Amay be substituted with one or more first substituent groups denoted by R4A1, R5Amay be substituted with one or more first substituent groups denoted by R5A 1and the like up to or exceeding an may be substituted with one or more first substituent groups denoted by As a further example, L1may be substituted with one or more first substituent groups denoted by RLL1, L2may be substituted with one or more first substituent groups denoted by RL2 1, L3may be substituted with one or more first substituent groups denoted by RL3 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 RL100 1. 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\ respectively. In turn, each first substituent group (e.g. R14, R2 1, R34. R41, R5 1... R100 1; R1A 1.R2A 1, R3A 1, R5A 1... R100A 1; RL2 1, RL3 1, RL41, RL5 1... R™) may be further substituted with one or more second substituent groups (e.g. R1 2, R22, R3 2, R42, R5 2. . . R1002;R1A2 2 1002 respectively). Thus, each first substituent group, which may alternatively be represented herein 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

[0062] Finally, each second substituent group (e.g. R1 2, R22, R3 2, R42, R5 2... R1002; R1A 2R2A2. R3A 2, R4A 2. R5A 2... R100A2.RL1.2,RL22,RL3.2RL42,RL52RL1002) may be furthersubstituted with one or more third substituent groups (e.g. R1 3, R23, R33. R43, R5 3.. . R100-3;R1A.3 RL2.3 respectively). Thus, each second substituent group, which may alternatively be represented herein as Rww 2as 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 firstsubstituent 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.

[0063] 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 R"w-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 may be unsubstituted or independently substituted with one or more third substituent groups, referred to herein as Rwu-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, RLWW 1?may be unsubstituted or independently substituted with one or more second substituent groups, referred to herein as.2.anjeachsecon(j substituent group may be unsubstituted or independently substituted with one or more third substituent groups, referred to herein as RLWW 3. Each 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 Rww 1groups as defined herein below, e.g. when Rww 1is RWW 2substituted alkyl, examples of groups so formed include but are not limited to itself optionally substituted by 1 or more RWW 2, which RWW 2is optionally substituted by one or more RWW 3. By way of example when RWW 1is alkyl, groups that could be formed, include but are not limited to:

[0064] RWW 1is independently oxo, halogen, -CXWW 13, -CHXWW■12, -CH2XWW-1, -OCXWWs, -OCH2XWW-1, -OCHXWW\ -CN. -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H. -OSO3H. -SO2NH2, -NHNH2. -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, RWW^-substituted or unsubstituted alkyl (e.g., Ci-Cs, Ci-Ce, C1-C4, or C1-C2), Rww'2-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 2-substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), RWW 2-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 2-substituted or unsubstituted aryl (e.g., Ce-Ci2, Ce-Cio, or phenyl), or Rww^-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 J2, -CH2XWW\ -OCXWW’3, -OCH2XWW-1, -OCHXWW J2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H. -SO2NH2, -NHNH2. -0NH2, -NHC(0)NHNH2, -NHC(O)NH2. -NHC(NH)NH2. -NHSO2H. -NHC(O)H, -NHC(0)0H. -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., Cs-Cg, C3-C6. C4-C6, or Cs-Ce), unsubstituted heterocy cloalkyl (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-Ci2, 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.

[0065] RWW2is independently oxo, halogen, -CXWW 23. -CHXW% 22, -CH2XW% 2. -OCXWW 23, -OCH2XWW 2, -OCHXWW 22, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(0)NHNH2, -NHC(O)NH2, -NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3. Rww 3-substituted or unsubstituted alkyl (e.g.. Ci-Cs, Ci-Ce, C1-C4. or C1-C2), Rww'3-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, C3-C6, 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). Rww^-substituted or unsubstituted aryl (e.g., C6-C12, 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 23, -CHXWW 22, -CH2XWW 2, -OCXWW 23, -0CH2XWW 2, -OCHXWW 22, -CN, -OH, -NH2. -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(0)NHNH2, -NHC(O)NH2, -NHC(NH)NH2. -NHSO2H, -NHC(O)H, -NHC(0)0H, -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, Cs-Ce, C4-C6, or Cs-Ce), unsubstituted heterocycloalkyd (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). xWW 2is independently -F, -Cl, -Br, or -I.

[0066] RWW 3is independently oxo, halogen, -CXWW 33, -CHXWW 32, -CH2XWW 3, -OCXWW 33, -OCH2XWW 3, -OCHXWW 32, -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(O)OH, -NHOH, -N3, unsubstituted alkyl (e.g., Ci-Cs, Ci-Ce, C1-C4, or C1-C2), unsubstituted heteroalkyd (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 ary l (e.g., C6-C12, Ce-Cio, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). xWW 3is independently -F, -Cl, -Br, or -I.

[0067] Where two different Rwwsubstituents are joined together to form an openly substituted ring (e.g., substituted cycloalkyl, substituted heterocycloalkyl, substituted ary l 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, RWW 2, may be unsubstituted or independently substituted with one or more third substituent groups, referred to herein as Rww'3; and each third substituent group, RWW'3. 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 Rww-1, RWW 2and RWW 3refers to the 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, RW-2isR100A 2, and R%w 3is R100A 3Alternatively, in embodiments where R100Aand R100Bare optionally joined together to form an openly substituted ring, RWW 1is R100B 1, RW"2is R100B 2, and RWW3is R100B 3. RWW 1, Rww-2and Rww ?in this paragraph are as defined in the preceding paragraphs.

[0068] R1™ isindependently oxo, halogen. -CXLWW 13. -CHXLWW 12. -CH2XLWW 1, -OCXLWW J3, -OCH2XLWW-1, -OCHXLWW\ -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, NHNH2, ONH2, NHC(0)NHNH2, NHC(O)NH2, -NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3. RLWW’-substituted or unsubstituted alkyl (e.g.. Ci-Cs, Ci-Ce, C1-C4. or C1-C2), RLWW’-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), RLWW’-substituted or unsubstituted cycloalkyl (e.g., Cs-Cs, C3-C6, C4-C6, or Cs-Ce), RLWW’-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., Ce-Ci2, Ce-Cio, or phenyl), or RLW" ’-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^3, -CHXLWWJ2, -CH2XLWW-1. -OCXLWW 13, -OCH2XLWW-1. -OCHXLWW’2, -CN, -OH, -NH2.-COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H. -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHC(NH)NH2, -NHSChH. -NHC(O)H, -NHC(O)OH, -NHOH, -N3, unsubstituted alkyd (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., 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 1is independently -F, -Cl, -Br, or -I.

[0069] RLWW 2is independently oxo. halogen, -CXLWW 23. -CHXLWW 22. -CH2XLWW 2. -OCXLWW 23, -OCH2XLWW 2, -OCHXLWW 22, -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(0)0H, -NHOH, -N3, RLWW’-substituted or unsubstituted alkyl (e.g.. Ci-Cs, Ci-Ce, C1-C4. or C1-C2), RL%W’-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’-substituted or unsubstituted cycloalkyl (e.g., Cs-Cs, C3-C6, C4-C6, or Cs-Ce), RLWW’-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’-substituted or unsubstituted aryl (e.g., C6-C12, Ce-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, RLWW 2is independently oxo, halogen, -CXLWW 23, -CHXLWW-22, -CH2XLWW'2, -OCXLWW-23, -OCH2XLWW'2, -OCHXLWW-22, -CN, -OH, -NH2.-COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(0)0H, -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 and (e.g., C6-C12, C6-C10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). XL1A w'2is independently -F, -Cl, -Br, or -I.

[0070] RLWW-3is independently oxo. halogen, -CXLWW 33, -CHXLWW 32, -CH2XLWW 3. -OCXLWW 33. -OCH2XLWW3, -OCHXLWW 32, -CN, -OH, -NH2, -COOH, -CONH2. -NO2, -SH. -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, 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., Cs-Cg, 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-Ci2, 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.

[0071] 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 (R\VV group) ishereby defined as independently oxo, halogen, -CXWW3, -CHXWW2, -CH2XWW, -OCXWW3, -OCH2XWW, -OCHXWW2, -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, Rww 1-substituted or unsubstituted alkyl (e.g., Ci-Cg, Ci-Ce, C1-C4, or C1-C2), RWW 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), Rxvxv' -substituted or unsubstituted cycloalkyl (e.g., Cs-Cg, C3-C6, C4-C6, or Cs-Ce), RWW I-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., Ce-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 independently -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.).RWWJ,RWW.2 and RWW 3are as defined above.

[0072] 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(O)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), RL% W 1-substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered. 4 to 6 membered, 2to 3 membered, or 4 to 5 membered), RLWW 1-substituted or unsubstituted cycloalkylene (e g., Cs-Cs, C3-C6, C4-C6, or Cs-Ce), RLWW^-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), RLWV 1-substituted or unsubstituted arylene (e.g., C6-C12, Ce-Cio, or phenyl), or RLWW 1. 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, 1A. 2A. 3A, IB, 2B, 3B, etc.). RLWW\ as well as RLWW-2and RLWW.3are asdefine(iabove.

[0073] 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.

[0074] As used herein, the term “isomers’7refers to compounds having the same number and kind of atoms, and hence the same molecular w eight, but differing in respect to the structural arrangement or configuration of the atoms.

[0075] 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.

[0076] 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.

[0077] 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 asymmetriccenter. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the disclosure.

[0078] 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.

[0079] 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 (?H), 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.

[0080] 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.

[0081] As used herein, the terms “bioconjugate” and “bioconjugate linker” refer to the resulting association between atoms or molecules of bioconjugate reactive groups or bioconjugate reactive moieties. The association can be direct or indirect. For example, a conjugate between a first bioconjugate reactive group (e.g., -NFb, -COOH, -N- hydroxysuccinimide, or -maleimide) and a second bioconjugate reactive group (e.g., sulfhydry l, sulfur-containing amino acid, amine, amine sidechain containing amino acid, or carboxylate) provided herein can be direct, e.g., by covalent bond or linker (e.g., a first linker of second linker), or indirect, e.g., by non-covalent bond (e.g., electrostatic interactions (e.g., ionic bond, hydrogen bond, halogen bond), van der Waals interactions (e.g., dipole-dipole, dipole-induced dipole, London dispersion), ring stacking (pi effects), hydrophobic interactions and the like). In embodiments, bioconjugates or bioconjugate linkers are formed using bioconjugate chemistry (i.e.. the association of two bioconjugate reactive groups) including, but are not limited to nucleophilic substitutions (e.g.. reactions of amines and alcohols with acyl halides, active esters), electrophilic substitutions (e g., enamine reactions)and additions to carbon-carbon and carbon-heteroatom multiple bonds (e.g., Michael reaction, Diels-Alder addition). These and other useful reactions are discussed in, for example, March, ADVANCED ORGANIC CHEMISTRY, 3rd Ed., John Wiley & Sons, New York, 1985; Hermanson, BIOCONJUGATE TECHNIQUES, Academic Press, San Diego, 1996; and Feeney et al., MODIFICATION OF PROTEINS; Advances in Chemistry Series, Vol. 198. American Chemical Society, Washington, D.C., 1982. In embodiments, the first bioconjugate reactive group (e.g., maleimide moiety) is covalently attached to the second bioconjugate reactive group (e.g., a sulfhydryl). In embodiments, the first bioconjugate reactive group (e.g., haloacetyl moiety) is covalently attached to the second bioconjugate reactive group (e.g., a sulfhydryl). In embodiments, the first bioconjugate reactive group (e.g., pyridyl moiety) is covalently attached to the second bioconjugate reactive group (e.g., a sulfhydryl). In embodiments, the first bioconjugate reactive group (e.g., -N- hydroxy succinimide moiety) is covalently attached to the second bioconjugate reactive group (e.g., an amine). In embodiments, the first bioconjugate reactive group (e.g., maleimide moiety) is covalently attached to the second bioconjugate reactive group (e.g., a sulfhydryl). In embodiments, the first bioconjugate reactive group (e.g., -sulfo-N-hydroxysuccinimide moiety) is covalently attached to the second bioconjugate reactive group (e.g., an amine).

[0082] Useful bioconjugate reactive moieties used for bioconjugate chemistries herein include, for example: (a) carboxyl groups and various derivatives thereof including, but not limited to, N-hydroxysuccinimide esters, N-hydroxybenztriazole esters, acid halides, acyl imidazoles, thioesters, p-nitrophenyl esters, alkyl, alkenyl, alkynyl and aromatic esters; (b) hydroxyl groups which can be converted to esters, ethers, aldehydes, etc.; (c) haloalkyl groups wherein the halide can be later displaced with a nucleophilic group such as, for example, an amine, a carboxylate anion, thiol anion, carbanion, or an alkoxide ion, thereby resulting in the covalent attachment of a new group at the site of the halogen atom; (d) dienophile groups which are capable of participating in Diels-Alder reactions such as, for example, maleimido or maleimide groups; (e) aldehyde or ketone groups such that subsequent derivatization is possible via formation of carbonyl derivatives such as. for example, imines, hydrazones, semicarbazones or oximes, or via such mechanisms as Grignard addition or alkyllithium addition; (f) sulfonyl halide groups for subsequent reaction with amines, for example, to form sulfonamides; (g) thiol groups, which can be converted to disulfides, reacted with acyl halides, or bonded to metals such as gold, or react with maleimides; (h) amine or sulfhydryl groups (e.g., present in cysteine), which can be, forexample, acylated, alky lated or oxidized; (i) alkenes, which can undergo, for example, cycloadditions, acylation, Michael addition, etc.; (j) epoxides, which can react with, for example, amines and hydroxyl compounds; (k) phosphoramidites and other standard functional groups useful in nucleic acid synthesis; (1) metal silicon oxide bonding; (m) metal bonding to reactive phosphorus groups (e.g., phosphines) to form, for example, phosphate diester bonds; (n) azides coupled to alkynes using copper catalyzed cycloaddition click chemistry; and (o) biotin conjugate can react with avidin or streptavidin to form an avidinbiotin complex or streptavidin-biotin complex.

[0083] The bioconjugate reactive groups can be chosen such that they do not participate in, or interfere with, the chemical stabili ty of the conjugate described herein. Alternatively, a reactive functional group can be protected from participating in the crosslinking reaction by the presence of a protecting group. In embodiments, the bioconjugate comprises a molecular entity derived from the reaction of an unsaturated bond, such as a maleimide, and a sulfhydryl group.

[0084] “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 functional group, or the absolute stereochemistry of one or more chiral centers of the reference compound.

[0085] 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.

[0086] 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 Rgroup. For example, where multiple R13substituents are present, each R13substituent may be distinguished as R13 A, R13 B, R13 C. R13 D, etc., wherein each of R13 A, R13 B, R13 c, R13 D. 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 ordinary7skill in the art will immediately recognize that the oxo is attached through a double bond in accordance with the normal rules of chemical valency.

[0087] 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 ordinary7skill 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.

[0088] The term “pharmaceutically acceptable salts7’ is meant to include salts of the active compounds that are prepared with relatively7nontoxic 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, hy drobromic, 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 ofamino 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.

[0089] 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, proprionates, tartrates (e.g., (+)-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.

[0090] 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.

[0091] 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 enzy me or chemical reagent.

[0092] Certain compounds of the present disclosure can exist in unsolvated forms as w ell 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.

[0093] A polypeptide, or a cell is “recombinant” when it is artificial or engineered, or derived from or contains an artificial or engineered protein or nucleic acid (e.g., non-naturalor not wild type). For example, a polynucleotide that is inserted into a vector or any other heterologous location, e.g., in a genome of a recombinant organism, such that it is not associated with nucleotide sequences that normally flank the polynucleotide as it is found in nature is a recombinant polynucleotide. A protein expressed in vitro or in vivo from a recombinant polynucleotide is an example of a recombinant polypeptide. Likewise, a polynucleotide sequence that does not appear in nature, for example a variant of a naturally occurring gene, is recombinant.

[0094] “Co-administer” 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 disclosed herein can be administered alone or can be co-administered 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).

[0095] 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. In embodiments, treating does not include preventing. In embodiments, the treating or treatment is not prophylactic treatment.

[0096] 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 enzy me 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 asymptom 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, pathology7or 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 “activity7increasing 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).

[0097] “Control” or “control experiment” is used in accordance w ith its plain ordinary7meaning 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).

[0098] “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 directlyfrom 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.

[0099] The term "contacting7’ 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.

[0100] 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.

[0101] 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%, 95%, 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.

[0102] 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 thecellular 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.

[0103] 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 activity7by 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 activity7in the absence of the antagonist.

[0104] 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, microorganism, vesicle, small molecule, protein complex, protein aggregate, or macromolecule)) relative to the absence of the composition.

[0105] The term “expression” includes any step involved in the production of the polypeptide including, but not limited to, transcription, post-transcriptional modification, translation, post-translational modification, and secretion. Expression can be detected using conventional techniques for detecting protein (e.g., ELISA, Western blotting, flow cytometry7, immunofluorescence, immunohistochemistry, etc.).

[0106] 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.

[0107] “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 byadministration 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 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.

[0108] “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 a cancer.

[0109] As used herein, the term “cancer” refers to all types of cancer, neoplasm or malignant tumors found in mammals (e.g., humans), including leukemia, lymphoma, carcinomas and sarcomas. Exemplary7cancers that may be treated with a compound or method provided herein include cancer of the thyroid, endocrine system, brain, breast, cervix, colon, head and neck, liver, kidney, lung, non-small cell lung, melanoma, mesothelioma, ovary, sarcoma, stomach, uterus medulloblastoma, colorectal cancer, or pancreatic cancer. Additional examples include Hodgkin’s Disease, Non-Hodgkin’s Lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, primary brain tumors, malignant pancreatic insulanoma, malignant carcinoid, urinary bladder cancer, premalignant skin lesions, testicular cancer, lymphomas, thyroid cancer, esophageal cancer, genitourinary7tract cancer, malignant hypercalcemia, endometrial cancer, adrenal cortical cancer, neoplasms of the endocrine or exocrine pancreas, medullary7thyroid cancer, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid cancer, hepatocellular carcinoma, or prostate cancer.

[0110] The term "leukemia" refers broadly to progressive, malignant diseases of the blood- forming organs and is generally characterized by a distorted proliferation and development of leukocytes and their precursors in the blood and bone marrow. Leukemia is generally clinically classified on the basis of (1) the duration and character of the disease-acute or chronic; (2) the type of cell involved; myeloid (myelogenous), lymphoid (lymphogenous), or monocytic; and (3) the increase or non-increase in the number abnormal cells in the blood-leukemic or aleukemic (subleukemic). Exemplary leukemias that may be treated with a compound or method provided herein include, for example, acute nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, a leukocythemic leukemia, basophylic leukemia, blast cell leukemia, bovine leukemia, chronic myelocytic leukemia, leukemia cutis, embryonal leukemia, eosinophilic leukemia, Gross' leukemia, hairy -cell leukemia, hemoblastic leukemia, hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphogenous leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myelocytic leukemia, myeloid granulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasmacytic leukemia, promyelocytic leukemia, Rieder cell leukemia, Schilling's leukemia, stem cell leukemia, subleukemic leukemia, or undifferentiated cell leukemia.

[0111] As used herein, the term “lymphoma” refers to a group of cancers affecting hematopoietic and lymphoid tissues. It begins in lymphocytes, the blood cells that are found primarily in lymph nodes, spleen, thymus, and bone marrow. Two main ty pes of lymphoma are non-Hodgkin lymphoma and Hodgkin’s disease. Hodgkin’s disease represents approximately 15% of all diagnosed lymphomas. This is a cancer associated with Reed- Sternberg malignant B lymphocytes. Non-Hodgkin’ s lymphomas (NHL) can be classified based on the rate at which cancer grows and the ty pe of cells involved. There are aggressive (high grade) and indolent (low grade) ty pes of NHL. Based on the ty pe of cells involved, there are B-cell and T-cell NHLs. Exemplary B-cell lymphomas that may be treated with a compound or method provided herein include, but are not limited to, small lymphocytic lymphoma, Mantle cell lymphoma, follicular lymphoma, marginal zone lymphoma, extranodal (MALT) lymphoma, nodal (monocytoid B-cell) lymphoma, splenic lymphoma, diffuse large cell B-lymphoma, Burkitt’s lymphoma, lymphoblastic lymphoma, immunoblastic large cell lymphoma, or precursor B-lymphoblastic lymphoma. Exemplary T- cell lymphomas that may be treated with a compound or method provided herein include, but are not limited to, cutaneous T-cell lymphoma, peripheral T-cell lymphoma, anaplastic large cell lymphoma, mycosis fungoides, and precursor T-lymphoblastic lymphoma.

[0112] The term "sarcoma" generally refers to a tumor which is made up of a substance like the embryonic connective tissue and is generally composed of closely packed cells embedded in a fibrillar or homogeneous substance. Sarcomas that may be treated with a compound or method provided herein include a chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abernethy’s sarcoma, adipose sarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloroma sarcoma, chorio carcinoma, embryonal sarcoma, Wilms’ tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing’s sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin’s sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma, immunoblastic sarcoma of B cells, lymphoma, immunoblastic sarcoma of T-cells, Jensen’s sarcoma, Kaposi’s sarcoma. Kupffer cell sarcoma, angiosarcoma, leukosarcoma, malignant mesenchymoma sarcoma, parosteal sarcoma, reticulocytic sarcoma, Rous sarcoma, serocystic sarcoma, synovial sarcoma, or telangiectaltic sarcoma.

[0113] The term "melanoma" is taken to mean a tumor arising from the melanocytic system of the skin and other organs. Melanomas that may be treated with a compound or method provided herein include, for example, acral-lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman’s melanoma, S91 melanoma, Harding-Passey melanomajuvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodular melanoma, subungal melanoma, or superficial spreading melanoma.

[0114] The term "carcinoma" refers to a malignant new growth made up of epithelial cells tending to infiltrate the surrounding tissues and give rise to metastases. Exemplary carcinomas that may be treated with a compound or method provided herein include, for example, medullary thyroid carcinoma, familial medullary thyroid carcinoma, acinar carcinoma, acinous carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, carcinoma adenomatosum, carcinoma of adrenal cortex, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinoma basocellulare, basaloid carcinoma, basosquamous cell carcinoma, bronchioalveolar carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, cerebriform carcinoma, cholangiocellular carcinoma, chorionic carcinoma, colloid carcinoma, comedo carcinoma, corpus carcinoma, cribriform carcinoma, carcinoma en cuirasse, carcinoma cutaneum, cylindrical carcinoma, cylindrical cell carcinoma, duct carcinoma, carcinoma durum, embryonal carcinoma, encephaloid carcinoma, epiermoid carcinoma, carcinoma epitheliale adenoides, exophytic carcinoma, carcinoma ex ulcere, carcinoma fibrosum, gelatinifomi carcinoma, gelatinous carcinoma, giant cell carcinoma, carcinomagigantocellulare, glandular carcinoma, granulosa cell carcinoma, hair-matrix carcinoma, hematoid carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma, hyaline carcinoma, hypemephroid carcinoma, infantile embryonal carcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelial carcinoma, Krompecher's carcinoma, Kulchitzky-cell carcinoma, large-cell carcinoma, lenticular carcinoma, carcinoma lenticulare, lipomatous carcinoma, lymphoepithelial carcinoma, carcinoma medullare, medullary carcinoma, melanotic carcinoma, carcinoma molle, mucinous carcinoma, carcinoma muciparum. carcinoma mucocellulare, mucoepidermoid carcinoma, carcinoma mucosum, mucous carcinoma, carcinoma myxomatodes, nasophary ngeal carcinoma, oat cell carcinoma, carcinoma ossificans, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, prickle cell carcinoma, pultaceous carcinoma, renal cell carcinoma of kidney, reserve cell carcinoma, carcinoma sarcomatodes, Schneiderian carcinoma, scirrhous carcinoma, carcinoma scroti, signet-ring cell carcinoma, carcinoma simplex, small-cell carcinoma, solanoid carcinoma, spheroidal cell carcinoma, spindle cell carcinoma, carcinoma spongiosum, squamous carcinoma, squamous cell carcinoma, string carcinoma, carcinoma telangiectaticum, carcinoma telangiectodes, transitional cell carcinoma, carcinoma tuberosum, tuberous carcinoma, verrucous carcinoma, or carcinoma villosum.

[0115] As used herein, the terms "metastasis," "metastatic," and "metastatic cancer" can be used interchangeably and refer to the spread of a proliferative disease or disorder, e.g., cancer, from one organ or another non-adjacent organ or body part. "‘Metastatic cancer” is also called ‘‘Stage IV cancer.” Cancer occurs at an originating site, e.g., breast, which site is referred to as a primary tumor, e.g., primary breast cancer. Some cancer cells in the primary7tumor or originating site acquire the ability7to penetrate and infiltrate surrounding normal tissue in the local area and / or the ability to penetrate the walls of the lymphatic system or vascular system circulating through the system to other sites and tissues in the body. A second clinically detectable tumor formed from cancer cells of a primary tumor is referred to as a metastatic or secondary tumor. When cancer cells metastasize, the metastatic tumor and its cells are presumed to be similar to those of the original tumor. Thus, if lung cancer metastasizes to the breast, the secondary tumor at the site of the breast consists of abnormal lung cells and not abnormal breast cells. The secondary7tumor in the breast is referred to a metastatic lung cancer. Thus, the phrase metastatic cancer refers to a disease in which a subject has or had a primary tumor and has one or more secondary7tumors. The phrases non- metastatic cancer or subjects with cancer that is not metastatic refers to diseases in whichsubjects have a primary tumor but not one or more secondary tumors. For example, metastatic lung cancer refers to a disease in a subject with or with a history of a primary lung tumor and with one or more secondary tumors at a second location or multiple locations, e.g., in the breast.

[0116] The terms “cutaneous metastasis” or “skin metastasis” refer to secondary malignant cell growths in the skin, wherein the malignant cells originate from a primary cancer site (e.g., breast). In cutaneous metastasis, cancerous cells from a primary cancer site may migrate to the skin where they divide and cause lesions. Cutaneous metastasis may result from the migration of cancer cells from breast cancer tumors to the skin.

[0117] The term “visceral metastasis” refer to secondary malignant cell growths in the interal organs (e.g., heart, lungs, liver, pancreas, intestines) or body cavities (e.g., pleura, peritoneum), wherein the malignant cells originate from a primary' cancer site (e.g., head and neck, liver, breast). In visceral metastasis, cancerous cells from a primary cancer site may migrate to the internal organs where they divide and cause lesions. Visceral metastasis may result from the migration of cancer cells from liver cancer tumors or head and neck tumors to internal organs.

[0118] The term “drug” is used in accordance with its common meaning and refers to a substance which has a physiological effect (e.g., beneficial effect, is useful for treating a subject) when introduced into or to a subject (e.g.. in or on the body of a subject or patient). A drug moiety is a radical of a drug

[0119] A “detectable agent,” “detectable compound,” “detectable label,” or “detectable moiety” is a substance (e.g., element), molecule, or composition detectable by spectroscopic, photochemical, biochemical, immunochemical, chemical, magnetic resonance imaging, or other physical means. For example, detectable agents include18F,32P,33P.45Ti,47Sc,52Fe,59Fe,62Cu,64Cu,67Cu,67Ga,68Ga,77As,86Y,90Y,89Sr,89Zr,94Tc,94Tc,99mTc, "Mo,105Pd,105Rh,i nAg,1 HIn,123I,124I,125I,131I,142Pr,143Pr,149Pm,153Sm,154-158iGd,161Tb,166Dy,166Ho.169Er,175LU,177LU,186Re,188Re,189Re,194Ir,198Au,199Au,211At,211Pb,212Bi,212Pb,213BI,223Ra,225Ac, Cr, V, Mn, Fe, Co, Ni, Cu, La, Ce, Pr, Nd. Pm, Sm, Eu, Gd. Tb. Dy, Ho, Er, Tm, Yb, Lu,32P, fluorophore (e.g., fluorescent dyes), modified oligonucleotides (e.g., moieties described in PCT / US2015 / 022063, which is incorporated herein by reference), electron-dense reagents, enzy mes (e.g., as commonly used in an ELISA), biotin, digoxigenin, paramagnetic molecules, paramagnetic nanoparticles, ultrasmall superparamagnetic ironoxide ("USPIO") nanoparticles, USPIO nanoparticle aggregates, superparamagnetic iron oxide ("SPIO") nanoparticles, SPIO nanoparticle aggregates, monochrystalline iron oxide nanoparticles, monochrystalline iron oxide, nanoparticle contrast agents, liposomes or other delivery vehicles containing Gadolinium chelate ("Gd-ch elate") molecules, Gadolinium, radioisotopes, radionuclides (e.g., carbon-11, nitrogen-13, oxygen-15, fluorine-18, rubidium- 82), fluorodeoxy glucose (e.g., fluorine-18 labeled), any gamma ray emitting radionuclides, positron-emitting radionuclide, radiolabeled glucose, radiolabeled water, radiolabeled ammonia, biocolloids, microbubbles (e g., including microbubble shells including albumin, galactose, lipid, and / or polymers; microbubble gas core including air, heavy gas(es), perfluorcarbon, nitrogen, octafluoropropane, perflexane lipid microsphere, perflutren, etc.), iodinated contrast agents (e.g.. iohexol, iodixanol. ioversol, iopamidol, ioxilan. iopromide. diatrizoate, metrizoate, ioxaglate), barium sulfate, thorium dioxide, gold, gold nanoparticles, gold nanoparticle aggregates, fluorophores, two-photon fluorophores, or haptens and proteins or other entities which can be made detectable, e.g., by incorporating a radiolabel into a peptide or antibody specifically reactive with a target peptide.

[0120] Radioactive substances (e.g.. radioisotopes) that may be used as imaging and / or labeling agents in accordance with the embodiments of the disclosure include, but are not limited to,18F,32P,33P,45Ti,47Sc,52Fe,59Fe,62Cu,64Cu,67Cu,67Ga,68Ga,77As,86Y,90Y,89Sr,89Zr,94TC,94TC, "mTc, "Mo,105Pd,105Rh,mAg,n iIn,123I,124I,125I,131I,142Pr,143Pr.149Pm,153Sm,154-158Gd,161Tb.166Dy,166HO.169Er,175Lu,177Lu.186Re,188Re,189Re.194Ir,198Au,199Au,211At,211Pb,212Bi,212Pb,213Bi,223Ra, and225Ac. Paramagnetic ions that may be used as additional imaging agents in accordance with the embodiments of the disclosure include, but are not limited to, ions of transition and lanthanide metals (e.g., metals having atomic numbers of 21-29, 42, 43, 44, or 57-71). These metals include ions of Cr, V, Mn, Fe, Co, Ni, Cu. La. Ce. Pr. Nd. Pm, Sm. Eu. Gd, Tb, Dy, Ho, Er, Tm. Yb, and Lu.

[0121] '‘Pharmaceutically acceptable excipient” and “pharmaceutically acceptable earner” 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 disclosed herein 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 disclosed herein. One of skill in the art will recognize that other pharmaceutical excipients are useful in the presently disclosed pharmaceutical compositions.

[0122] 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.

[0123] 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 measurements 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.

[0124] 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, intraarteriole, 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 disclosed herein can be administered alone or can be co-administered 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, whendesired, with other active substances (e.g., to reduce metabolic degradation). The compositions disclosed herein 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.

[0125] 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.

[0126] 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. Coadministration 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 active agents can be formulated separately. In another embodiment, the active and / or adjunctive agents may be linked or conjugated to one another.

[0127] In therapeutic use for the treatment of a disease, compound(s) utilized in the pharmaceutical compositions disclosed herein 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 seventy 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., cancer) diagnosed in a particular patient. The dose administered to a patient, in the context of the presently disclosed methods of therapeutic treatment, 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 smallincrements 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.

[0128] The term "associated” or "‘associated with” in the context of a substance or substance activity or function associated with a disease (e.g., a protein associated disease, disease associated with a cellular component) means that the disease (e.g., cancer) 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., cellular component). 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.

[0129] The term “aberrant” as used herein refers to different from normal. When used to describe enzymatic activity, aberrant refers to activity that is greater or less than a normal control or the average of normal non-diseased control samples. Aberrant activity may refer to an amount of activity that results in a disease, wherein returning the aberrant activity to a normal or non-disease-associated amount (e.g., by administering a compound or using a method as described herein), results in reduction of the disease or one or more disease symptoms.

[0130] The term “electrophilic” as used herein refers to a chemical group that is capable of accepting electron density. An “electrophilic substituent,” “electrophilic chemical moiety,” or “electrophilic moiety” refers to an electron-poor chemical group, substituent, or moiety (monovalent chemical group), which may react with an electron-donating group, such as a nucleophile, by accepting an electron pair or electron density to form a bond.

[0131] ‘‘Nucleophilic” as used herein refers to a chemical group that is capable of donating electron density.

[0132] The term “isolated,” when applied to a nucleic acid or protein, denotes that the nucleic acid or protein is essentially free of other cellular components with which it is associated in the natural state. It can be. for example, in a homogeneous state and may be in either a dry or aqueous solution. Purity and homogeneity are typically determined using analytical chemistry techniques such as polyacrylamide gel electrophoresis or high performance liquid chromatography. A protein that is the predominant species present in a preparation is substantially purified.

[0133] The term “amino acid’' refers to naturally occurring and synthetic amino acids, as well as amino acid analogs and amino acid mimetics that function in a manner similar to the naturally occurring amino acids. Naturally occurring amino acids are those encoded by the genetic code, as well as those amino acids that are later modified, e.g., hydroxy proline, y- carboxy glutamate, and O-phosphoserine. Amino acid analogs refers to compounds that have the same basic chemical structure as a naturally occurring amino acid, i.e., an a carbon that is bound to a hydrogen, a carboxyl group, an amino group, and an R group, e.g., homoserine, norleucine, methionine sulfoxide, methionine methyl sulfonium. Such analogs have modified R groups (e.g., norleucine) or modified peptide backbones, but retain the same basic chemical structure as a naturally occurring amino acid. Amino acid mimetics refers to chemical compounds that have a structure that is different from the general chemical structure of an amino acid, but that functions in a manner similar to a naturally occurring amino acid. The terms “non-naturally occurring amino acid” and “unnatural amino acid” refer to amino acid analogs, synthetic amino acids, and amino acid mimetics which are not found in nature.

[0134] Amino acids may be referred to herein by either their commonly known three letter symbols or by the one-letter symbols recommended by the IUPAC-IUB Biochemical Nomenclature Commission. Nucleotides, likewise, may be referred to by their commonly accepted single-letter codes.

[0135] The terms “polypeptide,” “peptide,” and “protein” are used interchangeably herein to refer to a polymer of amino acid residues, wherein the polymer may in embodiments be conjugated to a moiety that does not consist of amino acids. The terms apply to amino acid polymers in which one or more amino acid residue is an artificial chemical mimetic of a corresponding naturally occurring amino acid, as well as to naturally occurring amino acid polymers and non-naturally occurring amino acid polymers.

[0136] An amino acid or nucleotide base “position” is denoted by a number that sequentially identifies each amino acid (or nucleotide base) in the reference sequence based on its position relative to the N-terminus (or 5'-end). Due to deletions, insertions, truncations, fusions, and the like that must be taken into account when determining an optimal alignment, in general the amino acid residue number in a test sequence determined by simply counting from the N-terminus will not necessarily be the same as the number of its corresponding position in the reference sequence. For example, in a case where a variant has a deletion relative to an aligned reference sequence, there will be no amino acid in the variant thatcorresponds to a position in the reference sequence at the site of deletion. Where there is an insertion in an aligned reference sequence, that insertion will not correspond to a numbered amino acid position in the reference sequence. In the case of truncations or fusions there can be stretches of amino acids in either the reference or aligned sequence that do not correspond to any amino acid in the corresponding sequence.

[0137] The terms "numbered with reference to’' or “corresponding to,’' when used in the context of the numbering of a given amino acid or polynucleotide sequence, refers to the numbering of the residues of a specified reference sequence when the given amino acid or polynucleotide sequence is compared to the reference sequence.

[0138] The term “protein complex” is used in accordance with its plain ordinary meaning and refers to a protein which is associated with an additional substance (e.g., another protein, protein subunit, or a compound). Protein complexes typically have defined quaternary structure. The association between the protein and the additional substance may be a covalent bond. In embodiments, the association between the protein and the additional substance (e.g., compound) is via non-covalent interactions. In embodiments, a protein complex refers to a group of two or more polypeptide chains. Proteins in a protein complex are linked by non-covalent protein-protein interactions. A non-limiting example of a protein complex is the proteasome.

[0139] The term “protein aggregate” is used in accordance with its plain ordinary meaning and refers to an aberrant collection or accumulation of proteins (e.g., misfolded proteins). Protein aggregates are often associated with diseases (e.g., amyloidosis). In embodiments, when a protein misfolds as a result of a change in the amino acid sequence or a change in the native environment which disrupts normal non-covalent interactions, and the misfolded protein is not corrected or degraded, the unfolded / misfolded protein may aggregate. There are three main types of protein aggregates that may form: amorphous aggregates (also referred to herein as amorphous protein aggregates), oligomers (also referred to herein as protein oligomers), and amyloid fibrils.II. Compounds

[0140] In an aspect is provided a compound, or a pharmaceutically acceptable salt or tautomer thereof, having the formula:

[0141] Ring A is cycloalkyl (e.g., C3-Cs, C3-C6. or Cs-Ce), heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), aryl (e.g., Ce-Cio, C10, or phenyl), or heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0142] L1is a bond, substituted or unsubstituted alkylene (e.g., Ci-Cs, Ci-Ce, or C1-C4), or substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered).

[0143] R1is independently halogen. -CXS, -CHX^, -CH2X1. -OCX^, -OCH2X1, -OCHX^, -CN, -SOniR1D, -SOviNR1AR1B, -NR1CNR1AR1B, -ONR1AR1B, -NR1CC(0)NR1AR1B, -N(O)mi, -NR1AR1B, -C(O)R1C, -C(O)OR1C, -C(O)NR1AR1B, -OR1D, -NR1ASO2R1D, -NR1AC(O)R1C, -NR1AC(O)OR1C, -NR1A0R1C, -SF5, -N3, substituted or unsubstituted alkyl (e.g.. Ci-Cs, Ci-Ce, or C1-C4), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or Cs-Ce), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., Ce-Cio. C10, or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); two R1substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl (e.g., C3-Cs, C3-C6, or Cs-Cg), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., Cg-Cio, C10, or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0144] The symbol zl is an integer from 0 to 4.

[0145] R2is hydrogen, halogen, -CC13, -CBr3. -CF3. -CI3, -CHCh, -CHBr2. -CHF2. -CHI2, -CH2C1, -CH2Br. -CH2F. -CH2I, -CN, -OH, -NH2. -COOH, -CONH2. -OCCh, -OCF?, -OCBrs, -OCh, -OCHCh, -OCHBr2, -OCHI2, -OCHF2, -OCH2C1, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl (e.g., Ci-Cs, Ci-Ce, or C1-C4), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), substituted or unsubstituted cycloalkyl (e.g.. C3-C8, C3-C6, or Cs-Cg), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., Cg-Cio, C10, or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0146] R3is independently halogen, -CX33, -CHX32, -CH2X3, -OCX?3, -OCH2X3, -OCHX32, -CN, -SOn3R3D. -SOV3NR3AR3B, -NR3CNR3AR3B. -ONR3AR3B.-NR3CC(O)NR3AR3B-N(O)m3, -NR3AR3B, -C(O)R3C, -C(O)OR3C, -C(O)NR3AR3B, -OR3D, -NR3ASO2R3D, -NR3AC(O)R3C, -NR3AC(O)OR3C, -NR3AOR3C, -SF5, -N3, substituted or unsubstituted alkyl (e.g., Ci-Cs, Ci-Cg, or C1-C4), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), substituted or unsubstituted cycloalkyl (e.g., C3-Cg, C3-C6, or Cs-Cg), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., Cg-Cio, C10, or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); two R3substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-Cg, or Cs-Cg), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., Cg-Cio, C10, or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0147] The symbol z3 is an integer from 0 to 2.

[0148] R4is independently oxo, halogen, -CX43, -CHX42. -CH2X4, -OCX43, -OCH2X4. -OCHX42, -CN, -SOn4R4D, -SOv4NR4AR4B, -NR4CNR4AR4B, -ONR4AR4B, -NR4CC(O)NR4AR4B, -N(O)m4, -NR4AR4B, -C(O)R4C, -C(O)OR4C, -C(O)NR4AR4B, -OR4D, -NR4ASO2R4D, -NR4AC(O)R4C, -NR4AC(O)OR4C, -NR4AOR4C, -SF5, -N3, substituted or unsubstituted alkyl (e.g.. Ci-Cs, Ci-Cg, or C1-C4). substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), substituted or unsubstituted cycloalkyl (e.g., C3-Cs, C3-C6, or Cs-Cg), substituted or unsubstituted heterocycloalkyl (e.g., 3to 8 membered, 3 to 6 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C10. Cio, or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered): two R4substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl (e.g., Cs-Cs, C3-C6, or Cs-Ce), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., Ce-Cio, Cio, or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0149] The symbol z4 is an integer from 0 to 11.

[0150] R5is hydrogen, halogen, -CCI3, -CBr3, -CF3, -CI3, -CH2C1, -CH2Br, -CH2F, -CH2I, -CHC12, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -0NH2, -NHC(0)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI3, -OCBr3. -OCF3. -OCI3, -OCH2C1. -OCH2Br, -OCH2F, -OCH2I. -OCHCh, -OCHBr2, -OCHF2, -OCHI2, -SF5, -Ns, substituted or unsubstituted alkyl (e.g., Ci-Cs, Ci-Ce, or C1-C4), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or Cs-Ce). substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., Ce-Cio, Cio, or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0151] R1A, R1B, R1C, R1D, R3A, R3B, R3C, R3D, R4A, R4B, R4C, and R4Dare independently hydrogen, halogen. -CCI3, -CBr3, -CF3, -CI3, -CHCI2, -CHBr2, -CHF2, -CHI2. -CH2C1, -CH2Br, -CH2F, -CH2I, -CN. -OH. -NH2, -COOH. -CONH2, -OCCI3. -OCF3. -OCBr3, -OCI3, -OCHC12, -OCHBr2, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyd (e.g., Ci-Cs, Ci-Ce, or C1-C4), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or Cs-Ce), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., Ce-Cio, Cio, or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); R1Aand R1Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 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); R3Aand R3Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substitutedor unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 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); R4Aand R4Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 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).

[0152] Each X1, X3, and X4is independently -F, -Cl, -Br. or -I.

[0153] The symbols nl, n3, and n4 are independently an integer from 0 to 4.

[0154] The symbols ml, m3, m4, vl, v3, and v4 are independently 1 or 2.

[0155] In embodiments, when Ring A is phenyl and z4 is 0, then R3is not unsubstituted isopropyl, unsubstituted cyclopropyl, unsubstituted furanyl, or unsubstituted thienyl. In embodiments, when Ring A is phenyl and z4 is 0, then R3is not substituted or unsubstituted isopropyl, substituted or unsubstituted cyclopropyl, substituted or unsubstituted furanyl, or substituted or unsubstituted thienyl.

[0156] In embodiments, the compound has the formula: Ring A, L1, R1, zl, R2, R3, z3, R4, z4, andR3are as described herein, including in embodiments.

[0157] In embodiments, the compound has the formula:Ring A, L1, R1, zl, R2, R3, z3, R4, and z4 are as described herein, including in embodiments.

[0158] In embodiments, the compound has the formula:Ring A, L1, R1, zl, R2, R3, z3, R4, z4, and R5are as described herein, including in embodiments.

[0159] In embodiments, the compound has the formula:Ring A, L1, R1, zl, R2, R3, z3. R4. and z4 are as described herein, including in embodiments.

[0160] In embodiments, Ring A is Cs-Cs cycloalkyl, 3 to 8 membered heterocycloalkyl, phenyl, or 5 to 6 membered heteroaryl. In embodiments, Ring A is C’s-C's cycloalkyl. In embodiments, Ring A is 3 to 8 membered heterocycloalkyl. In embodiments, Ring A is phenyl. In embodiments, Ring A is 5 to 6 membered heteroaryl.

[0161] In embodiments. Ring A is phenyl, pyridyl, pyrazinyl, or pyrimidinyl. In embodiments, Ring A is phenyl. In embodiments, Ring A is pyridyl. In embodiments, Ring A is 2 -pyridyl. In embodiments, Ring A is 3-pyridyl. In embodiments, Ring A is 4-pyridyl. In embodiments, Ring A is pyrazinyl. In embodiments. Ring A is pyrimidinyl. In embodiments, Ring A is 2 -pyrimidinyl. In embodiments. Ring A is 4-pyrimidinyl. In embodiments, Ring A is 5-pyrimidinyl. In embodiments, Ring A is pyridazinyl. In embodiments, Ring A is 3-pyridazinyl. In embodiments, Ring A is 4-pyridazinyl. In embodiments, Ring A is thienyl. In embodiments, Ring A is 2-thienyl. In embodiments, Ring A is 3-thienyl.

[0164] In embodiments, a substituted L1(e.g.. substituted alkylene and / or substituted heteroalkylene) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted L1is 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 L1is substituted, it is substituted with at least one substituent group. In embodiments, when L1is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when L1is substituted, it is substituted with at least one lower substituent group.

[0165] In embodiments, L1is a bond, substituted or unsubstituted C1-C4 alkylene, or substituted or unsubstituted 2 to 6 membered heteroalkylene. In embodiments, L1is a bond. In embodiments, L1is substituted or unsubstituted C1-C4 alkylene. In embodiments, L1is unsubstituted C1-C4 alkylene. In embodiments, L1is unsubstituted methylene. In embodiments, L1is unsubstituted ethylene. In embodiments, L1is. In embodiments, L1is unsubstituted propylene. In embodiments, L1is unsubstituted n- propylene. In embodiments, L1is unsubstituted isopropylene. In embodiments, L1is unsubstituted butylene. In embodiments, L1is unsubstituted n-butylene. In embodiments, L1is unsubstituted isobuty lene. In embodiments, L1is unsubstituted tert-butylene. In embodiments, L1is substituted or unsubstituted 2 to 6 membered heteroalkylene. In embodiments, L1is oxo-substituted 2 to 6 membered heteroalkylene. In embodiments. L1is unsubstituted 2 to 6 membered heteroalkylene.

[0166] In embodiments, a substituted R1(e.g., substituted alkyl, substituted heteroalkyd, substituted cycloalkyl, substituted heterocycloalkyl, substituted ary l, and / or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R1is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituentgroups: each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, when R1is substituted, it is substituted with at least one substituent group. In embodiments, when R1is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R1is substituted, it is substituted with at least one lower substituent group.

[0167] In embodiments, a substituted ring formed when two R1substituents are joined (e.g., 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 ring formed when two R1substituents 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 two R1substituents are joined is substituted, it is substituted with at least one substituent group. In embodiments, when the substituted ring formed when two R1substituents are joined is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when the substituted ring formed when two R1substituents are joined is substituted, it is substituted with at least one lower substituent group.

[0168] In embodiments, a substituted R1A(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 R1Ais 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 R1Ais substituted, it is substituted with at least one substituent group. In embodiments, when R1Ais substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R1Ais substituted, it is substituted with at least one lower substituent group.

[0169] In embodiments, a substituted R1B(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyd, 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 R1Bis substituted with a plurality ofgroups 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 R1Bis substituted, it is substituted with at least one substituent group. In embodiments, when R1Bis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R1Bis substituted, it is substituted with at least one lower substituent group.

[0170] In embodiments, a substituted ring formed when R1Aand R1Bsubstituents bonded to the same nitrogen atom are joined (e.g., substituted heterocycloalkyl and / 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 R1Aand R1Bsubstituents bonded to the same nitrogen atom 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 R1Aand R1Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one substituent group. In embodiments, when the substituted ring formed when R1Aand R1Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when the substituted ring formed when R1Aand R1Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one lower substituent group.

[0171] In embodiments, a substituted R1C(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 R1Cis 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 R1Cis substituted, it is substituted with at least one substituent group. In embodiments, when R1Cis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R1Cis substituted, it is substituted with at least one lower substituent group.

[0172] In embodiments, a substituted R1D(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substitutedheteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R1Dis 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 R1Dis substituted, it is substituted with at least one substituent group. In embodiments, when R1Dis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R1Dis substituted, it is substituted with at least one lower substituent group.

[0173] In embodiments, R1Ais hydrogen. In embodiments, R1Ais unsubstituted C1-C4 alky l. In embodiments, R1Ais unsubstituted methyl. In embodiments, R1Ais unsubstituted ethyl. In embodiments, R1Ais unsubstituted propyl. In embodiments, R1Ais unsubstituted n- propyl. In embodiments, R1Ais unsubstituted isopropyl. In embodiments, R1Ais unsubstituted butyl. In embodiments, R1Ais unsubstituted n-butyl. In embodiments, R1Ais unsubstituted isobutyl. In embodiments, R1Ais unsubstituted tert-butyl.

[0174] In embodiments, R1Bis hydrogen. In embodiments, R1Bis unsubstituted C1-C4 alkyl. In embodiments, R1Bis unsubstituted methyl. In embodiments, R1Bis unsubstituted ethyl. In embodiments, R1Bis unsubstituted propyl. In embodiments, R1Bis unsubstituted n- propyl. In embodiments, R1Bis unsubstituted isopropyl. In embodiments, R1Bis unsubstituted butyl. In embodiments, R1Bis unsubstituted n-butyl. In embodiments, R1Bis unsubstituted isobutyl. In embodiments, R1Bis unsubstituted tert-butyl.

[0175] In embodiments, R1Cis hydrogen. In embodiments, R1Cis unsubstituted C1-C4 alkyl. In embodiments, R1Cis unsubstituted methyl. In embodiments, R1Cis unsubstituted ethyl. In embodiments, R1Cis unsubstituted propyl. In embodiments, R1Cis unsubstituted n- propyl. In embodiments, R1Cis unsubstituted isopropyl. In embodiments, R1Cis unsubstituted butyl. In embodiments, R1Cis unsubstituted n-butyl. In embodiments. R1Cis unsubstituted isobutyl. In embodiments, R1Cis unsubstituted tert-butyl.

[0176] In embodiments. R1Dis hydrogen. In embodiments. R1Dis unsubstituted C1-C4 alkyl. In embodiments, R1Dis unsubstituted methyl. In embodiments, R1Dis unsubstituted ethyl. In embodiments, R1Dis unsubstituted propyl. In embodiments, R1Dis unsubstituted n- propyl. In embodiments, R1Dis unsubstituted isopropyl. In embodiments, R1Dis unsubstituted butyl. In embodiments, R1Dis unsubstituted n-butyl. In embodiments. R1Dis unsubstituted isobutyl. In embodiments, R1Dis unsubstituted tert-butyl.

[0177] In embodiments, R1is independently halogen, -CCh, -CBn. -CF3, -CI3, -CH2CI, -CH2Br, -CH2F, -CH2I, -CHCh, -CHBr2, -CHF2, -CHI2. -CN. -OH. -NH2, -COOH. -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2,-NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI3, -OCBr3, -OCF3, -OCI3, -OCH2CI, -OCH2Br, -OCH2F, -OCH2I, -OCHCI2, -OCHBr2, -OCHF2, -OCHI2. -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0178] In embodiments, R1is independently halogen. In embodiments, R1is independently -F. In embodiments, R1is independently -Cl. In embodiments, R1is independently -Br. In embodiments, R1is independently -I. In embodiments. R1is independently -CCI3. In embodiments, R1is independently -CBr3. In embodiments, R1is independently -CFs. In embodiments, R1is independently -CI3. In embodiments, R1is independently -CH2C1. In embodiments, R1is independently -CH2Br. In embodiments, R1is independently -CH2F. In embodiments, R1is independently -CH2I. In embodiments. R1is independently -CHCh. In embodiments, R1is independently -CHBr2. In embodiments, R1is independently -CHF2. In embodiments, R1is independently -CHI2. In embodiments, R1is independently -CN. In embodiments, R1is independently -OH. In embodiments, R1is independently -NH2. In embodiments, R1is independently -COOH. In embodiments, R1is independently -CONH2. In embodiments. R1is independently -NO2. In embodiments. R1is independently -SH. In embodiments, R1is independently -SO3H. In embodiments, R1is independently -OSO3H. In embodiments, R1is independently -SO2NH2. In embodiments, R1is independently -NHNH2. In embodiments. R1is independently -ONH2. In embodiments, R1is independently -NHC(O)NH2. In embodiments, R1is independently -NHSO2H. In embodiments, R1is independently -NHC(O)H. In embodiments, R1is independently -NHC(O)OH. In embodiments, R1is independently -NHOH. In embodiments, R1is independently -OCCI3. In embodiments, R1is independently -OCBn. In embodiments, R1is independently -OCF3. In embodiments, R1is independently -OCI3. In embodiments, R1is independently -OCH2C1. In embodiments, R1is independently -OCH2Br. In embodiments, R1is independently -OCH2F. In embodiments, R1is independently -OCH2I. In embodiments, R1is independently -OCHCh. In embodiments, R1is independently -OCHBr2. In embodiments, R1is independently -OCHF2. In embodiments, R1is independently -OCHI2. In embodiments, R1is independently -SF5. In embodiments, R1is independently -N3. Inembodiments, R1is independently unsubstituted C1-C4 alkyl. In embodiments, R1is independently unsubstituted methyl. In embodiments, R1is independently unsubstituted ethyl. In embodiments, R1is independently unsubstituted propyl. In embodiments, R1is independently unsubstituted n-propyl. In embodiments, R1is independently unsubstituted isopropyl. In embodiments, R1is independently unsubstituted buty l. In embodiments, R1is independently unsubstituted n-butyl. In embodiments, R1is independently unsubstituted isobutyl. In embodiments. R1is independently unsubstituted tert-butyl. In embodiments, R1is independently unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R1is independently unsubstituted methoxy. In embodiments, R1is independently unsubstituted ethoxy. In embodiments, R1is independently unsubstituted propoxy. In embodiments, R1is independently unsubstituted n-propoxy. In embodiments. R1is independently unsubstituted isopropoxy. In embodiments, R1is independently unsubstituted butoxy.

[0179] In embodiments, R1is independently halogen, unsubstituted C1-C4 alkyd, or unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R1is independently -F, unsubstituted methyl, or. in embodiments. R is independently -(unsubstitutedC1-C4 alkyl)-NH-(unsubstituted C1-C4 alkyl). In embodiments, R1is independently. In embodiments, R1is independently unsubstituted C1-C4 alkynyl. In embodiments, R1is independently. In embodiments, R1is independently

[0180] In embodiments, two R1substituents are joined to form a substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, two R1substituents are joined to form a substituted or unsubstituted C3-C8 cycloalkyl. In embodiments, two R1substituents are joined to form a substituted or unsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, two R1substituents are joined to form a substituted or unsubstituted phenyl. In embodiments, two R1substituents are joined to form an unsubstituted phenyl. In embodiments, two R1substituentsare joined to form a substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, two R1substituents are joined to form an unsubstituted pyridyl.

[0181] In embodiments, two R1substituents are joined to form. In embodiments, two R1substituents are joined to form

[0182] In embodiments, zl is 0. In embodiments, zl is 1. In embodiments, zl is 2. In embodiments, zl is 3. In embodiments, zl is 4.

[0184] In embodiments, a substituted R2(e.g., substituted alkyl, substituted heteroalkyd, substituted cycloalkyl, substituted heterocycloalky 1, substituted ary l, and / or substituted heteroaryl) is 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 substituentgroups: 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 size-limited substituent group. In embodiments, when R2is substituted, it is substituted with at least one lower substituent group.

[0185] In embodiments, R2is hydrogen. In embodiments, R2is unsubstituted C1-C4 alkyl. In embodiments, R2is unsubstituted methyl. In embodiments, R2is unsubstituted ethyl. In embodiments, R2is unsubstituted propyl. In embodiments, R2is unsubstituted n-propyl. In embodiments, R2is unsubstituted isopropyl. In embodiments, R2is unsubstituted butyl. In embodiments, R2is unsubstituted n-butyl. In embodiments, R2is unsubstituted isobutyl. In embodiments, R2is unsubstituted tert-butyl.

[0186] In embodiments, a substituted R3(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 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 optionally 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 size-limited substituent group. In embodiments, when R3is substituted, it is substituted with at least one lower substituent group.

[0187] In embodiments, a substituted ring formed when two R3substituents are joined (e.g., 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 ring formed when two R3substituents 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 two R3substituents are joined is substituted, it is substituted with at least one substituent group. In embodiments, when the substituted ring formed when two R3substituents are joined is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when the substituted ringformed when two R3substituents are joined is substituted, it is substituted with at least one lower substituent group.

[0188] In embodiments, a substituted R3A(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 R3Ais 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 R3Ais substituted, it is substituted with at least one substituent group. In embodiments, when R3Ais substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R3Ais substituted, it is substituted with at least one lower substituent group.

[0189] In embodiments, a substituted R3B(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 R3Bis 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 R3Bis substituted, it is substituted with at least one substituent group. In embodiments, when R3Bis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R3Dis substituted, it is substituted with at least one lower substituent group.

[0190] In embodiments, a substituted ring formed when R3Aand R3Bsubstituents bonded to the same nitrogen atom are joined (e.g., substituted heterocycloalkyl and / 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 R3Aand R3Bsubstituents bonded to the same nitrogen atom are joined is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and low er substituent groups; each substituent group, size-limited substituent group, and / or low er substituent group may optionally be different. In embodiments, when the substituted ring formed when R3Aand R3Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one substituent group. In embodiments, when the substituted ring formed when R3Aand R3Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when the substituted ring formed when R3Aand R3Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one lower substituent group.

[0191] In embodiments, a substituted R3C(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 R3Cis 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 R3Cis substituted, it is substituted with at least one substituent group. In embodiments, when R3Cis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R3Cis substituted, it is substituted with at least one lower substituent group.

[0192] In embodiments, a substituted R3D(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyd, 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 R3Dis 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 R3Dis substituted, it is substituted with at least one substituent group. In embodiments, when R3Dis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R3Dis substituted, it is substituted with at least one lower substituent group.

[0193] In embodiments, R3Ais hydrogen. In embodiments, R3Ais unsubstituted C1-C4 alkyl. In embodiments, R3Ais unsubstituted methyl. In embodiments, R3Ais unsubstituted ethyl. In embodiments, R3Ais unsubstituted propyl. In embodiments, R3Ais unsubstituted n- propyl. In embodiments, R3Ais unsubstituted isopropyl. In embodiments, R3Ais unsubstituted butyl. In embodiments, R3Ais unsubstituted n-butyl. In embodiments. R3Ais unsubstituted isobutyl. In embodiments, R3Ais unsubstituted tert-butyl.

[0194] In embodiments, R3Bis hydrogen. In embodiments. R3Bis unsubstituted C1-C4 alkyl. In embodiments, R3Bis unsubstituted methyl. In embodiments, R3Bis unsubstitutedethyl. In embodiments, R3Bis unsubstituted propyl. In embodiments, R3Bis unsubstituted n- propyl. In embodiments, R3Bis unsubstituted isopropyl. In embodiments, R3Bis unsubstituted butyl. In embodiments, R3Bis unsubstituted n-butyl. In embodiments, R3Bis unsubstituted isobutyl. In embodiments, R3Bis unsubstituted tert-butyl.

[0195] In embodiments, R3Cis hydrogen. In embodiments, R3Cis unsubstituted C1-C4 alky l. In embodiments, R?cis unsubstituted methyl. In embodiments, R3Cis unsubstituted ethyl. In embodiments, R3Cis unsubstituted propyl. In embodiments, R3Cis unsubstituted n- propyl. In embodiments, R3Cis unsubstituted isopropyl. In embodiments, R3Cis unsubstituted butyl. In embodiments, R3Cis unsubstituted n-butyl. In embodiments, R3Cis unsubstituted isobutyl. In embodiments, R3Cis unsubstituted tert-buty l.

[0196] In embodiments, R3Dis hydrogen. In embodiments, R3Dis unsubstituted C1-C4 alkyl. In embodiments, R3Dis unsubstituted methyl. In embodiments, R3Dis unsubstituted ethyl. In embodiments, R3Dis unsubstituted propyl. In embodiments, R3Dis unsubstituted n- propyl. In embodiments, R3Dis unsubstituted isopropyl. In embodiments, R3Dis unsubstituted butyl. In embodiments, R3Dis unsubstituted n-butyl. In embodiments, R3Dis unsubstituted isobutyl. In embodiments, R3Dis unsubstituted tert-butyl. In embodiments, R3Dis unsubstituted Cs-Cs cycloalkyl. In embodiments, R3Dis unsubstituted cyclopropyl. In embodiments, R3Dis unsubstituted cyclobutyl. In embodiments, R3Dis unsubstituted cyclopentyl. In embodiments, R3Dis unsubstituted cyclohexyl. In embodiments, R3Dis unsubstituted cycloheptyl. In embodiments. R3Dis unsubstituted cyclooctyl. In embodiments, R3Dis substituted or unsubstituted phenyl. In embodiments. R3Dis substituted phenyl. In embodiments, R3Dis unsubstituted phenyl.

[0197] In embodiments, R3is independently halogen, -CCh, -CBn, -CF3, -CI3, -CH2CI, -CH2Br, -CH2F, -CH2I, -CHCI2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH. -SO3H. -OSO3H. -SO2NH2, -NHNH2. -ONH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI3, -OCBr3, -OCF3, -OCI3, -OCH2CI, -OCH2Br, -OCH2F, -OCH2I, -OCHCI2, -OCHBr2, -OCHF2, -OCHI2, -SF5, -NS, substituted or unsubstituted alkyd, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two R3substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroary 1.

[0198] In embodiments, R3is independently halogen. In embodiments, R3is independently -F. In embodiments, R3is independently -Cl. In embodiments, R3is independently -Br. In embodiments, R3is independently -I. In embodiments, R3is independently -CCh. In embodiments, R3is independently -CBr?. In embodiments, R3is independently -CF3. In embodiments, R3is independently -CI3. In embodiments, R3is independently -CH2CI. In embodiments, R3is independently -CFhBr. In embodiments, R3is independently -CH2F. In embodiments, R3is independently -CH2I. In embodiments. R3is independently -CHCI2. In embodiments, R3is independently -CHBr2. In embodiments, R3is independently -CHF2. In embodiments, R3is independently -CHI2. In embodiments, R3is independently -CN. In embodiments, R" is independently -OH. In embodiments, R3is independently -NH2. In embodiments, R3is independently -COOH. In embodiments, R3is independently -CONH2. In embodiments, R3is independently -NO2. In embodiments, R3is independently -SH. In embodiments, R3is independently -SO3H. In embodiments, R3is independently -OSO3H. In embodiments, R’ is independently -SO2NH2. In embodiments, R3is independently -NHNH2. In embodiments, R3is independently -ONH2. In embodiments, R3is independently -NHC(O)NH2. In embodiments, R3is independently -NHSO2H. In embodiments, R3is independently -NHC(O)H. In embodiments, R3is independently -NHC(O)OH. In embodiments, R3is independently -NHOH. In embodiments, R3is independently -OCCI3. In embodiments, R3is independently -OCBn. In embodiments, R3is independently -OCF3. In embodiments, R3is independently -OCI3. In embodiments, R3is independently -OCH2CI. In embodiments, R3is independently -OCH2BE In embodiments, R3is independently -OCH2F. In embodiments, R3is independently -OCH2I. In embodiments, R3is independently -OCHCI2. In embodiments, R3is independently -OCHBt2. In embodiments, R3is independently -OCHF2. In embodiments, R3is independently -OCHI2. In embodiments, R3is independently -SF5. In embodiments, R3is independently -N3. In embodiments, R3is independently unsubstituted C1-C4 alkyl. In embodiments. R3is independently unsubstituted methyl. In embodiments, R3is independently unsubstituted ethyl. In embodiments, R3is independently unsubstituted propyl. In embodiments, R3is independently unsubstituted n-propyl. In embodiments, R3is independently unsubstituted isopropyl. In embodiments, R3is independently unsubstituted butyl. In embodiments. R3is independently unsubstituted n-butyl. In embodiments, R3is independently unsubstituted isobutyl. In embodiments, R3is independently unsubstituted tert-butyl. In embodiments, R3is independently unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R3isindependently unsubstituted methoxy. In embodiments, R3is independently unsubstituted ethoxy. In embodiments, R3is independently unsubstituted propoxy. In embodiments, R3is independently unsubstituted n-propoxy. In embodiments, R3is independently unsubstituted isopropoxy. In embodiments, R3is independently unsubstituted butoxy.

[0199] In embodiments, R3is independently -CX33, -CHX32, -CH2X3, -NR'AC(O)R3<. -NR3ASO2R3D, substituted or unsubstituted C1-C4 alkyl, or substituted or unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R3is independently -NR3AC(O)R3C, wherein R3Aand R3Care as described herein, including in embodiments. In embodiments, R3is independently -NR3ASO2R3D, wherein R3Aand R3Dare as described herein, including in embodiments.

[0200] In embodiments, R3is independently -CF3, -CHF2, -CH2F, unsubstituted methyl,in embodiments, R3is independently. In embodiments.R’ is independentlyin embodiments, R’ is independently inembodiments, R3is independently in embodiments, R3is independently

[0201] In embodiments, two R3substituents are joined to form a substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, two R3substituents are joined to form a substituted or unsubstituted C3-C8 cycloalkyl. In embodiments, two R3substituents are joined to form a substituted or unsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, two R3substituents are joined to form a substituted or unsubstituted phenyl. In embodiments, two R3substituents are joined to form a substituted or unsubstituted 5 to 6 membered heteroaryl.

[0202] In embodiments, two R3substituents are joined to form. In embodiments, two R3substituents are j oined to form. In embodiments, two R3substituents are joined to form. In embodiments, two R3substituents are joined to form

[0203] In embodiments, z3 is 0. In embodiments. z3 is 1. In embodiments, z3 is 2.

[0204] In embodiments, a substituted R4(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 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.

[0205] In embodiments, a substituted ring formed when two R4substituents are joined (e g., 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 ring formed when two 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-limitedsubstituent group, and / or lower substituent group may optionally be different. In embodiments, when the substituted ring formed when two R4substituents are joined is substituted, it is substituted with at least one substituent group. In embodiments, when the substituted ring formed when two R4substituents are joined is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when the substituted ring formed when two R4substituents are joined is substituted, it is substituted with at least one lower substituent group.

[0206] In embodiments, a substituted R4A(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 R4Ais 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 R4Ais substituted, it is substituted with at least one substituent group. In embodiments, when R4Ais substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R4Ais substituted, it is substituted with at least one lower substituent group.

[0207] In embodiments, a substituted R4B(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 R4Bis 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 R4Bis substituted, it is substituted with at least one substituent group. In embodiments, when R4Bis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R4Bis substituted, it is substituted with at least one lower substituent group.

[0208] In embodiments, a substituted ring formed when R4Aand R4Bsubstituents bonded to the same nitrogen atom are joined (e.g., substituted heterocycloalky l and / 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 R4Aand R4Bsubstituents bonded to the same nitrogen atom are joined is substituted with a plurality of groups selectedfrom 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 R4Aand R4Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one substituent group. In embodiments, when the substituted ring formed when R4Aand R4Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when the substituted ring formed when R4Aand R4Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one lower substituent group.

[0209] In embodiments, a substituted R4C(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 R4Cis 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 R4Cis substituted, it is substituted with at least one substituent group. In embodiments, when R4Cis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R4Cis substituted, it is substituted with at least one lower substituent group.

[0210] In embodiments, a substituted R4D(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 R4Dis 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 R4Dis substituted, it is substituted with at least one substituent group. In embodiments, when R4Dis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R4Dis substituted, it is substituted with at least one lower substituent group.

[0211] In embodiments, R4Ais hydrogen. In embodiments. R4Ais unsubstituted C1-C4 alkyl. In embodiments, R4Ais unsubstituted methyl. In embodiments, R4Ais unsubstituted ethyl. In embodiments, R4Ais unsubstituted propyl. In embodiments, R4Ais unsubstituted n-propyl. In embodiments, R4Ais unsubstituted isopropyl. In embodiments, R4Ais unsubstituted butyl. In embodiments, R4Ais unsubstituted n-butyl. In embodiments. R4Ais unsubstituted isobutyl. In embodiments, R4Ais unsubstituted tert-butyl. In embodiments, R4Ais unsubstituted Cg-C'x cycloalkyl. In embodiments, R4Ais unsubstituted cyclopropyl. In embodiments, R4Ais unsubstituted cyclobutyl. In embodiments, R4Ais unsubstituted cyclopentyl. In embodiments, R4Ais unsubstituted cyclohexyl. In embodiments, R4Ais unsubstituted cycloheptyl. In embodiments. R4Ais unsubstituted cyclooctyl.

[0212] In embodiments, R4Bis hydrogen. In embodiments, R4Bis unsubstituted C1-C4 alkyl. In embodiments, R4Bis unsubstituted methyl. In embodiments, R4Bis unsubstituted ethyl. In embodiments, R4Bis unsubstituted propyl. In embodiments, R4Bis unsubstituted n- propyl. In embodiments, R4Bis unsubstituted isopropyl. In embodiments, R4Bis unsubstituted butyl. In embodiments. R4Bis unsubstituted n-butyl. In embodiments. R4Bis unsubstituted isobutyl. In embodiments, R4Bis unsubstituted tert-butyl.

[0213] In embodiments, R4Aand R4Bsubstituents bonded to the same nitrogen atom are joined to form a substituted or unsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, R4Aand R4Bsubstituents bonded to the same nitrogen atom are joined to form a substituted or unsubstituted morpholinyl. In embodiments, R4Aand R4Bsubstituents bonded to the same nitrogen atom are joined to form an unsubstituted morpholinyl. In embodiments, R4Aand R4Bsubstituents bonded to the same nitrogen atom are joined to form a substituted or unsubstituted piperazinyl.

[0214] In embodiments, R4Cis hydrogen. In embodiments, R4Cis unsubstituted C1-C4 alkyl. In embodiments, R4Cis unsubstituted methyl. In embodiments, R4Cis unsubstituted ethyl. In embodiments, R4Cis unsubstituted propyl. In embodiments, R4Cis unsubstituted n- propyl. In embodiments, R4Cis unsubstituted isopropyl. In embodiments, R4Cis unsubstituted butyl. In embodiments, R4Cis unsubstituted n-butyl. In embodiments. R4Cis unsubstituted isobutyl. In embodiments, R4Cis unsubstituted tert-butyl.

[0215] In embodiments. R4Dis hydrogen. In embodiments. R4Dis unsubstituted C1-C4 alkyl. In embodiments, R4Dis unsubstituted methyl. In embodiments, R4Dis unsubstituted ethyl. In embodiments, R4Dis unsubstituted propyl. In embodiments, R4Dis unsubstituted n- propyl. In embodiments, R4Dis unsubstituted isopropyl. In embodiments, R4Dis unsubstituted butyl. In embodiments, R4Dis unsubstituted n-butyl. In embodiments. R4Dis unsubstituted isobutyl. In embodiments, R4Dis unsubstituted tert-butyl.

[0216] In embodiments, R4is independently oxo, halogen, -CCk. -CBn, -CF3, -CI3, -CH2CI, -CH2Br. -CH2F. -CH2I, -CHCh, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI3, -OCBr3, -OCF3, -OCI3, -OCH2CI, -OCH2Br, -OCH2F, -OCH2I, -OCHCh, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two R4substituents may optionally be joined to form a substituted or unsubstituted cy cloalkyl, substituted or unsubstituted heterocycloalkyl. substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0217] In embodiments, R4is independently oxo. In embodiments. R4is independently halogen. In embodiments, R4is independently -F. In embodiments, R4is independently -Cl. In embodiments, R4is independently -Br. In embodiments, R4is independently -I. In embodiments, R4is independently -CCI3. In embodiments, R4is independently -CBr3. In embodiments, R4is independently -CF3. In embodiments, R4is independently -CI3. In embodiments, R4is independently -CH2CI. In embodiments, R4is independently -CH2Br. In embodiments, R4is independently -CH2F. In embodiments, R4is independently -CH2I. In embodiments, R4is independently -CHC12. In embodiments, R4is independently -CHBr2. In embodiments, R4is independently -CHF2. In embodiments, R4is independently -CHI2. In embodiments, R4is independently -CN. In embodiments, R4is independently -OH. In embodiments, R4is independently -NH2. In embodiments, R4is independently -COOH. In embodiments, R4is independently -CONH2. In embodiments, R4is independently -NO2. In embodiments, R4is independently -SH. In embodiments, R4is independently -SO3H. In embodiments, R4is independently -OSO3H. In embodiments, R4is independently -SO2NH2. In embodiments, R4is independently -NHNH2. In embodiments, R4is independently -ONH2. In embodiments, R4is independently -NHC(O)NH2. In embodiments, R4is independently -NHSO2H. In embodiments, R4is independently -NHC(O)H. In embodiments, R4is independently -NHC(O)OH. In embodiments, R4is independently -NHOH. In embodiments, R4is independently -OCCI3. In embodiments, R4is independently -OCBr; In embodiments, R4is independently -OCF3. In embodiments, R4is independently -OCI3. In embodiments, R4is independently -OCH2CI. In embodiments, R4is independently -OCftBr. In embodiments, R4is independently -OCH2F. In embodiments, R4is independently -OCH2I. In embodiments, R4is independently -OCHCh. In embodiments,R4is independently -OCHBrz. In embodiments, R4is independently -OCHF2. In embodiments, R4is independently -OCHI2. In embodiments. R4is independently -SF5. In embodiments, R4is independently -N3. In embodiments, R4is independently unsubstituted C1-C4 alkyl. In embodiments, R4is independently unsubstituted methyl. In embodiments, R4is independently unsubstituted ethyl. In embodiments, R4is independently unsubstituted propyl. In embodiments, R4is independently unsubstituted n-propyl. In embodiments, R4is independently unsubstituted isopropyl. In embodiments, R4is independently unsubstituted butyl. In embodiments, R4is independently unsubstituted n-butyl. In embodiments, R4is independently unsubstituted isobutyl. In embodiments, R4is independently unsubstituted tert-butyl. In embodiments, R4is independently unsubstituted 2 to 6 membered heteroalkyl. In embodiments. R4is independently unsubstituted methoxy. In embodiments. R4is independently unsubstituted ethoxy. In embodiments, R4is independently unsubstituted propoxy. In embodiments, R4is independently unsubstituted n-propoxy. In embodiments, R4is independently unsubstituted isopropoxy. In embodiments, R4is independently unsubstituted butoxy.

[0218] In embodiments, R4is independently halogen. -CX43, -OCX43, -SOn4R4D, -SOV4NR4AR4B, -C(O)OR4C, -C(O)NR4AR4B, substituted or unsubstituted C1-C4 alkyl, or substituted or unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R4is independently -SOn4R4D, wherein n4 and R4Dare as described herein, including in embodiments. In embodiments, R4is independently -SOV4NR4AR4B, wherein v4. R4A, and R4Bare as described herein, including in embodiments. In embodiments, R4is independently -C(O)OR4C, wherein R4Care as described herein, including in embodiments. In embodiments, R4is independently -C(O)NR4AR4B, wherein R4Aand R4Bare as described herein, including in embodiments.

[0219] In embodiments, R4is independently -F, -Cl, -CF3, -OCF3,embodiments, R4is independentlyembodiments, R4is independentlyIn embodiments, R4is independentlyIn embodiments, R4is independentlyIn embodiments, R4is independentlyIn embodiments, R4is independentlyembodiments, R4is independentlyIn embodiments, R4is independentlyV In embodiments, R is independently

[0220] In embodiments, z4 is 0. In embodiments, z4 is 1 . In embodiments, z4 is 2. In embodiments, z4 is 3. In embodiments, z4 is 4. In embodiments, z4 is 5. In embodiments, z4 is 6. In embodiments, z4 is 7. In embodiments, z4 is 8. In embodiments, z4 is 9. In embodiments, z4 is 10. In embodiments, z4 is 11.

[0221] In embodiments, a substituted R5(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 R5is 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 R5is substituted, it is substituted with at least one substituent group. In embodiments, when R5is substituted, it is substituted with atleast one size-limited substituent group. In embodiments, when R5is substituted, it is substituted with at least one lower substituent group.

[0222] In embodiments, R5is hydrogen. In embodiments, R5is halogen. In embodiments, R5is -F. In embodiments, R5is -Cl. In embodiments, R’ is -Br. In embodiments, R5is -I. In embodiments, R5is -CCI3. In embodiments, R5is -CBrs. In embodiments, R5is -CF3. In embodiments, R3is -CI3. In embodiments, R5is -CH2CI. In embodiments, R5is -CFhBr. In embodiments, R3is -CH2F. In embodiments, R5is -CH2I. In embodiments, R3is -CHCh. In embodiments, R5is -CHBr? In embodiments, R5is -CHF2. In embodiments, R5is -CHI2. In embodiments, R5is -CN. In embodiments, R ' is -OH. In embodiments, R5is -NH2. In embodiments, R3is -COOH. In embodiments, R5is -CONH2. In embodiments, R5is -NO2. In embodiments, R5is -SH. In embodiments, R5is -SO3H. In embodiments, R5is -OSO3H. In embodiments, R5is -SO2NH2. In embodiments, R5is -NHNH2. In embodiments, R3is -ONH2. In embodiments, R3is -NHC(O)NH2. In embodiments, R3is -NHSO2H. In embodiments, R3is -NHC(O)H. In embodiments, R3is -NHC(O)OH. In embodiments, R3is -NHOH. In embodiments, R3is -OCCI3. In embodiments. R3is -OCBrs. In embodiments, R3is -OCF3. In embodiments, R3is -OCI3. In embodiments, R3is -OCH2CI. In embodiments, R3is -OCH2BE In embodiments, R3is -OCH2F. In embodiments, R3is -OCH2I. In embodiments. R3is -OCHCh. In embodiments, R3is -OCHBr2. In embodiments, R3is -OCHF2. In embodiments, R3is -OCHI2. In embodiments, R3is -SF5. In embodiments, R3is -N3. In embodiments, R3is unsubstituted C1-C4 alkyl. In embodiments, R3is unsubstituted methyl. In embodiments, R3is unsubstituted ethyl. In embodiments, R3is unsubstituted propyl. In embodiments, R3is unsubstituted n-propyl. In embodiments, R3is unsubstituted isopropyl. In embodiments, R3is unsubstituted butyl. In embodiments, R3is unsubstituted n-butyl. In embodiments, R3is unsubstituted isobutyl. In embodiments, R3is unsubstituted lert-butyl. In embodiments, R3is unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R3is unsubstituted methoxy. In embodiments, R3is unsubstituted ethoxy. In embodiments, R3is unsubstituted propoxy. In embodiments, R3is unsubstituted n-propoxy. In embodiments, R3is unsubstituted isopropoxy. In embodiments, R3is unsubstituted butoxy.

[0223] In embodiments, when R1is substituted, R1is substituted with one or more first substituent groups denoted by R1 1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1 1substituent group is substituted, the R1 1substituent group is substituted with one or more second substituentgroups denoted by R1 2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1 2substituent group is substituted, the R1 2substituent group is substituted with one or more third substituent groups denoted by R1 3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R1, R1 1, R1 2, and R1 3have values corresponding to the values of Rww. RWW 1, RWW-2, and Rww-3, respectively, as explained in the definitions section above in the description of “first substituent group(s)7’, wherein Rww, RWWA, RWW2and RWW 3correspond to R1, R1 J, R1 2, and R1 3, respectively.

[0224] In embodiments, when two R1substituents are optionally j oined to form a moiety that is substituted (e.g., a substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl), the moiety is substituted with one or more first substituent groups denoted by R1 1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1 1substituent group is substituted, the R1 1substituent group is substituted with one or more second substituent groups denoted by R1 2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R12substituent group is substituted, the R1 2substituent group is substituted with one or more third substituent groups denoted by R1 3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R1, R1 1, R1 2, and R1 3have values corresponding to the values of Rww, RWW 1, Rww 2, and RWW 3, respectively, as explained in the definitions section above in the description of “first substituent group(s)’’, wherein Ru\ Rw^ \ R*W-2;and R"W 3correspond to R1, R1-1, R1 2, and R1 3, respectively.

[0225] In embodiments, when R1Ais substituted, R1Ais substituted with one or more first substituent groups denoted by R1A 1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1A 1substituent group is substituted, the R1A 1substituent group is substituted with one or more second substituent groups denoted by R1A2as explained in the definitions section above in the description of “first substituent group(s)’'. In embodiments, when an R1A 2substituent group is substituted, the R1A 2substituent group is substituted with one or more third substituent groups denoted by R1A 3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R1A, R1A-1, R1A 2, and R1A3have values corresponding to the values of R"w, Rww-1, Rww-2, and Rww-3, respectively, as explained in the definitionssection above in the description of “first substituent group(s)”, wherein Rww. R% w\ Rww-2, and RUW 3correspond to R1A, R1A\ R1A 2. and R1A 3, respectively.

[0226] In embodiments, when R1Bis substituted, R1Bis substituted with one or more first substituent groups denoted by R1B 1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1B 1substituent group is substituted, the R1B 1substituent group is substituted with one or more second substituent groups denoted by R1B 2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1B 2substituent group is substituted, the R1B 2substituent group is substituted with one or more third substituent groups denoted by R1B 3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R1B, R1B 1, R1B 2. and R1B 3have values corresponding to the values of Rww, Rww-1, RWW 2. and RWW 3_ respectively, as explained in the definitions section above in the description of “first substituent group(s)’’, wherein Rww, RWW 1Rww'2, and RWW 3correspond to R1B, R1B 1, R1B 2, and R1B 3, respectively.

[0227] In embodiments, when R1Aand R1Bsubstituents that are bonded to the same nitrogen atom are joined to form a moiety that is substituted (e.g., a substituted heterocycloalkyl or substituted heteroaryl), the moiety is substituted with one or more first substituent groups denoted by R1A 1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1A 1substituent group is substituted, the R1A 1substituent group is substituted with one or more second substituent groups denoted by R1A 2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1A 2substituent group is substituted, the R1A 2substituent group is substituted with one or more third substituent groups denoted by R1A 3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R1A, R1A-1, R1A 2. and R1A 3have values corresponding to the values of Rww, RWW 1, RWW.2ancj RWW.3reSpectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein Rww, Rww\ Rww'2, and RWW 3correspond to R1A, R1A-1, R1A 2, and R1A ?, respectively.

[0228] In embodiments, when R1Aand R1Bsubstituents that are bonded to the same nitrogen atom are joined to form a moiety that is substituted (e.g., a substituted heterocycloalkyl or substituted heteroaryl), the moiety is substituted with one or more first substituent groups denoted by R1B 1as explained in the definitions section above in thedescription of “first substituent group(s)”. In embodiments, when an R1B 1substituent group is substituted, the R1B 1substituent group is substituted with one or more second substituent groups denoted by R1B 2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1B 2substituent group is substituted, the R1B 2substituent group is substituted with one or more third substituent groups denoted by RiB.3eXpiaine(iinthe definitions section above in the description of “first substituent group(s)’; In the above embodiments. R1B, R1B 1, R1B 2. and R1B 3have values corresponding to the values of RVvW, R?w-'_ Rww-2, and RWW.3 respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein Rww, Rww\ Rww-2, and RWW3correspond to R1B, R1B', R1B 2, and R1B ?. respectively.

[0229] In embodiments, when R1Cis substituted, R1Cis substituted with one or more first substituent groups denoted by R1C 1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1C 1substituent group is substituted, the R1C 1substituent group is substituted with one or more second substituent groups denoted by R1C 2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1C 2substituent group is substituted, the R1C 2substituent group is substituted with one or more third substituent groups denoted by R1C 3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments. R1C, R1C-1, R1C 2, and R1C 3have values corresponding to the values of Rxw, RWXV 4. RWW2, and RWW3, respectively, as explained in the definitions section above in the description of “first substituent group(s)’’, wherein Rww, Rw\ RWW2and RWW 3correspond to R1C, R1C 1, R1C 2, and R1C 3, respectively.

[0230] In embodiments, when R1Dis substituted, R1Dis substituted with one or more first substituent groups denoted by R1D 1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1D 1substituent group is substituted, the R1D 1substituent group is substituted with one or more second substituent groups denoted by R1D 2as explained in the definitions section above in the description of “first substituent group(s)’'. In embodiments, when an R1D 2substituent group is substituted, the R1D 2substituent group is substituted with one or more third substituent groups denoted by R1D 3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R1D, R1D-1, R1D 2, and R1D 3have values corresponding to the values of R"w, Rww-1, Rww-2, and Rww-3, respectively, as explained in the definitionssection above in the description of “first substituent group(s)”, wherein Rww. R% w\ Rww-2, and RUW 3correspond to R1D, R1D\ R1D 2. and R1D 3, respectively.

[0231] In embodiments, when R2is substituted. R2is substituted with one or more first substituent groups denoted by R2 1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R2 1substituent group is substituted, the R2 1substituent group is substituted with one or more second substituent groups denoted by R22as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R22substituent group is substituted, the R22substituent group is substituted with one or more third substituent groups denoted by R23as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R2, R2 1, R22, and R23have values corresponding to the values of Rww. RWW.I ^»W,2ANC| RWW.3reSpectively, as explained in the definitions section above in the description of “first substituent group(s)’’, wherein R" "w, Rww\ R*w-2. and R'J"3correspond to R2, R2\ R22, and R23, respectively.

[0232] In embodiments, when R3is substituted, R3is substituted with one or more first substituent groups denoted by R3 1as explained in the definitions section above in the description of “first substituent group(s)7’. In embodiments, when an R3 1substituent group is substituted, the R3 1substituent group is substituted with one or more second substituent groups denoted by R3 2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R3 2substituent group is substituted, the R32substituent group is substituted with one or more third substituent groups denoted by R3 3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R3, R3 1, R32, and R3 3have values corresponding to the values of RWW RWW.I, RWW 2ANC| R'J WS respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein Rww, Rww-1, RU W 2. and RU W 3correspond to R3, R3-1, R3 2, and R3 3, respectively.

[0233] In embodiments, when two R3substituents are optionally joined to form a moiety that is substituted (e.g., a substituted cycloalkyl, substituted heterocycloalkyd, substituted ary l, or substituted heteroaryl), the moiety' is substituted with one or more first substituent groups denoted by R3 1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R3 1substituent group is substituted, the R3 1substituent group is substituted with one or more second substituent groups denoted by R3 2asexplained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R32substituent group is substituted, the R3 2substituent group is substituted with one or more third substituent groups denoted by R3 3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R3, R? 1, R3 2, and R3 3have values corresponding to the values of Rww, RWW 1, Rww 2, and Rww 3, respectively, as explained in the definitions section above in the description of “first substituent group(s)". wherein Rww, RWW 1, RWW 2_ and RWW 3correspond to R3, R3-1, R’2, and R3 3, respectively.

[0234] In embodiments, when R3Ais substituted, R3Ais substituted with one or more first substituent groups denoted by R3A 1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R3A 1substituent group is substituted, the R3A 1substituent group is substituted with one or more second substituent groups denoted by R3A 2as explained in the definitions section above in the description of “first substituent group(s)’'. In embodiments, when an R3A 2substituent group is substituted, the R3A2substituent group is substituted with one or more third substituent groups denoted by R3A 3as explained in the definitions section above in the description of “first substituent group(s)’’. In the above embodiments, R3A, R3A-1, R3A 2, and R3A 3have values corresponding to the values of Rww, Rww-1, Rww-2, and Rww-3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein Rww, R"w\ R™ and RWW3correspond to R3A, R3A-1, R3A 2, and R3A3, respectively.

[0235] In embodiments, when R3Bis substituted, R3Dis substituted with one or more first substituent groups denoted by R3B 1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R3B 1substituent group is substituted, the R3B 1substituent group is substituted with one or more second substituent groups denoted by R3B 2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R3B 2substituent group is substituted, the R3B 2substituent group is substituted with one or more third substituent groups denoted by R3B 3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R3B, R3B-1, R3B 2, and R3B 3have values corresponding to the values of Rww, Rww-1, RWW 2_ and RWW 3_ respectively, as explained in the definitions section above in the description of “first substituent group(s)’’, wherein Rww, RWW 1Rww-2, and RWW 3correspond to R3B, R?B 1, RJB 2, and R3B 3, respectively.

[0236] In embodiments, when R3Aand R3Bsubstituents that are bonded to the same nitrogen atom are joined to form a moiety that is substituted (e.g., a substituted heterocycloalkyl or substituted heteroaryl), the moiety is substituted with one or more first substituent groups denoted by R3A 1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R3A 1substituent group is substituted, the R3A 1substituent group is substituted with one or more second substituent groups denoted by R3A 2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R3A 2substituent group is substituted, the R3A2substituent group is substituted with one or more third substituent groups denoted by R3A ?as explained in the definitions section above in the description of “first substituent group(s)’; In the above embodiments, R3A, R3A\ R3A 2. and R3A 3have values corresponding to the values of Rww, R"WA, Rww-2, and Rww-3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein Rww, Rww\ Rww'2, and RWW 3correspond to R3A, R3A\ R3A 2, and R3A ?, respectively.

[0237] In embodiments, when R3Aand R3Bsubstituents that are bonded to the same nitrogen atom are joined to form a moiety that is substituted (e.g., a substituted heterocycloalkyl or substituted heteroaryl), the moiety is substituted with one or more first substituent groups denoted by R3B 1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R3B 1substituent group is substituted, the R3B 1substituent group is substituted with one or more second substituent groups denoted by R3B 2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R3B 2substituent group is substituted, the R3B 2substituent group is substituted with one or more third substituent groups denoted by R3B 3as explained in the definitions section above in the description of “first substituent group(s)’; In the above embodiments. R3B, R3B 1, R3B 2. and R3B 3have values corresponding to the values of Rww, RWW 1, Rww-2,anc] RWW.3 respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein Rww, Rww-1, Rww-2, and RWW 3correspond to R3B, R3B 1, R3B 2, and R3B 3. respectively.

[0238] In embodiments, when R3Cis substituted,is substituted with one or more first substituent groups denoted by R3C 1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R3C 1substituent group is substituted, the R3C 1substituent group is substituted with one or more second substituent groups denoted by R3C 2as explained in the definitions section above in the description of“first substituent group(s)’'. In embodiments, when an R?c 2substituent group is substituted, the R3C 2substituent group is substituted with one or more third substituent groups denoted by R3C 3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R3C, R3C-1, R3C 2, and R3C 3have values corresponding to the values of R"w, Rww-1, Rww-2, and RWW3?respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein Rww. RWW 1, RWW 2, and RWW 3correspond to R3C, R3C 1, R3C 2. and R3C 3. respectively.

[0239] In embodiments, when R3Dis substituted, R3Dis substituted with one or more first substituent groups denoted by R3D 1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R3D 1substituent group is substituted, the R3D 1substituent group is substituted with one or more second substituent groups denoted by R3D 2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R3D 2substituent group is substituted, the R3D 2substituent group is substituted with one or more third substituent groups denoted by R3D 3as explained in the definitions section above in the description of “first substituent group(s)’; In the above embodiments, R3D, R3D 1, R3D 2. and R3D 3have values corresponding to the values of Rww, R"WJ, Rww-2, and RWW3?respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein Rww, Rww-1, RWW2, and RWW 3correspond to R3D, R'D\ R3D 2, and R3D 3, respectively.

[0240] In embodiments, when R4is substituted, R4is substituted with one or more first substituent groups denoted by R4 1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R4 1substituent group is substituted, the R4 1substituent group is substituted with one or more second substituent groups denoted by R42as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R42substituent group is substituted, the R42substituent group is substituted with one or more third substituent groups denoted by R43as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R4, R4 1, R42, and R43have values corresponding to the values of Rww. RWW 1, RWW-2, and Rww-3, respectively, as explained in the definitions section above in the description of “first substituent group(s)7’, wherein Rww, Rww\ RWW2and RWW 3correspond to R4, R4 1, R42, and R43, respectively.

[0241] In embodiments, when two R4substituents are optionally j oined to form a moiety that is substituted (e.g., a substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl), the moiety is substituted with one or more first substituent groups denoted by R4 1as explained in the definitions section above in the description of “first substituent group(s)’'. In embodiments, when an R4 1substituent group is substituted, the R4 1substituent group is substituted with one or more second substituent groups denoted by R42as explained in the definitions section above in the description of “first substituent group(s)7’. In embodiments, when an R42substituent group is substituted, the R42substituent group is substituted with one or more third substituent groups denoted by R43as explained in the definitions section above in the description of “first substituent group(s)’'. In the above embodiments, R4, R4 1, R42, and R43have values corresponding to the values of Rww, RWW 1, RWW.2, gnj j^ww.3reSpectiVely , as explained in the definitions section above in the description of “first substituent group(s)”, wherein Rw\ RWW 1, RWW.2,anj RV W.3correSpOnc[ to R4, R4-1, R42, and R43. respectively.

[0242] In embodiments, when R4Ais substituted, R4Ais substituted with one or more first substituent groups denoted by R4A 1as explained in the definitions section above in the description of “first substituent group(s)’’. In embodiments, when an R4A 1substituent group is substituted, the R4A 1substituent group is substituted with one or more second substituent groups denoted by R4A 2as explained in the definitions section above in the description of “first substituent group(s)". In embodiments, when an R4A 2substituent group is substituted, the R4A 2substituent group is substituted with one or more third substituent groups denoted by R4A 3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R4A, R4A I. R4A 2, and R4A3have values corresponding to the values of Rww, Rww-1. RWW2, and RWW3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”. wherein Rww. Rw\ RWW.2, and RWW 3correspond to R4A, R4A 1, R4A 2, and R4A3, respectively.

[0243] In embodiments, when R4Bis substituted, R4Bis substituted with one or more first substituent groups denoted by R4B 1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R4B 1substituent group is substituted, the R4B 1substituent group is substituted with one or more second substituent groups denoted by R4B 2as explained in the definitions section above in the description of “first substituent group(s)’'. In embodiments, when an R4B 2substituent group is substituted, the R4B 2substituent group is substituted with one or more third substituent groups denoted byR4B 3as explained in the definitions section above in the description of ‘‘first substituent group(s)’; In the above embodiments, R4B, R4B-1, R4B 2. and R4B 3have values corresponding to the values of Rww, R"WJ, Rww-2, and Rww-3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein Rww, Rww\ Rww'2, and RWW 3correspond to R4B, R4B-1, R4B 2, and R4B 3, respectively.

[0244] In embodiments, when R4Aand R4Bsubstituents that are bonded to the same nitrogen atom are joined to form a moiety that is substituted (e.g., a substituted heterocycloalkyl or substituted heteroaryl), the moiety is substituted with one or more first substituent groups denoted by R4A 1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R4A 1substituent group is substituted, the R4A 1substituent group is substituted with one or more second substituent groups denoted by R4A 2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R4A 2substituent group is substituted, the R4A2substituent group is substituted with one or more third substituent groups denoted by R4A 3as explained in the definitions section above in the description of “first substituent group(s)". In the above embodiments, R4A, R4A I. R4A 2. and R4 A3have values corresponding to the values of Rww, R^W 1RWW.2ANC| RWW.3 respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein Rww, Rww-1, RWW2, and RWW 3correspond to R4A, R4A I. R4A 2, and R4A ?, respectively.

[0245] In embodiments, when R4Aand R4Bsubstituents that are bonded to the same nitrogen atom are joined to form a moiety that is substituted (e.g., a substituted heterocycloalkyl or substituted heteroaryl), the moiety is substituted with one or more first substituent groups denoted by R4B 1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R4B 1substituent group is substituted, the R4B 1substituent group is substituted with one or more second substituent groups denoted by R4B 2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R4B 2substituent group is substituted, the R4B 2substituent group is substituted with one or more third substituent groups denoted by R4B 3as explained in the definitions section above in the description of “first substituent group(s)’; In the above embodiments, R4B, R4B\ R4B 2. and R4B 3have values corresponding to the values of Rww, Rv W 1, Rww-2,anc| RWW.3reSpecpvetyasexplained in the definitions section above in the description of “first substituent group(s)”, wherein Rww, Rww\ Rww-2, and RWW3correspond to R4B, R4B 1, R4B 2, and R4B 3. respectively.

[0246] In embodiments, when R4Cis substituted, R4Cis substituted with one or more first substituent groups denoted by R4C 1as explained in the definitions section above in the description of ‘’first substituent group(s)’’. In embodiments, when an R4C 1substituent group is substituted, the R4C 1substituent group is substituted with one or more second substituent groups denoted by R4C 2as explained in the definitions section above in the description of “first substituent group(s)". In embodiments, when an R4C 2substituent group is substituted, the R4C 2substituent group is substituted with one or more third substituent groups denoted by R4C 3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R4C, R4C\ R4C 2, and R4C 3have values corresponding to the values of Rww, Rw%Rww 2,ancj RWW.3,reSpectively, as explained in the definitions section above in the description of “first substituent group(s)’; wherein Rw w. Rww\ RWW-2, and RWW 3correspond to R4C, R4C 1, R4C 2, and R4C 3, respectively.

[0247] In embodiments, when R4Dis substituted, R4Uis substituted with one or more first substituent groups denoted by R4D 1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R4D 1substituent group is substituted, the R4D 1substituent group is substituted with one or more second substituent groups denoted by R4D 2as explained in the definitions section above in the description of “first substituent group(s)’:. In embodiments, when an R4D 2substituent group is substituted, the R4D 2substituent group is substituted with one or more third substituent groups denoted by R4D 3as explained in the definitions section above in the description of “first substituent group(s)’’. In the above embodiments, R4D, R4D 1, R4D 2, and R4D 3have values corresponding to the values of Rww, Rww\ Rww-2,ancj RWW.3,reSpectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein Rww, RTO\ Rww-2, and RWW3correspond to R4D, R4D-1, R4D 2, and R4D 3, respectively.

[0248] In embodiments, when R5is substituted, R5is substituted with one or more first substituent groups denoted by R5 1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R3 1substituent group is substituted, the R5 1substituent group is substituted with one or more second substituent groups denoted by R5 2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R5 2substituent group is substituted, the R52substituent group is substituted with one or more third substituent groups denoted by R3 3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R5, R5R52, and R5 3have values corresponding to the values ofRWW RWW.I, R\\ W 2ANC| R'J WSreSpectiVely, as explained in the definitions section above in the description of " first substituent group(s)". wherein Rwu, Rww-1, Ruu 2. and Ruu 3correspond to R3, R3-1, R3 2, and R3 3, respectively.

[0249] In embodiments, when L1is substituted, L1is substituted with one or more first substituent groups denoted by RL1 1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an RL1 1substituent group is substituted, the RL1 1substituent group is substituted with one or more second substituent groups denoted by RL1 2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an RLL2substituent group is substituted, the RL1 2substituent group is substituted with one or more third substituent groups denoted by RL1 3as explained in the definitions section above in the description of “first substituent group(s)’; In the above embodiments. L1. RL1 1, RL1 2, and RLL3have values corresponding to the values of Lww, RLWU 1RLWW.2ancj RLW respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein Lww, RLWW\ RLWW.2, and RLWW 3are L1, RL1 1, RL1 2. and RL1 3, respectively.

[0250] In embodiments, the compound has the formula:embodiments, the compound has the formula:In embodiments, the compound has the formula:embodiments, the compound has the formula:embodiments, the compound has the formula:embodiments, the compound has the formula:embodiments, the compound has the formula:embodiments, the compound has the formula:embodiments, the compound has the formula:embodiments, the compound has the formula:embodiments, the compound has the formula:embodiments, the compound has the formula:embodiments, the compound has the formula:embodiments, the compound has the formula:embodiments, the compound has the formula:embodiments, the compound has the formula:. Inembodiments, the compound has the formula:embodiments, the compound has theembodiments, the compound has the formula:. In embodiments, the compound has the formula:embodiments, the compound has the formula:embodiments, the compound has the formula:embodiments, the compound has the formula:embodiments, the compound has the formula:embodiments, the compound has the formula:embodiments, the compound has the formula:embodiments, the compound has the formula:embodiments, the compound has the formula:embodiments, the compound has the formula:embodiments, the compound has the formula:embodiments, the compound has the formula:. In embodiments, the compound has the formula:. In embodiments, the compound has the formula:embodiments, the compound has the formula:embodiments, the compound has the formula:embodiments, the compound has the formula:embodiments, the compound has the formula:embodiments, the compound has the formula:embodiments, the compound has the formula:embodiments, the compound has the formula:embodiments, the compound has the formula:embodiments, the compound has the formula:embodiments, the compound has the formula:embodiments, the compound has the formula:embodiments, the compound has the formula:embodiments, the compound has the formula:embodiments, the compound has the formulaembodiments, the compound has the formulaembodiments, the compound has the formulaembodiments, the compound has the formulaembodiments, the compound has the formulaembodiments, the compound has the formula:embodiments, the compound has the formula:embodiments, the compound has the formula:embodiments, the compound has the formula:embodiments, the compound has the formula:embodiments, the compound has the formula:embodiments, the compound has the formula:embodiments, the compound has the formula:embodiments, the compound has the formula:embodiments, the compound has the formula:embodiments, the compound has theembodiments, the compound has the formula:embodiments, the compound has the formula:embodiments, the compound has the formula:embodiments, the compound has the formula:embodiments, the compound has the formula:5 embodiments, the compound has the formula:. In embodiments, the compound has theformula:. in embodiments, the compound has the

[0251] 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).

[0252] In embodiments, the compound is a compound as described herein, including in embodiments. In embodiments the compound is a compound described herein (e.g., in the examples section, figures, tables, or claims). In embodiments, the compound is a compound as described in Table 2.III. Pharmaceutical compositions

[0253] In an aspect is provided a pharmaceutical composition including a compound described herein, or a pharmaceutically acceptable salt or tautomer thereof, and a pharmaceutically acceptable excipient.

[0254] 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.

[0255] In embodiments, the compound is a compound of formula (I), (la), (II), or (Ila), including all embodiments thereof.

[0256] In therapeutic and / or diagnostic applications, the compounds disclosed herein can be formulated for a variety of modes of administration, including systemic and topical or localized administration. Techniques and formulations generally may be found in Remington: The Science and Practice of Pharmacy (20thed.) Lippincott, Williams & Wilkins (2000).

[0257] The compounds disclosed herein are effective over a wide dosage range. The exact dosage will depend upon the route of administration, the form in which the compound is administered, the subject to be treated, the body weight of the subject to be treated, and the preference and experience of the attending physician.

[0258] Pharmaceutically acceptable salts are generally well known to those of ordinary skill in the art, and may include, by way of example but not limitation, acetate, benzenesulfonate, besylate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate, carbonate, citrate, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, mucate, napsylate. nitrate, pamoate (embonate), pantothenate, phosphate / di phosphate, poly galacturonate, salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate, or teoclate. Other pharmaceutically acceptable salts may be found in, for example, Remington: The Science and Practice of Pharmacy (20thed.) Lippincott, Williams & Wilkins (2000). Preferred pharmaceutically acceptable salts include, for example, acetate, benzoate, bromide, carbonate, citrate, gluconate, hydrobromide, hydrochloride, maleate, mesylate, napsylate, pamoate (embonate), phosphate, salicylate, succinate, sulfate, or tartrate.

[0259] Depending on the specific conditions being treated, the compounds may be formulated into liquid or solid dosage forms and administered systemically or locally. The compounds may be delivered, for example, in a timed or sustained low release form as is known to those skilled in the art. Techniques for formulation and administration may be found in Remington: The Science and Practice of Pharmacy (20thed.) Lippincott, Williams & Wilkins (2000). Suitable routes may include oral, buccal, by inhalation spray, sublingual, rectal, transdermal, vaginal, transmucosal, nasal, or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intramedullary’ injections, as well as intrathecal, direct intraventricular, intravenous, intra-articullar, intra-stemal, intra-synovial.intra-hepatic, intralesional. intracranial, intraperitoneal, intranasal, or intraocular injections or other modes of delivery.

[0260] For injection, the compounds disclosed herein may be formulated and diluted in aqueous solutions, such as in physiologically compatible buffers such as Hank’s solution, Ringer's solution, or physiological saline buffer. For such transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.

[0261] Use of pharmaceutically acceptable inert carriers to formulate the compounds herein disclosed for the practice of the invention into dosages suitable for systemic administration is within the scope of the invention. With proper choice of carrier and suitable manufacturing practice, the compositions of the present invention, in particular, those formulated as solutions, may be administered parenterally, such as by intravenous injection. The compounds can be formulated readily using pharmaceutically acceptable carriers well known in the art into dosages suitable for oral administration. Such carriers enable the compounds of the invention to be formulated as tablets, pills, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a subject (e.g., patient) to be treated.

[0262] For nasal or inhalation delivery, the compounds disclosed herein may also be formulated by methods known to those of skill in the art, and may include, for example, but not limited to, examples of solubilizing, diluting, or dispersing substances such as, saline, preservatives, such as benzyl alcohol, absorption promoters, and fluorocarbons.

[0263] Pharmaceutical compositions suitable for use disclosed herein include compositions wherein the active ingredients are contained in an effective amount to achieve its intended purpose. Determination of the effective amounts is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein.

[0264] In addition to the active ingredients, these pharmaceutical compositions may contain suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. The preparations formulated for oral administration may be in the form of tablets, dragees, capsules, or solutions.

[0265] Pharmaceutical preparations for oral use can be obtained by combining the active compounds with solid excipients, optionally grinding a resulting mixture, and processing themixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethyl-cellulose (CMC), and / or poly vinylpyrrolidone (PVP: povidone). If desired, disintegrating agents may be added, such as the cross- linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.

[0266] Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol (PEG), and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dye-stuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.

[0267] Pharmaceutical preparations that can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin, and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty7oils, liquid paraffin, or liquid polyethylene glycols (PEGs). In addition, stabilizers may be added.

[0268] Dosage forms (e.g., compositions) suitable for internal administration contain from about 1.0 milligram to about 5,000 milligrams of active ingredient per unit. In these pharmaceutical compositions, the active ingredient may7be present in an amount of about 0.5 to about 95% by weight based on the total weight of the composition. Another convention for denoting the dosage form is in mg per meter squared (mg / m2) of body surface area (BSA). Typically, an adult will have approximately 1.75 m2of BSA. Based on the body weight of the patient, the dosage may be administered in one or more doses several times per day or per week. Multiple dosage units may be required to achieve a therapeutically effective amount. For example, if the dosage form is 1,000 mg, and the patient weighs 40 kg, one tablet or capsule will provide a dose of 25 mg per kg for that patient. It will provide a dose of only 12.5 mg / kg for a 80 kg patient.

[0269] By way of general guidance, for humans a dosage of as litle as about 1 milligram (mg) per kilogram (kg) of body weight and up to about 10,000 mg per kg of body weight is suitable as a therapeutically effective dose. Preferably, from about 5 mg / kg to about 2,500 mg / kg of body weight is used. Other preferred doses range between 25 mg / kg to about 1,000 mg / kg of body weight. However, a dosage of between about 2 milligrams (mg) per kilogram (kg) of body weight to about 400 mg per kg of body weight is also suitable for treating some cancers.

[0270] Intravenously, the most preferred rates of administration can range from about 1 to about 1,000 mg / kg / minute during a constant rate infusion. A pharmaceutical composition of the present invention can be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three, or four times daily. The composition is generally given in one or more doses on a daily basis or from one to three times a week.IV. Methods of use

[0271] In an aspect is provided a method of treating a cancer in a subject in need thereof, the method including administering to the subject in need thereof a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt or tautomer thereof.

[0272] In embodiments, the compound is a compound of formula (I), (la), (II), or (Ila), including all embodiments thereof.

[0273] In embodiments, the cancer is brain cancer. In embodiments, the cancer is breast cancer. In embodiments, the cancer is colon cancer. In embodiments, the cancer is esophageal cancer. In embodiments, the cancer is gastric cancer. In embodiments, the cancer is gastrointestinal stromal tumor. In embodiments, the cancer is head and neck cancer. In embodiments, the cancer is liver cancer. In embodiments, the cancer is lung cancer. In embodiments, the cancer is lymphoma. In embodiments, the cancer is melanoma. In embodiments, the cancer is pancreatic cancer. In embodiments, the cancer is prostate cancer. In embodiments, the cancer is rectal cancer. In embodiments, the cancer is soft tissue sarcoma. In embodiments, the cancer is bone cancer. In embodiments, the cancer is leukemia.

[0274] In an aspect is provided a method of reducing a Wnt-mediated effect on a cell, the method including contacting the cell with an effective amount of a compound as described herein, or a pharmaceutically acceptable salt or tautomer thereof.

[0275] In embodiments, the compound is a compound of formula (I), (la), (II), or (Ila), including all embodiments thereof.

[0276] In embodiments, the Wnt-mediated effect on a cell is reduced by about 1.5-, 2-. 3-. 4-, 5-?6-, 7-, 8-, 9-, 10-, 15-, 20-, 25-, 30-, 35-, 40-, 45-, 50-, 60-, 70-, 80-, 90-, 100-, 150-, 200-, 250-, 300-, 350-, 400-, 450-, 500-, 600-, 700-, 800-, 900-, or 1000-fold relative to a control (e.g., absence of the compound). In embodiments, the Wnt-mediated effect on a cell is reduced by about 1.5-fold relative to a control (e.g.. absence of the compound). In embodiments, the Wnt-mediated effect on a cell is reduced by about 2-fold relative to a control (e.g., absence of the compound). In embodiments, the Wnt-mediated effect on a cell is reduced by about 5-fold relative to a control (e.g., absence of the compound). In embodiments, the Wnt-mediated effect on a cell is reduced by about 10-fold relative to a control (e.g.. absence of the compound). In embodiments, the Wnt-mediated effect on a cell is reduced by about 25-fold relative to a control (e.g., absence of the compound). In embodiments, the Wnt-mediated effect on a cell is reduced by about 50-fold relative to a control (e.g., absence of the compound). In embodiments, the Wnt-mediated effect on a cell is reduced by about 100-fold relative to a control (e.g., absence of the compound). In embodiments, the Wnt-mediated effect on a cell is reduced by about 250-fold relative to a control (e.g., absence of the compound). In embodiments, the Wnt-mediated effect on a cell is reduced by about 500-fold relative to a control (e.g., absence of the compound). In embodiments, the Wnt-mediated effect on a cell is reduced by about 1000-fold relative to a control (e.g., absence of the compound).

[0277] In embodiments, the Wnt-mediated effect on a cell is reduced by at least 1 .5-, 2-, 3-, 4-, 5., 6-, 7-, 8-, 9-, 10-, 15-, 20-, 25-, 30-, 35-, 40-, 45-, 50-, 60-, 70-, 80-, 90-, 100-, 150-, 200-, 250-, 300-, 350-, 400-, 450-, 500-, 600-, 700-, 800-, 900-, or 1000-fold relative to a control (e.g., absence of the compound). In embodiments, the Wnt-mediated effect on a cell is reduced by at least 1.5-fold relative to a control (e.g., absence of the compound). In embodiments, the Wnt-mediated effect on a cell is reduced by at least 2-fold relative to a control (e.g., absence of the compound). In embodiments, the Wnt-mediated effect on a cell is reduced by at least 5-fold relative to a control (e.g., absence of the compound). In embodiments, the Wnt-mediated effect on a cell is reduced by at least 10-fold relative to a control (e.g., absence of the compound). In embodiments, the Wnt-mediated effect on a cell is reduced by at least 25-fold relative to a control (e.g., absence of the compound). In embodiments, the Wnt-mediated effect on a cell is reduced by at least 50-fold relative to acontrol (e.g., absence of the compound). In embodiments, the Wnt-mediated effect on a cell is reduced by at least 100-fold relative to a control (e.g., absence of the compound). In embodiments, the Wnt-mediated effect on a cell is reduced by at least 250-fold relative to a control (e.g., absence of the compound). In embodiments, the Wnt-mediated effect on a cell is reduced by at least 500-fold relative to a control (e.g., absence of the compound). In embodiments, the Wnt-mediated effect on a cell is reduced by at least 1000-fold relative to a control (e.g.. absence of the compound).

[0278] In embodiments, the Wnt-mediated effect is an increase in degradation of Pygopus (relative to the degradation of Pygopus in the absence of the compound). In embodiments, the Wnt-mediated effect is an increase in degradation of non-oncogenic beta-Catenin (relative to the degradation of beta-Catenin in the absence of the compound). In embodiments, the Wnt-mediated effect is a decrease in degradation of Axin (relative to the degradation of Axins in the absence of the compound). In embodiments, the Wnt-mediated effect is a decrease in activity7of Myc (relative to the activity of Myc in the absence of the compound). In embodiments, the Wnt-mediated effect is a decrease in activity of CD44 (relative to the activity of CD44 in the absence of the compound). In embodiments, the Wnt-mediated effect is a decrease in activity' of Axin2 (relative to the activity' of Axin 2 in the absence of the compound). In embodiments, the Wnt-mediated effect is a decrease in activity' of Bcl-9 (relative to the activity of Bcl-9 in the absence of the compound). In embodiments, the Wnt- mediated effect is a decrease in activity of cyclin D (relative to the activity of cyclin D in the absence of the compound). These Wnt-mediated effects may be assessed using standard assays known in the art.V. Embodiments

[0279] Embodiment P 1. A compound, or a pharmaceutically acceptable salt or tautomer thereof, having the formula:Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;L1is a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene;R1is independently halogen, -CX1?, -CHX^, -CH2X1, -OCX1?, -OCH2X1, -OCHX^, -CN, -SOniR1D, -SOviNR1AR1B, -NR1CNR1AR1B, -ONR1AR1B, -NR1CC(O)NR1AR1B. -N(0)mi. -NR1AR1B, -C(O)R1C, -C(O)OR1C. -C(O)NR1AR1B, -OR1D, -NR1ASO2R1D, -NR1AC(O)R1C, -NR1AC(O)OR1C, -NR1AOR1C, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two R1substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; zl is an integer from 0 to 4;R2is hydrogen, halogen, -CCI3, -CBr3, -CF3, -CI3, -CHCI2, -CHBr2, -CHF2,-CHI2, -CH2CI, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCI3. -OCF3. -OCBr3, -OCI3, -OCHC12, -OCHBr2, -OCHI2, -OCHF2, -OCH2C1, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R3is independently halogen, -CX33, -CHX32, -CH2X3, -0CX?3, -OCH2X3, -OCHX32, -CN, -SOn3R3D. -SOV3NR3AR3B, -NR3CNR3AR3B. -ONR3AR3B. -NR3CC(O)NR3AR3B-N(O)m3, -NR3AR3B, -C(O)R3C, -C(O)OR3C, -C(O)NR3AR3B, -OR3D, -NR3ASO2R3D, -NR3AC(O)R3C, -NR3AC(O)OR3C, -NR3AOR3C, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two R3substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted ary l, or substituted or unsubstituted heteroaryl; z3 is an integer from 0 to 2;R4is independently oxo, halogen, -CX43, -CHX42. -CH2X4, -OCX'S, -OCH2X4. -OCHX42, -CN, -SOn4R4D, -SOV4NR4AR4B, -NR4CNR4AR4B, -ONR4AR4B, -NR4CC(O)NR4AR4B, -N(0)m4, -NR4AR4B, -C(O)R4C, -C(O)OR4C, -C(O)NR4AR4B, -OR4D, -NR4ASO2R4D, -NR4AC(O)R4C, -NR4AC(O)OR4C, -NR4AOR4C, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted ary l, or substituted or unsubstituted heteroaryl; tyvo R4substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; z4 is an integer from 0 to 11;R5is hydrogen, halogen. -CCI3, -CBr,. -CF3, -CI3. -CH2CI, -CH2Br, -CH2F, -CH2I. -CHCI2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, NHNH2, ONH2, NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCh, -OCBr3, -OCF3, -OCI3, -OCH2C1. -OCH2Br, -OCH2F, -OCH2I. -OCHCI2, -OCHBr2, -OCHF2, -OCH12. -SF5. -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R1A, R1B, R1C, R1D, R3A, R3B. R3C, R3D, R4A, R4B, R4C, and R4Dare independently hydrogen, halogen, -CCI3, -CBr3, -CF3, -CI3, -CHCI2, -CHBr2, -CHF2, -CHI2, -CH2C1, -CH2Br, -CH2F. -CH2I, -CN, -OH, -NH2. -COOH, -CONH2. -OCCI3, -OCF3, -OCBr3. -OCI3, -OCHC12, -OCHBr2, -OCHI2, -OCHF2, -OCH2C1, -OCH2Br, -OCH2I, -OCH2F, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryk R1Aand R1Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R3Aand R3Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R4Aand R4Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; each X1, X3, and X4is independently -F, -Cl, -Br, or -I; nl, n3, and n4 are independently an integer from 0 to 4; and ml, m3, m4, v l, v3, and v4 are independently 1 or 2; wherein when Ring A is phenyl and z4 is 0, then R3is not unsubstituted isopropyl, unsubstituted cyclopropyl, unsubstituted furanyl, or unsubstituted thienyl.

[0280] Embodiment P2. The compound of embodiment Pl, having the formula:

[0281] Embodiment P3. The compound of embodiment Pl, having the formula:

[0282] Embodiment P4. The compound of one of embodiments Pl to P3, wherein R2is hydrogen or unsubstituted C1-C4 alkyl.

[0283] Embodiment P5. The compound of one of embodiments Pl to P3, wherein R2is hydrogen.

[0284] Embodiment P6. The compound of one of embodiments P l to P5. wherein L1is a bond, substituted or unsubstituted C1-C4 alkylene, or substituted or unsubstituted 2 to 6 membered heteroalkylene.

[0285] Embodiment P7. The compound of one of embodiments Pl to P5, wherein L1is a bond, unsubstituted methylene, or

[0286] Embodiment P8. The compound of one of embodiments Pl to P7, wherein Ring A is Cs-Cs cycloalkyl, 3 to 8 membered heterocycloalkyl, phenyl, or 5 to 6 membered heteroaryl.

[0287] Embodiment P9. The compound of one of embodiments Pl to P7, wherein Ring A is phenyl, pyridyl, pyrazinyl, or pyrimidinyl.

[0288] Embodiment P10. The compound of one of embodiments Pl to P7, wherein

[0289] Embodiment PH. The compound of one of embodiments P 1 to P 10, wherein R4is independently oxo, halogen, -CCI3, -CBn, -CF3, -CI3, -CH2CI, -CBEBr, -CH2F, -CH2L -CHCI2, -CHBr2, -CHF2, -CHE, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -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, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted ary l, or substituted or unsubstituted heteroaryl.

[0290] Embodiment P 12. The compound of one of embodiments Pl to P10, wherein R4is independently halogen, -CX43. -OCX43, -SOn4R4D, -SOv4NR4AR4B, -C(O)OR4C.-C(O)NR4AR4B, substituted or unsubstituted C1-C4 alkyl, or substituted or unsubstituted 2 to 6 membered heteroalkyl.

[0291] Embodiment P13. The compound of one of embodiments Pl to PIO, wherein R4is

[0292] Embodiment P14. The compound of one of embodiments Pl to Pl 3, wherein z4 is1 or 2.

[0293] Embodiment Pl 5. The compound of one of embodiments Pl to PIO, wherein z4 is0.

[0294] Embodiment Pl 6. The compound of one of embodiments Pl to P7, wherein

[0295] Embodiment Pl 7. The compound of one of embodiments Pl to Pl 6, wherein R1is independently halogen, -CCh, -CBn. -CF3, -CI3, -CH2CI, -CH2Br, -CH2F, -CH2I, -CHCI2, -CHBr2, -CHF2, -CHE, -CN. -OH. -NH2, -COOH. -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI3, -OCBr3, -OCF3, -OCI3, -OCH2C1, -OCH2Br, -OCH2F, -OCH2I, -OCHCh, -OCHBr2, -OCHF2, -OCHI2. -SF5, -N3, substituted or unsubstituted alky l, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0296] Embodiment Pl 8. The compound of one of embodiments Pl to Pl 6, wherein R1is independently halogen, unsubstituted C1-C4 alkyd, or unsubstituted 2 to 6 membered heteroalkyl.

[0297] Embodiment Pl 9. The compound of one of embodiments Pl to Pl 6, wherein R1is independently -F, unsubstituted methyl, or

[0298] Embodiment P20. The compound of one of embodiments Pl to Pl 9, wherein zl is1 or 2.

[0299] Embodiment P21. The compound of one of embodiments Pl to Pl 6, wherein zl is0.

[0300] Embodiment P22. The compound of one of embodiments Pl to Pl 6, wherein

[0301] Embodiment P23. The compound of one of embodiments Pl to P22, wherein R3is independently -CX33, -CHX32, -CH2X3, -NR3AC(O)R3C, -NR3ASO2R3D, substituted or unsubstituted C1-C4 alkyl, or substituted or unsubstituted 2 to 6 membered heteroalkyl.

[0302] Embodiment P24. The compound of one of embodiments Pl to P22, wherein R3is independently -CF3, -CHF2, -CH2F, unsubstituted methyl, unsubstituted isopropyl.

[0303] Embodiment P25. The compound of one of embodiments Pl to P22, wherein two R3substituents are joined to form a substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl.

[0304] Embodiment P26. The compound of one of embodiments Pl to P22, wherein two

[0305] Embodiment P27. The compound of one of embodiments Pl to P26, wherein z3 is 1 or 2.

[0306] Embodiment P28. The compound of one of embodiments Pl to P22, wherein z3 is 0.

[0307] Embodiment P29. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound, or a pharmaceutically acceptable salt or tautomer thereof, having the formula:Ring A is cycloalkyl, heterocycloalkyl, ary l, or heteroaryl;L1is a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene;R1is independently halogen, -CX^, -CHXS, -CH2X1, -OCX^, -OCH2X1, -OCHX^, -CN, -SOniR1D, -SOviNR1AR1B, -NR1CNR1AR1B, -ONR1AR1B, -NR1CC(O)NR1AR1B-N(O)mi. -NR1AR1B, -C(O)R1C, -C(O)OR1C, -C(O)NR1AR1B, -OR1D, -NR1ASO2R1D. -NR1AC(O)R1C, -NR1AC(O)OR1C, -NR1AOR1C, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted ary l, or substituted or unsubstituted heteroaryl; two R1substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; zl is an integer from 0 to 4;R2is hydrogen, halogen, -CCh, -CBn. -CF3, -CI3. -CHCh, -CHBr2, -CHF2,-CHI2, -CH2CI, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCh. -OCF3. -OCBr3, -OCI3, -OCHCh, -OCHBr2, -OCHI2, -OCHF2, -OCH2C1, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R3is independently halogen. -CX33, -CHX32, -CH2X3, -OCX33, -OCH2X3,-OCHX32, -CN, -SOn3R3D, -SOV3NR3AR3B, -NR3CNR3AR3B, -ONR3AR3B, -NR3CC(O)NR3AR3B, -N(O)m3, -NR3AR3B, -C(O)R3C, -C(O)OR3C, -C(O)NR3AR3B, -OR3D, -NR3ASO2R3D, -NR3AC(O)R3C, -NR3AC(O)OR3C, -NR3AOR3C, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two R3substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; z3 is an integer from 0 to 2;R4is independently oxo. halogen, -CXS, -CHX42. -CH2X4. -OCXS, -OCH2X4.-OCHX42, -CN, -SOn4R4D, -SOV4NR4AR4B, -NR4CNR4AR4B, -ONR4AR4B, -NR4CC(O)NR4AR4B. -N(O)m4, -NR4AR4B, -C(O)R4C, -C(O)OR4C, -C(O)NR4AR4B, -OR4D, -NR4ASO2R4D, -NR4AC(O)R4C, -NR4AC(O)OR4C, -NR4AOR4C, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two R4substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; z4 is an integer from 0 to 11 ;R5is hydrogen, halogen, -CCh, -CBr3, -CF3, -CI3, -CH2C1, -CH2Br, -CH2F, -CH2I, -CHCh, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCh, -OCBr3. -OCF3. -OCR, -OCH2C1. -OCH2Br, -OCH2F, -OCH21. -OCHCh, -OCHBr2, -OCHF2, -OCHI2, -SF5, -Ns, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R1A, R1B. R1C, R1D. R3A, R3B, R3C, R3D, R4A, R4B, R4C, and R4Dare independently hydrogen, halogen, -CC13, -CBr3, -CF3, -CI3, -CHCI2, -CHBr2, -CHF2, -CHI2, -CH2C1, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCC13, -OCF3, -OCBr3, -OCI3, -OCHCh, -OCHBr2, -OCHI2, -OCHF2, -OCH2C1, -OCH2Br, -OCH2I. -OCH2F. substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R1Aand R1Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R3Aand R3Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R4Aand R4Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; each X1, X3, and X4is independently -F, -Cl, -Br. or -I; nl, n3, and n4 are independently an integer from 0 to 4; and ml, m3, m4. vl, v3, and v4 are independently 1 or 2.

[0308] Embodiment P30. A method of treating a cancer in a subject in need thereof, said method comprising administering to the subject a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt or tautomer thereof, having the formula:Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;L1is a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene;R1is independently halogen, -CX1?, -CHX^, -CH2X1, -OCX1?, -OCH2X1, -OCHX^, -CN, -SOniR1D, -SOviNR1AR1B, -NR1CNR1AR1B, -ONR1AR1B, -NR1CC(O)NR1AR1B. -N(0)mi. -NR1AR1B, -C(O)R1C, -C(O)OR1C. -C(O)NR1AR1B, -OR1D, -NR1ASO2R1D, -NR1AC(O)R1C, -NR1AC(O)OR1C, -NR1AOR1C, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two R1substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; zl is an integer from 0 to 4;R2is hydrogen, halogen, -CCI3, -CBr3, -CF3, -CI3, -CHCI2, -CHBr2, -CHF2,-CHI2, -CH2CI, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCI3. -OCF3. -OCBr3, -OCI3, -OCHC12, -OCHBr2, -OCHI2, -OCHF2, -OCH2C1, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted ary l, or substituted or unsubstituted heteroaryl;R3is independently halogen, -CX33, -CHX32, -CH2X3, -0CX?3, -OCH2X3, -OCHX32, -CN, -SOn3R3D. -SOV3NR3AR3B, -NR3CNR3AR3B. -ONR3AR3B. -NR3CC(O)NR3AR3B-N(O)m3, -NR3AR3B, -C(O)R3C, -C(O)OR3C, -C(O)NR3AR3B, -OR3D, -NR3ASO2R3D, -NR3AC(O)R3C, -NR3AC(O)OR3C, -NR3AOR3C, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two R3substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted ary l, or substituted or unsubstituted heteroaryl; z3 is an integer from 0 to 2;R4is independently oxo, halogen, -CX43, -CHX42. -CH2X4, -OCX'S, -OCH2X4. -OCHX42, -CN, -SOn4R4D, -SOV4NR4AR4B, -NR4CNR4AR4B, -ONR4AR4B, -NR4CC(O)NR4AR4B, -N(0)m4, -NR4AR4B, -C(O)R4C, -C(O)OR4C, -C(O)NR4AR4B, -OR4D, -NR4ASO2R4D, -NR4AC(O)R4C, -NR4AC(O)OR4C, -NR4AOR4C, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted ary l, or substituted or unsubstituted heteroaryl; tyvo R4substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; z4 is an integer from 0 to 11;R5is hydrogen, halogen. -CCI3, -CBr,. -CF3, -CI3. -CH2CI, -CH2Br, -CH2F, -CH2I. -CHCI2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, NHNH2, ONH2, NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCh, -OCBr3, -OCF3, -OCI3, -OCH2C1. -OCH2Br, -OCH2F, -OCH2I. -OCHCI2, -OCHBr2, -OCHF2, -OCH12. -SF5. -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R1A, R1B, R1C, R1D, R3A, R3B. R3C, R3D, R4A, R4B, R4C, and R4Dare independently hydrogen, halogen, -CCI3, -CBr3, -CF3, -CI3, -CHCI2, -CHBr2, -CHF2, -CHI2, -CH2C1, -CH2Br, -CH2F. -CH2I, -CN, -OH, -NH2. -COOH, -CONH2. -OCCI3, -OCF3, -OCBr3. -OCI3, -OCHC12, -OCHBr2, -OCHI2, -OCHF2, -OCH2C1, -OCH2Br, -OCH2I, -OCH2F, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryk R1Aand R1Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R3Aand R3Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R4Aand R4Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; each X1, X3, and X4is independently -F, -Cl, -Br, or -I; nl, n3, and n4 are independently an integer from 0 to 4; and ml, m3, m4, v l, v3, and v4 are independently 1 or 2.

[0309] Embodiment P31. The method of embodiment P30, wherein the cancer is brain cancer, breast cancer, colon cancer, esophageal cancer, gastric cancer, gastrointestinal stromal tumor, head and neck cancer, liver cancer, lung cancer, lymphoma, melanoma, pancreatic cancer, prostate cancer, or rectal cancer.

[0310] It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety' for all purposes.EXAMPLESExperimental procedures and characterization data

[0311] General Procedure A (amide coupling)

[0312] To a stirred solution of an appropriately substituted aromatic carboxylic acid in a suitable organic solvent (e.g., DMF) at room temperature was added 1-2 equivalents of asuitable amide coupling reagent (e.g., HATU) followed by 2-3 equivalents of a suitable organic base (e.g., diisopropylethylamine). A solution of an appropriately substituted aromatic amine in a suitable organic solvent (e.g., DMF) was added to the reaction mixture. The resultant reaction mixture was stirred at room temperature with progress monitored periodically by TLC and / or LCMS. Upon satisfactory conversion of the amine to the desired amide, the reaction mixture was quenched w ith water and extracted 2-3x with a suitable, water immiscible organic solvent (e.g., EtOAc). The combined organic extracts were washed with aqueous sodium bicarbonate and / or other aqueous media, then dried over a suitable drying agent (e.g., anhydrous MgSCh). Filtration followed by removal of solvent via rotary evaporation provided a residue that was subsequently purified by normal or reverse phase chromatography to yield the purified amide product.

[0313] The following Examples were synthesized using General Procedure A, starting with commercially available or known amine and carboxylic acid building blocks, as shown in Table 1.

[0314] Table 1

[0315] Synthesis of Example 33

[0316] Step-1: Ethyl (E)-4-(dimethylamino)-2-oxobut-3-enoate (3)

[0317] To a stirred solution of ethyl 2-oxopropanoate (1, 20.0 g, 172.41 mmol) in DCM(300 mL), 1,1 -dimethoxy -N,N-dimethylmethanamine (2, 20.5 g, 172.41 mmol) was added and the reaction mixture was stirred at RT for 12 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was concentrated under reduced pressure. The crude compound was purified by 100-200 silica gel columnchromatography (2% MeOH / DCM) to afford compound 3 (12.5 g, 45%) as a dark brown solid. 'H NMR (400 MHz, DMSO-d6): 5 7.77 (d. J = 10.8 Hz, 1H), 5.55 (d, J = 10.4 Hz, 1H), 4.18-4.15 (m, 2H), 3.17 (s, 3H), 2.89 (s, 3H), 1.24 (t, J = 7.2 Hz, 3H).

[0318] Step-2: Ethyl 1 -(pyrazin-2-yl)-lH-pyrazole-5-carboxylate (5 A)

[0319] To a stirred solution of compound 3 (0.25 g, 1.7 mmol, 1 eq) in AcOH (5 rnL), 2- hydrazinylpyrazine hydrochloride (4, 0.298 g, 1.8 mmol, 1.1 eq) was added and the reaction mixture was stirred at 110 °C for 16 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was concentrated under reduced pressure. The crude material was dissolved in ethyl acetate and washed with water. The organic layer was dried over anhydrous Na2SC>4 and concentrated under reduced pressure. The crude compound was purified by flash column chromatography (40% EtOAc / hexane) to afford compound 5A (106 mg, 28%) as an off white solid along with compound 5B as a sticky solid. The structure of desired compound 5A was confirmed by NOE. 'H NMR (400 MHz, DMSO- d6) 5 9.07 (bs, 1H), 8.79 (d, J=2.4 Hz, 1H), 8.63 (bs, 1H), 7.96 (d, J=1.6 Hz, 1H), 7.14 (d, J= 2 Hz, 1H), 4.24 (q, J=7.34 Hz, 2H), 3.31 (s, 3H), 1.19 (t, J=7.09 Hz, 3H); LC-MS: m / z 219.0 [M+H]+.

[0320] Step-3: l-(pyrazin-2-yl)-lH-pyrazole-5-carboxylic acid (6)

[0321] To a stirred solution of compound 5A (100 mg, 0.45 mmol. 1 eq) in THF (1.5 mL). MeOH (2.5 mL), H2O (0.5 mL), LiOH.H2O (38.5 g, 0.9 mmol, 2 eq) was added and the reaction mixture was stirred at 60 °C for 1 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was concentrated under reduced pressure. The solid residue was diluted with water and pH was adjusted to ~3 by adding IN HC1 solution. The precipitated solid was filtered, washed with water and dried under reduced pressure to afford compound 6 (80 mg, 92%) as an off white solid.1H NMR (400 MHz, DMSO-d6) 5 13.61 (brs, 1H), 9.01 (bs, 1H), 8.77 (d, J=2.4 Hz, 1H), 8.72 (d, J=2.4 Hz, 1H), 8.63 (bs, 1H), 7.07 (bs, 1H); LC-MS: m / z 190.95 [M+H]+.

[0322] Step-4: Example 33

[0323] In line with General Procedure A, compound 6 (75 mg, 0.39 mmol. 1 eq) was coupled with 4-(pyridin-2-yl)thiazol-2-amine (7, 83 g, 0.47 mmol, 1.2 eq) to afford Example 33 (30 mg, 36%) as an off-white solid. 'H NMR (400 MHz, DMSO-d6) 5 13.10 (brs, 1H), 9.13 (s. 1H), 8.72 (d, J=3.91 Hz, 1H), 8.62 (d, J=8.31 Hz, 1H), 8.54 (t, J=7.83 Hz, 1H), 8.00(bs. 1H), 7.96-7.94 (m. 1H), 7.90-7.88 (m. 2H), 7.36 (t, J=8.80 Hz, 1H), 7.28 (s, 1H); LC- MS: m / z 350.10 [M+H]+; HPLC: 97.2%.

[0324] Synthesis of Example 34

[0325] Step-1: Ethyl l-(3-fluoropyridin-2-yl)-lH-pyrazole-5-carboxylate (9 A)

[0326] To a stirred solution of compound 3 (0.55 g, 3.45 mmol) in acetic acid (10 mL), 3- fluoro-2-hydrazinylpyridine (8, 0.40 g, 3.15 mmol) was added and the reaction mixture was stirred at 110 °C for 24 h in a sealed tube. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was concentrated under reduced pressure. The crude compound was purified by 100-200 silica gel column chromatography (5% EtOAc / hexane) to afford compound 9A (0.11 g, 15%) as a yellow solid along with some 9B. The structure of desired compound 9A was confirmed by NOE.1H NMR (400 MHz, DMSO-de) 5 8.44 (d, J=4.40 Hz. 1H), 8.06 (t, J=9.05 Hz, 1H), 7.94 (s, 1H), 7.69-7.76 (m, 1H), 7.17 (s, 1H), 4.17 (q, J=6.85 Hz, 2H), 1.1 1 (t, J=7.09 Hz, 3H); LC-MS: m / z 236.09 [M+H]+.

[0327] Step-2: l-(3-Fluoropyridin-2-yl)-lH-pyrazole-5-carboxylic acid (10)

[0328] To a stirred solution of compound 9A (0.09 g, 0.38 mmol) in THF (1 rnL), MeOH (2 mL), H2O (0.3 mL). LiOH.H2O (0.032 g, 0.76 mmol) was added and the reaction mixture was stirred at 65 °C for 2 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was concentrated under reduced pressure. The solid residue was diluted with water and pH was adjusted to ~3 by adding IN HC1 solution. The aqueous layer was extracted with 10% MeOH / DCM. The organic layer was dried over anhydrous Na2SC>4 and concentrated under reduced pressure to afford compound 10 (0.078 g, 99%) as an off-white solid. 'H NMR (400 MHz, DMSO-d6) 5 13.50 (brs, 1H), 8.43 (d.J=4.40 Hz, 1H), 7.98-8.07 (m, 1H), 7.89 (d, J=1.96 Hz, 1H), 7.65-7.74 (m, 1H), 7.08 (d, J=1.96 Hz, 1H); LC-MS: m / z 208.14 [M+H]+.

[0329] Step-3: Example 34

[0330] In line with General Procedure A, compound 10 (0.08 g, 0.38 mmol) was coupled with 4-(pyridin-2-yl)thiazol-2-amine (7, 0.08 g, 0.46 mmol) to afford Example 34 (0.014 g, 10%) as an off-white solid. 'H NMR (400 MHz, DMSO-d6) 5 13.17 (brs, 1H), 8.61 (d, J=2.99 Hz, 1H), 8.42 (d, J=3.99 Hz, 1H), 8.06 (t, J=8.73 Hz, 1H). 7.95-8.02 (m, 2H). 7.84- 7.93 (m, 2H), 7.65-7.76 (m, 1H), 7.56 (brs, 1H). 7.31-7.39 (m, 1H): LC-MS: m / z 367.15 [M+H]+; HPLC: 99.9%.

[0331] Synthesis of Example 35

[0332] Step 1: ethyl l-(2-fluoro-5-methylphenyl)-lH-pyrazole-5 -carboxylate (12A)

[0333] A solution of ethyl (E)-4-(dimethylamino)-2-oxobut-3-enoate (3) (400 mg, 2.34 mmol, 1 eq) and (2-fluoro-5-methylphenyl)hydrazine (11) (295 mg, 2.10 mmol, 0.9 eq) in AcOH (4 mL) was heated at reflux for 16 h. Progress of reaction was monitored by TLC. After completion, the reaction mixture was concentrated to dryness and the resultant residue dissolved in EtOAc (20 mL). The organic layer was washed with H2O (10 mL) and brine solution (10 mL), dried over anhydrous NazS2O4 and concentrated in vacuo to provide a mixture of 12A and 12B. The crude was purified by column chromatography (silica 100-200 mesh; 20% EtOAc in Hexanes) to afford 12A (205 mg, 35%) as a brown gum. LC-MS: m / z 249.01 [M+H]+.

[0334] Step 2: l-(2-fluoro-5-methylphenyl)-lH-pyrazole-5-carboxylic acid (13)

[0335] To a solution of ethyl l-(2-fluoro-5-methylphenyl)-lH-pyrazole-5-carboxylate(12A) (190 mg, 0.76 mmol, 1 eq) in THF:H2O (4: 1; 3 mL) was added LiOH (37 mg, 1.53mmol, 2 eq). The reaction mixture was stirred at rt for 2 h. Progress of reaction was monitored by TLC. After completion, the reaction mixture was concentrated and the resultant solid was washed with Et2O (10 mL). The solid was acidified with 2N HC1 solution and triturated with Et20 (10 mL) to afford 13 (150 mg crude). This was used as such for the next reaction. NMR (400 MHz, DMSO-d6) 5 = 13.44 - 13.27 (m, 1H), 7.83 (d, J = 2.0 Hz, 1H), 7.45 - 7.19 (m, 3H), 7.04 (d, J = 2.0 Hz, 1H), 2.34 (s, 3H).

[0336] Step-3: Example 35

[0337] In line with General Procedure A, compound 13 was coupled with 4-(pyridin-2- yl)thiazol-2-amine (7, 0.08 g, 0.46 mmol) to afford Example 35. 'H NMR (400 MHz, DMSO-d6) 5 13.05 (s, 1H), 8.61 (d, J = 4.0 Hz, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.94-7.85 (m, 3H), 7.54-7.52 (m, 1H), 7.42-7.25 (m, 4H), 2.37 (s, 3H); LC-MS: m / z 380.4 [M+H]+;HPLC: 99.4%.

[0338] Synthesis of Example 36

[0339] Step-1: Ethyl l-(2-fluorophenyl)-4-methyl-lH-pyrazole-5-carboxylate (16)

[0340] To a stirred solution of ethyl 4-methyl-lH-pyrazole-5-carboxylate (14) (1 g, 6.48 mmol, 1 eq) in DCM (50 mL). (2-fluorophenyl)boronic acid (15) (0.9 g, 6.48 mmol, 1 eq) and CU(OAC)2 (1.1 g, 6.48 mmol, 1 eq) were added. The mixture was degassed for 15 min. To this mixture, pyridine (3 g, 38.9 mmol, 6 eq) was added and the reaction mixture was stirred for 16h at RT. The progress of the reaction was monitored by TLC (M.Ph: 20% EtOAc in n-hexane; TLC shows formation of two significant non polar spots). After completion of reaction, the reaction mixture was concentrated under reduced pressure. The crude compound which contained two regioisomers w as purified by silica gel column chromatography (0-20% EtOAc in n-hexane) to afford 16 (0.3 mg, 19%) as an off-white solid. Desired compound was characterized by NOE. NMR (400 MHz, DMSO-ds) 5 7.75 (s, 1H). 7.55-7.50 (m, 2H), 7.41-7.31 (m, 2H). 4.17 (q, J = 6.8 Hz. 2H). 3.29 (s, 3H),1.10 (t, J = 6.8 Hz, 3H); LC-MS: m / z 249.1 1 [M+H]+.

[0341] Step-2: l -(2-Fluorophenyl)-4-methyl-lH-pyrazole-5-carboxylic acid (17)

[0342] To a stirred mixture of ethyl l-(2-fluorophenyl)-4-methyl-lH-pyrazole-5- carboxylate (16) (150 mg, 0.6 mmol, 1 eq) in THF:H2O (1: 1, 4 mL), LiOH FLO (28.6 mg, 1.6 mmol, 1.5 eq) was added at RT. The reaction mixture was stirred at RT for 3 h. The progress of the reaction was monitored by TLC (M.Ph: 20% EtOAc in n-hexane). After completion of reaction, the reaction mixture was concentrated under reduced pressure. The crude residue was diluted with water and pH was adjusted to ~3 by adding IN HC1 solution. The precipitated solid was extracted with EtOAc (2 x 50 mL). The organic layer was washed thoroughly with cold water and brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford 17 (200 mg, 77%) as an off-white solid. LC-MS: m / z 221.05 [M+H]+.

[0343] Step-3: Example 36

[0344] To a stirred solution of l-(2-fluorophenyl)-4-methyl-lH-pyrazole-5 -carboxylic acid (17) (200 mg, 0.9 mmol, 1 eq) in DMF (10 mL), DIPEA (175 mg, 1.35 mmol, 1.5 eq) and HATU (510 mg, 1.35 mmol, 1.5 eq) were added and the reaction mixture was stirred for 5 min. To the resulting reaction mixture, 4-(pyridin-2-yl)thiazol-2-amine (7) (176 mg, 0.99 mmol, 1.1 eq) was added and the reaction mixture was stirred at RT for 12 h. The progress of the reaction was monitored by TLC (M.Ph: 50% EtOAc in n-hexane). After completion of reaction, the reaction mixture was diluted with ice cold water. The aqueous layer was extracted with EtOAc (2 x 75 mL). The organic layer was washed thoroughly with cold water and brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude compound was purified through prep HPLC to afford SSY-318 (100 mg. 29%) as an off- white solid. 'H NMR (400 MHz, DMSO-d6) 8 12.83 (s, 1H), 8.61 (bs, 1H), 7.97(d, J = 8.0Hz, 1H), 7.90-7.88 (m, 2H), 7.75 (s, 1H), 7.62-7.58 (m, 1H), 7.51-7.45 (m, 1H), 7.39-7.32 (m, 3H), 2.30 (s, 3H); m / z 380.55 [M+H]+; HPLC: 99.0%.

[0345] Synthesis of Example 37

[0346] Step-1: Synthesis of ethyl l-(2,6-difluorophenyl)-lH-pyrazole-5-carboxylate (4a)

[0347] A solution of ethyl (E)-4-(dimethylamino)-2-oxobut-3-enoate (1) (600 mg, 3.50 mmol, 1 eq) and 2-(2,6-dimethylphenyl)hydrazine hydrochloride (18) (665 mg, 3.86 mmol) in EtOH (4 mL) was heated at reflux for 16 h. Progress of reaction was monitored by TLC. After completion, the reaction mixture was concentrated to dryness and the residue dissolved in EtOAc (20 mL) and washed with H2O (10 mL) and brine solution (10 mL), then dried over anhydrous Na2S2C>4 and concentrated to dryness. The crude was purified by column chromatography (silica 100-200 mesh; 15-20% EtOAc in Hexanes) to afford 19A (330 mg) and 19B (179 mg). The desired isomer 19A was used for the next reaction. 'H NMR (400 MHz, DMSO-d6) 5 = 7.98 (d, J = 2.0 Hz, 1H), 7.71 - 7.62 (m, 1H), 7.36 (t, J = 8.5 Hz, 2H), 7.20 (d, J = 2.0 Hz, 1H), 4.19 (q. J = 7.0 Hz, 2H), 1.14 (t, J = 7.0 Hz, 3H); LC-MS: m / z 252.9 [M+H]+.

[0348] Step-2: Synthesis of l-(2,6-difluorophenyl)-lH-pyrazole-5-carboxylic acid (20)

[0349] To a solution of ethyl l-(2.6-difluorophenyl)-lH-pyrazole-5-carboxylate (19A) (300 mg, 1.19 mmol, 1 eq) in THF:H2O (4: 1; 4 mL) was added LiOH (57 mg, 2.38 mmol, 2 eq). The reaction mixture was stirred at rt for 2 h. Progress of reaction was monitored by TLC. After completion, the reaction mixture was concentrated and solid was washed with Et20 (10 mL). The solid was acidified with 2N HC1 solution and triturated with Et2O (10 mL) to afford 20 (150 mg crude). This was used as such for the next reaction. 'H NMR (400 MHz, DMSO-de) 5 = 13.60 (brs, 1H), 7.93 (d, J = 1.5 Hz, 1H), 7.63 (t, J = 7.6 Hz, 1H), 7.34 (t, J = 8.3 Hz, 2H), 7.11 (d, J = 2.0 Hz, 1H); LC-MS: m / z 224.8 [M+H]+.

[0350] Step-3: Example 37

[0351] In line with General Procedure A, compound 20 was coupled with 4-(pyridin-2- yl)thiazol-2-amine (7, 0.08 g, 0.46 mmol) to afford Example 37. 'H NMR (400 MHz, DMSO-de) 5 13.13 (s, 1H), 8.61 (d, J = 4.4 Hz, 1H), 8.02-7.99 (m, 2H), 7.92 (d, J = 7.6 Hz, 1H), 7.87 (s, 1H), 7.68-7.62 (m, 2H), 7.39-7.33 (m, 3H); LC-MS: m / z 384.1 [M+H]+;HPLC: 99.4%.

[0352] Synthesis of Example 38

[0353] Step-1: Ethyl l-(4-fluorophenyl)-3,4-dimethyl-lH-pyrazole-5-carboxylate (23)

[0354] To a stirred solution of ethyl 3.4-dimethyl-lH-pyrazole-5-carboxylate (21, 250 mg, 1.49 mmol, 1.0 eq) in DCM (10 mL) were added (4-fluorophenyl)boronic acid (22, 208 mg, 1.49 mmol, 1.0 eq) and Cu(OAc)2 (268 mg, 1.49 mmol, 1.0 eq.) followed by pyridine (0.4 mL, 8.24 mmol, 1.5 eq) at RT. The reaction mixture was stirred for 12 h at RT in the presence of oxygen atmosphere. After completion of the reaction, the mixture was filtered, and filtrate was concentrated under reduced pressure. The crude compound was purified through combi -flash column chromatography (5% MeOH in DCM) to afford ethyl l-(4- fluorophenyl)-3,4-dimethyl-lH-pyrazole-5-carboxylate (23, 180 mg, 46%) as a light green solid. 'H NMR (400 MHz, DMSO-d6): 5 7.42-7.39 (m, 2H), 7.27 (t, J = 8.40 Hz, 2H), 4. 15 (q, J = 7.60 Hz, 2H). 2.19 (s. 6H), 1.10 (t, J = 7.60 Hz, 3H): LC-MS: m / z 263.10 [M+H]+.

[0355] Step-2: l-(4-fluorophenyl)-3,4-dimethyl-lH-pyrazole-5-carboxy lie acid (24)

[0356] To a stirred solution of ethyl 1 -(4-11 uorophenyl)-3,4-dimethy 1-1 H-pyrazole-5- carboxylate (23, 0.176 mg, 0.67 mmol, 1.0 eq) in THF: MeOH: H2O (2: l :0.5) (10 ml) was added LiOH.FhO (52 mg, 1 .2 mmol, 2.0 eq) at RT and stirred for Ih at 75 °C. After completion of the reaction, solvent was evaporated and diluted with H2O, acidified with IN HC1 to bring pH~2. The white precipitate formed was filtered through Buchner funnel and dried to get l-(4-fluorophenyl)-3,4-dimethyl-lH-pyrazole-5-carboxylic acid (24) (152 mg. 96%) as a white powder. 'H NMR (400 MHz, DMSO-d6): 5 13.22 (s, IH), 7.39 (t, J = 7.60 Hz, 2H), 7.26 (t, J = 8.80 Hz, 2H), 2.18 (s, 6H); LC-MS: m / z 235.30 [M+H]+.

[0357] Step-3: Example 38

[0358] In line with General Procedure A, compound 24 was coupled with 4-(pyridin-2- yl)thiazol-2-amine (7, 0.08 g, 0.46 mmol) to afford Example 38. 'H NMR (400 MHz, DMSO-d6) 5 12.96 (s, IH), 8.63 (d, J = 4.4 Hz, IH), 7.99-7.94 (m, 3H), 7.39-7.38 (m, 3H), 7.32-7.28 (m, 2H), 2.23 (s, 3H), 2. 13 (s, 3H); LC-MS: m / z 394.2 [M+H]+; HPLC: 98.2%.

[0359] Synthesis of Example 39

[0360] Step-1: Ethyl 2-(2-fluorophenyl)-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-3- carboxylate (27 A)

[0361] To a stirred solution of ethyl 2,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-carboxylate (25, 0.80 g, 4.44 mmol) and (2-fluorophenyl)boronic acid (26, 0.67 g, 4.80 mmol) in DCM (12 mL), pyridine (2.1 g. 26.60 mmol) was added followed by Cu(OAc)2 (0.88 g, 4.80 mmol) and the reaction mixture was stirred at RT for 24 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was diluted with DCMand washed with water. The organic layer was dried over anhydrous NaiSO-i and concentrated under reduced pressure. The crude compound was purified by flash column chromatography (5% EtOAc / hexane) to afford compound 27 A (0. 1 g, 8%) as an off white solid along with some 27B. The structure of desired compound 27A was confirmed by NOE. 'H NMR (400 MHz, DMSO-d6) 5 7.46-7.57 (m, 2H), 7.27-7.41 (m, 2H), 4.09-4.18 (m, 2H), 2.82 (t, J=7.23 Hz, 2H), 2.70-2.77 (m, 2H), 2.38-2.45 (m, 2H), 1.14 (t, J=6.98 Hz, 3H); LC- MS m / z 275.24 [M+H]+.

[0362] Step-2: 2-(2-Fluorophenyl)-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-carboxylic acid (28)

[0363] To a stirred solution of compound 27A (0.10 g, 0.36 mmol) in THF:H2O (1 : 1, 10 mL), LiOH.H2O (0.02 g, 0.54 mmol) was added and the reaction mixture was stirred at RT for 16 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was acidified to pH ~3 by adding IN HC1 solution. The aqueous layer was extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SC>4 and concentrated under reduced pressure. The crude compound was washed with hexane and dried under reduced pressure to afford compound 28 (0.08 g, 90%) as an off white solid. 'H NMR (400 MHz, DMSO-de) 5 13.05 (brs, 1H), 7.44-7.55 (m, 2H), 7.25-7.39 (m, 2H), 2.79 (t, J=7.23 Hz, 2H), 2.72 (t, J=7.23 Hz, 2H), 2.36-2.47 (m, 2H); LC-MS: m / z 247.19 [M+H]+.

[0364] Step-3: Example 39

[0365] In line with General Procedure A, compound 28 (0.08 g, 0.30 mmol) was coupled with 4-(pyridin-2-yl)thiazol-2-amine (5, 0.05 g, 0.30 mmol) to afford Example 39 (0.012 g, 10%) as an off white solid. 'H NMR (400 MHz, DMSO-de) 5 12.65 (bs, 1H), 8.61 (d, J = 4.4 Hz, 1H), 7.99 (d, J = 7.8 Hz, 1H), 7.81-7.92 (m, 2H), 7.60 (t, J = 7.8 Hz, 1H), 7.42-7.52 (m, 1H), 7.31-7.40 (m, 3H), 2.99 (t, J = 7.1 Hz, 2H), 2.77 (t, J = 7.3 Hz, 2H), 2.39-2.45 (m, 2H); LC-MS: m / z 406.60 [M+H]+; HPLC: 99.3%.

[0366] Synthesis of Example 40

[0367] Step-1: Ethyl l-(3-(methylsulfonyl)phenyl)-lH-pyrazole-5-carboxylate (31A)

[0368] To a stirred solution of compound 29 (1.00 g, 7.14 mmol) and (3- (methylsulfonyl)phenyl)boronic acid (30, 1.42 g, 7. 14 mmol) in DCM (50 mL), pyridine (3.5 mL, 42.85 mmol) was added followed by Cu(OAc)2 (1.30 g, 7. 14 mmol) and the reaction mixture was stirred at RT for 16 h under O2 atmosphere. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was filtered through celite, washed with DCM. The organic layer was dried over anhydrous Na2SC>4 and concentrated under reduced pressure. The crude compound was purified by 100-200 silica gel column chromatography (20% EtOAc / hexane) to afford compound 31A (0.21 g, 10%) as a yellow solid along with some 31B. The structure of desired compound 31A was confirmed by NOE. 'H NMR (400 MHz, DMSO-d6) 5 8.00-8.05 (m, 2H), 7.86-7.91 (m, 2H), 7.75-7.81 (m, 1H), 7.17 (s, 1H), 4.20 (q, J=6.98 Hz, 2H), 3.31 (d, J=5.98 Hz, 3H), 1.17 (t, J=6.98 Hz, 3H); LC-MS: m / z 295.02 [M+H]+.

[0369] Step-2: l-(3-(Methylsulfonyl)phenyl)-lH-pyrazole-5-carboxylic acid (32)

[0370] To a stirred solution of compound 31 A (0.20 g, 0.68 mmol) in THF (3 mL), MeOH (5 mL), H2O (1.5 mL), LiOH.LLO (0.06 g, 1.36 mmol) was added and the reaction mixture was stirred at 65 °C for 1 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was concentrated under reduced pressure. The solid residue was diluted with water and pH was adjusted to ~3 by adding IN HC1 solution. The aqueous layer was extracted with 10% MeOH / DCM. The organic layer was dried over anhydrous Na^SCL and concentrated under reduced pressure to afford compound 32 (0.177 g, 98%) as an off-white solid. 'H NMR (400 MHz, DMSO-d6) 5 13.52 (bs, J=2.99 Hz, 1H), 7.97-8.05 (m, 2H). 7.83-7.91 (m, 2H). 7.72-7.81 (m, 1H). 7.10 (d, J=1.50 Hz, 1H), 3.29 (s. 3H); LC-MS: m / z 267.05 [M+H]+.

[0371] Step-3: Example 40

[0372] In line with General Procedure A, compound 32 (0. 17 g, 0.63 mmol) was coupled with 4-(pyridin-2-yl)thiazol-2-amine (7. 0. 14 g, 0.76 mmol) to afford Example 40 (0.025 g, 12%) as an off-white solid. 'H NMR (400 MHz, DMSO-d6) 5 13.1 1 (s, 1H), 8.62 (d, J = 3.9 Hz, 1H), 8.05 (bs, 1H), 8.01 (d, J = 7.8 Hz, 2H), 7.96 (s, 1H), 7.85-7.93 (m, 3H), 7.75-7.82 (m, 1H), 7.54 (s, 1H), 7.32-7.39 (m, 1H), 3.30 (s, 3H); LC-MS: m / z 426.35 [M+H]+: HPLC: 99.7%.

[0373] Synthesis of Example 41

[0374] Step-1: Ethyl l-(2-(methylthio)phenyl)-lH-pyrazole-5-carboxylate (34A)

[0375] To a stirred solution of ethyl lH-pyrazole-3-carboxylate (32, 2.00 g, 14.20 mmol) and (2-(methylthio)phenyl)boronic acid (33, 2.39 g, 14.20 mmol) in DCM (100 mL), pyridine (7.3 mL, 85.20 mmol) was added followed by Cu(OAc)2 (2.57 g, 14.20 mmol) and the reaction mixture was purged with oxygen for 10 min. The reaction mixture was stirred at RT for 16 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was concentrated under reduced pressure. The crude compound was purified by flash column chromatography (10% EtOAc / hexane) to afford compound 34A (0.23 g, 6%) as a colorless liquid along with some 34B. The structure of desired compound 34A was confirmed by NOE. >H NMR (400 MHz, DMSO-d6) 5 7.82 (d, J=1.96 Hz, 1H), 7.48-7.54 (m, 1H), 7.41-7.46 (m, 1H), 7.26-7.34 (m, 2H), 7.07 (d, J=1.96 Hz, 1H), 4.10 (q, J=6.85 Hz, 2H), 2.33 (s, 3H), 1.07 (t, J=7.09 Hz, 3H): LC-MS: m / z 263.35 [M+H]+.

[0376] Step-2: Ethyl l-(2-(methylsulfonyl)phenyl)-lH-pyrazole-5-carboxylate (35)

[0377] To a stirred solution of compound 34A (0. 12 g, 0.46 mmol) in DCM (4 mL), mCPBA (0.39 g, 2.28 mmol) was added and the reaction mixture was stirred at RT for 16 h. The progress of the reaction w as monitored by TLC. After completion of reaction, thereaction mixture was diluted with DCM. The organic layer was washed with saturated NaHCCh solution and brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude compound was purified by 100-200 silica gel column chromatography (50% EtOAc / hexane) to afford compound 35 (0.12 g, 89%) as an off white solid.XH NMR (400 MHz, DMSO-d6) 5 8.09 (dd, J=1.47, 7.83 Hz, 1H), 7.82-7.92 (m, 3H), 7.60 (d, J=7.34 Hz. 1H), 7.10 (d, J=1.96 Hz, 1H), 4.07 (q, J=6.85 Hz, 2H), 3.06 (s, 3H), 1.04 (t, J=7.09 Hz, 3H); LC-MS m / z 294.90 [M+H]+.

[0378] Step-3: l-(2-(Methylsulfonyl)phenyl)-lH-pyrazole-5-carboxylic acid (36)

[0379] To a stirred solution of compound 35 (0. 1 1 g, 0.37 mmol) in THF (5 mL), LiOH.H2O (0.03 g, 0.75 mmol) was added dissolved in H2O (2 mL) at 0 °C and the reaction mixture was stirred at RT for 3 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was concentrated under reduced pressure. The solid residue was diluted with water and pH was adjusted to ~3 by adding IN HC1 solution. The aqueous layer was extracted with 10% MeOH / DCM. The organic layer was dried over anhydrous Na2SC>4 and concentrated under reduced pressure. The crude solid was triturated with diethyl ether followed by n-hexane and dried to afford compound 36 (0.095 g, 95%) as an off white solid. H NMR (400 MHz, DMSO-d6) 5 13.21 (brs, 1H), 8.07 (d, J=7.83 Hz, 1H), 7.75-7.88 (m, 3H), 7.52-7.60 (m, 1H), 7.02 (s, 1H), 3.10 (s, 3H); LC-MS: m / z 266.7 [M+H]+.

[0380] Step-4: Example 41

[0381] In line with General Procedure A, compound 36 (0.09 g, 0.34 mmol) was coupled with 4-(pyridin-2-yl)thiazol-2-amine (6. 0.06 g, 0.34 mmol) to afford Example 41 (0.032 g, 22%) as an off-white solid. NMR (400 MHz, DMSO-de) 5 12.94 (s, 1H), 8.61 (d, J = 3.9 Hz, 1H), 8.10 (d, J = 7.3 Hz, 1H), 7.98-8.03 (m, 1H), 7.80-7.95 (m, 5H), 7.58-7.66 (m, 2H), 7.34 (dd, J = 5.4, 6.36 Hz, 1H), 3.10 (s, 3H); LC-MS: m / z 426.00 [M+H]+; HPLC: 99.8%.

[0382] Synthesis of Example 42

[0383] Step-1: Ethyl l-(4-(tert-butoxycarbonyl)phenyl)-3-methyl-lH-pyrazole-5- carboxylate (38)

[0384] To a stirred solution of ethyl 5-methyl-lH-pyrazole-3-carboxylate (37, 7.00 g, 45.45 mmol) and (4-(tert-butoxycarbonyl)phenyl)boronic acid (38, 10.07 g, 45.45 mmol) in DCM (200 mL), pyridine (21.5 mL, 272.30 mmol) was added followed by Cu(OAc)2 (8.24 g, 45.45 mmol) and the reaction mixture was degassed with oxygen for 10 min. The reaction mixture was stirred at RT for 16 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was concentrated under reduced pressure. The crude compound was purified by 100-200 silica gel column chromatography (5% EtOAc / hexane) to afford compound 39 (3.2 g, 21%) as colorless oil. The structure of desired compound 39 was confirmed by NOE. 'H NMR (400 MHz, DMSO-de) 5 7.97 (d, J=8.31 Hz, 2H), 7.57 (d. J=8.31 Hz. 2H), 6.94 (s, 1H), 4.19 (q, J=7.01 Hz, 2H), 2.28 (s, 3H). 1.57 (s, 9H), 1.18 (t, J=7.09 Hz, 3H); LC-MS: m / z 331.09 [M+H]+.

[0385] Step-2: l-(4-(tert-Butoxycarbonyl)phenyl)-3-methyl-lH-pyrazole-5-carboxylic acid (40)

[0386] To a stirred solution of compound 39 (2.70 g, 8.18 mmol) in THF:H2O (1 : 1, 40 mL), LiOH.H2O (0.41 g. 9.82 mmol) was added and the reaction mixture was stirred at RT for 16 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was acidified to pH ~3 by adding IN HC1 solution. The precipitated solid was filtered, washed with water and dried under reduced pressure to afford compound 40 (2.2 g, 92%) as an off white solid. 'H NMR (400 MHz, DMSO-d6) 5 13.37 (brs, 1H). 7.92-7.99 (m, 2H). 7.55 (d, J=8.31 Hz, 2H). 6.88 (s. 1H), 2.27 (s. 3H), 1.57 (s, 9H); LC-MS: m / z 303.10 [M+H]+.

[0387] Step-3: Example 42

[0388] To a stirred solution of compound 40 (2.20 g, 7.28 mmol) in DMF (10 mL), DIPEA (1.4 g, 10.90 mmol) and HATU (4.1 g, 10.90 mmol) were added and the reaction mixture was stirred for 10 min. To the resulting reaction mixture 4-(pyri din-2 -yl)thiazol-2-amine (7, 1.41 g, 8.01 mmol) was added and the reaction mixture was stirred at RT for 16 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was diluted with ice cold water. The precipitated solid was filtered, washed with water and dried under reduced pressure to afford compound Example 42 (3.0 g, 91%) as an off white solid. 'H NMR (400 MHz, DMSO-d6) 5 13.06 (brs, 1H), 8.62 (d, J=4.40 Hz, 1H), 7.95-8.02 (m.3H), 7.87-7.94 (m, 2H), 7.56 (d, J=8.31 Hz, 2H), 7.32-7.37 (m, 1H), 7.19-7.24 (m, 1H), 2.33 (s, 3H). 1.57 (s, 9H) LC-MS m / z 462.20 [M+H]+; HPLC: 99.7%.

[0389] Synthesis of Example 43

[0390] Step-1: 4-(3-Methyl-5-((4-(pyridin-2-yl)thiazol-2-yl)carbamoyl)-lH-pyrazol-l- yl)benzoic acid (41)

[0391] To Example 42 (0.5 g, 1.08 mmol), TFA (10 mL) was added at 0 °C and the reaction mixture was stirred at 70 °C for 2 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was concentrated under reduced pressure, co-distilled twice with DCM and dried to afford compound 7 (0.35 g, 81%) as a yellow7solid. LC-MS: m / z 406. 15 [M+H]+.

[0392] Step-2: Example 43

[0393] To a stirred solution of compound 41 (0.15 g, 0.24 mmol, 1 eq) in DMF (5 mL), DIPEA (0.071 g. 0.55 mmol, 1.5 eq) and HATU (0.21 g, 0.55 mmol, 1.5 eq) were added and the reaction mixture was stirred for 10 min. To the resulting reaction mixture N-Me piperazine (42, 0.027 g, 0.27 mmol, 1.1 eq) w as added and the reaction mixture was stirred at RT for 16 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was diluted with ice water. The aqueous layer was extracted with ethyl acetate. The organic layer was washed thoroughly with cold water and brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude compound was purified by prep HPLC to afford Example 43 (0. 10 g, 55%) as a brown solid. 'H NMR (400 MHz, DMSO-d6) 5 13.02 (brs, 1H), 8.61 (d, J=4.8 Hz, 1H), 8.00 (d, J=7.6 Hz, 1H), 7.91-7.87 (m. 2H), 7.51-7.46 (m. 4H), 7.35 (dd, J=5.38, 6.85 Hz, 1H). 7.20 (s, 1H). 3.62 (brs, 4H). 2.54 (s, 2H), 2.32 (bs, 5H), 2. 19 (s, 3H); LC-MS: m / z 488.25 [M+H]+; HPLC: 99.4%.

[0394] Synthesis of Example 44

[0395] In line with the procedure outlined above for Example 43, compound 41 was coupled with dimethylamine (43) to afford Example 44 as an off-white solid. 'H NMR (400 MHz, DMSO-d6) 6 13.01 (s, 1H), 8.61 (d, J = 4.4 Hz, 1H), 8.00 (d, J = 7.6 Hz, 1H), 7.92-7.87 (m. 2H), 7.49 (s, 4H), 7.36-7.33 (m, 1H), 7.20 (s, 1H), 3.00 (d, J = 17.2 Hz, 6H), 2.31 (s. 3H);LC-MS m / z 433.2 [M+H]+; HPLC 99.9%.

[0396] Synthesis of Example 45

[0397] Step-1: Ethyl l-(3-(tert-butoxycarbonyl)phenyl)-3-methyl-lH-pyrazole-5- carboxylate (45)

[0398] To a stirred solution of ethyl 5-methyl-lH-pyrazole-3-carboxylate (37, 250 mg, 1.12 mmol, 1 eq) and (3-(tert-butoxycarbonyl)phenyl)boronic acid (44, 174 mg, 1.12 mmol, 1 eq) in DCM (25 mL), pyridine (0.7 mL, 6.7 mmol, 6 eq) was added followed by Cu(OAc)2 (200 mg, 1.12 mmol, 1 eq) and the reaction mixture was degassed with oxygen for 10 min. The reaction mixture was stirred at RT for 16 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was concentrated under reduced pressure. The crude compound was purified by 100-200 silica gel column chromatography (5% EtOAc / hexane) to afford compound 45 (120 mg, 32%) as colorless oil. The structure of desired compound 3 was confirmed by NOE. 'H NMR (400 MHz, DMSO-de) 8 7.97 (d, J=8.31 Hz. 2H), 7.57 (d, J=8.31 Hz, 2H), 6.94 (s, 1H), 4.19 (q, J=7.01 Hz, 2H), 2.28 (s, 3H). 1.57 (s, 9H), 1.18 (t, J=7.09 Hz, 3H); LC-MS: m / z 331.09 [M+H]+.

[0399] Step-2: l-(3-(tert-Butoxycarbonyl)phenyl)-3-methyl-lH-pyrazole-5-carboxylic acid(46)

[0400] To a stirred solution of compound 45 (200 mg, 0.6 mmol, 1 eq) in THF:H2O (1: 1, 10 mL), LiOH.H2O (51 mg, 12. 12 mmol, 2 eq) was added and the reaction mixture was stirred at RT for 16 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was acidified to pH ~3 by adding IN HC1 solution. The precipitated solid was filtered, washed with water and dried under reduced pressure to afford compound 46 (160 mg, 89%) as an off white solid. ’H NMR (400 MHz, DMSO-de) 5 13.22 (brs, 1H), 7.98-7.93 (m, 2H), 7.85 (s, 1H). 7.69 (d, J=6.8 Hz, 1H), 6.86 (s, 1H). 2.27 (s, 3H), 1.57 (s, 9H); LC-MS: m / z 302.8 [M+H]+.

[0401] Step-3: Example 45

[0402] To a stirred solution of compound 46 (150 mg, 0.49 mmol, 1 eq) in DMF (3 mL), DIPEA (0.3 mL, 1.49 mmol, 3 eq) and HATU (300 mg. 0.74 mmol, 3 eq) were added and the reaction mixture was stirred for 10 min. To the resulting reaction mixture 4-(pyridin-2- yl)thiazol-2-amine (7, 105 mg, 0.59 mmol, 1.2 eq) was added and the reaction mixture was stirred at RT for 16 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was diluted with ice cold water. The precipitated solid was filtered, washed with water and dried under reduced pressure to afford Example 45 (27 mg, 11%) as an off white solid. 'H NMR (400 MHz, DMSO-d6) 5 13.06 (brs, 1H), 8.62 (d, J=4.40 Hz, 1H), 7.95-7.91 (m, 2H), 7.86 (s, 1H), 7.71-7.69 (m, 1H), 7.62-7.58 (m, 1H), 7.39 (d, 1-8.31 Hz, 1H), 7.22 (s, 1H), 2.33 (s, 3H), 1.57 (s, 9H); LC-MS: m / z 462.05 [M+H]+;HPLC: 99.9%.

[0403] Synthesis of Example 46

[0404] Step-1: Ethyl l-(3-(tert-butoxycarbonyl)phenyl)-3-methyl-lH-pyrazole-5- carboxylate (48)

[0405] To a stirred solution of (3-(tert-butoxycarbonyl)phenyl)boronic acid (47) (5 g, 22.52 mmol, 1 eq) and ethyl 5-methyl-lH-pyrazole-3-carboxylate (37) (4.1 g, 27 mmol, 1.2 eq) in DCM (100 mL), pyridine (10.87 mL, 136.1 mmol, 6 eq) was added followed by Cu(OAc)2 (4.09 g, 22.52 mmol, 1 eq) and the reaction mixture was stirred at RT for 16 h. After completion of reaction, the reaction mixture was diluted with DCM and washed with water. The organic layer was dried over anhydrous NA’SCE and concentrated under reduced pressure. The crude compound was purified by flash column chromatography (5% EtOAc / hexane) to afford compound 3 (2.2 g, 30%) as an off -white solid. The structure was confirmed by NOE. H NMR (400 MHz, DMSO-d6) 5 7.97 (d, J = 8.0 Hz, 1H), 7.86 (bs, 1H), 7.71 (d. J = 7.6 Hz. 1H), 7.61 (t, J = 8.0 Hz, 1H). 6.93 (s, 1H). 4.20 (q, J = 7.2 Hz, 2H). 2.28 (s, 3H), 1.55 (s, 9H), 1.17 (t, J = 7.6 Hz, 3H); LC-MS: m / z 331.20 [M+H]+.

[0406] Step-2: l-(3-(tert-Butoxycarbonyl)phenyl)-3-methyl-lH-pyrazole-5-carboxylic acid (49)

[0407] To a stirred solution of ethyl l-(3-(tert-butoxycarbonyl)phenyl)-3-methyl-lH- pyrazole-5-carboxylate (48) (2.2 g, 6.66 mmol, 1 eq) in THF:H2O:MeOH (2.5:2.5: 1. 60 mL), LiOH.H2O (0.559 g, 13.31 mmol, 2 eq) was added at 0 °C and the reaction mixture was stirred at RT for 2 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was concentrated under reduced pressure. The solid residue was diluted with water and pH was adjusted to ~3 by adding IN HC1 solution. The precipitated solid was filtered, washed with water and dried under reduced pressure to afford compound 49 (1.8 g, 90%) as an off-white solid. LC-MS: m / z 303.0 [M+H]'.

[0408] Step-3: tert-Butyl 3-(3-methyl-5-((4-(pyridin-2-yl)thiazol-2-yl)carbamoyl)-lH- pyrazol-l-yl)benzoate (50)

[0409] To a stirred solution of l-(3-(tert-butoxycarbonyl)phenyl)-3-methyl-lH-pyrazole-5- carboxylic acid (49) (1.8 g, 5.9 mmol. 1 eq) in DMF (10 mL), DIPEA (4.5 g. 35.6 mmol, 6 eq) and HATU (3.3 g, 8.9 mmol, 1.5 eq) were added and the reaction mixture was stirred for 5 min. To the resulting reaction mixture, 4-(pyridin-2-yl)thiazol-2-amine (7) (1.1 g, 6.5 mmol, 1.1 eq) was added and the reaction mixture was stirred at RT for 16 h. The progress of the reaction was monitored by TLC (M.Ph: 50% EtOAc in n-hexane). After completion of reaction, the reaction mixture was diluted with ice cold water. The aqueous layer wasextracted with EtOAc (2 x 75 mL). The organic layer was washed thoroughly with cold water and brine, dried over anhydrous Na2SC>4 and concentrated under reduced pressure. The crude compound was purified by combi -flash (30% EtOAc / hexane) to afford 50 (1.5 g, 55%) as an off-white solid. LC-MS: m / z 462. 1 [M+H]+.

[0410] Step-4: 3-(3-Methyl-5-((4-(pyridin-2-yl)thiazol-2-yl)carbamoyl)-lH-pyrazol-l- yl)benzoic acid (51)

[0411] A mixture of tert-butyl 3-(3-methyl-5-((4-(pyridin-2-yl)thiazol-2-yl)carbamoyl)-lH- pyrazol-l-yl)benzoate (50) (0.3 g. 0.65 mmol, 1 eq) and TFA (10 mL) was heated at 80 °C for 16 h. The progress of the reaction was monitored by TLC (M.Ph: 50% EtOAc in n- hexane). After completion of reaction, the reaction mixture w as concentrated to dryness afford 51 (0.2 g, 77%) as an off-white solid. LC-MS: m / z 406.15 [M+H]+.

[0412] Step-5: Example 46

[0413] Under conditions comparable with General Procedure A, 3-(3-methyl-5-((4- (pyridin-2-yl)thiazol-2-yl)carbamoyl)-lH-pyrazol-l-yl)benzoic acid (51) (0.2 g, 0.49 mmol, 1 eq) was coupled with N-Boc piperazine (52) (1. 1 eq) to afford Example 46 (0. 12 g, 43%) as an off-white solid. 'H NMR (400 MHz, DMSO-d6) 5 13.0 (s, 1H), 8.60 (bs, 1H), 8.0 (d, J = 7.6 Hz, 1H), 7.90 (t, J = 7.6 Hz, 1H), 7.82 (bs. 1H), 7.57-7.55 (m. 2H), 7.48-7.45 (m. 2H), 7.35 (t. J = 6.8 Hz. 1H), 7.23 (s, 1H), 3.55 (bs. 2H). 3.42 (bs, 6H), 2.31 (s, 3H). 1.33 (bs. 9H); LC-MS: m / z 574.08 [M+H]+; HPLC: 98.3%.

[0414] Synthesis of Example 47

[0415] In line with the amidation procedure outlined above for Example 46, compound 51 was coupled with dimethylamine (43) to afford Example 47 as an off-white solid.1H NMR (400 MHz, DMSO-de) 5 12.98 (s, 1H), 8.61 (d, J = 4.4 Hz, 1H), 8.00 (d, J = 7.6 Hz, 1H). 7.92-7.87 (m, 1H). 7.88 (s. 1H), 7.57-7.51 (m. 2H), 7.44-7.43 (m. 2H), 7.36 (t, J = 6.4 Hz,1H), 7.23 (s, 1H), 2.95 (d, J = 11.6 Hz, 6H), 2.32 (s. 3H); LC-MS: m / z 433.2 [M+H]+;HPLC: 99.9%.

[0416] Synthesis of Example 48

[0417] Step-1: 3,4-Difluoro-N,N-dimethylbenzamide (54)

[0418] To a stirred solution of 3,4-difluorobenzoic acid (53) (1 g, 6.32 mmol, 1 eq) in DMF (10 mL), DIPEA (3.49 mL, 18.97 mmol, 3 eq) and HATU (3.6 g, 9.48 mmol, 1.5 eq) were added and the reaction mixture was stirred for 5 min. To the dimethyl amine hydrochloride (43) (0.77 g, 9.48 mmol, 1.5 eq) was added and the reaction mixture was stirred at RT for 16 h. The progress of the reaction was monitored by TLC (M.Ph: 30% EtOAc in n-hexane). After completion of reaction, the reaction mixture was diluted with ice cold water. The aqueous layer was extracted with EtOAc (2 x 100 mL). The organic layer was washed thoroughly with cold water and brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude compound was purified by flash column chromatography (25% EtOAc / hexane) to afford 54 (1.0 g, 90%) as an off-white solid. LC-MS: m / z 185.85 [M+H].+

[0419] Step-2: 3-Fluoro-4-hydrazinyl-N,N-dimethylbenzamide (55)

[0420] A mixture of 3,4-difluoro-N,N-dimethylbenzamide (54) (1.0 g, 5.40 mmol, 1 eq) and hydrazine hydrate (1.35 mL, 27.01 mmol. 1 eq) was stirred at 90 °C for 16 min. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was concentrated under reduced pressure and the crude compound was purified by 100-200 silica gel column chromatography (10% EtOAc / hexane) to afford compound 55(488 mg, 49%) as a light brown liquid.1H NMR (400 MHz, DMSO-d6) 5 7. 14-7. 11 (m, 2H), 7.08 (bs, 1H), 7.05 (bs, 1H), 7.01 (bs, 1H), 2.94 (s, 6H); LC-MS m / z 197.6 [M+H]+.

[0421] Step-3: l-(2,6-Difluorophenyl)-3-methyl-lH-pyrazole-5-carboxylic acid ethyl ester (57)

[0422] To a stirred solution of 3-fluoro-4-hydrazineyl-N,N-dimethylbenzamide (55) (480 mg, 2.43 mmol, 1 eq) in ethanol (5 mL), ethyl 2,4-dioxopentanoate (56) (384 mg, 2.43 mmol, 1 eq) and AcOK (286 mg, 2.92 mmol, 1.2 eq) in EtOH (50 mL, 10 vol.) was added and the mixture was stirred at 75 °C for 16 h. The progress of the reaction was monitored by TLC (M.Ph: 25% EtOAc in n-hexane). After completion of reaction, the reaction mixture was concentrated to dry ness and the reaction mixture was diluted with ice cold w ater. The aqueous layer was extracted with EtOAc (2 x 100 mL). The organic layer was washed thoroughly with cold water and brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure and the crude was purified by 100-200 silica gel column chromatography (10% EtOAc / hexane) to afford compound 57 (desired isomer, 45 mg, 6%) as an off-white solid. ’H NMR (400 MHz, DMSO-d6) 5 7.63 (t, J=7.2 Hz, 1H), 7.49 (d, J=10.8 Hz, 1H), 7.36 (d, J=7.6 Hz, 1H) 6.95 (s, 1H). 7.63 (q, J=6.8 Hz, 2H), 3.00 (s, 3H), 2.93 (s, H), 2.28 (s, 3H), 1.16 (t, J=6.8 Hz, 3H); LC-MS: m / z 320.10 [M+H]+.

[0423] Step-4: 1 -(4-(Dimethylcarbamoyl)-2-fluorophenyl)-3-methyl- lH-pyrazole-5- carboxylic acid (58)

[0424] To a stirred solution of l-(2,6-difluorophenyl)-3-methyl-lH-pyrazole-5-carboxylic acid (57) (45 mg, 0.14 mmol, 1 eq) in THF:H2O:MeOH (1 : 1: 1, 10 mL), LiOH.H2O (11.8 mg, 0.28 mmol, 2 eq) was added at 0 °C and the reaction mixture was stirred at RT for 2 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was concentrated under reduced pressure. The solid residue was diluted with water and pH was adjusted to ~3 by adding IN HC1 solution. The precipitated solid was filtered, washed with water and dried under reduced pressure to afford compound 58 (37 mg, 90%) as an off-white solid.JH NMR (400 MHz. DMSO-d6) 5 13.44 (s, 1H), 7.6 (t, J=7.6 Hz. 1H), 7.46 (d, J=10.4 Hz, 1H), 7.34 (d, J=8 Hz, 1H), 6.86 (s, 1H), 2.99 (s, 3H), 2.93 (s, H), 2.26 (s, 3H); LC-MS: m / z 291.8 [M+H]+.

[0425] Step-5: Example 48

[0426] To a stirred solution of l-(4-(dimethylcarbamoyl)-2-fluorophenyl)-3-methyl-lH- pyrazole-5-carboxylic acid (58) (36 mg, 0.12 mmol, 1 eq) in DMF (1 mL), DIPEA (23.27 mg, 0.18 mmol, 1.5 eq) and HATU (54.8 mg, 0.144 mmol, 1.2 eq) were added and the reaction mixture was stirred for 10 min. To the resulting reaction mixture 4-(pyridin-2- yl)thiazol-2-amine (7) (21 mg, 0.12 mmol, 1 eq) was added and the reaction mixture was stirred at RT for 16 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was diluted with ice water. The aqueous layer was extracted with ethyl acetate. The organic layer was washed thoroughly with cold water and brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude compound was purified by flash column chromatography (2% MeOH / DCM) to afford Example 48 (7 mg, 13%) as an off white solid. 'H NMR (400 MHz, DMSO-d6) 6 12.44 (s. 1H), 8.61 (d. J=3.91 Hz, 1H), 8.00 (d, J=8.0Hz, 1H), 7.91-7.89 (m, 1H), 7.82 (s, 1H), 7.64 (t, J=7.6 Hz, 1H), 7.47 (d, J=10.8Hz, 1H) 7.37-7.32 (m, 2H), 7.28 (s, 1H), 3.01 (s, 3H), 2.96 (s, H), 2.32 (s, 3H); LC- MS: m / z 451.20 [M+H]+; HPLC: 96.0%.

[0427] Synthesis of Example 49

[0428] Step-1: Ethyl l-(4-(dimethylcarbamoyl)-3-fluorophenyl)-3-methyl-lH-pyrazole-5- carboxylate (60)

[0429] To a stirred solution of ethyl 5-methyl-lH-pyrazole-3-carboxylate (37, 0.1 g, 0.64 mmol) and (4-(dimethylcarbamoyl)-3-fluorophenyl)boronic acid (59. 0.15 g. 0.71 mmol) in DCM (10 mL), pyridine (0.3 g, 3.89 mmol) was added followed by Cu(OAc)2 (0.13 g, 0.71 mmol) and the reaction mixture was stirred at RT for 16 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was diluted with DCM and washed with water. The organic layer was dried over anhydrous Na2SC>4 and concentrated under reduced pressure. The crude compound was purified by flash column chromatography (10% EtOAc / hexane) to afford compound 60 (0.04 g, 20%) as colorless oil. The structure of desired compound 60 was confirmed by NOE. 'II NMR (400 MHz, DMSO-de) 5 7.44-7.55 (m, 2H), 7.34-7.41 (m, 1H), 6.94 (d, J=2.45 Hz, 1H), 4.15-4.24 (m, 2H), 3.02 (d, J=1.96 Hz, 3H), 2.88 (d, J=1.47 Hz, 3H), 2.27 (d, J=2.45 Hz, 3H). 1.14-1.21 (m, 3H): LC- MS m / z 320.15 [M+H]+.

[0430] Step-2: 1 -(4-(Dimethylcarbamoyl)-3-fluorophenyl)-3-methyl-lH-pyrazole-5- carboxylic acid (61)

[0431] To a stirred solution of compound 60 (0.04 g, 0.12 mmol) in THF:H2O (1 : 1, 5 mL), LiOH.H2O (0.01 g, 0. 19 mmol) was added and the reaction mixture was stirred at RT for 16 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was acidified to pH ~3 by adding IN HC1 solution. The aqueous layer was extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SC>4 and concentrated under reduced pressure. The crude compound was w ashed with hexane and dried under reduced pressure to afford compound 61 (0.035 g, 97%) as brown solid. LC-MS: m / z 292.05 [M+H]+.

[0432] Step-3: Example 49

[0433] In line with the General Procedure A, compound 61 (0.04 g, 0.12 mmol) was coupled with 4-(pyridin-2-yl)thiazol-2-amine (7, 0.02 g, 0.13 mmol) to afford Example 49 (0.015 g, 28%) as an off-white solid. ‘H NMR (400 MHz, DMSO-d6) 5 13.01 (bs, 1H), 8.59- 8.63 (m, 1H), 8.00 (d, J = 7.8 Hz, 1H). 7.86-7.93 (m, 2H). 7.45-7.53 (m, 2H). 7.33-7.38 (m, 2H), 7.25 (s, 1H), 3.03 (s, 3H), 2.89 (s, 3H), 2.32 (s, 3H); LC-MS: m / z 451.20 [M+H]+; HPLC: 94.1%.

[0434] Synthesis of Example 50

[0435] Step-1: Ethyl 4-hyd...

Claims

WHAT IS CLAIMED IS:

1. A compound, or a pharmaceutically acceptable salt or tautomer thereof, having the formula:whereinRing A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;L1is a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene;R1is independently halogen, -CXS, -CHX^, -CH2X1, -OCXS, -OCH2X1, -OCHXS, -CN, -SOniR1D, -SOviNR1AR1B, -NR1CNR1AR1B, -ONR1AR1B, -NR1CC(O)NR1AR1B, -N(O)mi, -NR1AR1B, -C(O)R1C, -C(O)OR1C, -C(O)NR1AR1B, -OR1D, -NR1ASO2R1D, -NR1AC(O)R1C, -NR1AC(O)OR1C, -NR1AOR1C, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two R1substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; zl is an integer from 0 to 4;R2is hydrogen, halogen, -CCI3, -CBrs, -CF3, -CI3, -CHCI2, -CHBr2, -CHF2, -CHI2, -CH2CI, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCI3, -OCF3, -OCBrs, -OCI3, -OCHCb, -OCHBr2, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I, -OCH2F. substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R3is independently halogen, -CX33, -CHX32, -CH2X3, -OCX33, -OCH2X3, -OCHX32, -CN, -SOn3R3D, -SOV3NR3AR3B, -NR3CNR3AR3B, -ONR3AR3B, -NR3CC(O)NR3AR3B-N(0)m3. -NR3AR3B, -C(O)R3C, -C(O)OR3C, -C(O)NR3AR3B, -OR3D, -NR3ASO2R3D, -NR3AC(O)R3C, -NR3AC(O)OR3C, -NR3AOR3C, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two R3substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; z3 is an integer from 0 to 2;R4is independently oxo, halogen, -CX43, -CHX42, -CH2X4, -OCX'S, -OCH2X4, -OCHX42, -CN, -SOn4R4D, -SOV4NR4AR4B, -NR4CNR4AR4B. -ONR4AR4B.-NR4CC(O)NR4AR4B, -N(O)m4, -NR4AR4B, -C(O)R4C, -C(O)OR4C, -C(O)NR4AR4B, -OR4D, -NR4ASO2R4D, -NR4AC(O)R4C, -NR4AC(O)OR4C, -NR4AOR4C, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two R4substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted and, or substituted or unsubstituted heteroaryl; z4 is an integer from 0 to 11;R5is hydrogen, halogen, -CCh, -CBr3. -CF3. -CI3. -CH2CI, -CFhBr. -CH2F.-CH2I, -CHCh, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -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, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R1A, R1B, R1C, R1D, R3A, R3D. R3C, R3D. R4A, R4B. R4C, and R4Dare independently hydrogen, halogen, -CCI3, -CBr3, -CF3, -CI3, -CHC12, -CHBr2, -CHF2, -CHI2, -CH2CI, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCC13, -OCF3,-OCBn. -OCI3, -OCHCh, -OCHBr2, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R1Aand R1Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R3Aand R3Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R4Aand R4Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; each X1, X3, and X4is independently -F. -Cl, -Br, or -I; nl, n3, and n4 are independently an integer from 0 to 4; and ml, m3, m4, vl, v3, and v4 are independently 1 or 2; wherein when Ring A is phenyl and z4 is 0, then R3is not unsubstituted isopropyl, unsubstituted cyclopropyl, unsubstituted furanyl. or unsubstituted thienyl.

2. The compound of claim 1, having the formula:

3. The compound of claim 1, having the formula:

4. The compound of claim 1, wherein R2is hydrogen or unsubstituted Ci-C4alkyl.

5. The compound of claim 1, wherein R2is hydrogen.

6. The compound of claim 1, wherein L1is a bond, substituted or unsubstituted C1-C4 alkylene, or substituted or unsubstituted 2 to 6 membered heteroalkylene.

7. The compound of claim 1, wherein L1is a bond, unsubstituted methylene,8. The compound of claim 1, wherein Ring A is C3-C8 cycloalkyl, 3 to 8 membered heterocycloalkyl, phenyl, or 5 to 6 membered heteroaryl.

9. The compound of claim 1, wherein Ring A is phenyl, pyridyl, pyrazinyl, or pyrimidinyl.

11. The compound of claim 1, wherein R4is independently oxo, halogen, -CCI3, -CBr3, -CF3, -CI3, -CH2CI, -CH2Br, -CH2F, -CH2I, -CHC12, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2. -COOH, -CONH2. -NO2, -SH. -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI3, -OCBr3, -OCF3, -OCI3, -OCH2C1, -OCH2Br, -OCH2F, -OCH2I, -OCHCh, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

12. The compound of claim 1, wherein R4is independently halogen, -CX43, -OCXS, -SOn4R4D, -SOV4NR4AR4B. -C(O)OR4C, -C(O)NR4AR4B. substituted or unsubstituted C1-C4 alkyl, or substituted or unsubstituted 2 to 6 membered heteroalkyl.

13. The compound of claim 1, wherein R4is independently -F, -Cl, -CF3,14. The compound of claim 1, wherein z4 is 1 or 2.

15. The compound of claim 1, wherein z4 is 0.The compound of claim 1, wherein17. The compound of claim 1, wherein R1is independently halogen, -CCI3, -CBrs, -CF3, -CI3, -CH2CL -CH2Br, -CH2F, -CH2I, -CHCh, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NH2. -NHSO2H. -NHC(O)H, -NHC(O)OH. -NHOH, -OCCI3, -OCBr3, -OCF3, -OCI3, -OCH2CL -OCH2Br, -OCH2F, -OCH2I, -OCHC12, -OCHBr2, -OCHF2, -OCHI2, -SF5, -Ns, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyd, substituted or unsubstituted heterocycloalky l, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

18. The compound of claim 1, wherein R1is independently halogen, unsubstituted C1-C4 alkyl, or unsubstituted 2 to 6 membered heteroalkyl.

19. The compound of claim 1, wherein R1is independently -F, unsubstituted methyl, or20. The compound of claim 1, wherein zl is 1 or 2.

21. The compound of claim 1, wherein zl is 0.

23. The compound of one of claims 1 to 22, wherein R3is independently -CX33, -CHX32, -CH2X3, -NR3AC(O)R3C, -NR3ASO2R3D, substituted or unsubstituted C1-C4 alkyl, or substituted or unsubstituted 2 to 6 membered heteroalkyl.

24. The compound of one of claims 1 to 22, wherein R3is independently-CF3, -CHF2, -CH2F, unsubstituted methyl, unsubstituted isopropyl,25. The compound of one of claims 1 to 22, wherein two R3substituents are joined to form a substituted or unsubstituted Cs-Cs cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl.

26. The compound of one of claims 1 to 22, wherein two R3substituents27. The compound of one of claims 1 to 22, wherein z3 is 1 or 2.

28. The compound of one of claims 1 to 22, wherein z3 is 0.

29. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound, or a pharmaceutically acceptable salt or tautomer thereof, having the formula:whereinRing A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;L1is a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene;R1is independently halogen, -CXS, -CHX^, -CH2X1, -OCXS, -OCH2X1, -OCHXS, -CN, -SOniR1D, -SOviNR1AR1B, -NR1CNR1AR1B, -ONR1AR1B, -NR1CC(O)NR1AR1B, -N(O)mi, -NR1AR1B, -C(O)R1C, -C(O)OR1C, -C(O)NR1AR1B, -OR1D, -NR1ASO2R1D, -NR1AC(O)R1C, -NR1AC(O)OR1C, -NR1AOR1C, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two R1substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; zl is an integer from 0 to 4;R2is hydrogen, halogen, -CCI3, -CBrs, -CF3, -CI3, -CHCI2, -CHBr2, -CHF2, -CHI2, -CH2CI, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCI3, -OCF3, -OCBrs, -OCI3, -OCHCb, -OCHBr2, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I, -OCH2F. substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R3is independently halogen, -CX33, -CHX32, -CH2X3, -OCX33, -OCH2X3, -OCHX32, -CN, -SOn3R3D, -SOV3NR3AR3B, -NR3CNR3AR3B, -ONR3AR3B, -NR3CC(O)NR3AR3B-N(0)m3. -NR3AR3B, -C(O)R3C, -C(O)OR3C, -C(O)NR3AR3B, -OR3D, -NR3ASO2R3D, -NR3AC(O)R3C, -NR3AC(O)OR3C, -NR3AOR3C, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two R3substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; z3 is an integer from 0 to 2;R4is independently oxo, halogen, -CX43, -CHX42, -CH2X4, -OCX'S, -OCH2X4, -OCHX42, -CN, -SOn4R4D, -SOV4NR4AR4B, -NR4CNR4AR4B. -ONR4AR4B.-NR4CC(O)NR4AR4B, -N(O)m4, -NR4AR4B, -C(O)R4C, -C(O)OR4C, -C(O)NR4AR4B, -OR4D, -NR4ASO2R4D, -NR4AC(O)R4C, -NR4AC(O)OR4C, -NR4AOR4C, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two R4substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted and, or substituted or unsubstituted heteroaryl; z4 is an integer from 0 to 11;R5is hydrogen, halogen, -CCh, -CBr3. -CF3. -CI3. -CH2CI, -CFhBr. -CH2F.-CH2I, -CHCh, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -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, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R1A, R1B, R1C, R1D, R3A, R3D. R3C, R3D. R4A, R4B. R4C, and R4Dare independently hydrogen, halogen, -CCI3, -CBr3, -CF3, -CI3, -CHC12, -CHBr2, -CHF2, -CHI2, -CH2CI, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCC13, -OCF3,-OCBn. -OCI3, -OCHCh, -OCHBr2, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R1Aand R1Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R3Aand R3Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R4Aand R4Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; each X1, X3, and X4is independently -F. -Cl, -Br, or -I; nl, n3, and n4 are independently an integer from 0 to 4; and ml, m3, m4, vl, v3, and v4 are independently 1 or 2.

30. A method of treating a cancer in a subject in need thereof, said method comprising administering to the subject a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt or tautomer thereof, having the formula:whereinRing A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;L1is a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene;R1is independently halogen, -CXS, -CHX^, -CH2X1, -OCX's, -OCH2X1, -OCHX12, -CN, -SOniR1D. -SOviNR1AR1B, -NR1CNR1AR1B. -ONR1AR1B. -NR1CC(O)NR1AR1B-N(O)mi, -NR1AR1B, -C(O)R1C, -C(O)OR1C, -C(O)NR1AR1B, -OR1D, -NR1ASO2R1D, -NR1AC(O)R1C, -NR1AC(O)OR1C, -NR1AOR1C, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two R1substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted ary l, or substituted or unsubstituted heteroaryl; zl is an integer from 0 to 4;R2is hydrogen, halogen, -CCI3, -CBr3, -CF3, -CI3, -CHCb, -CHBr2, -CHF2, -CHI2, -CH2CL -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCI3, -OCF3, -OCBrs, -OCI3, -OCHCh, -OCHBr2, -OCHI2, -OCHF2, -OCH2C1, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R3is independently halogen, -CX33, -CHX32, -CH2X3, -OCX33, -OCH2X3, -OCHX32, -CN, -SOn3R3D, -SOV3NR3AR3B, -NR3CNR3AR3B. -ONR3AR3B. -NR3CC(O)NR3AR3B, -N(O)m3, -NR3AR3B, -C(O)R3C, -C(O)OR3C, -C(O)NR3AR3B, -OR3D, -NR3ASO2R3D, -NR3AC(O)R3C, -NR3AC(O)OR3C, -NR3AOR3C, -SF5, -N3, substituted or unsubstituted alkyd, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two R3substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroary l; z3 is an integer from 0 to 2;R4is independently oxo, halogen, -CX43, -CHX42, -CH2X4, -OCX43, -OCH2X4, -OCHX42, -CN, -SOn4R4D, -SOV4NR4AR4B-NR4CNR4AR4B, -ONR4AR4B, -NR4CC(O)NR4AR4B, -N(O)m4, -NR4AR4B, -C(O)R4C, -C(O)OR4C, -C(O)NR4AR4B, -OR4D, -NR4ASO2R4D, -NR4AC(O)R4C, -NR4AC(O)OR4C, -NR4AOR4C, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted ary l, or substituted or unsubstituted heteroaryl; two R4substituents may optionally be joined to forma substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryk z4 is an integer from 0 to 1 1;R5is hydrogen, halogen, -CCls, -CBrs, -CF3, -CI3, -CH2CI, -CH2Br, -CH2F, -CH2I, -CHCI2. -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H. -OSO3H. -SO2NH2, -NHNH2. -ONH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCI3, -OCBr3, -OCF3, -OCI3, -OCH2CI, -OCH2Br, -OCH2F, -OCH2I, -OCHCI2, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R1A, R1B, R1C, R1D, R3A, R3B, R3C, R3D, R4A, R4B, R4C, and R4Dare independently hydrogen, halogen, -CCI3, -CBrs, -CF3, -CI3, -CHCI2, -CHBr2, -CHF2, -CHI2, -CH2CI, -CH2Br. -CH2F. -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCI3, -OCF?, -OCBr3, -OCI3, -OCHC12, -OCHBr2, -OCH12. -OCHF2. -OCH2C1, -OCH2Br. -OCH21, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroary l; R1Aand R1Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R3Aand R3Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R4Aand R4Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; each X1, X3, and X4is independently -F, -Cl, -Br, or -I; nl, n3, and n4 are independently an integer from 0 to 4; and ml, m3, m4, vl, v3, and v4 are independently 1 or 2.

31. The method of claim 30, wherein the cancer is brain cancer, breast cancer, colon cancer, esophageal cancer, gastric cancer, gastrointestinal stromal tumor, head and neck cancer, liver cancer, lung cancer, lymphoma, melanoma, pancreatic cancer, prostate cancer, or rectal cancer.

Images