Notch Inhibitors and Uses Thereof

BACKGROUND

Notch is a major developmental pathway that regulates cancer stem cells (CSCs) in Notch-driven cancers. Notch signaling is initiated upon the physical interaction of cells expressing ligands with neighboring cells expressing Notch receptors. Notch ligand/receptor interaction results in irreversible cleavage of Notch receptors by gamma-secretase and subsequent generation of Notch intracellular domains (NICDs). NICDs translocate to the nucleus and are required for the stepwise formation of an active Notch Transcription Complex (NTC) that includes recruitment of the DNA-binding protein CSL, followed by the transcriptional coactivator Mastermind-like 1. The NTC subsequently recruits additional coactivators and drives transcription of target genes. Compounds and methods that prevent NTC assembly will inhibit NICDs-directed transcription, thus reducing the growth of Notch associated cancers. Disclosed herein, inter alia, are solutions to these and other problems known in the art.

BRIEF SUMMARY

In an aspect is provided a compound having the formula:

embedded image

or a salt (e.g., pharmaceutically acceptable salt) thereof.

L¹is a bond, —N(R^L1)—, —O—, —S—, —SO₂—, —C(O)—, —C(O)N(R^L1)—, —N(R^L1)C(O)—, —N(R^L1)C(O)NH—, —NHC(O)N(R^L1)—, —C(O)O—, —OC(O)—, —SO₂N(R^L1)—, —N(R^L1)SO₂—, substituted or unsubstituted alkylene, or, substituted or unsubstituted heteroalkylene.

R¹is independently hydrogen, halogen, —CX¹₃, —CHX¹₂, —CH₂X¹, —OCX¹₃, —OCH₂X¹, —OCHX¹₂, —CN, —SO_n1R^1D, —SO_v1NR^1AR^1B, —NR^1CNR^1AR^1B, —ONR^1AR^1B, —NHC(O)NR^1CNR^1AR^1B, —NHC(O)NR^1AR^1B, —N(O)_m1, —NR^1AR^1B, —C(O)R^1C, —C(O)—OR^1C, —C(O)NR^1AR^1B, —OR^1D, —NR^1ASO₂R^1D, —NR^1AC(O)R^1C, —NR^1AC(O)OR^1C, —NR^1AOR^1C, 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.

Ring A is phenyl or 5 to 6 membered heteroaryl.

z3 is independently an integer from 0 to 4.

Ring B is phenyl or 5 to 6 membered heteroaryl.

z4 is an integer from 0 to 4.

Ring C is C₃-C₆cycloalkyl, 3 to 6 membered heterocycloalkyl, phenyl, or 5 to 6 membered heteroaryl.

L²is a bond, —N(R^L2)—, —O—, —S—, —SO₂—, —C(O)—, —C(O)N(R^L2)—, —N(R^L2)C(O)—, —N(R^L2)C(O)NH—, —NHC(O)N(R^L2)—, —C(O)O—, —OC(O)—, —SO₂N(R^L2)—, —N(R^L2)SO₂—, substituted or unsubstituted alkylene, or, substituted or unsubstituted heteroalkylene.

z5 is an integer from 0 to 5.

X¹is independently —F, —Cl, —Br, or —I.

n1 is independently an integer from 0 to 4.

m1 and v1 are independently 1 or 2.

In an aspect is provided a pharmaceutical composition including a compound described herein, or a salt (e.g., pharmaceutically acceptable salt) thereof, and a pharmaceutically acceptable excipient.

DETAILED DESCRIPTION
I. Definitions

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.

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

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-C₁₀means one to ten carbons). Alkyl is an uncyclized chain. Examples of saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, methyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. An unsaturated alkyl group is one having one or more double bonds or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-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 alkyl moiety may be fully saturated. An alkenyl may include more than one double bond and/or one or more triple bonds in addition to the one or more double bonds. An alkynyl may include more than one triple bond and/or one or more double bonds in addition to the one or more triple bonds. In embodiments, the alkyl is fully saturated. In embodiments, the alkyl is monounsaturated. In embodiments, the alkyl is polyunsaturated.

The term “alkylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkyl, as exemplified, but not limited by, —CH₂CH₂CH₂CH₂—. Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred herein. A “lower alkyl” or “lower alkylene” is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms. The term “alkenylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkene. The term “alkynylene” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkyne. The term “alkynylene” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkyne. In embodiments, the alkylene is fully saturated. In embodiments, the alkylene is monounsaturated. In embodiments, the alkylene is polyunsaturated. In embodiments, an alkenylene includes one or more double bonds. In embodiments, an alkynylene includes one or more triple bonds.

The term “heteroalkyl,” by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or combinations thereof, including at least one carbon atom and at least one heteroatom (e.g., O, N, P, Si, and S), and wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. The heteroatom(s) (e.g., O, N, S, Si, or P) may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. 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, —CH₂—S—CH₂, —S(O)—CH₃, —CH₂—CH₂—S(O)₂—CH₃, —CH═CHO—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—OCH₃and —CH₂—O—Si(CH₃)₃. A heteroalkyl moiety may include one heteroatom (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include two optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include three optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include four optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include five optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include up to 8 optionally different heteroatoms (e.g., O, N, S, Si, or P). The term “heteroalkenyl,” by itself or in combination with another term, means, unless otherwise stated, a heteroalkyl including at least one double bond. A heteroalkenyl may optionally include more than one double bond and/or one or more triple bonds in 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.

Similarly, the term “heteroalkylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from heteroalkyl, as exemplified, but not limited by, —CH₂—CH₂—S—CH₂—CH₂— and —CH₂—S—CH₂—CH₂—NH—CH₂—. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula —C(O)₂R′— represents both —C(O)₂R′— and —R′C(O)₂—. As described above, heteroalkyl groups, as used herein, include those groups that are attached to the remainder of the molecule through a heteroatom, such as —C(O)R′, —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 heteroalkyl and —NR′R″ are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity. Thus, the term “heteroalkyl” should not be interpreted herein as excluding specific heteroalkyl groups, such as —NR′R″ or the like. The term “heteroalkenylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from a heteroalkene. The term “heteroalkynylene” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from a heteroalkyne. In embodiments, the heteroalkylene is fully saturated. In embodiments, the heteroalkylene is monounsaturated. In embodiments, the heteroalkylene is polyunsaturated. In embodiments, a heteroalkenylene includes one or more double bonds. In embodiments, a heteroalkynylene includes one or more triple bonds.

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

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. Examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. Bicyclic cycloalkyl ring systems are bridged monocyclic rings or fused bicyclic rings. In embodiments, bridged monocyclic rings contain a monocyclic cycloalkyl ring where two non adjacent carbon atoms of the monocyclic ring are linked by an alkylene bridge of between one and three additional carbon atoms (i.e., a bridging group of the form (CH₂)_w, where w is 1, 2, or 3). Representative examples of bicyclic ring systems include, but are not limited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, and bicyclo[4.2.1]nonane. In embodiments, fused bicyclic cycloalkyl ring systems contain a monocyclic cycloalkyl ring fused to either a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocyclyl, or a monocyclic heteroaryl. The bridged or fused bicyclic cycloalkyl is attached to the parent molecular moiety through any carbon atom contained within the monocyclic cycloalkyl ring. In embodiments, cycloalkyl groups are optionally substituted with one or two groups which are independently oxo or thia. In embodiments, the fused bicyclic cycloalkyl is a 5 or 6 membered monocyclic cycloalkyl ring fused to either a phenyl ring, a 5 or 6 membered monocyclic cycloalkyl, a 5 or 6 membered monocyclic cycloalkenyl, a 5 or 6 membered monocyclic heterocyclyl, or a 5 or 6 membered monocyclic heteroaryl, wherein the fused bicyclic cycloalkyl is optionally substituted by one or two groups which are independently oxo or thia. In embodiments, multicyclic cycloalkyl ring systems are a monocyclic cycloalkyl ring (base ring) fused to either (i) one ring system selected from the group consisting of a bicyclic aryl, a bicyclic heteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and a bicyclic heterocyclyl; or (ii) two other ring systems independently selected from the group consisting of a phenyl, a bicyclic aryl, a monocyclic or bicyclic heteroaryl, a monocyclic or bicyclic cycloalkyl, a monocyclic or bicyclic cycloalkenyl, and a monocyclic or bicyclic heterocyclyl. The multicyclic cycloalkyl is attached to the parent molecular moiety through any carbon atom contained within the base ring. In embodiments, multicyclic cycloalkyl ring systems are a monocyclic cycloalkyl ring (base ring) fused to either (i) one ring system selected from the group consisting of a bicyclic aryl, a bicyclic heteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and a bicyclic heterocyclyl; or (ii) two other ring systems independently selected from the group consisting of a phenyl, a monocyclic heteroaryl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, and a monocyclic heterocyclyl. Examples of multicyclic cycloalkyl groups include, but are not limited to tetradecahydrophenanthrenyl, perhydrophenothiazin-1-yl, and perhydrophenoxazin-1-yl.

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. In embodiments, monocyclic cycloalkenyl ring systems are cyclic hydrocarbon groups containing from 3 to 8 carbon atoms, where such groups are unsaturated (i.e., containing at least one annular carbon carbon double bond), but not aromatic. Examples of monocyclic cycloalkenyl ring systems include cyclopentenyl and cyclohexenyl. In embodiments, bicyclic cycloalkenyl rings are bridged monocyclic rings or a fused bicyclic rings. In embodiments, bridged monocyclic rings contain a monocyclic cycloalkenyl ring where two non adjacent carbon atoms of the monocyclic ring are linked by an alkylene bridge of between one and three additional carbon atoms (i.e., a bridging group of the form (CH₂)_w, where w is 1, 2, or 3). Representative examples of bicyclic cycloalkenyls include, but are not limited to, norbornenyl and bicyclo[2.2.2]oct 2 enyl. In embodiments, fused bicyclic cycloalkenyl ring systems contain a monocyclic cycloalkenyl ring fused to either a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocyclyl, or a monocyclic heteroaryl. The bridged or fused bicyclic cycloalkenyl is attached to the parent molecular moiety through any carbon atom contained within the monocyclic cycloalkenyl ring. In embodiments, cycloalkenyl groups are optionally substituted with one or two groups which are independently oxo or thia. In embodiments, multicyclic cycloalkenyl rings contain a monocyclic cycloalkenyl ring (base ring) fused to either (i) one ring system selected from the group consisting of a bicyclic aryl, a bicyclic heteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and a bicyclic heterocyclyl; or (ii) two ring systems independently selected from the group consisting of a phenyl, a bicyclic aryl, a monocyclic or bicyclic heteroaryl, a monocyclic or bicyclic cycloalkyl, a monocyclic or bicyclic cycloalkenyl, and a monocyclic or bicyclic heterocyclyl. The multicyclic cycloalkenyl is attached to the parent molecular moiety through any carbon atom contained within the base ring. In embodiments, multicyclic cycloalkenyl rings contain a monocyclic cycloalkenyl ring (base ring) fused to either (i) one ring system selected from the group consisting of a bicyclic aryl, a bicyclic heteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and a bicyclic heterocyclyl; or (ii) two ring systems independently selected from the group consisting of a phenyl, a monocyclic heteroaryl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, and a monocyclic heterocyclyl.

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

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

The term “acyl” means, unless otherwise stated, —C(O)R where R is a substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

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

A fused ring heterocyloalkyl-aryl is an aryl fused to a heterocycloalkyl. A fused ring heterocycloalkyl-heteroaryl is a heteroaryl fused to a heterocycloalkyl. A fused ring heterocycloalkyl-cycloalkyl is a heterocycloalkyl fused to a cycloalkyl. A fused ring heterocycloalkyl-heterocycloalkyl is a heterocycloalkyl fused to another heterocycloalkyl. Fused ring heterocycloalkyl-aryl, fused ring heterocycloalkyl-heteroaryl, fused ring heterocycloalkyl-cycloalkyl, or fused ring heterocycloalkyl-heterocycloalkyl may each independently be unsubstituted or substituted with one or more of the substituents described herein.

Spirocyclic rings are two or more rings wherein adjacent rings are attached through a single atom. The individual rings within spirocyclic rings may be identical or different. Individual rings in spirocyclic rings may be substituted or unsubstituted and may have different substituents from other individual rings within a set of spirocyclic rings. Possible substituents for individual rings within spirocyclic rings are the possible substituents for the same ring when not part of spirocyclic rings (e.g., substituents for cycloalkyl or heterocycloalkyl rings). Spirocylic rings may be substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heterocycloalkylene and individual rings within a spirocyclic ring group may be any of the immediately previous list, including having all rings of one type (e.g., all rings being substituted heterocycloalkylene wherein each ring may be the same or different 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.

The symbol “ custom-character ” denotes the point of attachment of a chemical moiety to the remainder of a molecule or chemical formula.

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

The term “alkylsulfonyl,” as used herein, means a moiety having the formula —S(O₂)—R′, where R′ is a substituted or unsubstituted alkyl group as defined above. R′ may have a specified number of carbons (e.g., “C₁-C₄alkylsulfonyl”).

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

embedded image

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, —CCl₃, —CBr₃, —CI₃, —CN, —CHO, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂CH₃—SO₃H, —OSO₃H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, substituted or unsubstituted C₁-C₅alkyl or substituted or unsubstituted 2 to 5 membered heteroalkyl). In embodiments, the alkylarylene is unsubstituted.

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

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′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′, -halogen, —SiR′R″R″′, —OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′—C(O)NR″R″′, —NR″C(O)₂R′, —NR—C(NR′R″R″′)═NR″″, —NR—C(NR′R″)═NR″′, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NRSO₂R′, —NR′NR″R″′, —ONR′R″, —NR′C(O)NR″NR″′R″″, —CN, —NO₂, —NR′SO₂R″, —NR′C(O)R″, —NR′C(O)—OR″, —NR′OR″, in a number ranging from zero to (2m′+1), 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., —CF₃and —CH₂CF₃) and acyl (e.g., —C(O)CH₃, —C(O)CF₃, —C(O)CH₂OCH₃, and the like).

Similar to the substituents described for the alkyl radical, substituents for the aryl and heteroaryl groups are varied and are selected from, for example: —OR′, —NR′R″, —SR′, -halogen, —SiR′R″R″′, —OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′—C(O)NR″R″′, —NR″C(O)₂R′, —NR—C(NR′R″R″′)═NR″″, —NR—C(NR′R″)═NR″′, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NRSO₂R′, —NR′NR″R″′, —ONR′R″, —NR′C(O)NR″NR″′R″″, —CN, —NO₂, —R′, —N₃, —CH(Ph)₂, fluoro(C₁-C₄)alkoxy, and fluoro(C₁-C₄)alkyl, —NR′SO₂R″, —NR′C(O)R″, —NR′C(O)—OR″, —NR′OR″, in a number ranging from zero to the total number of open valences on the aromatic ring system; and where R′, R″, R″′, and R″″ are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. When a compound described herein includes more than one R group, for example, each of the R groups is independently selected as are each R′, R″, R″′, and R″″ groups when more than one of these groups is present.

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.

Two or more substituents may optionally be joined to form aryl, heteroaryl, cycloalkyl, or heterocycloalkyl groups. Such so-called ring-forming substituents are typically, though not necessarily, found attached to a cyclic base structure. In one embodiment, the ring-forming substituents are attached to adjacent members of the base structure. For example, two ring-forming substituents attached to adjacent members of a cyclic base structure create a fused ring structure. In another embodiment, the ring-forming substituents are attached to a single member of the base structure. For example, two ring-forming substituents attached to a single member of a cyclic base structure create a spirocyclic structure. In yet another embodiment, the ring-forming substituents are attached to non-adjacent members of the base structure.

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.

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

A “substituent group” or “substituent” as used herein, means a group selected from the following moieties:

- (A) oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —N₃, unsubstituted alkyl (e.g., C₁-C₈alkyl, C₁-C₆alkyl, or C₁-C₄alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆cycloalkyl, or C₅-C₆cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C₆-C₁₀aryl, C₁₀aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), and
- (B) alkyl (e.g., C₁-C₂₀alkyl, C₁-C₁₂alkyl, C₁-C₈alkyl, C₁-C₆alkyl, C₁-C₄alkyl, or C₁-C₂alkyl), heteroalkyl (e.g., 2 to 20 membered heteroalkyl, 2 to 12 membered heteroalkyl, 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, 4 to 6 membered heteroalkyl, 2 to 3 membered heteroalkyl, or 4 to 5 membered heteroalkyl), cycloalkyl (e.g., C₃-C₁₀cycloalkyl, C₃-C₈cycloalkyl, C₃-C₆cycloalkyl, C₄-C₆cycloalkyl, or C₅-C₆cycloalkyl), heterocycloalkyl (e.g., 3 to 10 membered heterocycloalkyl, 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, 4 to 6 membered heterocycloalkyl, 4 to 5 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), aryl (e.g., C₆-C₁₂aryl, C₆-C₁₀aryl, or phenyl), or heteroaryl (e.g., 5 to 12 membered heteroaryl, 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), substituted with at least one substituent selected from:
  - (i) oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —N₃, unsubstituted alkyl (e.g., C₁-C₈alkyl, C₁-C₆alkyl, or C₁-C₄alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆cycloalkyl, or C₅-C₆cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C₆-C₁₀aryl, C₁₀aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), and
  - (ii) alkyl (e.g., C₁-C₂₀alkyl, C₁-C₁₂alkyl, C₁-C₈alkyl, C₁-C₆alkyl, C₁-C₄alkyl, or C₁-C₂alkyl), heteroalkyl (e.g., 2 to 20 membered heteroalkyl, 2 to 12 membered heteroalkyl, 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, 4 to 6 membered heteroalkyl, 2 to 3 membered heteroalkyl, or 4 to 5 membered heteroalkyl), cycloalkyl (e.g., C₃-C₁₀cycloalkyl, C₃-C₈cycloalkyl, C₃-C₆cycloalkyl, C₄-C₆cycloalkyl, or C₅-C₆cycloalkyl), heterocycloalkyl (e.g., 3 to 10 membered heterocycloalkyl, 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, 4 to 6 membered heterocycloalkyl, 4 to 5 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), aryl (e.g., C₆-C₁₂aryl, C₆-C₁₀aryl, or phenyl), or heteroaryl (e.g., 5 to 12 membered heteroaryl, 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, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —N₃, unsubstituted alkyl (e.g., C₁-C₈alkyl, C₁-C₆alkyl, or C₁-C₄alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆cycloalkyl, or C₅-C₆cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C₆-C₁₀aryl, C₁₀aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), and
    - (b) alkyl (e.g., C₁-C₂₀alkyl, C₁-C₁₂alkyl, C₁-C₈alkyl, C₁-C₆alkyl, C₁-C₄alkyl, or C₁-C₂alkyl), heteroalkyl (e.g., 2 to 20 membered heteroalkyl, 2 to 12 membered heteroalkyl, 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, 4 to 6 membered heteroalkyl, 2 to 3 membered heteroalkyl, or 4 to 5 membered heteroalkyl), cycloalkyl (e.g., C₃-C₁₀cycloalkyl, C₃-C₈cycloalkyl, C₃-C₆cycloalkyl, C₄-C₆cycloalkyl, or C₅-C₆cycloalkyl), heterocycloalkyl (e.g., 3 to 10 membered heterocycloalkyl, 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, 4 to 6 membered heterocycloalkyl, 4 to 5 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), aryl (e.g., C₆-C₁₂aryl, C₆-C₁₀aryl, or phenyl), or heteroaryl (e.g., 5 to 12 membered heteroaryl, 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, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —N₃, unsubstituted alkyl (e.g., C₁-C₈alkyl, C₁-C₆alkyl, or C₁-C₄alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C₃-C₈cycloalkyl, C₃-C₆cycloalkyl, or C₅-C₆cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C₆-C₁₀aryl, C₁₀aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

A “size-limited substituent” or “size-limited substituent group,” as used herein, means a group selected from all of the substituents described above for a “substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C₁-C₂₀alkyl, 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-C₈cycloalkyl, 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 C₆-C₁₀aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 10 membered heteroaryl.

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 C₁-C₈alkyl, 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-C₇cycloalkyl, 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.

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

In other embodiments of the compounds herein, each substituted or unsubstituted alkyl may be a substituted or unsubstituted C₁-C₂₀alkyl, 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-C₈cycloalkyl, 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 C₆-C₁₀aryl, 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-C₂₀alkylene, 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-C₈cycloalkylene, 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 C₆-C₁₀arylene, and/or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5 to 10 membered heteroarylene.

In some embodiments, each substituted or unsubstituted alkyl is a substituted or unsubstituted C₁-C₈alkyl, 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-C₇cycloalkyl, 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/or each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 6 membered heteroaryl. In some embodiments, each substituted or unsubstituted alkylene is a substituted or unsubstituted C₁-C₈alkylene, 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-C₇cycloalkylene, 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 phenylene, and/or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5 to 6 membered heteroarylene. In some embodiments, the compound is a chemical species set forth herein, for example in the Examples section, FIGURES, or tables below.

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

In embodiments, a substituted moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene) is substituted with at least one size-limited substituent group, wherein if the substituted moiety is substituted with a plurality of size-limited substituent groups, each size-limited substituent group may optionally be different. In embodiments, if the substituted moiety is substituted with a plurality of size-limited substituent groups, each size-limited substituent group is different.

In embodiments, a substituted moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted moiety is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, if the substituted moiety is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group is different.

In a recited claim or chemical formula description herein, each R substituent or L linker that is described as being “substituted” without reference as to the identity of any chemical moiety that composes the “substituted” group (also referred to herein as an “open substitution” on a R substituent or L linker or an “openly substituted” R substituent or L linker), the recited R substituent or L linker may, in embodiments, be substituted with one or more first substituent groups as defined below.

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 R^1.1, R²may be substituted with one or more first substituent groups denoted by R^2.1, R³may be substituted with one or more first substituent groups denoted by R^3.1, R⁴may be substituted with one or more first substituent groups denoted by R^4.1, R⁵may be substituted with one or more first substituent groups denoted by R^5.1, and the like up to or exceeding an R¹⁰⁰that may be substituted with one or more first substituent groups denoted by R^100.1. As a further example, R^1Amay be substituted with one or more first substituent groups denoted by R^1A.1, R^2Amay be substituted with one or more first substituent groups denoted by R^2A.1, R^3Amay be substituted with one or more first substituent groups denoted by R^3A.1, R^4Amay be substituted with one or more first substituent groups denoted by R^4A.1, R^5Amay be substituted with one or more first substituent groups denoted by R^5A.1and the like up to or exceeding an R^100Amay be substituted with one or more first substituent groups denoted by R^100A.1As a further example, L¹may be substituted with one or more first substituent groups denoted by R^L1.1, L²may be substituted with one or more first substituent groups denoted by R^L2.1, L³may be substituted with one or more first substituent groups denoted by R^L3.1, L⁴may be substituted with one or more first substituent groups denoted by R^LA.1, L⁵may be substituted with one or more first substituent groups denoted by R^L5.1and the like up to or exceeding an L¹⁰⁰which may be substituted with one or more first substituent groups denoted by R^L100.1. Thus, each numbered R group or L group (alternatively referred to herein as R^WWor L^WWwherein “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 R^WW.1or R^LWW.1, respectively. In turn, each first substituent group (e.g. R^1.1, R^2.1, R^3.1, R^4.1, R^5.1. . . R^100.1; R^1A.1, R^2A.1, R^3A.1, R^4A.1, R^5A.1. . . R^100A.1; R^L1.1, R^L2.1, R^L3.1, R^L4.1, R^L5.1. . . R^L100.1) may be further substituted with one or more second substituent groups (e.g. R^1.2, R^2.2, R^3.2, R^4.2, R^5.2. . . R^100.2; R^1A.2, R^2A.2, R^3A.2, R^4A.2, R^5A.2. . . R^100A.2; R^L1.2, R^L2.2, R^L3.2, R^L4.2, R^L5.2. . . R^L100.2, respectively). Thus, each first substituent group, which may alternatively be represented herein as R^WW.1as described above, may be further substituted with one or more second substituent groups, which may alternatively be represented herein as R^WW.2.

Finally, each second substituent group (e.g. R^1.2, R^2.2, R^3.2, R^4.2, R^5.2. . . R^100.2; R^1A.2, R^2A.2, R^3A.2, R^4A.2, R^5A.2. . . R^100A.2; R^L1.2, R^L2.2, R^L3.2, R^L4.2, R^L5.2. . . R^L100.2) may be further substituted with one or more third substituent groups (e.g. R^1.3, R^2.3, R^3.3, R^4.3, R^5.3. . . R^100.3; R^1A.3, R^2A.3, R^3A.3, R^4A.3, R^5A.3. . . R^100A.3; R^L1.3, R^L2.3, R^L3.3, R^L4.3, R^L5.3. . . R^L100.3; respectively). Thus, each second substituent group, which may alternatively be represented herein as R^WW.2as described above, may be further substituted with one or more third substituent groups, which may alternatively be represented herein as R^WW.3. Each of the first substituent groups may be optionally different. Each of the second substituent groups may be optionally different. Each of the third substituent groups may be optionally different.

Thus, as used herein, R^WWrepresents 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, 1A, 2A, 3A, 1B, 2B, 3B etc.). Likewise, L^WWis 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, 1B, 2B, 3B etc.). As stated above, in embodiments, each R^WWmay be unsubstituted or independently substituted with one or more first substituent groups, referred to herein as R^WW.1; each first substituent group, R^WW.1, may be unsubstituted or independently substituted with one or more second substituent groups, referred to herein as R^WW.2; and each second substituent group may be unsubstituted or independently substituted with one or more third substituent groups, referred to herein as R^WW.3. Similarly, each L^WWlinker may be unsubstituted or independently substituted with one or more first substituent groups, referred to herein as R^LWW.1; each first substituent group, R^LWW.1, may be unsubstituted or independently substituted with one or more second substituent groups, referred to herein as R^LWW.2; and each second substituent group may be unsubstituted or independently substituted with one or more third substituent groups, referred to herein as R^LWW.2. Each first substituent group is optionally different. Each second substituent group is optionally different. Each third substituent group is optionally different. For example, if R^WWis phenyl, the said phenyl group is optionally substituted by one or more R^WW.1groups as defined herein below, e.g. when R^WW.1is R^WW.2substituted alkyl, examples of groups so formed include but are not limited to itself optionally substituted by 1 or more R^WW.2, which R^WW.2is optionally substituted by one or more R^WW.3. By way of example when R^WW.1is alkyl, groups that could be formed, include but are not limited to:

embedded image

R^WW.1is independently oxo, halogen, —CX^WW.1₃, —CHX^WW.1₂, —CH₂X^WW.1, —OCX^WW.1₃, —OCH₂X^WW.1, —OCHX^WW.1₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —N₃, R^WW.2-substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), R^WW.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), R^WW.2-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), R^WW.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), R^WW.2-substituted or unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or R^WW.2-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R^WW.1is independently oxo, halogen, —CX^WW.1₃, —CHX^WW.1₂, —CH₂X^WW.1, —OCX^WW.1₃, —OCH₂X^WW.1, —OCHX^WW.1₁, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —N₃, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), 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, 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). X^WW.1is independently —F, —Cl, —Br, or —I.

R^WW.2is independently oxo, halogen, —CX^WW.2₃, —CHX^WW.2₂, —CH₂X^WW.2, —OCX^WW.2₃, —OCH₂X^WW.2, —OCHX^WW.2₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —N₃, R^WW.3-substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), R^WW.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), R^WW.3-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), R^WW.3-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), R^WW.3-substituted or unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or R^WW.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, R^WW.2is independently oxo, halogen, —CX^WW.2₃, —CHX^WW.2₂, —CH₂X^WW.2, —OCX^WW.2₃, —OCH₂X^WW.2, —OCHX^WW.2₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —N₃, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), 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, 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). X^WW.2is independently —F, —Cl, —Br, or —I.

R^WW.3is independently oxo, halogen, —CX^WW.3₃, —CHX^WW.3₂, —CH₂X^WW.3, —OCX^WW.3₃, —OCH₂X^WW.3, —OCHX^WW.3₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —N₃, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), 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, 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). X^WW.3is independently —F, —Cl, —Br, or —I.

Where two different R^WWsubstituents are joined together to form an openly substituted ring (e.g., substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl or substituted heteroaryl), in embodiments the openly substituted ring may be independently substituted with one or more first substituent groups, referred to herein as R^WW.1; each first substituent group, R^WW.1, may be unsubstituted or independently substituted with one or more second substituent groups, referred to herein as R^WW.2; and each second substituent group, R^WW.2, may be unsubstituted or independently substituted with one or more third substituent groups, referred to herein as R^WW.3; and each third substituent group, R^WW.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 R^WWsubstituents joined together to form an openly substituted ring, the “WW” symbol in the R^WW.1, R^WW.2and R^WW.3refers to the designated number of one of the two different R^WWsubstituents. For example, in embodiments where R^100Aand R^100Bare optionally joined together to form an openly substituted ring, R^WW.1is R^100A.1, R^WW.2is R^100A.2, and R^WW.3is R^100A.3. Alternatively, in embodiments where R^100Aand R^100Bare optionally joined together to form an openly substituted ring, R^WW.1is R^100B.1, R^WW.2is R^100B.2, and R^WW.3is R^100B.3. R^WW.1, R^WW.2and R^WW.3in this paragraph are as defined in the preceding paragraphs.

R^LWW.1is independently oxo, halogen, —CX^LWW.1₃, —CHX^LWW.1₂, —CH₂X^LWW.1, —OCX^LWW.1₃, —OCH₂X^LWW.1, —OCHX^LWW.1₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —N₃, R^LWW.2-substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), R^LWW.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), R^LWW.2-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), R^LWW.2substituted 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), R^LWW.2-substituted or unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or R^L0.2-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R^LWW.1is independently oxo, halogen, —CX^LWW.1₃, —CHX^LWW.1, —CH₂X^LWW.1, —OCX^LWW.1₃, —OCH₂X^LWW.1, —OCHXL^WW.1₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —N₃, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), 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, 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). X^LWW.1is independently —F, —Cl, —Br, or —I.

R^LWW.2is independently oxo, halogen, —CX^LWW.2₃, —CHX^LWW.2₂, —CH₂X^LWW.2, —OCX^LWW.2₃, —OCH₂X^LWW.2, —OCHX^LWW.2₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —N₃, R^LWW.3-substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), R^LWW0.3-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), R^WW.3-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), R^LWW.3-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), R^LWW.3-substituted or unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or R^LWW.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, R^LWW.2is independently oxo, halogen, —CX^LWW.2₃, —CHX^LWW.2₂, —CH₂X^LWW.2, —OCX^LWW.2₃, —OCH₂X^LWW.2, —OCHX^LWW.2₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —N₃, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), 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, 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). X^LWW.2is independently —F, —Cl, —Br, or —I.

R^LWW.3is independently oxo, halogen, —CX^LWW.3₃, —CHX^LWW.3₂, —CH₂X^LWW.3, —OCX^LWW.3₃, —OCH₂X^LWW.3, —OCHX^LWW.3₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —N₃, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), 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, 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). X^LWW.3is independently —F, —Cl, —Br, or —I.

In the event that any R group recited in a claim or chemical formula description set forth herein (R^WWsubstituent) is not specifically defined in this disclosure, then that R group (R^WWgroup) is hereby defined as independently oxo, halogen, —CX^WW₃, —CHX^WW₂, —CH₂X^WW, —OCX^WW₃, —OCH₂X^WW, —OCHX^WW₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —N₃, R^WW.1-substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), R^WW.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), R^WW.1-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), R^WW.1-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R^WW.1-substituted or unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or R^WW.1-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X^WWis 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, 1B, 2B, 3B, etc.). R^WW.1, R^WW.2, and R^WW.3, are as defined above.

In the event that any L linker group recited in a claim or chemical formula description set forth herein (i.e. an L^WWsubstituent) is not explicitly defined, then that L group (L^WWgroup) is herein defined as independently a bond, —O—, —NH—, —C(O)—, —C(O)NH—, —NHC(O)—, —NHC(O)NH—, —C(O)O—, —OC(O)—, —S—, —SO₂NH—, —NHSO₂—, R^LWW.1-substituted or unsubstituted alkylene (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), R^LWW.1-substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R^LWW.1-substituted or unsubstituted cycloalkylene (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), R^LWW.1-substituted or unsubstituted heterocycloalkylene (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R^LWW.1-substituted or unsubstituted arylene (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or R^LWW.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, 1B, 2B, 3B, etc.). R^LWW.1, as well as R^LWW.2and R^LWW.3, are as defined above.

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.

As used herein, the term “isomers” refers to compounds having the same number and kind of atoms, and hence the same molecular weight, but differing in respect to the structural arrangement or configuration of the atoms.

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.

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.

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

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 by ¹³C- or ¹⁴C-enriched carbon are within the scope of this disclosure.

The compounds of the present disclosure may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium (³H), iodine-125 (¹²¹I), 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.

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.

As used herein, the term “bioconjugate” and “bioconjugate linker” refers 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., —NH₂, —C(O)OH, —N-hydroxysuccinimide, or -maleimide) and a second bioconjugate reactive group (e.g., sulfhydryl, sulfur-containing amino acid, amine, amine sidechain containing amino acid, or carboxylate) provided herein may be bound, for example, by covalent bond, linker (e.g., a first linker of second linker), or 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-hydroxysuccinimide 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).

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, for example, acylated, alkylated 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;
- (l) 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 avidin-biotin complex or streptavidin-biotin complex.

The bioconjugate reactive groups can be chosen such that they do not participate in, or interfere with, the chemical stability 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.

“Analog,” or “analogue” 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. Accordingly, an analog is a compound that is similar or comparable in function and appearance but not in structure or origin to a reference compound.

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-C₂₀alkyl, or unsubstituted 2 to 20 membered heteroalkyl,” the group may contain one or more unsubstituted C₁-C₂₀alkyls, and/or one or more unsubstituted 2 to 20 membered heteroalkyls.

Moreover, where a moiety is substituted with an R substituent, the group may be referred to as “R-substituted.” Where a moiety is R-substituted, the moiety is substituted with at least one R substituent and each R substituent is optionally different. Where a particular R group is present in the description of a chemical genus (such as Formula (I)), a Roman alphabetic symbol may be used to distinguish each appearance of that particular R group. For example, where multiple R¹³substituents are present, each R¹³substituent may be distinguished as R^13.A, R^13.B, R^13.C, R^13.D, etc., wherein each of R^13.A, R^13.B, R^13.C, R^13.D, etc. is defined within the scope of the definition of R¹³and optionally differently.

Descriptions of compounds of the present disclosure are limited by principles of chemical bonding known to those skilled in the art. Accordingly, where a group may be substituted by one or more of a number of substituents, such substitutions are selected so as to comply with principles of chemical bonding and to give compounds which are not inherently unstable and/or would be known to one of ordinary skill in the art as likely to be unstable under ambient conditions, such as aqueous, neutral, and several known physiological conditions. For example, a heterocycloalkyl or heteroaryl is attached to the remainder of the molecule via a ring heteroatom in compliance with principles of chemical bonding known to those skilled in the art thereby avoiding inherently unstable compounds.

A person of ordinary skill in the art will understand when a variable (e.g., moiety or linker) of a compound or of a compound genus (e.g., a genus described herein) is described by a name or formula of a standalone compound with all valencies filled, the unfilled valence(s) of the variable will be dictated by the context in which the variable is used. For example, when a variable of a compound as described herein is connected (e.g., bonded) to the remainder of the compound through a single bond, that variable is understood to represent a monovalent form (i.e., capable of forming a single bond due to an unfilled valence) of a standalone compound (e.g., if the variable is named “methane” in an embodiment but the variable is known to be attached by a single bond to the remainder of the compound, a person of ordinary skill in the art would understand that the variable is actually a monovalent form of methane, i.e., methyl or —CH₃). Likewise, for a linker variable (e.g., L¹, L², or L³as described herein), a person of ordinary skill in the art will understand that the variable is the divalent form of a standalone compound (e.g., if the variable is assigned to “PEG” or “polyethylene glycol” in an embodiment but the variable is connected by two separate bonds to the remainder of the compound, a person of ordinary skill in the art would understand that the variable is a divalent (i.e., capable of forming two bonds through two unfilled valences) form of PEG instead of the standalone compound PEG).

As used herein, the term “salt” refers to acid or base salts of the compounds used in the methods of the present invention. Illustrative examples of acceptable salts are mineral acid (hydrochloric acid, hydrobromic acid, phosphoric acid, and the like) salts, organic acid (acetic acid, propionic acid, glutamic acid, citric acid and the like) salts, quaternary ammonium (methyl iodide, ethyl iodide, and the like) salts.

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

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.

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.

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

Certain compounds of the present disclosure can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present disclosure. Certain compounds of the present disclosure may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present disclosure and are intended to be within the scope of the present disclosure.

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

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.

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.

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

The term “contacting” may include allowing two species to react, interact, or physically touch, wherein the two species may be a compound as described herein and a protein or enzyme. In some embodiments contacting includes allowing a compound described herein to interact with a protein or enzyme that is involved in a signaling pathway.

As defined herein, the term “activation”, “activate”, “activating”, “activator” and the like in reference to a protein-inhibitor interaction means positively affecting (e.g., increasing) the activity or function of the protein relative to the activity or function of the protein in the absence of the activator. In embodiments activation means positively affecting (e.g., increasing) the concentration or levels of the protein relative to the concentration or level of the protein in the absence of the activator. The terms may reference activation, or activating, sensitizing, or up-regulating signal transduction or enzymatic activity or the amount of a protein decreased in a disease. Thus, activation may include, at least in part, partially or totally increasing stimulation, increasing or enabling activation, or activating, sensitizing, or up-regulating signal transduction or enzymatic activity or the amount of a protein associated with a disease (e.g., a protein which is decreased in a disease relative to a non-diseased control). Activation may include, at least in part, partially or totally increasing stimulation, increasing or enabling activation, or activating, sensitizing, or up-regulating signal transduction or enzymatic activity or the amount of a protein

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 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more 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.

As defined herein, the term “inhibition”, “inhibit”, “inhibiting” and the like in reference to a protein-inhibitor interaction means negatively affecting (e.g., decreasing) the activity or function of the protein relative to the activity or function of the protein in the absence of the inhibitor. In embodiments inhibition means negatively affecting (e.g., decreasing) the concentration or levels of the protein relative to the concentration or level of the protein in the absence of the inhibitor. In embodiments inhibition refers to reduction of a disease or symptoms of disease. In embodiments, inhibition refers to a reduction in the activity of a particular protein target. Thus, inhibition includes, at least in part, partially or totally blocking stimulation, decreasing, preventing, or delaying activation, or inactivating, desensitizing, or down-regulating signal transduction or enzymatic activity or the amount of a protein. In embodiments, inhibition refers to a reduction of activity of a target protein resulting from a direct interaction (e.g., an inhibitor binds to the target protein). In embodiments, inhibition refers to a reduction of activity of a target protein from an indirect interaction (e.g., an inhibitor binds to a protein that activates the target protein, thereby preventing target protein activation).

A “Notch inhibitor” refers to a compound (e.g., a compound described herein) that decreases the activity of Notch (e.g., Notch intracellular domain (NICD), Notch 1, Notch 2, Notch 3, or Notch 4; or intracellular domain thereof), level of activity of Notch (e.g., Notch intracellular domain (NICD), level of activity of Notch Transcription Complex (NTC), level of NTC, level of activity of Notch 1, level of activity of Notch 2, level of activity of Notch 3, or level of activity of Notch 4; or level of activity of intracellular domain thereof) when compared to a control, such as absence of the compound or a compound with known inactivity.

The terms “inhibitor,” “repressor” or “antagonist” or “downregulator” interchangeably refer to a substance capable of detectably decreasing the expression or activity of a given gene or protein. The antagonist can decrease expression or activity 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more in comparison to a control in the absence of the antagonist. In certain instances, expression or activity is 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold or lower than the expression or activity in the absence of the antagonist.

The term “Notch” refers to one or more (e.g., 1, 2, 3, or 4) of the four human transcription factors Notch 1, Notch 2, Notch 3, and/or Notch 4. The term includes any recombinant or naturally-occurring form of Notch (e.g., one or more of Notch 1, Notch 2, Notch 3, and/or Notch 4), including variants thereof that maintain Notch (e.g., one or more of Notch 1, Notch 2, Notch 3, and/or Notch 4) function or activity (e.g., within at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% function or activity compared to wildtype Notch (e.g., one or more of Notch 1, Notch 2, Notch 3, and/or Notch 4)). In embodiments, Notch (e.g., one or more of Notch 1, Notch 2, Notch 3, and/or Notch 4) protein is a cleaved form of the full length protein. In embodiments, the Notch (e.g., one or more of Notch 1, Notch 2, Notch 3, and/or Notch 4) protein is the intracellular domain of the full length protein. In embodiments, Notch refers to Notch 1. In embodiments, Notch refers to Notch 2. In embodiments, Notch refers to Notch 3. In embodiments, Notch refers to Notch 4.

The terms “Notch homolog 1”, “Notch1”, and “Notch 1”, refer to the human transcription factor Notch1. The term includes any recombinant or naturally-occurring form of Notch1, including variants thereof that maintain Notch1 function or activity (e.g., within at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% function or activity compared to wildtype Notch1). In embodiments, Notch1 is encoded by the NOTCH1 gene. In embodiments, Notch1 has the amino acid sequence set forth in or corresponding to Entrez 4851, UniProt P46531, or RefSeq (protein) NP_060087. In embodiments, Notch1 has the amino acid sequence set forth in or corresponding to RefSeq (protein) NP_060087.3. In embodiments, the Notch1 protein is a cleaved form of the full length protein. In embodiments, the Notch1 protein is the intracellular domain of the full length protein.

The terms “Notch homolog 2”, “Notch2”, “Neurogenic locus notch homolog protein 2”, and “Notch 2”, refer to the human transcription factor Notch2. The term includes any recombinant or naturally-occurring form of Notch2, including variants thereof that maintain Notch2 function or activity (e.g., within at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% function or activity compared to wildtype Notch2). In embodiments, Notch2 is encoded by the NOTCH2 gene. In embodiments, Notch2 has the amino acid sequence set forth in or corresponding to Entrez 4853, UniProt Q04721, or RefSeq (protein) NP_077719. In embodiments, Notch2 has the amino acid sequence set forth in or corresponding to RefSeq (protein) NP_077719.2. In embodiments, the Notch2 protein is a cleaved form of the full length protein. In embodiments, the Notch2 protein is the intracellular domain of the full length protein.

The term “Notch homolog 3”, “Notch3”, “Neurogenic locus notch homolog protein 3”, and “Notch 3”, refer to the human transcription factor Notch3. The term includes any recombinant or naturally-occurring form of Notch3, including variants thereof that maintain Notch3 function or activity (e.g., within at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% function or activity compared to wildtype Notch3). In embodiments, Notch3 is encoded by the NOTCH3 gene. In embodiments, Notch3 has the amino acid sequence set forth in or corresponding to Entrez 4854, UniProt Q9UM47, or RefSeq (protein) NP 000426. In embodiments, Notch3 has the amino acid sequence set forth in or corresponding to RefSeq (protein) NP_000426.2. In embodiments, the Notch3 protein is a cleaved form of the full length protein. In embodiments, the Notch3 protein is the intracellular domain of the full length protein.

The term “Notch homolog 4”, “Notch4”, “Neurogenic locus notch homolog protein 4”, and “Notch 4”, refer to the human transcription factor Notch4. The term includes any recombinant or naturally-occurring form of Notch4, including variants thereof that maintain Notch4 function or activity (e.g., within at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% function or activity compared to wildtype Notch4). In embodiments, Notch4 is encoded by the NOTCH4 gene. In embodiments, Notch4 has the amino acid sequence set forth in or corresponding to Entrez 4855, UniProt Q99466, or RefSeq (protein) NP_004548. In embodiments, Notch4 has the amino acid sequence set forth in or corresponding to RefSeq (protein) NP_004548.3. In embodiments, the Notch4 protein is a cleaved form of the full length protein. In embodiments, the Notch4 protein is the intracellular domain of the full length protein.

The term “Recombination signal binding protein for immunoglobulin kappa J region”, “RBPJ”, “CSL”, and “CBF1” refer to the human protein RBPJ, which is the human homolog of the Drosophila gene Suppressor of Hairless. The term includes any recombinant or naturally-occurring form of CSL, including variants thereof that maintain CSL function or activity (e.g., within at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% function or activity compared to wildtype CSL). In embodiments, CSL is encoded by the RBPJ gene. In embodiments, CSL has the amino acid sequence set forth in or corresponding to Entrez 3516, UniProt Q06330, or RefSeq (protein) NP_005340. In embodiments, CSL has the amino acid sequence set forth in or corresponding to RefSeq (protein) NP 005340.2.

The term “Mastermind”, “Mastermind-like protein 1”, and “MAML1” refer to the human protein Mastermind-like protein 1. The term includes any recombinant or naturally-occurring form of Mastermind, including variants thereof that maintain Mastermind function or activity (e.g., within at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% function or activity compared to wildtype Mastermind). In embodiments, Mastermind is encoded by the MAML1 gene. In embodiments, Mastermind has the amino acid sequence set forth in or corresponding to Entrez 9794, UniProt Q92585, or RefSeq (protein) NP 055572. In embodiments, Mastermind has the amino acid sequence set forth in or corresponding to RefSeq (protein) NP 055572.1.

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 cytometry, immunofluorescence, immunohistochemistry, etc.).

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 relative to the absence of the modulator. In some embodiments, a Notch (e.g., one or more of Notch 1, Notch 2, Notch 3, and/or Notch 4) associated disease modulator is a compound that reduces the severity of one or more symptoms of a disease associated with Notch (e.g., one or more of Notch 1, Notch 2, Notch 3, and/or Notch 4) (e.g., cancer). A Notch (e.g., one or more of Notch 1, Notch 2, Notch 3, and/or Notch 4) modulator is a compound that increases or decreases the activity or function or level of activity or level of function of Notch (e.g., one or more of Notch 1, Notch 2, Notch 3, and/or Notch 4). In some embodiments, a Notch (e.g., one or more of Notch 1, Notch 2, Notch 3, and/or Notch 4) associated disease modulator is a compound that reduces the severity of one or more symptoms of a disease associated with Notch (e.g., one or more of Notch 1, Notch 2, Notch 3, and/or Notch 4) (e.g., cancer). A Notch (e.g., one or more of Notch 1, Notch 2, Notch 3, and/or Notch 4) modulator is a compound that increases or decreases the activity or function or level of activity or level of function of Notch (e.g., one or more of Notch 1, Notch 2, Notch 3, and/or Notch 4).

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.

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, a cancer associated with Notch (e.g., one or more of Notch 1, Notch 2, Notch 3, and/or Notch 4) activity, Notch (e.g., one or more of Notch 1, Notch 2, Notch 3, and/or Notch 4) associated cancer, Notch (e.g., one or more of Notch 1, Notch 2, Notch 3, and/or Notch 4) associated disease (e.g., cancer)) 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. For example, a cancer associated with Notch (e.g., one or more of Notch 1, Notch 2, Notch 3, and/or Notch 4) activity or function may be a cancer that results (entirely or partially) from aberrant Notch (e.g., one or more of Notch 1, Notch 2, Notch 3, and/or Notch 4) function (e.g., enzyme activity, protein-protein interaction, signaling pathway) or a cancer wherein a particular symptom of the disease is caused (entirely or partially) by aberrant Notch (e.g., one or more of Notch 1, Notch 2, Notch 3, and/or Notch 4) activity or function. 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. For example, a cancer associated with Notch (e.g., one or more of Notch 1, Notch 2, Notch 3, and/or Notch 4) activity or function or a Notch (e.g., one or more of Notch 1, Notch 2, Notch 3, and/or Notch 4) associated disease (e.g., cancer), may be treated with a Notch (e.g., one or more of Notch 1, Notch 2, Notch 3, and/or Notch 4) modulator or Notch (e.g., one or more of Notch 1, Notch 2, Notch 3, and/or Notch 4) inhibitor, in the instance where increased Notch (e.g., one or more of Notch 1, Notch 2, Notch 3, and/or Notch 4) activity or function (e.g. signaling pathway activity) causes the disease (e.g., cancer). A cancer associated with Notch (e.g., one or more of Notch 1, Notch 2, Notch 3, and/or Notch 4) activity or function or a Notch (e.g., one or more of Notch 1, Notch 2, Notch 3, and/or Notch 4) associated disease (e.g., cancer), may be treated with a Notch (e.g., one or more of Notch 1, Notch 2, Notch 3, and/or Notch 4) modulator or Notch (e.g., one or more of Notch 1, Notch 2, Notch 3, and/or Notch 4) activator, in the instance where decreased Notch (e.g., one or more of Notch 1, Notch 2, Notch 3, and/or Notch 4) activity or function (e.g., signaling pathway activity) causes the disease (e.g., cancer).

The term “aberrant” as used herein refers to different from normal. When used to describe enzymatic activity or protein function, aberrant refers to activity or function 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.

The term “signaling pathway” as used herein refers to a series of interactions between cellular and optionally extra-cellular components (e.g., proteins, nucleic acids, small molecules, ions, lipids) that conveys a change in one component to one or more other components, which in turn may convey a change to additional components, which is optionally propagated to other signaling pathway components. For example, binding of a Notch (e.g., one or more of Notch 1, Notch 2, Notch 3, and/or Notch 4) with a compound as described herein may reduce the interactions between the Notch (e.g., one or more of Notch 1, Notch 2, Notch 3, and/or Notch 4) and downstream effectors or signaling pathway components, resulting in changes in cell growth, proliferation, or survival.

In this disclosure, “comprises,” “comprising,” “containing” and “having” and the like can have the meaning ascribed to them in U.S. patent law and can mean “includes,” “including,” and the like. “Consisting essentially of or “consists essentially” likewise has the meaning ascribed in U.S. patent law and the term is open-ended, allowing for the presence of more than that which is recited so long as basic or novel characteristics of that which is recited is not changed by the presence of more than that which is recited, but excludes prior art embodiments.

The terms “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. The disease may be a cancer. In some further instances, “cancer” refers to human cancers and carcinomas, sarcomas, adenocarcinomas, lymphomas, leukemias, etc., including solid and lymphoid cancers, kidney, breast, lung, bladder, colon, ovarian, prostate, pancreas, stomach, brain, head and neck, skin, uterine, testicular, glioma, esophagus, and liver cancer, including hepatocarcinoma, lymphoma, including B-acute lymphoblastic lymphoma, non-Hodgkin's lymphomas (e.g., Burkitt's, Small Cell, and Large Cell lymphomas), Hodgkin's lymphoma, leukemia (including AML, ALL, and CML), or multiple myeloma.

As used herein, the term “cancer” refers to all types of cancer, neoplasm or malignant tumors found in mammals (e.g., humans), including leukemias, lymphomas, carcinomas and sarcomas. Exemplary cancers that may be treated with a compound or method provided herein include brain cancer, glioma, glioblastoma, neuroblastoma, prostate cancer, colorectal cancer, pancreatic cancer, Medulloblastoma, melanoma, cervical cancer, gastric cancer, ovarian cancer, lung cancer, cancer of the head, Hodgkin's Disease, and Non-Hodgkin's Lymphomas. Exemplary cancers that may be treated with a compound or method provided herein include cancer of the thyroid, endocrine system, brain, breast, cervix, colon, head & neck, liver, kidney, lung, ovary, pancreas, rectum, stomach, and uterus. Additional examples include, thyroid carcinoma, cholangiocarcinoma, pancreatic adenocarcinoma, skin cutaneous melanoma, colon adenocarcinoma, rectum adenocarcinoma, stomach adenocarcinoma, esophageal carcinoma, head and neck squamous cell carcinoma, breast invasive carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, non-small cell lung carcinoma, mesothelioma, 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, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, endometrial cancer, adrenal cortical cancer, neoplasms of the endocrine or exocrine pancreas, medullary thyroid cancer, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid cancer, hepatocellular carcinoma, or prostate cancer.

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, acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), 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, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), 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, myelodysplastic syndrome (MDS), 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.

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 types 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 type of cells involved. There are aggressive (high grade) and indolent (low grade) types of NHL. Based on the type 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 (MCL), follicular lymphoma, marginal zone B-cell lymphoma (MZL), mucosa-associated lymphatic tissue lymphoma (MALT), extranodal lymphoma, nodal (monocytoid B-cell) lymphoma, splenic lymphoma, diffuse large cell B-lymphoma (DLBCL), activated B-cell subtype diffuse large B-cell lymphoma (ABC-DBLCL), germinal center B-cell like diffuse large B-cell 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 fungocides, and precursor T-lymphoblastic lymphoma.

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, Abemethy'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.

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 melanoma, juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodular melanoma, subungal melanoma, or superficial spreading melanoma.

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, gelatiniforni carcinoma, gelatinous carcinoma, giant cell carcinoma, carcinoma gigantocellulare, glandular carcinoma, granulosa cell carcinoma, hair-matrix carcinoma, hematoid carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma, hyaline carcinoma, hypernephroid 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, nasopharyngeal 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.

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 primary tumor or originating site acquire the ability to 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 secondary tumor 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 secondary tumors. The phrases non-metastatic cancer or subjects with cancer that is not metastatic refers to diseases in which subjects 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.

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.

The term “visceral metastasis” refer to secondary malignant cell growths in the internal 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.

The terms “treating”, or “treatment” refers to any indicia of success in the therapy 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, may include prevention of an injury, pathology, condition, or disease. In embodiments, treating is preventing. In embodiments, treating does not include preventing.

“Treating” or “treatment” as used herein (and as well-understood in the art) also broadly includes any approach for obtaining beneficial or desired results in a subject's condition, including clinical results. Beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of the extent of a disease, stabilizing (i.e., not worsening) the state of disease, prevention of a disease's transmission or spread, delay or slowing of disease progression, amelioration or palliation of the disease state, diminishment of the reoccurrence of disease, and remission, whether partial or total and whether detectable or undetectable. In other words, “treatment” as used herein includes any cure, amelioration, or prevention of a disease. Treatment may prevent the disease from occurring; inhibit the disease's spread; relieve the disease's symptoms (e.g., ocular pain, seeing halos around lights, red eye, very high intraocular pressure), fully or partially remove the disease's underlying cause, shorten a disease's duration, or do a combination of these things.

“Treating” and “treatment” as used herein include prophylactic treatment. Treatment methods include administering to a subject a therapeutically effective amount of an active agent. The administering step may consist of a single administration or may include a series of administrations. The length of the treatment period depends on a variety of factors, such as the severity of the condition, the age of the patient, the concentration of active agent, the activity of the compositions used in the treatment, or a combination thereof. It will also be appreciated that the effective dosage of an agent used for the treatment or prophylaxis may increase or decrease over the course of a particular treatment or prophylaxis regime. Changes in dosage may result and become apparent by standard diagnostic assays known in the art. In some instances, chronic administration may be required. For example, the compositions are administered to the subject in an amount and for a duration sufficient to treat the patient. In embodiments, the treating or treatment is not prophylactic treatment (e.g., the patient has a disease, the patient suffers from a disease).

The term “prevent” refers to a decrease in the occurrence of Notch (e.g., one or more of Notch 1, Notch 2, Notch 3, and/or Notch 4) associated disease symptoms or Notch (e.g., one or more of Notch 1, Notch 2, Notch 3, and/or Notch 4) associated disease symptoms in a patient. As indicated above, the prevention may be complete (no detectable symptoms) or partial, such that fewer symptoms are observed than would likely occur absent treatment.

“Patient” or “subject in need thereof” refers to a living organism suffering from or prone to a disease or condition that can be treated by administration of a pharmaceutical composition as provided herein. Non-limiting examples include humans, other mammals, bovines, rats, mice, dogs, monkeys, goat, sheep, cows, deer, and other non-mammalian animals. In some embodiments, a patient is human.

An “effective amount” is an amount sufficient for a compound to accomplish a stated purpose relative to the absence of the compound (e.g., achieve the effect for which it is administered, treat a disease, reduce enzyme activity, increase enzyme activity, reduce a signaling pathway, or 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.” A “reduction” of a symptom or symptoms (and grammatical equivalents of this phrase) means decreasing of the severity or frequency of the symptom(s), or elimination of the symptom(s). A “prophylactically effective amount” of a drug is an amount of a drug that, when administered to a subject, will have the intended prophylactic effect, e.g., preventing or delaying the onset (or reoccurrence) of an injury, disease, pathology or condition, or reducing the likelihood of the onset (or reoccurrence) of an injury, disease, pathology, or condition, or their symptoms. The full prophylactic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses. Thus, a prophylactically effective amount may be administered in one or more administrations. An “activity decreasing amount,” as used herein, refers to an amount of antagonist required to decrease the activity of an enzyme relative to the absence of the antagonist. A “function disrupting amount,” as used herein, refers to the amount of antagonist required to disrupt the function of an enzyme or protein relative to the absence of the antagonist. 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).

For any compound described herein, the therapeutically effective amount can be initially determined from cell culture assays. Target concentrations will be those concentrations of active compound(s) that are capable of achieving the methods described herein, as measured using the methods described herein or known in the art.

As is well known in the art, therapeutically effective amounts for use in humans can also be determined from animal models. For example, a dose for humans can be formulated to achieve a concentration that has been found to be effective in animals. The dosage in humans can be adjusted by monitoring compounds effectiveness and adjusting the dosage upwards or downwards, as described above. Adjusting the dose to achieve maximal efficacy in humans based on the methods described above and other methods is well within the capabilities of the ordinarily skilled artisan.

The term “therapeutically effective amount,” as used herein, refers to that amount of the therapeutic agent sufficient to ameliorate the disorder, as described above. For example, for the given parameter, a therapeutically effective amount will show an increase or decrease of at least 5%, 10%, 15%, 20%, 25%, 40%, 50%, 60%, 75%, 80%, 90%, or at least 100%. Therapeutic efficacy can also be expressed as “-fold” increase or decrease. For example, a therapeutically effective amount can have at least a 1.2-fold, 1.5-fold, 2-fold, 5-fold, or more effect over a control.

Dosages may be varied depending upon the requirements of the patient and the compound being employed. The dose administered to a patient, in the context of the present disclosure, should be sufficient to effect a beneficial therapeutic response in the patient over time. The size of the dose also will be determined by the existence, nature, and extent of any adverse side-effects. Determination of the proper dosage for a particular situation is within the skill of the practitioner. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under circumstances is reached. Dosage amounts and intervals can be adjusted individually to provide levels of the administered compound effective for the particular clinical indication being treated. This will provide a therapeutic regimen that is commensurate with the severity of the individual's disease state.

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

“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 provided herein can be administered alone or can be coadministered to the patient. Coadministration is meant to include simultaneous or sequential administration of the compounds individually or in combination (more than one compound). Thus, the preparations can also be combined, when desired, with other active substances (e.g., to reduce metabolic degradation). The compositions of the present disclosure can be delivered transdermally, by a topical route, or formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols.

“Anti-cancer agent” is used in accordance with its plain ordinary meaning and refers to a composition (e.g., compound, drug, antagonist, inhibitor, modulator) having antineoplastic properties or the ability to inhibit the growth or proliferation of cells. In some embodiments, an anti-cancer agent is a chemotherapeutic. In some embodiments, an anti-cancer agent is an agent identified herein having utility in methods of treating cancer. In some embodiments, an anti-cancer agent is an agent approved by the FDA or similar regulatory agency of a country other than the USA, for treating cancer. In embodiments, an anti-cancer agent is an agent with antineoplastic properties that has not (e.g., yet) been approved by the FDA or similar regulatory agency of a country other than the USA, for treating cancer. Examples of anti-cancer agents include, but are not limited to, MEK (e.g., MEK1, MEK2, or MEK1 and MEK2) inhibitors (e.g., XL518, CI-1040, PD035901, selumetinib/AZD6244, GSK1120212/trametinib, GDC-0973, ARRY-162, ARRY-300, AZD8330, PD0325901, U0126, PD98059, TAK-733, PD318088, AS703026, BAY 869766), alkylating agents (e.g., cyclophosphamide, ifosfamide, chlorambucil, busulfan, melphalan, mechlorethamine, uramustine, thiotepa, nitrosoureas, nitrogen mustards (e.g., mechloroethamine, cyclophosphamide, chlorambucil, meiphalan), ethylenimine and methylmelamines (e.g., hexamethlymelamine, thiotepa), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomusitne, semustine, streptozocin), triazenes (decarbazine)), anti-metabolites (e.g., 5-azathioprine, leucovorin, capecitabine, fludarabine, gemcitabine, pemetrexed, raltitrexed, folic acid analog (e.g., methotrexate), or pyrimidine analogs (e.g., fluorouracil, floxouridine, Cytarabine), purine analogs (e.g., mercaptopurine, thioguanine, pentostatin), etc.), plant alkaloids (e.g., vincristine, vinblastine, vinorelbine, vindesine, podophyllotoxin, paclitaxel, docetaxel, etc.), topoisomerase inhibitors (e.g., irinotecan, topotecan, amsacrine, etoposide (VP16), etoposide phosphate, teniposide, etc.), antitumor antibiotics (e.g., doxorubicin, adriamycin, daunorubicin, epirubicin, actinomycin, bleomycin, mitomycin, mitoxantrone, plicamycin, etc.), platinum-based compounds (e.g., cisplatin, oxaloplatin, carboplatin), anthracenedione (e.g., mitoxantrone), substituted urea (e.g., hydroxyurea), methyl hydrazine derivative (e.g., procarbazine), adrenocortical suppressant (e.g., mitotane, aminoglutethimide), epipodophyllotoxins (e.g., etoposide), antibiotics (e.g., daunorubicin, doxorubicin, bleomycin), enzymes (e.g., L-asparaginase), inhibitors of mitogen-activated protein kinase signaling (e.g., U0126, PD98059, PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY 43-9006, wortmannin, or LY294002, Syk inhibitors, mTOR inhibitors, antibodies (e.g., rituxan), gossyphol, genasense, polyphenol E, Chlorofusin, all trans-retinoic acid (ATRA), bryostatin, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), 5-aza-2′-deoxycytidine, all trans retinoic acid, doxorubicin, vincristine, etoposide, gemcitabine, imatinib (Gleevec®), geldanamycin, 17-N-Allylamino-17-Demethoxygeldanamycin (17-AAG), flavopiridol, LY294002, bortezomib, trastuzumab, BAY 11-7082, PKC412, PD184352, 20-epi-1, 25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti-dorsalizing morphogenetic protein-1; antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccatin III derivatives; balanol; batimastat; BCR/ABL antagonists; benzochlorins; benzoylstaurosporine; beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid; bFGF inhibitor; bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistratene A; bizelesin; breflate; bropirimine; budotitane; buthionine sulfoximine; calcipotriol; calphostin C; camptothecin derivatives; canarypox IL-2; capecitabine; carboxamide-amino-triazole; carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor; carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorins; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine; clomifene analogues; clotrimazole; collismycin A; collismycin B; combretastatin A4; combretastatin analogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A; cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; diaziquone; didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine; 9-dioxamycin; diphenyl spiromustine; docosanol; dolasetron; doxifluridine; droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolomab; eflornithine; elemene; emitefur; epirubicin; epristeride; estramustine analogue; estrogen agonists; estrogen antagonists; etanidazole; etoposide phosphate; exemestane; fadrozole; fazarabine; fenretinide; filgrastim; finasteride; flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicin hydrochloride; forfenimex; formestane; fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix; gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam; heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene; idramantone; ilmofosine; ilomastat; imidazoacridones; imiquimod; immunostimulant peptides; insulin-like growth factor-1 receptor inhibitor; interferon agonists; interferons; interleukins; iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact; irsogladine; isobengazole; isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide; leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia inhibiting factor; leukocyte alpha interferon; leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole; linear polyamine analogue; lipophilic disaccharide peptide; lipophilic platinum compounds; lissoclinamide 7; lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides; maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone; meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone; miltefosine; mirimostim; mismatched double stranded RNA; mitoguazone; mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growth factor-saporin; mitoxantrone; mofarotene; molgramostim; monoclonal antibody, human chorionic gonadotrophin; monophosphoryl lipid A+myobacterium cell wall sk; mopidamol; multiple drug resistance gene inhibitor; multiple tumor suppressor 1-based therapy; mustard anticancer agent; mycaperoxide B; mycobacterial cell wall extract; myriaporone; N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip; naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid; neutral endopeptidase; nilutamide; nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn; 06-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone; ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin; oxaunomycin; palauamine; palmitoylrhizoxin; pamidronic acid; panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin; pentrozole; perflubron; perfosfamide; perillyl alcohol; phenazinomycin; phenylacetate; phosphatase inhibitors; picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A; placetin B; plasminogen activator inhibitor; platinum complex; platinum compounds; platinum-triamine complex; porfimer sodium; porfiromycin; prednisone; propyl bis-acridone; prostaglandin J2; proteasome inhibitors; protein A-based immune modulator; protein kinase C inhibitor; protein kinase C inhibitors, microalgal; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine; pyridoxylated hemoglobin polyoxyethylerie conjugate; raf antagonists; raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors; ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin; ribozymes; RII retinamide; rogletimide; rohitukine; romurtide; roquinimex; rubiginone B1; ruboxyl; safmgol; saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics; semustine; senescence derived inhibitor 1; sense oligonucleotides; signal transduction inhibitors; signal transduction modulators; single chain antigen-binding protein; sizofuran; sobuzoxane; sodium borocaptate; sodium phenylacetate; solverol; somatomedin binding protein; sonermin; sparfosic acid; spicamycin D; spiromustine; splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem-cell division inhibitors; stipiamide; stromelysin inhibitors; sulfinosine; superactive vasoactive intestinal peptide antagonist; suradista; suramin; swainsonine; synthetic glycosaminoglycans; tallimustine; tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium; tegafur; tellurapyrylium; telomerase inhibitors; temoporfin; temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocene bichloride; topsentin; toremifene; totipotent stem cell factor; translation inhibitors; tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenital sinus-derived growth inhibitory factor; urokinase receptor antagonists; vapreotide; variolin B; vector system, erythrocyte gene therapy; velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; zinostatin stimalamer, Adriamycin, Dactinomycin, Bleomycin, Vinblastine, Cisplatin, acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine; ambomycin; ametantrone acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone; caracemide; carbetimer; carboplatin; carmustine; carubicin hydrochloride; carzelesin; cedefingol; chlorambucil; cirolemycin; cladribine; crisnatol mesylate; cyclophosphamide; cytarabine; dacarbazine; daunorubicin hydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate; diaziquone; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin; edatrexate; eflornithine hydrochloride; elsamitrucin; enloplatin; enpromate; epipropidine; epirubicin hydrochloride; erbulozole; esorubicin hydrochloride; estramustine; estramustine phosphate sodium; etanidazole; etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride; fazarabine; fenretinide; floxuridine; fludarabine phosphate; fluorouracil; fluorocitabine; fosquidone; fostriecin sodium; gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide; iimofosine; interleukin II (including recombinant interleukin II, or rlL.sub.2), interferon alfa-2a; interferon alfa-2b; interferon alfa-n1; interferon alfa-n3; interferon beta-1a; interferon gamma-1b; iproplatin; irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; liarozole hydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; masoprocol; maytansine; mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate; melphalan; menogaril; mercaptopurine; methotrexate; methotrexate sodium; metoprine; meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazoie; nogalamycin; ormaplatin; oxisuran; pegaspargase; peliomycin; pentamustine; peplomycin sulfate; perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride; plicamycin; plomestane; porfimer sodium; porfiromycin; prednimustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin; riboprine; rogletimide; safingol; safingol hydrochloride; semustine; simtrazene; sparfosate sodium; sparsomycin; spirogermanium hydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin; sulofenur; talisomycin; tecogalan sodium; tegafur; teloxantrone hydrochloride; temoporfin; teniposide; teroxirone; testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin; tirapazamine; toremifene citrate; trestolone acetate; triciribine phosphate; trimetrexate; trimetrexate glucuronate; triptorelin; tubulozole hydrochloride; uracil mustard; uredepa; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; vinglycinate sulfate; vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate; vinzolidine sulfate; vorozole; zeniplatin; zinostatin; zorubicin hydrochloride, agents that arrest cells in the G2-M phases and/or modulate the formation or stability of microtubules, (e.g., Taxol™ (i.e., paclitaxel), Taxotere™, compounds comprising the taxane skeleton, Erbulozole (i.e., R-55104), Dolastatin 10 (i.e., DLS-10 and NSC-376128), Mivobulin isethionate (i.e., as CI-980), Vincristine, NSC-639829, Discodermolide (i.e., as NVP-XX-A-296), ABT-751 (Abbott, i.e., E-7010), Altorhyrtins (e.g., Altorhyrtin A and Altorhyrtin C), Spongistatins (e.g., Spongistatin 1, Spongistatin 2, Spongistatin 3, Spongistatin 4, Spongistatin 5, Spongistatin 6, Spongistatin 7, Spongistatin 8, and Spongistatin 9), Cemadotin hydrochloride (i.e., LU-103793 and NSC-D-669356), Epothilones (e.g., Epothilone A, Epothilone B, Epothilone C (i.e., desoxyepothilone A or dEpoA), Epothilone D (i.e., KOS-862, dEpoB, and desoxyepothilone B), Epothilone E, Epothilone F, Epothilone B N-oxide, Epothilone A N-oxide, 16-aza-epothilone B, 21-aminoepothilone B (i.e., BMS-310705), 21-hydroxyepothilone D (i.e., Desoxyepothilone F and dEpoF), 26-fluoroepothilone, Auristatin PE (i.e., NSC-654663), Soblidotin (i.e., TZT-1027), LS-4559-P (Pharmacia, i.e., LS-4577), LS-4578 (Pharmacia, i.e., LS-477-P), LS-4477 (Pharmacia), LS-4559 (Pharmacia), RPR-112378 (Aventis), Vincristine sulfate, DZ-3358 (Daiichi), FR-182877 (Fujisawa, i.e., WS-9885B), GS-164 (Takeda), GS-198 (Takeda), KAR-2 (Hungarian Academy of Sciences), BSF-223651 (BASF, i.e., ILX-651 and LU-223651), SAH-49960 (Lilly/Novartis), SDZ-268970 (Lilly/Novartis), AM-97 (Armad/Kyowa Hakko), AM-132 (Armad), AM-138 (Armad/Kyowa Hakko), IDN-5005 (Indena), Cryptophycin 52 (i.e., LY-355703), AC-7739 (Ajinomoto, i.e., AVE-8063A and CS-39.HCl), AC-7700 (Ajinomoto, i.e., AVE-8062, AVE-8062A, CS-39-L-Ser.HCl, and RPR-258062A), Vitilevuamide, Tubulysin A, Canadensol, Centaureidin (i.e., NSC-106969), T-138067 (Tularik, i.e., T-67, TL-138067 and TI-138067), COBRA-1 (Parker Hughes Institute, i.e., DDE-261 and WHI-261), H10 (Kansas State University), H16 (Kansas State University), Oncocidin A1 (i.e., BTO-956 and DIME), DDE-313 (Parker Hughes Institute), Fijianolide B, Laulimalide, SPA-2 (Parker Hughes Institute), SPA-1 (Parker Hughes Institute, i.e., SPIKET-P), 3-IAABU (Cytoskeleton/Mt. Sinai School of Medicine, i.e., MF-569), Narcosine (also known as NSC-5366), Nascapine, D-24851 (Asta Medica), A-105972 (Abbott), Hemiasterlin, 3-BAABU (Cytoskeleton/Mt. Sinai School of Medicine, i.e., MF-191), TMPN (Arizona State University), Vanadocene acetylacetonate, T-138026 (Tularik), Monsatrol, lnanocine (i.e., NSC-698666), 3-IAABE (Cytoskeleton/Mt. Sinai School of Medicine), A-204197 (Abbott), T-607 (Tuiarik, i.e., T-900607), RPR-115781 (Aventis), Eleutherobins (such as Desmethyleleutherobin, Desaetyleleutherobin, lsoeleutherobin A, and Z-Eleutherobin), Caribaeoside, Caribaeolin, Halichondrin B, D-64131 (Asta Medica), D-68144 (Asta Medica), Diazonamide A, A-293620 (Abbott), NPI-2350 (Nereus), Taccalonolide A, TUB-245 (Aventis), A-259754 (Abbott), Diozostatin, (−)-Phenylahistin (i.e., NSCL-96F037), D-68838 (Asta Medica), D-68836 (Asta Medica), Myoseverin B, D-43411 (Zentaris, i.e., D-81862), A-289099 (Abbott), A-318315 (Abbott), HTI-286 (i.e., SPA-110, trifluoroacetate salt) (Wyeth), D-82317 (Zentaris), D-82318 (Zentaris), SC-12983 (NCI), Resverastatin phosphate sodium, BPR-OY-007 (National Health Research Institutes), and SSR-250411 (Sanofi)), steroids (e.g., dexamethasone), finasteride, aromatase inhibitors, gonadotropin-releasing hormone agonists (GnRH) such as goserelin or leuprolide, adrenocorticosteroids (e.g., prednisone), progestins (e.g., hydroxyprogesterone caproate, megestrol acetate, medroxyprogesterone acetate), estrogens (e.g., diethlystilbestrol, ethinyl estradiol), antiestrogen (e.g., tamoxifen), androgens (e.g., testosterone propionate, fluoxymesterone), antiandrogen (e.g., flutamide), immunostimulants (e.g., Bacillus Calmette-Guérin (BCG), levamisole, interleukin-2, alpha-interferon, etc.), monoclonal antibodies (e.g., anti-CD20, anti-HER2, anti-CD52, anti-HLA-DR, and anti-VEGF monoclonal antibodies), immunotoxins (e.g., anti-CD33 monoclonal antibody-calicheamicin conjugate, anti-CD22 monoclonal antibody-pseudomonas exotoxin conjugate, etc.), radioimmunotherapy (e.g., anti-CD20 monoclonal antibody conjugated to ¹¹¹In, ⁹⁰Y, or ¹³¹I, etc.), triptolide, homoharringtonine, dactinomycin, doxorubicin, epirubicin, topotecan, itraconazole, vindesine, cerivastatin, vincristine, deoxyadenosine, sertraline, pitavastatin, irinotecan, clofazimine, 5-nonyloxytryptamine, vemurafenib, dabrafenib, erlotinib, gefitinib, EGFR inhibitors, epidermal growth factor receptor (EGFR)-targeted therapy or therapeutic (e.g., gefitinib (Iressa™), erlotinib (Tarceva™), cetuximab (Erbitux™), lapatinib (Tykerb™), panitumumab (Vectibix™), vandetanib (Caprelsa™), afatinib/BIBW2992, CI-1033/canertinib, neratinib/IKI-272, CP-724714, TAK-285, AST-1306, ARRY334543, ARRY-380, AG-1478, dacomitinib/PF299804, OSI-420/desmethyl erlotinib, AZD8931, AEE788, pelitinib/EKB-569, CUDC-101, WZ8040, WZ4002, WZ3146, AG-490, XL647, PD153035, BMS-599626), sorafenib, imatinib, sunitinib, dasatinib, or the like. A moiety of an anti-cancer agent is a monovalent anti-cancer agent (e.g., a monovalent form of an agent listed above).

A “cell” as used herein, refers to a cell carrying out metabolic or other function sufficient to preserve or replicate its genomic DNA. A cell can be identified by well-known methods in the art including, for example, presence of an intact membrane, staining by a particular dye, ability to produce progeny or, in the case of a gamete, ability to combine with a second gamete to produce a viable offspring. Cells may include prokaryotic and eukaroytic cells. Prokaryotic cells include but are not limited to bacteria. Eukaryotic cells include but are not limited to yeast cells and cells derived from plants and animals, for example mammalian, insect (e.g., spodoptera) and human cells. Cells may be useful when they are naturally nonadherent or have been treated not to adhere to surfaces, for example by trypsinization.

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

“CSL-Notch-Mastermind complex” is used in accordance with its well understood meaning in biology and refers to the protein complex including the proteins CSL, Notch (e.g., one or more of Notch 1, Notch 2, Notch 3, and/or Notch 4), and Mastermind, which may each interact with one or both of the other proteins either directly or indirectly through another component of the complex. In embodiments, the CSL-Notch (e.g., one or more of Notch 1, Notch 2, Notch 3, and/or Notch 4)-Mastermind complex modulates transcription. The Notch (e.g., one or more of Notch 1, Notch 2, Notch 3, and/or Notch 4) protein included in the CSL-Notch-Mastermind complex may be an intracellular portion of the full length Notch (e.g., one or more of Notch 1, Notch 2, Notch 3, and/or Notch 4) receptor. In embodiments, the Notch in the CSL-Notch-Mastermind complex is Notch 1. In embodiments, the Notch in the CSL-Notch-Mastermind complex is Notch 2. In embodiments, the Notch in the CSL-Notch-Mastermind complex is Notch 3. In embodiments, the Notch in the CSL-Notch-Mastermind complex is Notch 4.

II. Compounds

In an aspect is provided a compound having the formula:

embedded image

or a salt (e.g., pharmaceutically acceptable salt) thereof.

R¹is independently hydrogen, halogen, —CX¹₃, —CHX¹₂, —CH₂X¹, —OCX¹₃, —OCH₂X¹, —OCHX¹², —CN, —SO_n1R^1D, —SO_v1NR^1AR^1B, —NR^1CNR^1AR^1B, —ONR^1AR^1B, —NHC(O)NR^1CNR^1AR^1B, —NHC(O)NR^1AR^1B, —N(O)_m1, —NR^1AR^1B, —C(O)R^1C, —C(O)—OR^1C, —C(O)NR^1AR^1B, —OR^1D, —NR^1ASO₂R^1D, —NR^1AC(O)R^1C, —NR^1AC(O)OR^1C, —NR^1AOR^1C, substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, 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 C₅-C₆), 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., C₆-C₁₀, C₁₀, or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered),

R²is independently hydrogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, 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 C₅-C₆), 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., C₆-C₁₀, C₁₀, or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

Ring A is phenyl or 5 to 6 membered heteroaryl.

R³is independently halogen, oxo, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —SF₅, —N₃, substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, 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 C₅-C₆), 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., C₆-C₁₀, C₁₀, or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); two adjacent R³substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆), 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., C₆-C₁₀, C₁₀, or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

z3 is independently an integer from 0 to 4.

Ring B is phenyl or 5 to 6 membered heteroaryl.

R⁴is independently halogen, oxo, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —SF₅, —N₃, substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, 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 C₅-C₆), 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., C₆-C₁₀, C₁₀, or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); two adjacent R⁴substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆), 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., C₆-C₁₀, C₁₀, or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

z4 is an integer from 0 to 4.

Ring C is C₃-C₆cycloalkyl, 3 to 6 membered heterocycloalkyl, phenyl, or 5 to 6 membered heteroaryl.

L²is a bond, —N(R^L2)—, —O—, —S—, —SO₂—, —C(O)—, —C(O)N(R^L2)—, —N(R^L)C(O)—, —N(R^L2)C(O)NH—, —NHC(O)N(R^L2)—, —C(O)O—, —OC(O)—, —SO₂N(R^L2)—, —N(R^L2)SO₂—, substituted or unsubstituted alkylene (e.g., C₁-C₈, C₁-C₆, or C₁-C₄) or substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered).

R⁵is independently halogen, oxo, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —SF₅, —N₃, substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, 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 C₅-C₆), 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., C₆-C₁₀, C₁₀, or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); two adjacent R⁵substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆), 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., C₆-C₁₀, C₁₀, or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

z5 is an integer from 0 to 5.

R^1A, R^1B, R^1C, R^1D, R^L1, and R^L2are independently hydrogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, 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 C₅-C₆), 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., C₆-C₁₀, C₁₀, or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); R^1Aand R^1Bsubstituents 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).

X¹is independently —F, —Cl, —Br, or —I.

n1 is independently an integer from 0 to 4.

m1 and v1 are independently 1 or 2.

In embodiments, Ring A is phenyl. In embodiments, Ring A is a 5 to 6 membered heteroaryl. In embodiments, Ring A is a 5 membered heteroaryl. In embodiments, Ring A is a 6 membered heteroaryl. In embodiments, Ring A is pyridyl. In embodiments, Ring A is pyrazinyl. In embodiments, Ring A is pyridazinyl. In embodiments, Ring A is pyrimidinyl. In embodiments, Ring A is triazinyl.

In embodiments, Ring B is phenyl. In embodiments, Ring B is pyridyl, pyrazinyl, pyridazinyl, pyridonyl, or pyrimidinyl. In embodiments, Ring B is pyridyl. In embodiments, Ring B is pyrazinyl. In embodiments, Ring B is pyridazinyl. In embodiments, Ring B is pyridonyl. In embodiments, Ring B is pyrimidinyl.

In embodiments, Ring B is phenylene. In embodiments, Ring B is pyridylene, pyrazinylene, pyridazinylene, pyridonylene, or pyrimidinylene. In embodiments, Ring B is pyridylene. In embodiments, Ring B is pyrazinylene. In embodiments, Ring B is pyridazinylene. In embodiments, Ring B is pyridonylene. In embodiments, Ring B is pyrimidinylene. In embodiments, Ring B is pyrazolylene. In embodiments, Ring B is imidazolylene. In embodiments, Ring B is isoxazolylene. In embodiments, Ring B is thiazolylene.

In embodiments, Ring B is

embedded image

wherein the two bonds ending in “ custom-character ” are the bonds attached to Ring A and L²(as described herein, including embodiments) and R⁴and z4 are as described herein. In embodiments, Ring B is

embedded image

wherein the two bonds ending in “ custom-character ” are the bonds attached to Ring A and L²(as described herein, including embodiments) and R⁴and z4 are as described herein.

In embodiments, Ring B is

embedded image

wherein the two bonds ending in “ custom-character ” are the bonds attached to Ring A and L²(as described herein, including embodiments) and R^4.A, R^4.B, R^4.C, R^4.D, and R^4.Eare independently hydrogen or any value of R⁴described herein, including in embodiments.

In embodiments, Ring B is

embedded image

In embodiments, Ring B is

embedded image

In embodiments, Ring B is

embedded image

wherein the two bonds ending in “ custom-character ” are the bonds attached to Ring A and L²(as described herein, including embodiments) and R^4.Aand R^4.Bare independently hydrogen or any value of R⁴described herein, including in embodiments.

In embodiments, R^4.A, R^4.B, R^4.C, R^4.D, and R^4.Eare independently hydrogen, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —N₃, substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, 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 C₅-C₆), 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., C₆-C₁₀, C₁₀, or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

R^4.AD, R^4.BD, R^4.CD, and R^4.DDare independently hydrogen, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —N₃, substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, 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 C₅-C₆), 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., C₆-C₁₀, C₁₀, or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered),

In embodiments, Ring C is 5 membered heteroaryl. In embodiments, Ring C is triazolyl. In embodiments, Ring C is 1,2,4-triazolyl. In embodiments, Ring C is pyrrolyl. In embodiments, Ring C is pyrazolyl. In embodiments, Ring C is imidazolyl. In embodiments, Ring C is tetrazolyl. In embodiments, Ring C is furanyl. In embodiments, Ring C is thienyl. In embodiments, Ring C is oxazolyl. In embodiments, Ring C is isoxazolyl. In embodiments, Ring C is thiazolyl. In embodiments, Ring C is isothiazolyl. In embodiments, Ring C is oxadiazolyl. In embodiments, Ring C is 1,3,4-oxadiazolyl. In embodiments, Ring C is 1,2,4-oxadiazolyl. In embodiments, Ring C is thiadiazolyl.

In embodiments, Ring C is C₃-C₆cycloalkyl. In embodiments, Ring C is C₄-C₆cycloalkyl. In embodiments, Ring C is C₅-C₆cycloalkyl. In embodiments, Ring C is C₃cycloalkyl. In embodiments, Ring C is C₄cycloalkyl. In embodiments, Ring C is C₅cycloalkyl. In embodiments, Ring C is C₆cycloalkyl. In embodiments, Ring C is C₃cycloalkenyl. In embodiments, Ring C is C₄cycloalkenyl. In embodiments, Ring C is C₅cycloalkenyl. In embodiments, Ring C is C₆cycloalkenyl.

In embodiments, Ring C is 3 to 6 membered heterocycloalkyl. In embodiments, Ring C is 4 to 6 membered heterocycloalkyl. In embodiments, Ring C is 5 to 6 membered heterocycloalkyl. In embodiments, Ring C is 3 membered heterocycloalkyl. In embodiments, Ring C is 4 membered heterocycloalkyl. In embodiments, Ring C is 5 membered heterocycloalkyl. In embodiments, Ring C is 6 membered heterocycloalkyl. In embodiments, Ring C is 3 membered heterocycloalkenyl. In embodiments, Ring C is 4 membered heterocycloalkenyl. In embodiments, Ring C is 5 membered heterocycloalkenyl. In embodiments, Ring C is 6 membered heterocycloalkenyl.

In embodiments, Ring C is phenyl. In embodiments, Ring C is 5 to 6 membered heteroaryl. In embodiments, Ring C is 6 membered heteroaryl.

In embodiments, the compound has the formula:

embedded image

R¹, L¹, R², L², R³, R⁴, R⁵, z3, z4, and z5 are as described herein, including in embodiments.

In embodiments, the compound has the formula:

embedded image

R¹, L¹, R², L², R³, R^4.A, and R^4.Bare as described herein, including in embodiments.

In embodiments, the compound has the formula:

embedded image

and R^1A, R^1B, R², and R³are as described herein, including in embodiments.

In embodiments, the compound has the formula:

embedded image

and R¹, R^L1, R², and R³are as described herein, including in embodiments.

In embodiments, the compound has the formula:

embedded image

R¹, L¹, R², L², R³, R^4.A, and R^4.Bare as described herein, including in embodiments.

In embodiments, the compound has the formula:

embedded image

R¹, L¹, R², L², R³, R^4.A, and R^4.Bare as described herein, including in embodiments.

In embodiments, the compound has the formula:

embedded image

R¹, L¹, R², L², R³, R⁴, R⁵, z3, z4, and z5 are as described herein, including in embodiments.

In embodiments, L¹is a bond. In embodiments, L¹is —N(R^L1)—. In embodiments, L¹is —O—. In embodiments, L¹is —S—. In embodiments, L¹is —SO₂—. In embodiments, L¹is —C(O)—. In embodiments, L¹is —C(O)N(R^L1)—. In embodiments, L¹is —N(R^L1)C(O)—. In embodiments, L¹is —N(R^L1)C(O)NH—. In embodiments, L¹is —NHC(O)N(R^L1)—. In embodiments, L¹is —C(O)O—. In embodiments, L¹is —OC(O)—. In embodiments, L¹is —SO₂N(R^L1)—. In embodiments, L¹is —N(R^L1)SO₂—. In embodiments, L¹is substituted or unsubstituted alkylene (e.g., C₁-C₈, C₁-C₆, or C₁-C₄). In embodiments, L¹is substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered). In embodiments, L¹is a bond, —NH—, —O—, —S—, —SO₂—, —C(O)—, —C(O)NH—, —NHC(O)—, —NHC(O)NH—, —C(O)O—, —OC(O)—, —SO₂NH—, —NHSO₂—, substituted or unsubstituted C₁-C₆alkylene, or, substituted or unsubstituted 2 to 6 membered heteroalkylene.

In embodiments, L¹is substituted or unsubstituted heteroalkylene. In embodiments, L¹is —(C₁-C₆alkyl)-C(O)N(R^L1)— or —(C₁-C₆alkyl)-SO₂N(R^L1)—. In embodiments, L¹is —CH₂C(O)N(R^L1)— or —CH₂SO₂N(R^L1)—. In embodiments, L¹is —CH₂C(O)N(R^L1)—. In embodiments, L¹is a substituted or unsubstituted alkylene. In embodiments, L¹is an unsubstituted C₁-C₆alkylene. In embodiments, L¹is an unsubstituted methylene. In embodiments, L¹is a substituted alkylene. In embodiments, L¹is a substituted C₁-C₆alkylene. In embodiments, L¹is —CH₂C(O)—. In embodiments, L¹is —(C₁-C₆alkyl)-C(O)N(R^L1)—. In embodiments, L¹is —(C₁-C₆alkyl)-SO₂N(R^L1)—. In embodiments, L¹is —CH₂C(O)N(R^L1)—. In embodiments, L¹is —CH₂SO₂N(R^L1)—. In embodiments, L¹is —(C₁-C₆alkyl)-C(O)NH—. In embodiments, L¹is —(C₁-C₆alkyl)-SO₂NH—. In embodiments, L¹is —CH₂C(O)NH—. In embodiments, L¹is —CH₂SO₂NH—. In embodiments, the right atom in the mainchain of the linker depicted for L¹is directly bonded to R¹(e.g., the —NH— of —CH₂C(O)NH— is directly bonded to R¹). In embodiments, the left atom in the mainchain of the linker depicted for L¹is directly bonded to R¹(e.g., the —CH₂— of —CH₂C(O)NH— is directly bonded to R¹).

In embodiments, R^L1is independently hydrogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, unsubstituted alkyl, or unsubstituted cycloalkyl. In embodiments, RY is independently hydrogen, unsubstituted C₁-C₆alkyl, or unsubstituted C₃-C₆cycloalkyl. In embodiments, R^L1is independently hydrogen, unsubstituted methyl, unsubstituted ethyl, unsubstituted isopropyl, or unsubstituted cyclopropyl. In embodiments, R^L1is independently hydrogen. In embodiments, R^L1is independently hydrogen. In embodiments, R^L1is independently unsubstituted methyl. In embodiments, R^L1is independently unsubstituted ethyl. In embodiments, R^L1is independently unsubstituted isopropyl. In embodiments, R^L1is independently unsubstituted cyclopropyl.

In embodiments, R^L1is hydrogen or substituted or unsubstituted alkyl. In embodiments, R^L1is hydrogen or substituted or unsubstituted C₁-C₆alkyl. In embodiments, RY is substituted C₁-C₆alkyl. In embodiments, R^L1is —CH₂-(substituted or unsubstituted heteroaryl). In embodiments, R^Uis —CH₂-(unsubstituted heteroaryl). In embodiments, R^L1is —CH₂-(unsubstituted triazolyl). In embodiments, R^L1is

embedded image

In embodiments, R¹is independently substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl. In embodiments, R¹is independently substituted phenyl or substituted 5 to 6 membered heteroaryl.

In embodiments, R¹is independently hydrogen, oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —SF₅, —N₃, substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, 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 C₅-C₆), 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., C₆-C₁₀, C₁₀, or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, R¹is independently —SO_n1R^1D. In embodiments, R¹is independently —SO_v1NR^1AR^1B. In embodiments, R¹is independently —NR^1CNR^1AR^1B, —ONR^1AR^1B. In embodiments, R¹is independently —NHC(O)NR^1CNR^1AR^1B. In embodiments, R¹is independently —NHC(O)NR^1AR^1B. In embodiments, R¹is independently —N(O)_m1. In embodiments, R¹is independently —NR^1AR^1B. In embodiments, R¹is independently —C(O)R^1C. In embodiments, R¹is independently —C(O)—OR^1C. In embodiments, R¹is independently —C(O)NR^1AR^1B. In embodiments, R¹is independently —OR^1D. In embodiments, R¹is independently —NR^1AS02R^1D. In embodiments, R¹is independently —NR^1AC(O)R^1C. In embodiments, R¹is independently —NR^1AC(O)OR^1CIn embodiments, R¹is independently —NR^1AOR^1C. In embodiments, R¹is independently substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄). In embodiments, R¹is independently substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered). In embodiments, R¹is independently substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆). In embodiments, R¹is independently substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered). In embodiments, R¹is independently substituted or unsubstituted aryl (e.g., C₆-C₁₀, C₁₀, or phenyl). In embodiments, R¹is independently substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, R¹is independently R¹⁰-substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄). In embodiments, R¹is independently R¹⁰-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered). In embodiments, R¹is independently R¹⁰-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆). In embodiments, R¹is independently R¹⁰-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered). In embodiments, R¹is independently R¹⁰-substituted or unsubstituted aryl (e.g., C₆-C₁₀, C₁₀, or phenyl). In embodiments, R¹is independently R¹⁰-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, R¹is independently R¹⁰-substituted phenyl or R¹⁰-substituted 5 to 6 membered heteroaryl. In embodiments, R¹is independently R¹⁰-substituted phenyl. In embodiments, R¹is independently R¹⁰-substituted 5 to 6 membered heteroaryl. In embodiments, R¹is independently

embedded image

and R¹⁰is as described herein and z10 is independently an integer from 0 to 5. z10 is independently an integer from 0 to 9. In embodiments, z10 is independently 0. In embodiments, z10 is independently 1. In embodiments, z10 is independently 2. In embodiments, z10 is independently 3. In embodiments, z10 is independently 4. In embodiments, z10 is independently 5. In embodiments, z10 is independently 6. In embodiments, z10 is independently 7. In embodiments, z10 is independently 8. In embodiments, z10 is independently 9. In embodiments, z10 is independently an integer from 0 to 5. In embodiments, R¹is independently

embedded image

and R¹⁰is as described herein and z10 is independently an integer from 0 to 3. In embodiments, R¹is independently

embedded image

and R¹⁰is as described herein and z10 is independently an integer from 0 to 3. In embodiments, R¹is independently

embedded image

and R¹⁰is as described herein and z10 is independently an integer from 0 to 3. In embodiments, R¹is independently

embedded image

and R¹⁰is as described herein and z10 is independently an integer from 0 to 3. In embodiments, R¹is independently

embedded image

and R¹⁰is as described herein and z10 is independently an integer from 0 to 3.

In embodiments, R¹is

embedded image

and R^10.A, R^10.B, R^10.C, R^10.D, and R^10.Eare independently hydrogen or any value of R¹⁰described herein, including in embodiments. In embodiments, R¹is

embedded image

and R^10.A, R^10.B, R^10.C, R^10.D, and R^10.Eare independently hydrogen or any value of R¹⁰described herein, including in embodiments.

In embodiments, R¹is independently

embedded image

and R^10.A, R^10.B, and R^10.Care independently hydrogen or any value of R¹⁰described herein, including in embodiments.

In embodiments, R¹is independently

embedded image

and R^10.A, R^10.B, and R^10.Care independently hydrogen or any value of R¹⁰described herein, including in embodiments.

In embodiments, R¹is independently

embedded image

In embodiments, R¹is independently

embedded image

In embodiments, R¹is independently —SO₂NR^1AR^1B, —NR^1AR^1B, or —C(O)NR^1AR^1BIn embodiments, R¹is independently —SO₂NR^1AR^1Bor —C(O)NR^1AR^1B. In embodiments, R¹is independently —C(O)NR^1AR^1B.

In embodiments, R¹is independently —NR^1AR^1B.

In embodiments, X¹is independently —F. In embodiments, X¹is independently —Cl. In embodiments, X¹is independently —Br. In embodiments, X¹is independently —I.

In embodiments, n1 is independently 0. In embodiments, n1 is independently 1. In embodiments, n1 is independently 2. In embodiments, n1 is independently 3. In embodiments, n1 is independently 4.

In embodiments, m1 is independently 1. In embodiments, m1 is independently 2. In embodiments, v1 is independently 1. In embodiments, v1 is independently 2.

In embodiments, R^1Aand R^1Bare independently hydrogen, substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, 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 C₅-C₆), 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., C₆-C₁₀, C₁₀, or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, R^1Aand R^1Bare independently hydrogen, substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄), substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆), substituted or unsubstituted aryl (e.g., C₆-C₁₀, C₁₀, or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, R^1Aand R^1Bare independently hydrogen, substituted or unsubstituted C₁-C₆alkyl, substituted or unsubstituted C₃-C₆cycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl.

In embodiments, R^1Ais independently hydrogen. In embodiments, R^1Ais independently —CCl₃. In embodiments, R^1Ais independently —CBr₃. In embodiments, R^1Ais independently —CF₃. In embodiments, R^1Ais independently —CI₃. In embodiments, R^1Ais independently —CHCl₂. In embodiments, R^1Ais independently —CHBr₂. In embodiments, R^1Ais independently —CHF₂. In embodiments, R^1Ais independently —CHI₂. In embodiments, R^1Ais independently —CH₂Cl. In embodiments, R^1Ais independently —CH₂Br. In embodiments, R^1Ais independently —CH₂F. In embodiments, R^1Ais independently —CH₂I. In embodiments, R^1Ais independently —CN. In embodiments, R^1Ais independently —OH. In embodiments, R^1Ais independently —NH₂. In embodiments, R^1Ais independently —COOH. In embodiments, R^1Ais independently —CONH₂. In embodiments, R^1Ais independently —OCCl₃. In embodiments, R^1Ais independently —OCF₃. In embodiments, R^1Ais independently —OCBr₃. In embodiments, R^1Ais independently —OCI₃. In embodiments, R^1Ais independently —OCHCl₂. In embodiments, R^1Ais independently —OCHBr₂. In embodiments, R^1Ais independently —OCHI₂. In embodiments, R^1Ais independently —OCHF₂. In embodiments, R^1Ais independently —OCH₂Cl. In embodiments, R^1Ais independently —OCH₂Br. In embodiments, R^1Ais independently —OCH₂I. In embodiments, R^1Ais independently —OCH₂F. In embodiments, R^1Ais independently halogen. In embodiments, R^1Ais independently —NO₂. In embodiments, R^1Ais independently —OCH₃. In embodiments, R^1Ais independently —OCH₂CH₃. In embodiments, R^1Ais independently —OCH(CH₃)₂. In embodiments, R^1Ais independently —OC(CH₃)₃. In embodiments, R^1Ais independently —CH₃. In embodiments, R^1Ais independently —CH₂CH₃. In embodiments, R^1Ais independently —CH(CH₃)₂. In embodiments, R^1Ais independently —C(CH₃)₃. In embodiments, R^1Ais independently unsubstituted cyclopropyl. In embodiments, R^1Ais independently unsubstituted cyclobutyl. In embodiments, R^1Ais independently unsubstituted cyclopentyl. In embodiments, R^1Ais independently unsubstituted cyclohexyl. In embodiments, R^1Ais independently substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄). In embodiments, R^1Ais independently substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered). In embodiments, R^1Ais independently substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆). In embodiments, R^1Ais independently substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered). In embodiments, R^1Ais independently substituted or unsubstituted aryl (e.g., C₆-C₁₀, C₁₀, or phenyl). In embodiments, R^1Ais independently substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, R^1Ais independently hydrogen, unsubstituted C₁-C₄alkyl, or unsubstituted cyclopropyl.

In embodiments, R^1Aare independently substituted or unsubstituted phenyl or substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R^1Ais independently R¹⁰-substituted phenyl or R¹⁰-substituted 5 to 6 membered heteroaryl. In embodiments, R^1Ais independently

embedded image

and R¹⁰is as described herein and z10 is independently an integer from 0 to 5. In embodiments, R^1Ais independently

embedded image

and R¹⁰is as described herein and z10 is independently an integer from 0 to 4. In embodiments, R^1Ais independently

embedded image

and R¹⁰is as described herein and z10 is independently an integer from 0 to 3. In embodiments, R^1Ais independently

embedded image

and R¹⁰is as described herein and z10 is independently an integer from 0 to 3. In embodiments, R^1Ais independently

embedded image

and R¹⁰is as described herein and z10 is independently an integer from 0 to 3. In embodiments, R^1Ais independently

embedded image

and R¹⁰is as described herein and z10 is independently an integer from 0 to 3.

In embodiments, R^1Ais independently

embedded image

R^10.A, R^10.B, and R^10.Care independently hydrogen or any value of R¹⁰described herein, including in embodiments.

In embodiments, R^1Ais independently

embedded image

R^10.A. R^10.B, and R^10.Care independently hydrogen or any value of R¹⁰described herein, including in embodiments.

In embodiments, R^1Ais independently

embedded image

In embodiments, R^1Ais independently

embedded image

In embodiments, R^1Bis independently hydrogen. In embodiments, R^1Bis independently —CCl₃. In embodiments, R^1Bis independently —CBr₃. In embodiments, R^1Bis independently —CF₃. In embodiments, R^1Bis independently —CI₃. In embodiments, R^1Bis independently —CHCl₂. In embodiments, R^1Bis independently —CHBr₂. In embodiments, R^1Bis independently —CHF₂. In embodiments, R^1Bis independently —CHI₂. In embodiments, R^1Bis independently —CH₂Cl. In embodiments, R^1Bis independently —CH₂Br. In embodiments, R^1Bis independently —CH₂F. In embodiments, R^1Bis independently —CH₂I. In embodiments, R^1Bis independently —CN. In embodiments, R^1Bis independently —OH. In embodiments, R^1Bis independently —NH₂. In embodiments, R^1Bis independently —COOH. In embodiments, R^1Bis independently —CONH₂. In embodiments, R^1Bis independently —OCCl₃. In embodiments, R^1Bis independently —OCF₃. In embodiments, R^1Bis independently —OCBr₃. In embodiments, R^1Bis independently —OCI₃. In embodiments, R^1Bis independently —OCHCl₂. In embodiments, R^1Bis independently —OCHBr₂. In embodiments, R^1Bis independently —OCHI₂. In embodiments, R^1Bis independently —OCHF₂. In embodiments, R^1Bis independently —OCH₂Cl. In embodiments, R^1Bis independently —OCH₂Br. In embodiments, R^1Bis independently —OCH₂I. In embodiments, R^1Bis independently —OCH₂F. In embodiments, R^1Bis independently halogen. In embodiments, R^1Bis independently —NO₂. In embodiments, R^1Bis independently —OCH₃. In embodiments, R^1Bis independently —OCH₂CH₃. In embodiments, R^1Bis independently —OCH(CH₃)₂. In embodiments, R^1Bis independently —OC(CH₃)₃. In embodiments, R^1Bis independently —CH₃. In embodiments, R^1Bis independently —CH₂CH₃. In embodiments, R^1Bis independently —CH(CH₃)₂. In embodiments, R^1Bis independently —C(CH₃)₃. In embodiments, R^1Bis independently unsubstituted cyclopropyl. In embodiments, R^1Bis independently unsubstituted cyclobutyl. In embodiments, R^1Bis independently unsubstituted cyclopentyl. In embodiments, R^1Bis independently unsubstituted cyclohexyl. In embodiments, R^1Bis independently substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄). In embodiments, R^1Bis independently substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered). In embodiments, R^1Bis independently substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆). In embodiments, R^1Bis independently substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered). In embodiments, R^1Bis independently substituted or unsubstituted aryl (e.g., C₆-C₁₀, C₁₀, or phenyl). In embodiments, R^1Bis independently substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, R^1Bis independently hydrogen, unsubstituted C₁-C₄alkyl, or unsubstituted cyclopropyl.

In embodiments, R^1Bare independently substituted or unsubstituted phenyl or substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R^1Bis independently R¹⁰-substituted phenyl or R¹⁰-substituted 5 to 6 membered heteroaryl. In embodiments, R^1Bis independently

embedded image

and R¹⁰is as described herein and z10 is independently an integer from 0 to 5. In embodiments, R^1Bis independently

embedded image

and R¹⁰is as described herein and z10 is independently an integer from 0 to 4. In embodiments, R^1Bis independently

embedded image

and R¹⁰is as described herein and z10 is independently an integer from 0 to 3. In embodiments, R^1Bis independently

embedded image

and R¹⁰is as described herein and z10 is independently an integer from 0 to 3. In embodiments, R^1Bis independently

embedded image

and R¹⁰is as described herein and z10 is independently an integer from 0 to 3. In embodiments, R^1Bis independently

embedded image

and R¹⁰is as described herein and z10 is independently an integer from 0 to 3.

In embodiments, R^1Bis independently

embedded image

R^10.A, R^10.B, and R^10.Care independently hydrogen or any value of R¹⁰described herein, including in embodiments.

In embodiments, R^1Bis independently

embedded image

R^10.A. R^10.A, R^10.Band R^10.Care independently hydrogen or any value of R¹⁰described herein, including in embodiments.

In embodiments, R^1Bis independently

embedded image

In embodiments, R^1Bis independently

embedded image

In embodiments, R^1Aand R^1Bsubstituents bonded to the same nitrogen atom are joined to form a substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered). In embodiments, R^1Aand R^1Bsubstituents bonded to the same nitrogen atom are joined to form a substituted or unsubstituted C₃-C₆heterocycloalkyl. In embodiments, R^1Aand R^1Bbonded to the same nitrogen atom are joined to form a substituted or unsubstituted piperazinyl. In embodiments, R^1Aand R^1Bsubstituents bonded to the same nitrogen atom are joined to form a substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R^1Aand R^1Bsubstituents bonded to the same nitrogen atom are joined to form a substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R^1Aand R^1Bbonded to the same nitrogen atom are joined to form

embedded image

In embodiments, R^1Aand R^1Bbonded to the same nitrogen atom are joined to form

embedded image

wherein R¹⁰and z10 are as described herein. In embodiments, R^1Aand R^1Bbonded to the same nitrogen atom are joined to form

embedded image

In embodiments, R^1Cis independently hydrogen. In embodiments, R^1Cis independently —CCl₃. In embodiments, R^1Cis independently —CBr₃. In embodiments, R^1Cis independently —CF₃. In embodiments, R^1Cis independently —CI₃. In embodiments, R^1Cis independently —CHCl₂. In embodiments, R^1Cis independently —CHBr₂. In embodiments, R^1Cis independently —CIF₂. In embodiments, R^1Cis independently —CHI₂. In embodiments, R^1Cis independently —CH₂Cl. In embodiments, R^1Cis independently —CH₂Br. In embodiments, R^1Cis independently —CH₂F. In embodiments, R^1Cis independently —CH₂I. In embodiments, R^1Cis independently —CN. In embodiments, R^1Cis independently —OH. In embodiments, R^1Cis independently —NH₂. In embodiments, R^1Cis independently —COOH. In embodiments, R^1Cis independently —CONH₂. In embodiments, R^1Cis independently —OCCl₃. In embodiments, R^1Cis independently —OCF₃. In embodiments, R^1Cis independently —OCBr₃. In embodiments, R^1Cis independently —OCI₃. In embodiments, R^1Cis independently —OCHCl₂. In embodiments, R^1Cis independently —OCHBr₂. In embodiments, R^1Cis independently —OCHI₂. In embodiments, R^1Cis independently —OCHF₂. In embodiments, R^1Cis independently —OCH₂Cl. In embodiments, R^1Cis independently —OCH₂Br. In embodiments, R^1Cis independently —OCH₂I. In embodiments, R^1Cis independently —OCH₂F. In embodiments, R^1Cis independently halogen. In embodiments, R^1Cis independently —NO₂. In embodiments, R^1Cis independently —OCH₃. In embodiments, R^1Cis independently —OCH₂CH₃. In embodiments, R^1Cis independently —OCH(CH₃)₂. In embodiments, R^1Cis independently —OC(CH₃)₃. In embodiments, R^1Cis independently —CH₃. In embodiments, R^1Cis independently —CH₂CH₃. In embodiments, R^1Cis independently —CH(CH₃)₂. In embodiments, R^1Cis independently —C(CH₃)₃. In embodiments, R^1Cis independently unsubstituted cyclopropyl. In embodiments, R^1Cis independently unsubstituted cyclobutyl. In embodiments, R^1Cis independently unsubstituted cyclopentyl. In embodiments, R^1Cis independently unsubstituted cyclohexyl. In embodiments, R^1Cis independently substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄). In embodiments, R^1Cis independently substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered). In embodiments, R^1Cis independently substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆). In embodiments, R^1Cis independently substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered). In embodiments, R^1Cis independently substituted or unsubstituted aryl (e.g., C₆-C₁₀, C₁₀, or phenyl). In embodiments, R^1Cis independently substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, R^1Dis independently hydrogen. In embodiments, R^1Dis independently —CCl₃. In embodiments, R^1Dis independently —CBr₃. In embodiments, R^1Dis independently —CF₃. In embodiments, R^1Dis independently —CI₃. In embodiments, R^1Dis independently —CHCl₂. In embodiments, R^1Dis independently —CHBr₂. In embodiments, R^1Dis independently —CHF₂. In embodiments, R^1Dis independently —CHI₂. In embodiments, R^1Dis independently —CH₂Cl. In embodiments, R^1Dis independently —CH₂Br. In embodiments, R^1Dis independently —CH₂F. In embodiments, R^1Dis independently —CH₂I. In embodiments, R^1Dis independently —CN. In embodiments, R^1Dis independently —OH. In embodiments, R^1Dis independently —NH₂. In embodiments, R^1Dis independently —COOH. In embodiments, R^1Dis independently —CONH₂. In embodiments, R^1Dis independently —OCCl₃. In embodiments, R^1Dis independently —OCF₃. In embodiments, R^1Dis independently —OCBr₃. In embodiments, R^1Dis independently —OCI₃. In embodiments, R^1Dis independently —OCHCl₂. In embodiments, R^1Dis independently —OCHBr₂. In embodiments, R^1Dis independently —OCHI₂. In embodiments, R^1Dis independently —OCHF₂. In embodiments, R^1Dis independently —OCH₂Cl. In embodiments, R^1Dis independently —OCH₂Br. In embodiments, R^1Dis independently —OCH₂I. In embodiments, R^1Dis independently —OCH₂F. In embodiments, R^1Dis independently halogen. In embodiments, R^1Dis independently —NO₂. In embodiments, R^1Dis independently —OCH₃. In embodiments, R^1Dis independently-OCH₂CH₃. In embodiments, R^1Dis independently —OCH(CH₃)₂. In embodiments, R^1Dis independently —OC(CH₃)₃. In embodiments, R^1Dis independently —CH₃. In embodiments, R^1Dis independently —CH₂CH₃. In embodiments, R^1Dis independently —CH(CH₃)₂. In embodiments, R^1Dis independently —C(CH₃)₃. In embodiments, R^1Dis independently unsubstituted cyclopropyl. In embodiments, R^1Dis independently unsubstituted cyclobutyl. In embodiments, R^1Dis independently unsubstituted cyclopentyl. In embodiments, R^1Dis independently unsubstituted cyclohexyl. In embodiments, R^1Dis independently substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄). In embodiments, R^1Dis independently substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered). In embodiments, R^1Dis independently substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆). In embodiments, R^1Dis independently substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered). In embodiments, R^1Dis independently substituted or unsubstituted aryl (e.g., C₆-C₁₀, C₁₀, or phenyl). In embodiments, R^1Dis independently substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

R¹⁰is independently oxo, halogen, —CX¹⁰₃, —CHX¹⁰₂, —CH₂X¹⁰, —OCX¹⁰₃, —OCH₂X¹⁰, —OCHX¹⁰₂, —CN, —SO_n10R^10D, —SO_v10NR^10AR^10B, —NR^10CNR^10AR^10B, —ONR^10AR^10B, —NHC(O)NR^10CNR^10AR^10B, —NHC(O)NR^10AR^10B, —N(O)_m10, —NR^10AR^10B, —C(O)R^10C, —C(O)—OR^10C, —C(O)NR^10AR^10B, —OR^10D, —NR^10ASO₂R^10D, —NR^10AC(O)R^10C, —NR^10AC(O)OR^10C, —NR^10AOR^10C, —SF₅, —N₃, substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, 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 C₅-C₆), 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., C₆-C₁₀, C₁₀, or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); two adjacent R¹⁰substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆), 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., C₆-C₁₀, C₁₀, or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

X¹⁰is independently —F, —Cl, —Br, or —I. In embodiments, X¹⁰is independently —F. In embodiments, X¹⁰is independently —Cl. In embodiments, X¹⁰is independently —Br. In embodiments, X¹⁰is independently —I.

n10 is independently an integer from 0 to 4. In embodiments, n10 is independently 0. In embodiments, n10 is independently 1. In embodiments, n10 is independently 2. In embodiments, n10 is independently 3. In embodiments, n10 is independently 4.

m10 and v10 are independently 1 or 2. In embodiments, m10 is independently 1. In embodiments, m10 is independently 2. In embodiments, v10 is independently 1. In embodiments, v10 is independently 2.

In embodiments, R¹⁰is independently halogen, —CX¹⁰₃, —CHX¹⁰₂, —CH₂X¹⁰, —OCX¹⁰₃, —OCH₂X¹⁰, —OCHX¹⁰₂, —CN, —SO_v10R^10D, —SO_v10NR^10AR^10B, —NR^10CNR^10AR^10B, —ONR^10AR^10B, —NHC(O)NR^10CNR^10AR^10B, —NHC(O)NR^10AR^10B, —N(O)_m10, —NR^10AR^10B, —C(O)R^10C, —C(O)—OR^10C, —C(O)NR^10AR^10B, —OR^10D, —NR^10ASO₂R^10D, —NR^10AC(O)R^10C, —NR^10AC(O)OR^10C, —NR^10AOR^10C, —SF₅, —N₃, substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, 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 C₅-C₆), 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., C₆-C₁₀, C₁₀, or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); two adjacent R¹⁰substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆), 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., C₆-C₁₀, C₁₀, or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R¹⁰is independently halogen, —CX¹⁰₃, —CHX¹⁰₂, —CH₂X¹⁰, —OCX¹⁰₃, —OCH₂X¹⁰, —OCHX¹⁰₂, —CN, —SO₂R^10D, —SR^10D, —C(O)R^10C, —OR^10D, substituted or unsubstituted C₁-C₆alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C₃-C₆cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R¹⁰is independently halogen, —CX¹⁰₃, —CHX¹⁰₂, —CH₂X¹⁰, —OCX¹⁰₃, —OCH₂X¹⁰, —OCHX¹⁰₂, —CN, —SO₂R^10D, —SR^10D, —OR^10D, unsubstituted C₁-C₄alkyl, unsubstituted 2 to 6 membered heteroalkyl, unsubstituted C₃-C₄cycloalkyl, or unsubstituted phenyl. In embodiments, R¹⁰is independently halogen, —CF₃, —CHF₂, —CH₂F, —OCF₃, —OCH₂F, —OCHF₂, —OCH₃, —CH₂OCH₃, —CN, —SO₂CH₃, —SCH₃, —OCH₃, unsubstituted C₁-C₄alkyl, unsubstituted cyclopropyl, or unsubstituted phenyl. In embodiments, R¹⁰is independently halogen, —CF₃, —CHF₂, —CH₂F, —OCF₃, —OCH₂F, —OCHF₂, —OCH₃, —CH₂OCH₃, —CN, —SO₂CH₃, —SCH₃, —OCH₃, unsubstituted C₁-C₄alkyl, unsubstituted cyclopropyl, or unsubstituted phenyl.

In embodiments, R¹⁰is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —SF₅, —N₃, substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, 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 C₅-C₆), 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., C₆-C₁₀, C₁₀, or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, R¹⁰is independently halogen. In embodiments, R¹⁰is independently oxo. In embodiments, R¹⁰is independently —CX¹⁰₃. In embodiments, R¹⁰is independently —CHX¹⁰₂. In embodiments, R¹⁰is independently —CH₂X¹⁰. In embodiments, R¹⁰is independently —OCX¹⁰₃. In embodiments, R¹⁰is independently —OCH₂X¹⁰. In embodiments, R¹⁰is independently —OCHX¹⁰₂. In embodiments, R¹⁰is independently —CN. In embodiments, R¹⁰is independently —SO_n10R^10D. In embodiments, R¹⁰is independently —SO_v10NR^10AR^10BIn embodiments, R¹⁰is independently —NR^10CNR^10AR^10BIn embodiments, R¹⁰is independently —ONR^10AR^10B. In embodiments, R¹⁰is independently —NHC(O)NR^10CNR^10AR^10B. In embodiments, R¹⁰is independently —NHC(O)NR^10AR^10BIn embodiments, R¹⁰is independently —N(O)_m10. In embodiments, R¹⁰is independently —NR^10AR^10B. In embodiments, R¹⁰is independently —C(O)R^10C. In embodiments, R¹⁰is independently —C(O)—OR^10C. In embodiments, R¹⁰is independently —C(O)NR^10AR^10B. In embodiments, R¹⁰is independently —OR^10Dn embodiments, R¹⁰is independently —NR^10ASO₂R^10D. In embodiments, R¹⁰is independently —NR^10AC(O)R^10CIn embodiments, R¹⁰is independently —NR^10AC(O)OR^10C. In embodiments, R¹⁰is independently —NR^10AOR^10CIn embodiments, R¹⁰is independently —SF₅. In embodiments, R¹⁰is independently —N₃.

In embodiments, R¹⁰is independently halogen. In embodiments, R¹⁰is independently —CH₂OCH₃. In embodiments, R¹⁰is independently —SO₂CH₃. In embodiments, R¹⁰is independently —SCH₃. In embodiments, R¹⁰is independently —OCH₃. In embodiments, R¹⁰is independently unsubstituted C₁-C₄alkyl. In embodiments, R¹⁰is independently unsubstituted cyclopropyl. In embodiments, R¹⁰is independently unsubstituted phenyl. In embodiments, R¹⁰is independently hydrogen. In embodiments, R¹⁰is independently —CCl₃. In embodiments, R¹⁰is independently —CBr₃. In embodiments, R¹⁰is independently —CF₃. In embodiments, R¹⁰is independently —CI₃. In embodiments, R¹⁰is independently —CHCl₂. In embodiments, R¹⁰is independently —CHBr₂. In embodiments, R¹⁰is independently —CHF₂. In embodiments, R¹⁰is independently —CHI₂. In embodiments, R¹⁰is independently —CH₂Cl. In embodiments, R¹⁰is independently —CH₂Br. In embodiments, R¹⁰is independently —CH₂F. In embodiments, R¹⁰is independently —CH₂I. In embodiments, R¹⁰is independently —CN. In embodiments, R¹⁰is independently —OH. In embodiments, R¹⁰is independently —NH₂. In embodiments, R¹⁰is independently —COOH. In embodiments, R¹⁰is independently —CONH₂. In embodiments, R¹⁰is independently —OCCl₃. In embodiments, R¹⁰is independently —OCF₃. In embodiments, R¹⁰is independently —OCBr₃. In embodiments, R¹⁰is independently —OCI₃. In embodiments, R¹⁰is independently —OCHCl₂. In embodiments, R¹⁰is independently —OCHBr₂. In embodiments, R¹⁰is independently —OCHI₂. In embodiments, R¹⁰is independently —OCHF₂. In embodiments, R¹⁰is independently —OCH₂Cl. In embodiments, R¹⁰is independently —OCH₂Br. In embodiments, R¹⁰is independently —OCH₂I. In embodiments, R¹⁰is independently —OCH₂F. In embodiments, R¹⁰is independently halogen. In embodiments, R¹⁰is independently —NO₂. In embodiments, R¹⁰is independently —OCH₃. In embodiments, R¹⁰is independently —OCH₂CH₃. In embodiments, R¹⁰is independently —OCH(CH₃)₂. In embodiments, R¹⁰is independently —OC(CH₃)₃. In embodiments, R¹⁰is independently —CH₃. In embodiments, R¹⁰is independently —CH₂CH₃. In embodiments, R¹⁰is independently —CH(CH₃)₂. In embodiments, R¹⁰is independently —C(CH₃)₃. In embodiments, R¹⁰is independently unsubstituted cyclopropyl. In embodiments, R¹⁰is independently unsubstituted cyclobutyl. In embodiments, R¹⁰is independently unsubstituted cyclopentyl. In embodiments, R¹⁰is independently unsubstituted cyclohexyl. In embodiments, R¹⁰is independently substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄). In embodiments, R¹⁰is independently substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered). In embodiments, R¹⁰is independently substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆). In embodiments, R¹⁰is independently substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered). In embodiments, R¹⁰is independently substituted or unsubstituted aryl (e.g., C₆-C₁₀, C₁₀, or phenyl). In embodiments, R¹⁰is independently substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R¹⁰is independently unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄). In embodiments, R¹⁰is independently unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered). In embodiments, R¹⁰is independently unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆). In embodiments, R¹⁰is independently unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered). In embodiments, R¹⁰is independently unsubstituted aryl (e.g., C₆-C₁₀, C₁₀, or phenyl). In embodiments, R¹⁰is independently unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, two adjacent R¹⁰substituents are joined to form a substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆). In embodiments, two adjacent R¹⁰substituents are joined to form a substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered). In embodiments, two adjacent R¹⁰substituents are joined to form a substituted or unsubstituted aryl (e.g., C₆-C₁₀, C₁₀, or phenyl). In embodiments, two adjacent R¹⁰substituents are joined to form a substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, two adjacent R¹⁰substituents are joined to form an unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆). In embodiments, two adjacent R¹⁰substituents are joined to form an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered). In embodiments, two adjacent R¹⁰substituents are joined to form an unsubstituted aryl (e.g., C₆-C₁₀, C₁₀, or phenyl). In embodiments, two adjacent R¹⁰substituents are joined to form an unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

R^10A, R^10B, R^10C, and R^10Dare independently hydrogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, 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 C₅-C₆), 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., C₆-C₁₀, C₁₀, or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered), R^10Aand R^10Bsubstituents 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).

In embodiments, R^10A, R^10B, R^10C, and R^10Dare independently hydrogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, unsubstituted C₁-C₆alkyl, or unsubstituted C₃-C₆cycloalkyl. In embodiments, R^10A, R^10B, R^10C, and R^10Dare independently hydrogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, or unsubstituted methyl.

In embodiments, R^10Ais independently halogen. In embodiments, R^10Ais independently —CH₂OCH₃. In embodiments, R^10Ais independently —SO₂CH₃. In embodiments, R^10Ais independently —SCH₃. In embodiments, R^10Ais independently —OCH₃. In embodiments, R^10Ais independently unsubstituted C₁-C₄alkyl. In embodiments, R^10Ais independently unsubstituted cyclopropyl. In embodiments, R^10Ais independently unsubstituted phenyl. In embodiments, R^10Ais independently hydrogen. In embodiments, R^10Ais independently —CCl₃. In embodiments, R^10Ais independently —CBr₃. In embodiments, R^10Ais independently —CF₃. In embodiments, R^10Ais independently —CI₃. In embodiments, R^10Ais independently —CHCl₂. In embodiments, R^10Ais independently —CHBr₂. In embodiments, R^10Ais independently —CHF₂. In embodiments, R^10Ais independently —CHI₂. In embodiments, R^10Ais independently —CH₂Cl. In embodiments, R^10Ais independently —CH₂Br. In embodiments, R^10Ais independently —CH₂F. In embodiments, R^10Ais independently —CH₂I. In embodiments, R^10Ais independently —CN. In embodiments, R^10Ais independently —OH. In embodiments, R^10Ais independently —NH₂. In embodiments, R^10Ais independently —COOH. In embodiments, R^10Ais independently —CONH₂. In embodiments, R^10Ais independently —OCCl₃. In embodiments, R^10Ais independently —OCF₃. In embodiments, R^10Ais independently —OCBr₃. In embodiments, R^10Ais independently —OCI₃. In embodiments, R^10Ais independently —OCHCl₂. In embodiments, R^10Ais independently —OCHBr₂. In embodiments, R^10Ais independently —OCHI₂. In embodiments, R^10Ais independently —OCHF₂. In embodiments, R^10Ais independently —OCH₂Cl. In embodiments, R^10Ais independently —OCH₂Br. In embodiments, R^10Ais independently —OCH₂I. In embodiments, R^10Ais independently —OCH₂F. In embodiments, R^10Ais independently halogen. In embodiments, R^10Ais independently —NO₂. In embodiments, R^10Ais independently —OCH₃. In embodiments, R^10Ais independently —OCH₂CH₃. In embodiments, R^10Ais independently —OCH(CH₃)₂. In embodiments, R^10Ais independently —OC(CH₃)₃. In embodiments, R^10Ais independently —CH₃. In embodiments, R^10Ais independently —CH₂CH₃. In embodiments, R^10Ais independently —CH(CH₃)₂. In embodiments, R^10Ais independently —C(CH₃)₃. In embodiments, R^10Ais independently unsubstituted cyclopropyl. In embodiments, R^10Ais independently unsubstituted cyclobutyl. In embodiments, R^10Ais independently unsubstituted cyclopentyl. In embodiments, R^10Ais independently unsubstituted cyclohexyl. In embodiments, R^10Ais independently substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄). In embodiments, R^10Ais independently substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered). In embodiments, R^10Ais independently substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆). In embodiments, R^10Ais independently substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered). In embodiments, R^10Ais independently substituted or unsubstituted aryl (e.g., C₆-C₁₀, C₁₀, or phenyl). In embodiments, R^10Ais independently substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R^10Ais independently unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄). In embodiments, R^10Ais independently unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered). In embodiments, R^10Ais independently unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆). In embodiments, R^10Ais independently unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered). In embodiments, R^10Ais independently unsubstituted aryl (e.g., C₆-C₁₀, C₁₀, or phenyl). In embodiments, R^10Ais independently unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, R^10Bis independently halogen. In embodiments, R^10Bis independently —CH₂OCH₃. In embodiments, R^10Bis independently —SO₂CH₃. In embodiments, R^10Bis independently —SCH₃. In embodiments, R^10Bis independently —OCH₃. In embodiments, R^10Bis independently unsubstituted C₁-C₄alkyl. In embodiments, R^10Bis independently unsubstituted cyclopropyl. In embodiments, R^10Bis independently unsubstituted phenyl. In embodiments, R^10Bis independently hydrogen. In embodiments, R^10Bis independently —CCl₃. In embodiments, R^10Bis independently —CBr₃. In embodiments, R^10Bis independently —CF₃. In embodiments, R^10Bis independently —CI₃. In embodiments, R^10Bis independently —CHCl₂. In embodiments, R^10Bis independently —CHBr₂. In embodiments, R^10Bis independently —CHF₂. In embodiments, R^10Bis independently —CHI₂. In embodiments, R^10Bis independently —CH₂Cl. In embodiments, R^10Bis independently —CH₂Br. In embodiments, R^10Bis independently —CH₂F. In embodiments, R^10Bis independently —CH₂I. In embodiments, R^10Bis independently —CN. In embodiments, R^10Bis independently —OH. In embodiments, R^10Bis independently —NH₂. In embodiments, R^10Bis independently —COOH. In embodiments, R^10Bis independently —CONH₂. In embodiments, R^10Bis independently —OCCl₃. In embodiments, R^10Bis independently —OCF₃. In embodiments, R^10Bis independently —OCBr₃. In embodiments, R^10Bis independently —OCI₃. In embodiments, R^10Bis independently —OCHCl₂. In embodiments, R^10Bis independently —OCHBr₂. In embodiments, R^10Bis independently —OCHI₂. In embodiments, R^10Bis independently —OCHF₂. In embodiments, R^10Bis independently —OCH₂Cl. In embodiments, R^10Bis independently —OCH₂Br. In embodiments, R^10Bis independently —OCH₂I. In embodiments, R^10Bis independently —OCH₂F. In embodiments, R^10Bis independently halogen. In embodiments, R^10Bis independently —NO₂. In embodiments, R^10Bis independently —OCH₃. In embodiments, R^10Bis independently —OCH₂CH₃. In embodiments, R^10Bis independently —OCH(CH₃)₂. In embodiments, R^10Bis independently —OC(CH₃)₃. In embodiments, R^10Bis independently —CH₃. In embodiments, R^10Bis independently —CH₂CH₃. In embodiments, R^10Bis independently —CH(CH₃)₂. In embodiments, R^10Bis independently —C(CH₃)₃. In embodiments, R^10Bis independently unsubstituted cyclopropyl. In embodiments, R^10Bis independently unsubstituted cyclobutyl. In embodiments, R^10Bis independently unsubstituted cyclopentyl. In embodiments, R^10Bis independently unsubstituted cyclohexyl. In embodiments, R^10Bis independently substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄). In embodiments, R^10Bis independently substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered). In embodiments, R^10Bis independently substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆). In embodiments, R^10Bis independently substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered). In embodiments, R^10Bis independently substituted or unsubstituted aryl (e.g., C₆-C₁₀, C₁₀, or phenyl). In embodiments, R^10Bis independently substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R^10Bis independently unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄). In embodiments, R^10Bis independently unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered). In embodiments, R^10Bis independently unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆). In embodiments, R^10Bis independently unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered). In embodiments, R^10Bis independently unsubstituted aryl (e.g., C₆-C₁₀, C₁₀, or phenyl). In embodiments, R^10Bis independently unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, R^10Aand R^10Bsubstituents bonded to the same nitrogen atom are joined to form a substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered). In embodiments, R^10Aand R^10Bsubstituents bonded to the same nitrogen atom are joined to form a substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R^10Aand R^10Bsubstituents bonded to the same nitrogen atom are joined to form an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered). In embodiments, R^10Aand R^10Bsubstituents bonded to the same nitrogen atom are joined to form an unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, R^10Cis independently halogen. In embodiments, R^10Cis independently —CH₂OCH₃. In embodiments, R^10Cis independently —SO₂CH₃. In embodiments, R^10Cis independently —SCH₃. In embodiments, R^10Cis independently —OCH₃. In embodiments, R^10Cis independently unsubstituted C₁-C₄alkyl. In embodiments, R^10Cis independently unsubstituted cyclopropyl. In embodiments, R^10Cis independently unsubstituted phenyl. In embodiments, R^10Cis independently hydrogen. In embodiments, R^10Cis independently —CCl₃. In embodiments, R^10Cis independently —CBr₃. In embodiments, R^10Cis independently —CF₃. In embodiments, R^10Cis independently —CI₃. In embodiments, R^10Cis independently —CHCl₂. In embodiments, R^10Cis independently —CHBr₂. In embodiments, R^10Cis independently —CHF₂. In embodiments, R^10Cis independently —CHI₂. In embodiments, R^10Cis independently —CH₂Cl. In embodiments, R^10Cis independently —CH₂Br. In embodiments, R^10Cis independently —CH₂F. In embodiments, R^10Cis independently —CH₂I. In embodiments, R^10Cis independently —CN. In embodiments, R^10Cis independently —OH. In embodiments, R^10Cis independently —NH₂. In embodiments, R^10Cis independently —COOH. In embodiments, R^10Cis independently —CONH₂. In embodiments, R^10Cis independently —OCCl₃. In embodiments, R^10Cis independently —OCF₃. In embodiments, R^10Cis independently —OCBr₃. In embodiments, R^10Cis independently —OCI₃. In embodiments, R^10Cis independently —OCHCl₂. In embodiments, R^10Cis independently —OCHBr₂. In embodiments, R^10Cis independently —OCHI₂. In embodiments, R^10Cis independently —OCHF₂. In embodiments, R^10Cis independently —OCH₂Cl. In embodiments, R^10Cis independently —OCH₂Br. In embodiments, R^10Cis independently —OCH₂I. In embodiments, R^10Cis independently —OCH₂F. In embodiments, R^10Cis independently halogen. In embodiments, R^10Cis independently —NO₂. In embodiments, R^10Cis independently —OCH₃. In embodiments, R^10Cis independently —OCH₂CH₃. In embodiments, R^10Cis independently —OCH(CH₃)₂. In embodiments, R^10Cis independently —OC(CH₃)₃. In embodiments, R^10Cis independently —CH₃. In embodiments, R^10Cis independently —CH₂CH₃. In embodiments, R^10Cis independently —CH(CH₃)₂. In embodiments, R^10Cis independently —C(CH₃)₃. In embodiments, R^10Cis independently unsubstituted cyclopropyl. In embodiments, R^10Cis independently unsubstituted cyclobutyl. In embodiments, R^10Cis independently unsubstituted cyclopentyl. In embodiments, R^10Cis independently unsubstituted cyclohexyl. In embodiments, R^10Cis independently substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄). In embodiments, R^10Cis independently substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered). In embodiments, R^10Cis independently substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆). In embodiments, R^10Cis independently substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered). In embodiments, R^10Cis independently substituted or unsubstituted aryl (e.g., C₆-C₁₀, C₁₀, or phenyl). In embodiments, R^10Cis independently substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R^10Cis independently unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄). In embodiments, R^10Cis independently unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered). In embodiments, R^10Cis independently unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆). In embodiments, R^10Cis independently unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered). In embodiments, R^10Cis independently unsubstituted aryl (e.g., C₆-C₁₀, C₁₀, or phenyl). In embodiments, R^10Cis independently unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, R^10Dis independently halogen. In embodiments, R^10Dis independently —CH₂OCH₃. In embodiments, R^10Dis independently —SO₂CH₃. In embodiments, R^10Dis independently —SCH₃. In embodiments, R^10Dis independently —OCH₃. In embodiments, R^10Dis independently unsubstituted C₁-C₄alkyl. In embodiments, R^10Dis independently unsubstituted cyclopropyl. In embodiments, R^10Dis independently unsubstituted phenyl. In embodiments, R^10Dis independently hydrogen. In embodiments, R^10Dis independently —CCl₃. In embodiments, R^10Dis independently —CBr₃. In embodiments, R^10Dis independently —CF₃. In embodiments, R^10Dis independently —CI₃. In embodiments, R^10Dis independently —CHCl₂. In embodiments, R^10Dis independently —CHBr₂. In embodiments, R^10Dis independently —CHF₂. In embodiments, R^10Dis independently —CHI₂. In embodiments, R^10Dis independently —CH₂Cl. In embodiments, R^10Dis independently —CH₂Br. In embodiments, R^10Dis independently —CH₂F. In embodiments, R^10Dis independently —CH₂I. In embodiments, R^10Dis independently —CN. In embodiments, R^10Dis independently —OH. In embodiments, R^10Dis independently —NH₂. In embodiments, R^10Dis independently —COOH. In embodiments, R^10Dis independently —CONH₂. In embodiments, R^10Dis independently —OCCl₃. In embodiments, R^10Dis independently —OCF₃. In embodiments, R^10Dis independently —OCBr₃. In embodiments, R^10Dis independently —OCI₃. In embodiments, R^10Dis independently —OCHCl₂. In embodiments, R^10Dis independently —OCHBr₂. In embodiments, R^10Dis independently —OCHI₂. In embodiments, R^10Dis independently —OCHF₂. In embodiments, R^10Dis independently —OCH₂Cl. In embodiments, R^10Dis independently —OCH₂Br. In embodiments, R^10Dis independently —OCH₂I. In embodiments, R^10Dis independently —OCH₂F. In embodiments, R^10Dis independently halogen. In embodiments, R^10Dis independently —NO₂. In embodiments, R^10Dis independently —OCH₃. In embodiments, R^10Dis independently-OCH₂CH₃. In embodiments, R^10Dis independently —OCH(CH₃)₂. In embodiments, R^10Dis independently —OC(CH₃)₃. In embodiments, R^10Dis independently —CH₃. In embodiments, R^10Dis independently —CH₂CH₃. In embodiments, R^10Dis independently —CH(CH₃)₂. In embodiments, R^10Dis independently —C(CH₃)₃. In embodiments, R^10Dis independently unsubstituted cyclopropyl. In embodiments, R^10Dis independently unsubstituted cyclobutyl. In embodiments, R^10Dis independently unsubstituted cyclopentyl. In embodiments, R^10Dis independently unsubstituted cyclohexyl. In embodiments, R^10Dis independently substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄). In embodiments, R^10Dis independently substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered). In embodiments, R^10Dis independently substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆). In embodiments, R^10Dis independently substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered). In embodiments, R^10Dis independently substituted or unsubstituted aryl (e.g., C₆-C₁₀, C₁₀, or phenyl). In embodiments, R^10Dis independently substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R^10Dis independently unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄). In embodiments, R^10Dis independently unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered). In embodiments, R^10Dis independently unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆). In embodiments, R^10Dis independently unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered). In embodiments, R^10Dis independently unsubstituted aryl (e.g., C₆-C₁₀, C₁₀, or phenyl). In embodiments, R^10Dis independently unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, R^10.A, R^10.B, and R^10.Care independently halogen, —CF₃, —CHF₂, —CH₂F, —OCF₃, —OCH₂F, —OCHF₂, —OCH₃, —CH₂OCH₃, —CN, —SO₂CH₃, —SCH₃, —OCH₃, unsubstituted C₁-C₄alkyl, unsubstituted cyclopropyl, or unsubstituted phenyl.

In embodiments, R^10.Cis unsubstituted C₁-C₄alkyl.

In embodiments, R^10.Ais independently hydrogen, halogen, —CX^10.A₃, —CHX^10.A₂, —CH₂X^10.A, —OCX^10.A₃, —OCH₂X^10.A, —OCHX^10.A₂, —CN, —SO_n10R^10D, —SO_v10NR^10AR^10B, —NR^10CNR^10AR^10B, —ONR^10AR^10B, —NHC(O)NR^10CNR^10AR^10B, —NHC(O)NR^10AR^10B, —N(O)_m10, —NR^10AR^10B, —C(O)R^10C, —C(O)—OR^10C, —C(O)NR^10AR^10B, —OR^10D, —NR^10ASO₂R^10D, —NR^10AC(O)R^10C, —NR^10AC(O)OR^10C, —NR^10AOR^10C, —SF₅, —N₃, substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, 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 C₅-C₆), 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., C₆-C₁₀, C₁₀, or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X^10.Ais independently halogen.

In embodiments, R^10.Ais independently hydrogen, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —SF₅, —N₃, substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, 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 C₅-C₆), 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., C₆-C₁₀, C₁₀, or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, R^10.Ais independently hydrogen. In embodiments, R^10.Ais independently halogen. In embodiments, R^10.Ais independently —CX^10.A₃. In embodiments, R^10.Ais independently —CHX^10.A₂. In embodiments, R^10.Ais independently —CH₂X^10.A. In embodiments, R^10.Ais independently —OCX^10.A₃. In embodiments, R^10Ais independently —OCH₂X^10.A. In embodiments, R^10.Ais independently —OCHX^10.A₂. In embodiments, R^10.Ais independently —CN. In embodiments, R^10.Ais independently —SO_n10R^10D. In embodiments, R^10.Ais independently —SO_v10NR^10AR^10BIn embodiments, R^10Ais independently —NR^10CNR^1AR^10BIn embodiments, R^10.Ais independently —ONR^10AR^10B. In embodiments, R^10.Ais independently —NHC(O)NR^10CNR^10AR^10B. In embodiments, R^10Ais independently —NHC(O)NR^10AR^10B. In embodiments, R^10.Ais independently —N(O)_m10. In embodiments, R^10.Ais independently —NR^10AR^10B. In embodiments, R^10Ais independently —C(O)R^10C. In embodiments, R^10.Ais independently —C(O)—OR^10C. In embodiments, R^10.Ais independently —C(O)NR^10AR^10B. In embodiments, R^10Ais independently —OR^10D. In embodiments, R^10.Ais independently —NR^10AS02R^10DIn embodiments, R^10.Ais independently —NR^10AC(O)R^10CIn embodiments, R^10.Ais independently —NR^10AC(O)OR^10CIn embodiments, R^10.Ais independently —NR^10AOR^10C. In embodiments, R^10.Ais independently —SF₅. In embodiments, R^10.Ais independently —N₃. In embodiments, R^10.Ais independently —F. In embodiments, R^10.Ais independently —Cl. In embodiments, R^10.Ais independently —Br. In embodiments, R^10.Ais independently —I. In embodiments, R^10.Ais independently —CH₂OCH₃. In embodiments, R^10.Ais independently —SO₂CH₃. In embodiments, R^10.Ais independently —SCH₃. In embodiments, R^10.Ais independently —OCH₃. In embodiments, R^10.Ais independently —CH₂CH₂OCH₃. In embodiments, R^10.Ais independently —SO₂CH₂CH₃. In embodiments, R^10.Ais independently —SCH₂CH₃. In embodiments, R^10.Ais independently —OCH₂CH₃. In embodiments, R^10.Ais independently —CH₂OCH₂CH₃. In embodiments, R^10.Ais independently unsubstituted C₁-C₄alkyl. In embodiments, R^10.Ais independently unsubstituted cyclopropyl. In embodiments, R^10.Ais independently unsubstituted phenyl. In embodiments, R^10.Ais independently hydrogen. In embodiments, R^10.Ais independently —CCl₃. In embodiments, R^10.Ais independently —CBr₃. In embodiments, R^10.Ais independently —CF₃. In embodiments, R^10.Ais independently —CI₃. In embodiments, R^10.Ais independently —CHCl₂. In embodiments, R^10.Ais independently —CHBr₂. In embodiments, R^10.Ais independently —CHF₂. In embodiments, R^10.Ais independently —CHI₂. In embodiments, R^10.Ais independently —CH₂Cl. In embodiments, R^10.Ais independently —CH₂Br. In embodiments, R^10.Ais independently —CH₂F. In embodiments, R^10.Ais independently —CH₂I. In embodiments, R^10.Ais independently —CN. In embodiments, R^10.Ais independently —OH. In embodiments, R^10.Ais independently —NH₂. In embodiments, R^10.Ais independently —COOH. In embodiments, R^10.Ais independently —CONH₂. In embodiments, R^10.Ais independently —OCCl₃. In embodiments, R^10.Ais independently —OCF₃. In embodiments, R^10.Ais independently —OCBr₃. In embodiments, R^10.Ais independently —OCI₃. In embodiments, R^10.Ais independently —OCHCl₂. In embodiments, R^10.Ais independently —OCHBr₂. In embodiments, R^10.Ais independently —OCHI₂. In embodiments, R^10.Ais independently —OCHF₂. In embodiments, R^10.Ais independently —OCH₂Cl. In embodiments, R^10.Ais independently —OCH₂Br. In embodiments, R^10.Ais independently —OCH₂I. In embodiments, R^10.Ais independently —OCH₂F. In embodiments, R^10.Ais independently halogen. In embodiments, R^10.Ais independently —NO₂. In embodiments, R^10.Ais independently —OCH₃. In embodiments, R^10.Ais independently —OCH₂CH₃. In embodiments, R^10.Ais independently —OCH(CH₃)₂. In embodiments, R^10.Ais independently —OC(CH₃)₃. In embodiments, R^10.Ais independently —CH₃. In embodiments, R^10.Ais independently —CH₂CH₃. In embodiments, R^10.Ais independently —CH(CH₃)₂. In embodiments, R^10.Ais independently —C(CH₃)₃. In embodiments, R^10.Ais independently unsubstituted cyclopropyl. In embodiments, R^10.Ais independently unsubstituted cyclobutyl. In embodiments, R^10.Ais independently unsubstituted cyclopentyl. In embodiments, R^10.Ais independently unsubstituted cyclohexyl. In embodiments, R^10.Ais independently substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄). In embodiments, R^10.Ais independently substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered). In embodiments, R^10Ais independently substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆). In embodiments, R^10.Ais independently substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered). In embodiments, R^10Ais independently substituted or unsubstituted aryl (e.g., C₆-C₁₀, C₁₀, or phenyl). In embodiments, R^10.Ais independently substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R^10.Ais independently unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄). In embodiments, R^10.Ais independently unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered). In embodiments, R^10.Ais independently unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆). In embodiments, R^10.Ais independently unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered). In embodiments, R^10.Ais independently unsubstituted aryl (e.g., C₆-C₁₀, C₁₀, or phenyl). In embodiments, R^10.Ais independently unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, X^10.Ais independently —F. In embodiments, X^10.Ais independently —Cl. In embodiments, X^10.Ais independently —Br. In embodiments, X^10.Ais independently —I.

In embodiments, R^10.Bis independently hydrogen, halogen, —CX^10.B₃, —CHX^10.B₂, —CH₂X^10.B, —OCX^10.B₃, —OCH₂X^10.B, —OCHX^10.B₂, —CN, —SO_n10R^10D, —SO_v10NR^10AR^10B, —NR^10CNR^10AR^10B, —ONR^10AR^10B, —NHC(O)NR^10CNR^10AR^10B, —NHC(O)NR^10AR^10B, —N(O)_m10, —NR^10AR^10B, —C(O)R^10C, —C(O)—OR^10C, —C(O)NR^10AR^10B, —OR^10D, —NR^10ASO₂R^10D, —NR^10AC(O)R^10C, —NR^10AC(O)OR^10C, —NR^10AOR^10C, —SF₅, —N₃, substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, 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 C₅-C₆), 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., C₆-C₁₀, C₁₀, or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered), X^10.Bis independently halogen.

In embodiments, R^10.Bis independently hydrogen, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —SF₅, —N₃, substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, 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 C₅-C₆), 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., C₆-C₁₀, C₁₀, or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, R^10.Bis independently hydrogen. In embodiments, R^10.Bis independently halogen. In embodiments, R^10.Bis independently —CX^10.B₃. In embodiments, R^10.Bis independently —CHX^10.B₂. In embodiments, R^10.Bis independently —CH₂X^10B. In embodiments, R^10.Bis independently —OCX^10.B₃. In embodiments, R^10.Bis independently —OCH₂X^10B. In embodiments, R^10.Bis independently —OCHX^10.B₂. In embodiments, R^10.Bis independently —CN. In embodiments, R^10.Bis independently —SO_n10R^10D. In embodiments, R^10.Bis independently —SO_v10NR^10AR^10B. In embodiments, R^10.Bis independently —NR^10CNR^1AR^10B. In embodiments, R^10.Bis independently —ONR^10AR^10B. In embodiments, R^10.Bis independently —NHC(O)NR^10CNR^10AR^10B. In embodiments, R^10.Bis independently —NHC(O)NR^10AR^10B. In embodiments, R^10.Bis independently —N(O)_m10. In embodiments, R^10.Bis independently —NR^10AR^10B. In embodiments, R^10.Bis independently —C(O)R^10C. In embodiments, R^10.Bis independently —C(O)—OR^10C. In embodiments, R^10.Bis independently —C(O)NR^10AR^10B. In embodiments, R^10.Bis independently —OR^10D. In embodiments, R^10.Bis independently —NR^10AS02R^10DIn embodiments, R^10.Bis independently —NR^10AC(O)R^10CIn embodiments, R^10.Bis independently —NR^10AC(O)OR^10CIn embodiments, R^10.Bis independently —NR^10AOR^10C. In embodiments, R^10.Bis independently —SF₅. In embodiments, R^10.Bis independently —N₃. In embodiments, R^10.Bis independently —F. In embodiments, R^10.Bis independently —Cl. In embodiments, R^10.Bis independently —Br. In embodiments, R^10.Bis independently —I. In embodiments, R^10.Bis independently —CH₂OCH₃. In embodiments, R^10.Bis independently —SO₂CH₃. In embodiments, R^10.Bis independently —SCH₃. In embodiments, R^10.Bis independently —OCH₃. In embodiments, R^10.Bis independently —CH₂CH₂OCH₃. In embodiments, R^10.Bis independently —SO₂CH₂CH₃. In embodiments, R^10.Bis independently —SCH₂CH₃. In embodiments, R^10.Bis independently —OCH₂CH₃. In embodiments, R^10.Bis independently —CH₂OCH₂CH₃. In embodiments, R^10.Bis independently unsubstituted C₁-C₄alkyl. In embodiments, R^10.Bis independently unsubstituted cyclopropyl. In embodiments, R^10.Bis independently unsubstituted phenyl. In embodiments, R^10.Bis independently hydrogen. In embodiments, R^10.Bis independently —CCl₃. In embodiments, R^10.Bis independently —CBr₃. In embodiments, R^10.Bis independently —CF₃. In embodiments, R^10.Bis independently —CI₃. In embodiments, R^10.Bis independently —CHCl₂. In embodiments, R^10.Bis independently —CHBr₂. In embodiments, R^10.Bis independently —CHF₂. In embodiments, R^10.Bis independently —CHI₂. In embodiments, R^10.Bis independently —CH₂Cl. In embodiments, R^10.Bis independently —CH₂Br. In embodiments, R^10.Bis independently —CH₂F. In embodiments, R^10.Bis independently —CH₂I. In embodiments, R^10.Bis independently —CN. In embodiments, R^10.Bis independently —OH. In embodiments, R^10.Bis independently —NH₂. In embodiments, R^10.Bis independently —COOH. In embodiments, R^10.Bis independently —CONH₂. In embodiments, R^10.Bis independently —OCCl₃. In embodiments, R^10.Bis independently —OCF₃. In embodiments, R^10.Bis independently —OCBr₃. In embodiments, R^10.Bis independently —OCI₃. In embodiments, R^10.Bis independently —OCHCl₂. In embodiments, R^10.Bis independently —OCHBr₂. In embodiments, R^10.Bis independently —OCHI₂. In embodiments, R^10.Bis independently —OCHF₂. In embodiments, R^10.Bis independently —OCH₂Cl. In embodiments, R^10.Bis independently —OCH₂Br. In embodiments, R^10.Bis independently —OCH₂I. In embodiments, R^10.Bis independently —OCH₂F. In embodiments, R^10.Bis independently halogen. In embodiments, R^10.Bis independently —NO₂. In embodiments, R^10.Bis independently —OCH₃. In embodiments, R^10.Bis independently —OCH₂CH₃. In embodiments, R^10.Bis independently —OCH(CH₃)₂. In embodiments, R^10.Bis independently —OC(CH₃)₃. In embodiments, R^10.Bis independently —CH₃. In embodiments, R^10.Bis independently —CH₂CH₃. In embodiments, R^10.Bis independently —CH(CH₃)₂. In embodiments, R^10.Bis independently —C(CH₃)₃. In embodiments, R^10.Bis independently unsubstituted cyclopropyl. In embodiments, R^10.Bis independently unsubstituted cyclobutyl. In embodiments, R^10.Bis independently unsubstituted cyclopentyl. In embodiments, R^10.Bis independently unsubstituted cyclohexyl. In embodiments, R^10.Bis independently substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄). In embodiments, R^10.Bis independently substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered). In embodiments, R^10.Bis independently substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆). In embodiments, R^10.Bis independently substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered). In embodiments, R^10.Bis independently substituted or unsubstituted aryl (e.g., C₆-C₁₀, C₁₀, or phenyl). In embodiments, R^10.Bis independently substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R^10.Bis independently unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄). In embodiments, R^10.Bis independently unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered). In embodiments, R^10.Bis independently unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆). In embodiments, R^10.Bis independently unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered). In embodiments, R^10.Bis independently unsubstituted aryl (e.g., C₆-C₁₀, C₁₀, or phenyl). In embodiments, R^10.Bis independently unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, X^10.Bis independently —F. In embodiments, X^10.Bis independently —Cl. In embodiments, X^10.Bis independently —Br. In embodiments, X^10.Bis independently —I.

In embodiments, R^10.Cis independently hydrogen, halogen, —CX^10.C₃, —CHX^10.C₂, —CH₂X^10.C, —OCX^10.C₃, —OCH₂X^10.C, —OCHX^10.C₂, —CN, —SO_n10R^10D, —SO_v10NR^10AR^10B, —NR^10CNR^10AR^10B, —ONR^10AR^10B′ _NHC(O)NR^10CNR^10AR^10B, —NHC(O)NR^10AR^10B, —N(O)_m10, —NR^10AR^10B, —C(O)R^10C, —C(O)—OR^10C, —C(O)NR^10AR^10B, —OR^10D, —NR^10ASO₂R^10D, —NR^10AC(O)R^10C, —NR^10AC(O)OR^10C, —NR^10AOR^10C, —SF₅, —N₃, substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, 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 C₅-C₆), 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., C₆-C₁₀, C₁₀, or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered), X^10.Cis independently halogen.

In embodiments, R^10.Cis independently hydrogen, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —SF₅, —N₃, substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, 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 C₅-C₆), 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., C₆-C₁₀, C₁₀, or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, R^10.Cis independently hydrogen. In embodiments, R^10.Cis independently halogen. In embodiments, R^10.Cis independently —CX^10.C₃. In embodiments, R^10.Cis independently —CHX^10.C₂. In embodiments, R^10.Cis independently —CH₂X^10.C. In embodiments, R^10.Cis independently —OCX^10.C₃. In embodiments, R^10.Cis independently —OCH₂X^10.C. In embodiments, R^10.Cis independently —OCHX^10.C₂. In embodiments, R^10.Cis independently —CN. In embodiments, R^10.Cis independently —SO_n10R^10D. In embodiments, R^10.Cis independently —SO_v10NR^10AR^10B. In embodiments, R^10.Cis independently —NR^10CNR^1AR^10BIn embodiments, R^10.Cis independently —ONR^10AR^10B. In embodiments, R^10.Cis independently —NHC(O)NR^10CNR^10AR^10B. In embodiments, R^10.Cis independently —NHC(O)NR^10AR^10B. In embodiments, R^10.Cis independently —N(O)_m10. In embodiments, R^10.Cis independently —NR^10AR^10B. In embodiments, R^10.Cis independently —C(O)R^10C. In embodiments, R^10.Cis independently —C(O)—OR^10C. In embodiments, R^10.Cis independently —C(O)NR^10AR^10B. In embodiments, R^10.Cis independently —OR^10D. In embodiments, R^10.Cis independently —NR^10AS02R^10.D. In embodiments, R^10.Cis independently —NR^10AC(O)R^10CIn embodiments, R^10.Cis independently —NR^10AC(O)OR^10CIn embodiments, R^10.Cis independently —NR^10AOR^10.C. In embodiments, R^10.Cis independently —SF₅. In embodiments, R^10.Cis independently —N₃. In embodiments, R^10.Cis independently —F. In embodiments, R^10.Cis independently —Cl. In embodiments, R^10.Cis independently —Br. In embodiments, R^10.Cis independently —I. In embodiments, R^10.Cis independently —CH₂OCH₃. In embodiments, R^10.Cis independently —SO₂CH₃. In embodiments, R^10.Cis independently —SCH₃. In embodiments, R^10.Cis independently —OCH₃. In embodiments, R^10.Cis independently —CH₂CH₂OCH₃. In embodiments, R^10.Cis independently —SO₂CH₂CH₃. In embodiments, R^10.Cis independently —SCH₂CH₃. In embodiments, R^10.Cis independently —OCH₂CH₃. In embodiments, R^10.Cis independently —CH₂OCH₂CH₃. In embodiments, R^10.Cis independently unsubstituted C₁-C₄alkyl. In embodiments, R^10.Cis independently unsubstituted cyclopropyl. In embodiments, R^10.Cis independently unsubstituted phenyl. In embodiments, R^10.Cis independently hydrogen. In embodiments, R^10.Cis independently —CCl₃. In embodiments, R^10.Cis independently —CBr₃. In embodiments, R^10.Cis independently —CF₃. In embodiments, R^10.Cis independently —CI₃. In embodiments, R^10.Cis independently —CHCl₂. In embodiments, R^10.Cis independently —CHBr₂. In embodiments, R^10.Cis independently —CHF₂. In embodiments, R^10.Cis independently —CHI₂. In embodiments, R^10.Cis independently —CH₂Cl. In embodiments, R^10.Cis independently —CH₂Br. In embodiments, R^10.Cis independently —CH₂F. In embodiments, R^10.Cis independently —CH₂I. In embodiments, R^10.Cis independently —CN. In embodiments, R^10.Cis independently —OH. In embodiments, R^10.Cis independently —NH₂. In embodiments, R^10.Cis independently —COOH. In embodiments, R^10.Cis independently —CONH₂. In embodiments, R^10.Cis independently —OCCl₃. In embodiments, R^10.Cis independently —OCF₃. In embodiments, R^10.Cis independently —OCBr₃. In embodiments, R^10.Cis independently —OCI₃. In embodiments, R^10.Cis independently —OCHCl₂. In embodiments, R^10.Cis independently —OCHBr₂. In embodiments, R^10.Cis independently —OCHI₂. In embodiments, R^10.Cis independently —OCHF₂. In embodiments, R^10.Cis independently —OCH₂Cl. In embodiments, R^10.Cis independently —OCH₂Br. In embodiments, R^10.Cis independently —OCH₂I. In embodiments, R^10.Cis independently —OCH₂F. In embodiments, R^10.Cis independently halogen. In embodiments, R^10.Cis independently —NO₂. In embodiments, R^10.Cis independently —OCH₃. In embodiments, R^10.Cis independently —OCH₂CH₃. In embodiments, R^10.Cis independently —OCH(CH₃)₂. In embodiments, R^10.Cis independently —OC(CH₃)₃. In embodiments, R^10.Cis independently —CH₃. In embodiments, R^10.Cis independently —CH₂CH₃. In embodiments, R^10.Cis independently —CH(CH₃)₂. In embodiments, R^10.Cis independently —C(CH₃)₃. In embodiments, R^10.Cis independently unsubstituted cyclopropyl. In embodiments, R^10.Cis independently unsubstituted cyclobutyl. In embodiments, R^10.Cis independently unsubstituted cyclopentyl. In embodiments, R^10.Cis independently unsubstituted cyclohexyl. In embodiments, R^10.Cis independently substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄). In embodiments, R^10.Cis independently substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered). In embodiments, R^10.Cis independently substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆). In embodiments, R^10.Cis independently substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered). In embodiments, R^10.Cis independently substituted or unsubstituted aryl (e.g., C₆-C₁₀, C₁₀, or phenyl). In embodiments, R^10.Cis independently substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R^10.Cis independently unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄). In embodiments, R^10.Cis independently unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered). In embodiments, R^10.Cis independently unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆). In embodiments, R^10.Cis independently unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered). In embodiments, R^10.Cis independently unsubstituted aryl (e.g., C₆-C₁₀, C₁₀, or phenyl). In embodiments, R^10.Cis independently unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, X^10.Cis independently —F. In embodiments, X^10.Cis independently —Cl. In embodiments, X^10.Cis independently —Br. In embodiments, X^10.Cis independently —I.

R^10.Dis independently hydrogen or any value of R¹⁰described herein, including in embodiments. In embodiments, R^10.Dis independently hydrogen, halogen, —CX^10.D₃, —CHX^10.D₂, —CH₂X^10.D, —OCX^10.D₃, —OCH₂X^10.D, —OCHX^10.D₂, —CN, —SO_n10R^10D, —SO_v10NR^10AR^10B, —NR^10CNR^10AR^10B, —ONR^10AR^10B, —NHC(O)NR^10CNR^10AR^10B, —NHC(O)NR^10AR^10B, —N(O)_m10, —NR^10AR^10B, —C(O)R^10C, —C(O)—OR^10C, —C(O)NR^10AR^10B, —OR^10D, —NR^10ASO₂R^10D, —NR^10AC(O)R^10C, —NR^10AC(O)OR^10C, —NR^10AOR^10C, —SF₅, —N₃, substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, 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 C₅-C₆), 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., C₆-C₁₀, C₁₀, or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered), X^10.Dis independently halogen.

In embodiments, R^10.Dis independently hydrogen, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —SF₅, —N₃, substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, 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 C₅-C₆), 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., C₆-C₁₀, C₁₀, or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, R^10.Dis independently hydrogen. In embodiments, R^10.Dis independently halogen. In embodiments, R^10.Dis independently —CX^10.D₃. In embodiments, R^10.Dis independently —CHX^10.D₂. In embodiments, R^10.Dis independently —CH₂X^10D. In embodiments, R^10.Dis independently —OCX^10.D₃. In embodiments, R^10Dis independently —OCH₂X^10D. In embodiments, R^10.Dis independently —OCHX^10.D₂. In embodiments, R^10.Dis independently —CN. In embodiments, R^10.Dis independently —SO_n10R^10D. In embodiments, R^10.Dis independently —SO_v10NR^10AR^10B. In embodiments, R^10Dis independently —NR^10CNR^1AR^10BIn embodiments, R^10.Dis independently —ONR^10AR^10B. In embodiments, R^10.Dis independently —NHC(O)NR^10CNR^10AR^10B. In embodiments, R^10Dis independently —NHC(O)NR^10AR^10B. In embodiments, R^10.Dis independently —N(O)_m10. In embodiments, R^10.Dis independently —NR^10AR^10B. In embodiments, R^10Dis independently —C(O)R^10C. In embodiments, R^10.Dis independently —C(O)—OR^10.C. In embodiments, R^10.Dis independently —C(O)NR^10AR^10B. In embodiments, R^10Dis independently —OR^10D. In embodiments, R^10.Dis independently —NR^10AS02R^10Dn embodiments, R^10.Dis independently —NR^10AC(O)R^10.C. In embodiments, R^10Dis independently —NR^10AC(O)OR^10C. In embodiments, R^10.Dis independently —NR^10AOR^10.C. In embodiments, R^10.Dis independently —SF₅. In embodiments, R^10.Dis independently —N₃. In embodiments, R^10.Dis independently —F. In embodiments, R^10Dis independently —Cl. In embodiments, R^10.Dis independently —Br. In embodiments, R^10Dis independently —I. In embodiments, R^10.Dis independently —CH₂OCH₃. In embodiments, R^10Dis independently —SO₂CH₃. In embodiments, R^10.Dis independently —SCH₃. In embodiments, R^10.Dis independently —OCH₃. In embodiments, R^10.Dis independently —CH₂CH₂OCH₃. In embodiments, R^10.Dis independently —SO₂CH₂CH₃. In embodiments, R^10.Dis independently —SCH₂CH₃. In embodiments, R^10.Dis independently —OCH₂CH₃. In embodiments, R^10.Dis independently —CH₂OCH₂CH₃. In embodiments, R^10Dis independently unsubstituted C₁-C₄alkyl. In embodiments, R^10Dis independently unsubstituted cyclopropyl. In embodiments, R^10.Dis independently unsubstituted phenyl. In embodiments, R^10.Dis independently hydrogen. In embodiments, R^10Dis independently —CCl₃. In embodiments, R^10.Dis independently —CBr₃. In embodiments, R^10.Dis independently —CF₃. In embodiments, R^10.Dis independently —CI₃. In embodiments, R^10.Dis independently —CHCl₂. In embodiments, R^10.Dis independently —CHBr₂. In embodiments, R^10.Dis independently —CHF₂. In embodiments, R^10.Dis independently —CHI₂. In embodiments, R^10.Dis independently —CH₂Cl. In embodiments, R^10.Dis independently —CH₂Br. In embodiments, R^10.Dis independently —CH₂F. In embodiments, R^10.Dis independently —CH₂I. In embodiments, R^10.Dis independently —CN. In embodiments, R^10.Dis independently —OH. In embodiments, R^10.Dis independently —NH₂. In embodiments, R^10.Dis independently —COOH. In embodiments, R^10.Dis independently —CONH₂. In embodiments, R^10.Dis independently —OCCl₃. In embodiments, R^10.Dis independently —OCF₃. In embodiments, R^10.Dis independently —OCBr₃. In embodiments, R^10.Dis independently —OCI₃. In embodiments, R^10.Dis independently —OCHCl₂. In embodiments, R^10.Dis independently —OCHBr₂. In embodiments, R^10.Dis independently —OCHI₂. In embodiments, R^10.Dis independently —OCHF₂. In embodiments, R^10.Dis independently —OCH₂Cl. In embodiments, R^10.Dis independently —OCH₂Br. In embodiments, R^10.Dis independently —OCH₂I. In embodiments, R^10.Dis independently —OCH₂F. In embodiments, R^10.Dis independently halogen. In embodiments, R^10.Dis independently —NO₂. In embodiments, R^10.Dis independently —OCH₃. In embodiments, R^10.Dis independently —OCH₂CH₃. In embodiments, R^10.Dis independently —OCH(CH₃)₂. In embodiments, R^10.Dis independently —OC(CH₃)₃. In embodiments, R^10.Dis independently —CH₃. In embodiments, R^10.Dis independently —CH₂CH₃. In embodiments, R^10.Dis independently —CH(CH₃)₂. In embodiments, R^10.Dis independently —C(CH₃)₃. In embodiments, R^10.Dis independently unsubstituted cyclopropyl. In embodiments, R^10.Dis independently unsubstituted cyclobutyl. In embodiments, R^10.Dis independently unsubstituted cyclopentyl. In embodiments, R^10.Dis independently unsubstituted cyclohexyl. In embodiments, R^10.Dis independently substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄). In embodiments, R^10.Dis independently substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered). In embodiments, R^10.Dis independently substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆). In embodiments, R^10.Dis independently substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered). In embodiments, R^10.Dis independently substituted or unsubstituted aryl (e.g., C₆-C₁₀, C₁₀, or phenyl). In embodiments, R^10.Dis independently substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R^10.Dis independently unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄). In embodiments, R^10.Dis independently unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered). In embodiments, R^10.Dis independently unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆). In embodiments, R^10.Dis independently unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered). In embodiments, R^10.Dis independently unsubstituted aryl (e.g., C₆-C₁₀, C₁₀, or phenyl). In embodiments, R^10.Dis independently unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, X^10.Dis independently —F. In embodiments, X^10.Dis independently —Cl. In embodiments, X^10.Dis independently —Br. In embodiments, X^10.Dis independently —I.

In embodiments, L²is a bond. In embodiments, L²is —N(R^L2)—. In embodiments, L²is —O—. In embodiments, L²is —S—. In embodiments, L²is —SO₂—. In embodiments, L²is —C(O)—. In embodiments, L²is —C(O)N(R^L2)—. In embodiments, L²is —N(R^L2)C(O)—. In embodiments, L²is —N(R²)C(O)NH—. In embodiments, L²is —NHC(O)N(R^L)—. In embodiments, L²is —C(O)O—. In embodiments, L²is —OC(O)—. In embodiments, L²is —SO₂N(R^L)—. In embodiments, L²is —N(R^L)SO₂—. In embodiments, L²is substituted or unsubstituted alkylene (e.g., C₁-C₈, C₁-C₆, or C₁-C₄). In embodiments, L²is substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered). In embodiments, L²is a substituted or unsubstituted 2 to 6 membered heteroalkylene.

In embodiments, L²is substituted or unsubstituted heteroalkylene. In embodiments, L²is —O(C₁-C₆alkyl)-, —S(C₁-C₆alkyl)- or —N(R^L)(C₁-C₆alkyl)-. In embodiments, L²is —O(C₁-C₆alkyl)-. In embodiments, L²is —S(C₁-C₆alkyl)-. In embodiments, L²is —N(R^L)(C₁-C₆alkyl)-. In embodiments, L²is —OCH₂— or —NHCH₂—. In embodiments, L²is —OCH₂—. In embodiments, L²is a substituted or unsubstituted heteroalkylene. In embodiments, L²is an unsubstituted 2 to 4 membered heteroalkylene. In embodiments, L²is a bond. In embodiments, L²is —N(R^L2)—. In embodiments, L²is —O—. In embodiments, L²is —S—. In embodiments, L²is —SO₂—. In embodiments, L²is —C(O)—. In embodiments, L²is —C(O)N(R^L2)—. In embodiments, L²is —N(R²)C(O)—. In embodiments, L²is —N(R²)C(O)NH—. In embodiments, L²is —NHC(O)N(R^L)—. In embodiments, L²is —C(O)O—. In embodiments, L²is —OC(O)—. In embodiments, L²is —SO₂N(R^L)—. In embodiments, L²is —N(R^L)SO_2-.

In embodiments, R^Lis independently hydrogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, unsubstituted alkyl, or unsubstituted cycloalkyl. In embodiments, R^Lis independently hydrogen, unsubstituted C₁-C₆alkyl, or unsubstituted C₃-C₆cycloalkyl. In embodiments, R^L2is independently hydrogen, unsubstituted methyl, unsubstituted ethyl, unsubstituted isopropyl, or unsubstituted cyclopropyl. In embodiments, R^Lis independently hydrogen. In embodiments, R^Lis independently unsubstituted methyl. In embodiments, R^L2is independently unsubstituted ethyl. In embodiments, R^L2is independently unsubstituted isopropyl. In embodiments, R^L2is independently unsubstituted cyclopropyl.

In embodiments, L²is an unsubstituted 2 to 6 membered heteroalkylene. In embodiments, L²is an unsubstituted —O—(C₁-C₆alkyl)-. In embodiments, L²is —OCH₂—.

In embodiments, L²is a substituted or unsubstituted alkylene. In embodiments, L²is a substituted or unsubstituted C₂-C₈alkylene. In embodiments, L²is an unsubstituted C₂-C₈alkylene. In embodiments, L²is an unsubstituted methylene. In embodiments, L²is an unsubstituted ethylene. In embodiments, L²is an unsubstituted propylene. In embodiments, L²is an unsubstituted butylene.

In embodiments, R²is independently substituted or unsubstituted C₁-C₄alkyl or substituted or unsubstituted C₃-C₆cycloalkyl. In embodiments, R²is independently unsubstituted C₁-C₄alkyl or unsubstituted C₃-C₆cycloalkyl. In embodiments, R²is independently unsubstituted methyl or unsubstituted cyclopropyl. In embodiments, R²is independently unsubstituted methyl. In embodiments, R²is independently hydrogen.

In embodiments, R²is independently —F. In embodiments, R²is independently —Cl. In embodiments, R²is independently —Br. In embodiments, R²is independently —I. In embodiments, R²is independently —CH₂OCH₃. In embodiments, R²is independently —SCH₃. In embodiments, R²is independently —OCH₃. In embodiments, R²is independently —CH₂CH₂OCH₃. In embodiments, R²is independently —SCH₂CH₃. In embodiments, R²is independently —OCH₂CH₃. In embodiments, R²is independently —CH₂OCH₂CH₃. In embodiments, R²is independently unsubstituted C₁-C₄alkyl. In embodiments, R²is independently unsubstituted cyclopropyl. In embodiments, R²is independently hydrogen. In embodiments, R²is independently —CCl₃. In embodiments, R²is independently —CBr₃. In embodiments, R²is independently —CF₃. In embodiments, R²is independently —CI₃. In embodiments, R²is independently —CHCl₂. In embodiments, R²is independently —CHBr₂. In embodiments, R²is independently —CHF₂. In embodiments, R²is independently —CHI₂. In embodiments, R²is independently —CH₂Cl. In embodiments, R²is independently —CH₂Br. In embodiments, R²is independently —CH₂F. In embodiments, R²is independently —CH₂I. In embodiments, R²is independently —CN. In embodiments, R²is independently —OH. In embodiments, R²is independently —NH₂. In embodiments, R²is independently —COOH. In embodiments, R²is independently —CONH₂. In embodiments, R²is independently —OCCl₃. In embodiments, R²is independently —OCF₃. In embodiments, R²is independently —OCBr₃. In embodiments, R²is independently —OCI₃. In embodiments, R²is independently —OCHCl₂. In embodiments, R²is independently —OCHBr₂. In embodiments, R²is independently —OCHI₂. In embodiments, R²is independently —OCHF₂. In embodiments, R²is independently —OCH₂Cl. In embodiments, R²is independently —OCH₂Br. In embodiments, R²is independently —OCH₂I. In embodiments, R²is independently —OCH₂F. In embodiments, R²is independently —OCH₃. In embodiments, R²is independently —OCH₂CH₃. In embodiments, R²is independently —OCH(CH₃)₂. In embodiments, R²is independently —OC(CH₃)₃. In embodiments, R²is independently —CH₃. In embodiments, R²is independently —CH₂CH₃. In embodiments, R²is independently —CH(CH₃)₂. In embodiments, R²is independently —C(CH₃)₃. In embodiments, R²is independently unsubstituted cyclopropyl. In embodiments, R²is independently unsubstituted cyclobutyl. In embodiments, R²is independently unsubstituted cyclopentyl. In embodiments, R²is independently unsubstituted cyclohexyl. In embodiments, R²is independently substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄). In embodiments, R²is independently substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered). In embodiments, R²is independently substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆). In embodiments, R²is independently substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered). In embodiments, R²is independently substituted or unsubstituted aryl (e.g., C₆-C₁₀, C₁₀, or phenyl). In embodiments, R²is independently substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R²is independently unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄). In embodiments, R²is independently unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered). In embodiments, R²is independently unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆). In embodiments, R²is independently unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered). In embodiments, R²is independently unsubstituted aryl (e.g., C₆-C₁₀, C₁₀, or phenyl). In embodiments, R²is independently unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, R³is independently halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —NO₂, —SH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —CH₃, —CH₂CH₃, —OCH₃, or —OCH₂CH₃. In embodiments, R³is independently halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, or —CH₂I. In embodiments, R³is independently —F or —CF₃. In embodiments, R³is independently oxo. In embodiments, R³is independently —CF₃. In embodiments, R³is independently halogen. In embodiments, R³is independently —CCl₃. In embodiments, R³is independently —CBr₃. In embodiments, R³is independently —CF₃. In embodiments, R³is independently —CI₃. In embodiments, R³is independently —CHCl₂. In embodiments, R³is independently —CHBr₂. In embodiments, R³is independently —CHF₂. In embodiments, R³is independently —CHI₂. In embodiments, R³is independently —CH₂Cl. In embodiments, R³is independently —CH₂Br. In embodiments, R³is independently —CH₂F. In embodiments, R³is independently —CH₂I. In embodiments, R³is independently —CN. In embodiments, R³is 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 —SO₄H. In embodiments, R³is independently —SO₂NH₂. In embodiments, R³is independently —NHNH₂, —ONH₂. In embodiments, R³is independently —NHC(O)NHNH₂. 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 —OCCl₃. In embodiments, R³is independently —OCF₃. In embodiments, R³is independently —OCBr₃. In embodiments, R³is independently —OCI₃. In embodiments, R³is independently —OCHCl₂. In embodiments, R³is independently —OCHBr₂. In embodiments, R³is independently —OCHI₂. In embodiments, R³is independently —OCHF₂. In embodiments, R³is independently —OCH₂Cl. In embodiments, R³is independently —OCH₂Br. In embodiments, R³is independently —OCH₂I. In embodiments, R³is independently —OCH₂F. In embodiments, R³is independently —SF₅. In embodiments, R³is independently —N₃. In embodiments, R³is independently —F. In embodiments, R³is independently —Cl. In embodiments, R³is independently —Br. In embodiments, R³is independently —I. In embodiments, R³is independently —CH₂OCH₃. In embodiments, R³is independently —SCH₃. In embodiments, R³is independently —OCH₃. In embodiments, R³is independently —CH₂CH₂OCH₃. In embodiments, R³is independently —SCH₂CH₃. In embodiments, R³is independently —OCH₂CH₃. In embodiments, R³is independently —CH₂OCH₂CH₃. In embodiments, R³is independently unsubstituted C₁-C₄alkyl. In embodiments, R³is independently unsubstituted cyclopropyl. In embodiments, R³is independently hydrogen. In embodiments, R³is independently —OCH₃. In embodiments, R³is independently —OCH₂CH₃. In embodiments, R³is independently —OCH(CH₃)₂. In embodiments, R³is independently —OC(CH₃)₃. In embodiments, R³is independently —CH₃. In embodiments, R³is independently —CH₂CH₃. In embodiments, R³is independently —CH(CH₃)₂. In embodiments, R³is independently —C(CH₃)₃. In embodiments, R³is independently unsubstituted cyclopropyl. In embodiments, R³is independently unsubstituted cyclobutyl. In embodiments, R³is independently unsubstituted cyclopentyl. In embodiments, R³is independently unsubstituted cyclohexyl. In embodiments, R³is independently substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄). In embodiments, R³is independently substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered). In embodiments, R³is independently substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆). In embodiments, R³is independently substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered). In embodiments, R³is independently substituted or unsubstituted aryl (e.g., C₆-C₁₀, C₁₀, or phenyl). In embodiments, R³is independently substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R³is independently unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄). In embodiments, R³is independently unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered). In embodiments, R³is independently unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆). In embodiments, R³is independently unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered). In embodiments, R³is independently unsubstituted aryl (e.g., C₆-C₁₀, C₁₀, or phenyl). In embodiments, R³is independently unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, two adjacent R³substituents are joined to form a substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆). In embodiments, two adjacent R³substituents are joined to form a substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered). In embodiments, two adjacent R³substituents are joined to form a substituted or unsubstituted aryl (e.g., C₆-C₁₀, C₁₀, or phenyl). In embodiments, two adjacent R³substituents are joined to form a substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, two adjacent R³substituents are joined to form an unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆). In embodiments, two adjacent R³substituents are joined to form an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered). In embodiments, two adjacent R³substituents are joined to form an unsubstituted aryl (e.g., C₆-C₁₀, C₁₀, or phenyl). In embodiments, two adjacent R³substituents are joined to form an unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, z3 is independently 0. In embodiments, z3 is independently 1. In embodiments, z3 is independently 2. In embodiments, z3 is independently 3. In embodiments, z3 is independently 4.

In embodiments, R⁴is independently oxo. In embodiments, R⁴is independently —CF₃. In embodiments, R⁴is independently halogen. In embodiments, R⁴is independently —CCl₃. In embodiments, R⁴is independently —CBr₃. In embodiments, R⁴is independently —CF₃. In embodiments, R⁴is independently —CI₃. In embodiments, R⁴is independently —CHCl₂. In embodiments, R⁴is independently —CHBr₂. In embodiments, R⁴is independently —CHF₂. In embodiments, R⁴is independently —CHI₂. In embodiments, R⁴is independently —CH₂Cl. In embodiments, R⁴is independently —CH₂Br. In embodiments, R⁴is independently —CH₂F. In embodiments, R⁴is independently —CH₂I. In embodiments, R⁴is independently —CN. In embodiments, R⁴is independently —OH. In embodiments, R⁴is independently —NH₂. In embodiments, R⁴is independently —COOH. In embodiments, R⁴is independently —COOCH₃. In embodiments, R⁴is independently —CONH₂. In embodiments, R⁴is independently —NO₂. In embodiments, R⁴is independently —SH. In embodiments, R⁴is independently —SO₃H. In embodiments, R⁴is independently —SO₄H. In embodiments, R⁴is independently —SO₂NH₂. In embodiments, R⁴is independently —NHNH₂, —ONH₂. In embodiments, R⁴is independently —NHNH₂. In embodiments, R⁴is independently —ONH₂. In embodiments, R⁴is independently —NHC(O)NHNH₂. 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 —OCCl₃. In embodiments, R⁴is independently —OCF₃. In embodiments, R⁴is independently —OCBr₃. In embodiments, R⁴is independently —OCI₃. In embodiments, R⁴is independently —OCHCl₂. In embodiments, R⁴is independently —OCHBr₂. In embodiments, R⁴is independently —OCHI₂. In embodiments, R⁴is independently —OCHF₂. In embodiments, R⁴is independently —OCH₂Cl. In embodiments, R⁴is independently —OCH₂Br. In embodiments, R⁴is independently —OCH₂I. In embodiments, R⁴is independently —OCH₂F. In embodiments, R⁴is independently —SF₅. In embodiments, R⁴is independently —N₃. In embodiments, R⁴is independently —F. In embodiments, R⁴is independently —Cl. In embodiments, R⁴is independently —Br. In embodiments, R⁴is independently —I. In embodiments, R⁴is independently —CH₂OCH₃. In embodiments, R⁴is independently —SCH₃. In embodiments, R⁴is independently —OCH₃. In embodiments, R⁴is independently —CH₂CH₂OCH₃. In embodiments, R⁴is independently —SCH₂CH₃. In embodiments, R⁴is independently —OCH₂CH₃. In embodiments, R⁴is independently —CH₂OCH₂CH₃. In embodiments, R⁴is independently unsubstituted C₁-C₄alkyl. In embodiments, R⁴is independently unsubstituted cyclopropyl. In embodiments, R⁴is independently hydrogen. In embodiments, R⁴is independently —OCH₃. In embodiments, R⁴is independently —OCH₂CH₃. In embodiments, R⁴is independently —OCH(CH₃)₂. In embodiments, R⁴is independently —OC(CH₃)₃. In embodiments, R⁴is independently —CH₃. In embodiments, R⁴is independently —CH₂CH₃. In embodiments, R⁴is independently —CH(CH₃)₂. In embodiments, R⁴is independently —C(CH₃)₃. In embodiments, R⁴is independently unsubstituted cyclopropyl. In embodiments, R⁴is independently unsubstituted cyclobutyl. In embodiments, R⁴is independently unsubstituted cyclopentyl. In embodiments, R⁴is independently unsubstituted cyclohexyl. In embodiments, R⁴is independently substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄). In embodiments, R⁴is independently substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered). In embodiments, R⁴is independently substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆). In embodiments, R⁴is independently substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered). In embodiments, R⁴is independently substituted or unsubstituted aryl (e.g., C₆-C₁₀, C₁₀, or phenyl). In embodiments, R⁴is independently substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R⁴is independently unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄). In embodiments, R⁴is independently unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered). In embodiments, R⁴is independently unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆). In embodiments, R⁴is independently unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered). In embodiments, R⁴is independently unsubstituted aryl (e.g., C₆-C₁₀, C₁₀, or phenyl). In embodiments, R⁴is independently unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, two adjacent R⁴substituents are joined to form a substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆). In embodiments, two adjacent R⁴substituents are joined to form a substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered). In embodiments, two adjacent R⁴substituents are joined to form a substituted or unsubstituted aryl (e.g., C₆-C₁₀, C₁₀, or phenyl). In embodiments, two adjacent R⁴substituents are joined to form a substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, two adjacent R⁴substituents are joined to form an unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆). In embodiments, two adjacent R⁴substituents are joined to form an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered). In embodiments, two adjacent R⁴substituents are joined to form an unsubstituted aryl (e.g., C₆-C₁₀, C₁₀, or phenyl). In embodiments, two adjacent R⁴substituents are joined to form an unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, z4 is independently 0. In embodiments, z4 is independently 1. In embodiments, z4 is independently 2. In embodiments, z4 is independently 3. In embodiments, z4 is independently 4.

R^4.Ais independently hydrogen, oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —SF₅, —N₃, substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, 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 C₅-C₆), 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., C₆-C₁₀, C₁₀, or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); two adjacent R^4.Asubstituents may optionally be joined to form a substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆), 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., C₆-C₁₀, C₁₀, or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, R^4.Ais independently hydrogen. In embodiments, R^4.Ais independently oxo. In embodiments, R^4.Ais independently —CF₃. In embodiments, R^4.Ais independently halogen. In embodiments, R^4.Ais independently —CCl₃. In embodiments, R^4.Ais independently —CBr₃. In embodiments, R^4.Ais independently —CF₃. In embodiments, R^4.Ais independently —CI₃. In embodiments, R^4.Ais independently —CHCl₂. In embodiments, R^4.Ais independently —CHBr₂. In embodiments, R^4.Ais independently —CHF₂. In embodiments, R^4.Ais independently —CHI₂. In embodiments, R^4.Ais independently —CH₂Cl. In embodiments, R^4.Ais independently —CH₂Br. In embodiments, R^4.Ais independently —CH₂F. In embodiments, R^4.Ais independently —CH₂I. In embodiments, R^4.Ais independently —CN. In embodiments, R^4.Ais independently —OH. In embodiments, R^4.Ais independently —NH₂. In embodiments, R^4.Ais independently —COOH. In embodiments, R^4.Ais independently —COOCH₃. In embodiments, R^4.Ais independently —CONH₂. In embodiments, R^4Ais independently —NO₂. In embodiments, R^4.Ais independently —SH. In embodiments, R^4.Ais independently —SO₃H. In embodiments, R^4.Ais independently —SO₄H. In embodiments, R^4.Ais independently —SO₂NH₂. In embodiments, R^4.Ais independently —NHNH₂. In embodiments, R^4.Ais independently —ONH₂. In embodiments, R^4.Ais independently —NHC(O)NHNH₂. In embodiments, R^4.Ais independently —NHC(O)NH₂. In embodiments, R^4.Ais independently —NHSO₂H. In embodiments, R^4.Ais independently —NHC(O)H. In embodiments, R^4.Ais independently —NHC(O)OH. In embodiments, R^4Ais independently —NHOH. In embodiments, R^4.Ais independently —OCCl₃. In embodiments, R^4.Ais independently —OCF₃. In embodiments, R^4.Ais independently —OCBr₃. In embodiments, R^4.Ais independently —OCI₃. In embodiments, R^4.Ais independently —OCHCl₂. In embodiments, R^4.Ais independently —OCHBr₂. In embodiments, R^4.Ais independently —OCHI₂. In embodiments, R^4.Ais independently —OCHF₂. In embodiments, R^4.Ais independently —OCH₂Cl. In embodiments, R^4.Ais independently —OCH₂Br. In embodiments, R^4.Ais independently —OCH₂I. In embodiments, R^4.Ais independently —OCH₂F. In embodiments, R^4.Ais independently —SF₅. In embodiments, R^4.Ais independently —N₃. In embodiments, R^4.Ais independently —F. In embodiments, R^4.Ais independently —Cl. In embodiments, R^4.Ais independently —Br. In embodiments, R^4.Ais independently —I. In embodiments, R^4.Ais independently —CH₂OCH₃. In embodiments, R^4.Ais independently —SCH₃. In embodiments, R^4.Ais independently —OCH₃. In embodiments, R^4.Ais independently —CH₂CH₂OCH₃. In embodiments, R^4.Ais independently —SCH₂CH₃. In embodiments, R^4.Ais independently —OCH₂CH₃. In embodiments, R^4.Ais independently —CH₂OCH₂CH₃. In embodiments, R^4.Ais independently unsubstituted C₁-C₄alkyl. In embodiments, R^4.Ais independently unsubstituted cyclopropyl. In embodiments, R^4.Ais independently hydrogen. In embodiments, R^4.Ais independently —OCH₃. In embodiments, R^4.Ais independently —OCH₂CH₃. In embodiments, R^4Ais independently —OCH(CH₃)₂. In embodiments, R^4.Ais independently —OC(CH₃)₃. In embodiments, R^4Ais independently —CH₃. In embodiments, R^4.Ais independently —CH₂CH₃. In embodiments, R^4.Ais independently —CH(CH₃)₂. In embodiments, R^4.Ais independently —C(CH₃)₃. In embodiments, R^4.Ais independently unsubstituted cyclopropyl. In embodiments, R^4.Ais independently unsubstituted cyclobutyl. In embodiments, R^4.Ais independently unsubstituted cyclopentyl. In embodiments, R^4.Ais independently unsubstituted cyclohexyl. In embodiments, R^4.Ais independently substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄). In embodiments, R^4.Ais independently substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered). In embodiments, R^4.Ais independently substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆). In embodiments, R^4.Ais independently substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered). In embodiments, R^4.Ais independently substituted or unsubstituted aryl (e.g., C₆-C₁₀, C₁₀, or phenyl). In embodiments, R^4.Ais independently substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R^4.Ais independently unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄). In embodiments, R^4.Ais independently unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered). In embodiments, R^4.Ais independently unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆). In embodiments, R^4.Ais independently unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered). In embodiments, R^4.Ais independently unsubstituted aryl (e.g., C₆-C₁₀, C₁₀, or phenyl). In embodiments, R^4.Ais independently unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

R^4.Bis independently hydrogen, oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —SF₅, —N₃, substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, 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 C₅-C₆), 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., C₆-C₁₀, C₁₀, or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); two adjacent R^4.Bsubstituents may optionally be joined to form a substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆), 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., C₆-C₁₀, C₁₀, or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, R^4.Bis independently hydrogen. In embodiments, R^4.Bis independently oxo. In embodiments, R^4.Bis independently —CF₃. In embodiments, R^4.Bis independently halogen. In embodiments, R^4.Bis independently —CCl₃. In embodiments, R^4.Bis independently —CBr₃. In embodiments, R^4.Bis independently —CF₃. In embodiments, R^4.Bis independently —CI₃. In embodiments, R^4.Bis independently —CHCl₂. In embodiments, R^4.Bis independently —CHBr₂. In embodiments, R^4.Bis independently —CHF₂. In embodiments, R^4.Bis independently —CHI₂. In embodiments, R^4.Bis independently —CH₂Cl. In embodiments, R^4.Bis independently —CH₂Br. In embodiments, R^4.Bis independently —CH₂F. In embodiments, R^4.Bis independently —CH₂I. In embodiments, R^4.Bis independently —CN. In embodiments, R^4.Bis independently —OH. In embodiments, R^4.Bis independently —NH₂. In embodiments, R^4.Bis independently —COOH. In embodiments, R^4.Bis independently —COOCH₃. In embodiments, R^4.Bis independently —CONH₂. In embodiments, R^4.Bis independently —NO₂. In embodiments, R^4.Bis independently —SH. In embodiments, R^4.Bis independently —SO₃H. In embodiments, R^4.Bis independently —SO₄H. In embodiments, R^4.Bis independently —SO₂NH₂. In embodiments, R^4.Bis independently —NHNH₂. In embodiments, R^4.Bis independently —ONH₂. In embodiments, R^4.Bis independently —NHC(O)NHNH₂. In embodiments, R^4.Bis independently —NHC(O)NH₂. In embodiments, R^4.Bis independently —NHSO₂H. In embodiments, R^4.Bis independently —NHC(O)H. In embodiments, R^4.Bis independently —NHC(O)OH. In embodiments, R^4Bis independently —NHOH. In embodiments, R^4.Bis independently —OCCl₃. In embodiments, R^4.Bis independently —OCF₃. In embodiments, R^4.Bis independently —OCBr₃. In embodiments, R^4.Bis independently —OCI₃. In embodiments, R^4.Bis independently —OCHCl₂. In embodiments, R^4.Bis independently —OCHBr₂. In embodiments, R^4.Bis independently —OCHI₂. In embodiments, R^4.Bis independently —OCHF₂. In embodiments, R^4.Bis independently —OCH₂Cl. In embodiments, R^4.Bis independently —OCH₂Br. In embodiments, R^4.Bis independently —OCH₂I. In embodiments, R^4.Bis independently —OCH₂F. In embodiments, R^4.Bis independently —SF₅. In embodiments, R^4.Bis independently —N₃. In embodiments, R^4.Bis independently —F. In embodiments, R^4.Bis independently —Cl. In embodiments, R^4.Bis independently —Br. In embodiments, R^4.Bis independently —I. In embodiments, R^4.Bis independently —CH₂OCH₃. In embodiments, R^4.Bis independently —SCH₃. In embodiments, R^4.Bis independently —OCH₃. In embodiments, R^4.Bis independently —CH₂CH₂OCH₃. In embodiments, R^4.Bis independently —SCH₂CH₃. In embodiments, R^4.Bis independently —OCH₂CH₃. In embodiments, R^4.Bis independently —CH₂OCH₂CH₃. In embodiments, R^4.Bis independently unsubstituted C₁-C₄alkyl. In embodiments, R^4.Bis independently unsubstituted cyclopropyl. In embodiments, R^4.Bis independently hydrogen. In embodiments, R^4.Bis independently —OCH₃. In embodiments, R^4.Bis independently —OCH₂CH₃. In embodiments, R^4.Bis independently —OCH(CH₃)₂. In embodiments, R^4.Bis independently —OC(CH₃)₃. In embodiments, R^4.Bis independently —CH₃. In embodiments, R^4.Bis independently —CH₂CH₃. In embodiments, R^4.Bis independently —CH(CH₃)₂. In embodiments, R^4.Bis independently —C(CH₃)₃. In embodiments, R^4.Bis independently unsubstituted cyclopropyl. In embodiments, R^4.Bis independently unsubstituted cyclobutyl. In embodiments, R^4.Bis independently unsubstituted cyclopentyl. In embodiments, R^4.Bis independently unsubstituted cyclohexyl. In embodiments, R^4.Bis independently substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄). In embodiments, R^4.Bis independently substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered). In embodiments, R^4.Bis independently substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆). In embodiments, R^4.Bis independently substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered). In embodiments, R^4Bis independently substituted or unsubstituted aryl (e.g., C₆-C₁₀, C₁₀, or phenyl). In embodiments, R^4Bis independently substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R^4Bis independently unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄). In embodiments, R^4Bis independently unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered). In embodiments, R^4.Bis independently unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆). In embodiments, R^4.Bis independently unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered). In embodiments, R^4Bis independently unsubstituted aryl (e.g., C₆-C₁₀, C₁₀, or phenyl). In embodiments, R^4Bis independently unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

R^4.Cis independently hydrogen, oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —SF₅, —N₃, substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, 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 C₅-C₆), 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., C₆-C₁₀, C₁₀, or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); two adjacent R^4.Csubstituents may optionally be joined to form a substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆), 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., C₆-C₁₀, C₁₀, or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, R^4.Cis independently hydrogen. In embodiments, R^4.Cis independently oxo. In embodiments, R^4.Cis independently —CF₃. In embodiments, R^4.Cis independently halogen. In embodiments, R^4.Cis independently —CCl₃. In embodiments, R^4.Cis independently —CBr₃. In embodiments, R^4.Cis independently —CF₃. In embodiments, R^4.Cis independently —CI₃. In embodiments, R^4.Cis independently —CHCl₂. In embodiments, R^4.Cis independently —CHBr₂. In embodiments, R^4.Cis independently —CHF₂. In embodiments, R^4.Cis independently —CHI₂. In embodiments, R^4.Cis independently —CH₂Cl. In embodiments, R^4.Cis independently —CH₂Br. In embodiments, R^4.Cis independently —CH₂F. In embodiments, R^4.Cis independently —CH₂I. In embodiments, R^4.Cis independently —CN. In embodiments, R^4.Cis independently —OH. In embodiments, R^4.Cis independently —NH₂. In embodiments, R^4.Cis independently —COOH. In embodiments, R^4.Cis independently —COOCH₃. In embodiments, R^4.Cis independently —CONH₂. In embodiments, R^4.Cis independently —NO₂. In embodiments, R^4.Cis independently —SH. In embodiments, R^4.Cis independently —SO₃H. In embodiments, R^4.Cis independently —SO₄H. In embodiments, R^4.Cis independently —SO₂NH₂. In embodiments, R^4.Cis independently —NHNH₂. In embodiments, R^4.Cis independently —ONH₂. In embodiments, R^4.Cis independently —NHC(O)NHNH₂. In embodiments, R^4.Cis independently —NHC(O)NH₂. In embodiments, R^4.Cis independently —NHSO₂H. In embodiments, R^4.Cis independently —NHC(O)H. In embodiments, R^4.Cis independently —NHC(O)OH. In embodiments, R^4.Cis independently —NHOH. In embodiments, R^4.Cis independently —OCCl₃. In embodiments, R^4.Cis independently —OCF₃. In embodiments, R^4.Cis independently —OCBr₃. In embodiments, R^4.Cis independently —OCI₃. In embodiments, R^4.Cis independently —OCHCl₂. In embodiments, R^4.Cis independently —OCHBr₂. In embodiments, R^4.Cis independently —OCHI₂. In embodiments, R^4.Cis independently —OCHF₂. In embodiments, R^4.Cis independently —OCH₂Cl. In embodiments, R^4.Cis independently —OCH₂Br. In embodiments, R^4.Cis independently —OCH₂I. In embodiments, R^4.Cis independently —OCH₂F. In embodiments, R^4.Cis independently —SF₅. In embodiments, R^4.Cis independently —N₃. In embodiments, R^4.Cis independently —F. In embodiments, R^4.Cis independently —Cl. In embodiments, R^4.Cis independently —Br. In embodiments, R^4.Cis independently —I. In embodiments, R^4.Cis independently —CH₂OCH₃. In embodiments, R^4.Cis independently —SCH₃. In embodiments, R^4.Cis independently —OCH₃. In embodiments, R^4.Cis independently —CH₂CH₂OCH₃. In embodiments, R^4.Cis independently —SCH₂CH₃. In embodiments, R^4.Cis independently —OCH₂CH₃. In embodiments, R^4.Cis independently —CH₂OCH₂CH₃. In embodiments, R^4.Cis independently unsubstituted C₁-C₄alkyl. In embodiments, R^4.Cis independently unsubstituted cyclopropyl. In embodiments, R^4.Cis independently hydrogen. In embodiments, R^4.Cis independently —OCH₃. In embodiments, R^4.Cis independently —OCH₂CH₃. In embodiments, R^4.Cis independently —OCH(CH₃)₂. In embodiments, R^4.Cis independently —OC(CH₃)₃. In embodiments, R^4.Cis independently —CH₃. In embodiments, R^4.Cis independently —CH₂CH₃. In embodiments, R^4.Cis independently —CH(CH₃)₂. In embodiments, R^4.Cis independently —C(CH₃)₃. In embodiments, R^4.Cis independently unsubstituted cyclopropyl. In embodiments, R^4.Cis independently unsubstituted cyclobutyl. In embodiments, R^4.Cis independently unsubstituted cyclopentyl. In embodiments, R^4.Cis independently unsubstituted cyclohexyl. In embodiments, R^4.Cis independently substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄). In embodiments, R^4.Cis independently substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered). In embodiments, R^4.Cis independently substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆). In embodiments, R^4.Cis independently substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered). In embodiments, R^4.Cis independently substituted or unsubstituted aryl (e.g., C₆-C₁₀, C₁₀, or phenyl). In embodiments, R^4.Cis independently substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R^4.Cis independently unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄). In embodiments, R^4.Cis independently unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered). In embodiments, R^4.Cis independently unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆). In embodiments, R^4.Cis independently unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered). In embodiments, R^4.Cis independently unsubstituted aryl (e.g., C₆-C₁₀, C₁₀, or phenyl). In embodiments, R^4.Cis independently unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

R^4.Dis independently hydrogen, oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —SF₅, —N₃, substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, 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 C₅-C₆), 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., C₆-C₁₀, C₁₀, or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); two adjacent R^4.Dsubstituents may optionally be joined to form a substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆), 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., C₆-C₁₀, C₁₀, or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, R^4.Dis independently hydrogen. In embodiments, R^4.Dis independently oxo. In embodiments, R^4.Dis independently —CF₃. In embodiments, R^4.Dis independently halogen. In embodiments, R^4.Dis independently —CCl₃. In embodiments, R^4.Dis independently —CBr₃. In embodiments, R^4.Dis independently —CF₃. In embodiments, R^4.Dis independently —CI₃. In embodiments, R^4.Dis independently —CHCl₂. In embodiments, R^4.Dis independently —CHBr₂. In embodiments, R^4.Dis independently —CHF₂. In embodiments, R^4.Dis independently —CHI₂. In embodiments, R^4.Dis independently —CH₂Cl. In embodiments, R^4.Dis independently —CH₂Br. In embodiments, R^4.Dis independently —CH₂F. In embodiments, R^4.Dis independently —CH₂I. In embodiments, R^4.Dis independently —CN. In embodiments, R^4.Dis independently —OH. In embodiments, R^4.Dis independently —NH₂. In embodiments, R^4.Dis independently —COOH. In embodiments, R^4.Dis independently —COOCH₃. In embodiments, R^4.Dis independently —CONH₂. In embodiments, R^4Dis independently —NO₂. In embodiments, R^4.Dis independently —SH. In embodiments, R^4.Dis independently —SO₃H. In embodiments, R^4.Dis independently —SO₄H. In embodiments, R^4.Dis independently —SO₂NH₂. In embodiments, R^4.Dis independently —NHNH₂. In embodiments, R^4.Dis independently —ONH₂. In embodiments, R^4Dis independently —NHC(O)NHNH₂. In embodiments, R^4.Dis independently —NHC(O)NH₂. In embodiments, R^4.Dis independently —NHSO₂H. In embodiments, R^4.Dis independently —NHC(O)H. In embodiments, R^4.Dis independently —NHC(O)OH. In embodiments, R^4Dis independently —NHOH. In embodiments, R^4.Dis independently —OCCl₃. In embodiments, R^4.Dis independently —OCF₃. In embodiments, R^4.Dis independently —OCBr₃. In embodiments, R^4.Dis independently —OCI₃. In embodiments, R^4.Dis independently —OCHCl₂. In embodiments, R^4.Dis independently —OCHBr₂. In embodiments, R^4.Dis independently —OCHI₂. In embodiments, R^4.Dis independently —OCHF₂. In embodiments, R^4.Dis independently —OCH₂Cl. In embodiments, R^4.Dis independently —OCH₂Br. In embodiments, R^4.Dis independently —OCH₂I. In embodiments, R^4.Dis independently —OCH₂F. In embodiments, R^4.Dis independently —SF₅. In embodiments, R^4.Dis independently —N₃. In embodiments, R^4.Dis independently —F. In embodiments, R^4.Dis independently —Cl. In embodiments, R^4.Dis independently —Br. In embodiments, R^4.Dis independently —I. In embodiments, R^4.Dis independently —CH₂OCH₃. In embodiments, R^4.Dis independently —SCH₃. In embodiments, R^4.Dis independently —OCH₃. In embodiments, R^4.Dis independently —CH₂CH₂OCH₃. In embodiments, R^4.Dis independently —SCH₂CH₃. In embodiments, R^4.Dis independently —OCH₂CH₃. In embodiments, R^4.Dis independently —CH₂OCH₂CH₃. In embodiments, R^4.Dis independently unsubstituted C₁-C₄alkyl. In embodiments, R^4.Dis independently unsubstituted cyclopropyl. In embodiments, R^4.Dis independently hydrogen. In embodiments, R^4.Dis independently —OCH₃. In embodiments, R^4.Dis independently —OCH₂CH₃. In embodiments, R^4.Dis independently —OCH(CH₃)₂. In embodiments, R^4.Dis independently —OC(CH₃)₃. In embodiments, R^4.Dis independently —CH₃. In embodiments, R^4.Dis independently —CH₂CH₃. In embodiments, R^4.Dis independently —CH(CH₃)₂. In embodiments, R^4.Dis independently —C(CH₃)₃. In embodiments, R^4.Dis independently unsubstituted cyclopropyl. In embodiments, R^4Dis independently unsubstituted cyclobutyl. In embodiments, R^4.Dis independently unsubstituted cyclopentyl. In embodiments, R^4.Dis independently unsubstituted cyclohexyl. In embodiments, R^4.Dis independently substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄). In embodiments, R^4.Dis independently substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered). In embodiments, R^4.Dis independently substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆). In embodiments, R^4.Dis independently substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered). In embodiments, R^4Dis independently substituted or unsubstituted aryl (e.g., C₆-C₁₀, C₁₀, or phenyl). In embodiments, R^4Dis independently substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R^4Dis independently unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄). In embodiments, R^4Dis independently unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered). In embodiments, R^4.Dis independently unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆). In embodiments, R^4.Dis independently unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered). In embodiments, R^4.Dis independently unsubstituted aryl (e.g., C₆-C₁₀, C₁₀, or phenyl). In embodiments, R^4.Dis independently unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

R^4.Eis independently hydrogen, oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —SF₅, —N₃, substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, 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 C₅-C₆), 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., C₆-C₁₀, C₁₀, or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); two adjacent R^4.Esubstituents may optionally be joined to form a substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆), 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., C₆-C₁₀, C₁₀, or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, R^4.Eis independently hydrogen. In embodiments, R^4.Eis independently oxo. In embodiments, R^4.Eis independently —CF₃. In embodiments, R^4.Eis independently halogen. In embodiments, R^4.Eis independently —CCl₃. In embodiments, R^4.Eis independently —CBr₃. In embodiments, R^4Eis independently —CF₃. In embodiments, R^4Eis independently —CI₃. In embodiments, R^4.Eis independently —CHCl₂. In embodiments, R^4.Eis independently —CHBr₂. In embodiments, R^4.Eis independently —CHF₂. In embodiments, R^4Eis independently —CHI₂. In embodiments, R^4.Eis independently —CH₂Cl. In embodiments, R^4.Eis independently —CH₂Br. In embodiments, R^4.Eis independently —CH₂F. In embodiments, R^4.Eis independently —CH₂I. In embodiments, R^4.Eis independently —CN. In embodiments, R^4.Eis independently —OH. In embodiments, R^4.Eis independently —NH₂. In embodiments, R^4.Eis independently —COOH. In embodiments, R^4.Eis independently —COOCH₃. In embodiments, R^4.Eis independently —CONH₂. In embodiments, R^4.Eis independently —NO₂. In embodiments, R^4.Eis independently —SH. In embodiments, R^4.Eis independently —SO₃H. In embodiments, R^4.Eis independently —SO₄H. In embodiments, R^4.Eis independently —SO₂NH₂. In embodiments, R^4.Eis independently —NHNH₂. In embodiments, R^4.Eis independently —ONH₂. In embodiments, R^4.Eis independently —NHC(O)NHNH₂. In embodiments, R^4.Eis independently —NHC(O)NH₂. In embodiments, R^4Eis independently —NHSO₂H. In embodiments, R^4.Eis independently —NHC(O)H. In embodiments, R^4.Eis independently —NHC(O)OH. In embodiments, R^4.Eis independently —NHOH. In embodiments, R^4.Eis independently —OCCl₃. In embodiments, R^4Eis independently —OCF₃. In embodiments, R^4.Eis independently —OCBr₃. In embodiments, R^4.Eis independently —OCI₃. In embodiments, R^4.Eis independently —OCHCl₂. In embodiments, R^4.Eis independently —OCHBr₂. In embodiments, R^4.Eis independently —OCHI₂. In embodiments, R^4Eis independently —OCHF₂. In embodiments, R^4Eis independently —OCH₂Cl. In embodiments, R^4.Eis independently —OCH₂Br. In embodiments, R^4.Eis independently —OCH₂I. In embodiments, R^4.Eis independently —OCH₂F. In embodiments, R^4.Eis independently —SF₅. In embodiments, R^4.Eis independently —N₃. In embodiments, R^4.Eis independently —F. In embodiments, R^4.Eis independently —Cl. In embodiments, R^4.Eis independently —Br. In embodiments, R^4.Eis independently —I. In embodiments, R^4.Eis independently —CH₂OCH₃. In embodiments, R^4.Eis independently —SCH₃. In embodiments, R^4.Eis independently —OCH₃. In embodiments, R^4.Eis independently —CH₂CH₂OCH₃. In embodiments, R^4.Eis independently —SCH₂CH₃. In embodiments, R^4.Eis independently —OCH₂CH₃. In embodiments, R^4.Eis independently —CH₂OCH₂CH₃. In embodiments, R^4.Eis independently unsubstituted C₁-C₄alkyl. In embodiments, R^4.Eis independently unsubstituted cyclopropyl. In embodiments, R^4Eis independently hydrogen. In embodiments, R^4.Eis independently —OCH₃. In embodiments, R^4.Eis independently —OCH₂CH₃. In embodiments, R^4.Eis independently —OCH(CH₃)₂. In embodiments, R^4.Eis independently —OC(CH₃)₃. In embodiments, R^4.Eis independently —CH₃. In embodiments, R^4Eis independently —CH₂CH₃. In embodiments, R^4.Eis independently —CH(CH₃)₂. In embodiments, R^4.Eis independently —C(CH₃)₃. In embodiments, R^4.Eis independently unsubstituted cyclopropyl. In embodiments, R^4.Eis independently unsubstituted cyclobutyl. In embodiments, R^4.Eis independently unsubstituted cyclopentyl. In embodiments, R^4.Eis independently unsubstituted cyclohexyl. In embodiments, R^4.Eis independently substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄). In embodiments, R^4.Eis independently substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered). In embodiments, R^4Eis independently substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆). In embodiments, R^4.Eis independently substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered). In embodiments, R^4.Eis independently substituted or unsubstituted aryl (e.g., C₆-C₁₀, C₁₀, or phenyl). In embodiments, R^4.Eis independently substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R^4.Eis independently unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄). In embodiments, R^4.Eis independently unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered). In embodiments, R^4.Eis independently unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆). In embodiments, R^4.Eis independently unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered). In embodiments, R^4.Eis independently unsubstituted aryl (e.g., C₆-C₁₀, C₁₀, or phenyl). In embodiments, R^4Eis independently unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, R^4.Aand R^4.Bare independently halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —SF₅, —N₃, substituted or unsubstituted C₁-C₆alkyl, or substituted or unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R^4.Ais unsubstituted C₁-C₄alkoxy and R^4.Bis halogen. In embodiments, R^4.Ais unsubstituted methoxy and R^4.Bis —F.

In embodiments, R^4.ADis independently hydrogen. In embodiments, R^4.ADis independently oxo. In embodiments, R^4.ADis independently —CF₃. In embodiments, R^4.Ais independently halogen. In embodiments, R^4.ADis independently —CCl₃. In embodiments, R^4.ADis independently —CBr₃. In embodiments, R^4.ADis independently —CF₃. In embodiments, R^4.ADis independently —CI₃. In embodiments, R^4.ADis independently —CHCl₂. In embodiments, R^4.ADis independently —CHBr₂. In embodiments, R^4.ADis independently —CHF₂. In embodiments, R^4.ADis independently —CHI₂. In embodiments, R^4.ADis independently —CH₂Cl. In embodiments, R^4.ADis independently —CH₂Br. In embodiments, R^4.ADis independently —CH₂F. In embodiments, R^4.ADis independently —CH₂I. In embodiments, R^4.ADis independently —CN. In embodiments, R^4.ADis independently —OH. In embodiments, R^4.ADis independently —NH₂. In embodiments, R^4.ADis independently —COOH. In embodiments, R^4.ADis independently —COOCH₃. In embodiments, R^4.ADis independently —CONH₂. In embodiments, R^4.ADis independently —NO₂. In embodiments, R^4.ADis independently —SH. In embodiments, R^4.ADis independently —SO₃H. In embodiments, R^4.ADis independently —SO₄H. In embodiments, R^4.ADis independently —SO₂NH₂. In embodiments, R^4.Ais independently —NHNH₂, —ONH₂. In embodiments, R^4.ADis independently —NHNH₂. In embodiments, R^4.ADis independently —ONH₂. In embodiments, R^4.ADis independently —NHC(O)NHNH₂. In embodiments, R^4.ADis independently —NHC(O)NH₂. In embodiments, R^4.ADis independently —NHSO₂H. In embodiments, R^4.ADis independently —NHC(O)H. In embodiments, R^4.ADis independently —NHC(O)OH. In embodiments, R^4.ADis independently —NHOH. In embodiments, R^4.ADis independently —OCCl₃. In embodiments, R^4.ADis independently —OCF₃. In embodiments, R^4.ADis independently —OCBr₃. In embodiments, R^4.ADis independently —OCI₃. In embodiments, R^4.ADis independently —OCHCl₂. In embodiments, R^4.ADis independently —OCHBr₂. In embodiments, R^4.ADis independently —OCHI₂. In embodiments, R^4.ADis independently —OCHF₂. In embodiments, R^4.ADis independently —OCH₂Cl. In embodiments, R^4.ADis independently —OCH₂Br. In embodiments, R^4.ADis independently —OCH₂I. In embodiments, R^4.ADis independently —OCH₂F. In embodiments, R^4.ADis independently —SF₅. In embodiments, R^4.ADis independently —N₃. In embodiments, R^4.ADis independently —F. In embodiments, R^4.ADis independently —Cl. In embodiments, R^4.ADis independently —Br. In embodiments, R^4.ADis independently —I. In embodiments, R^4.ADis independently —CH₂OCH₃. In embodiments, R^4.ADis independently —SCH₃. In embodiments, R^4.ADis independently —OCH₃. In embodiments, R^4.ADis independently —CH₂CH₂OCH₃. In embodiments, R^4.ADis independently —SCH₂CH₃. In embodiments, R^4.ADis independently —OCH₂CH₃. In embodiments, R^4.ADis independently —CH₂OCH₂CH₃. In embodiments, R^4.Ais independently unsubstituted C₁-C₄alkyl. In embodiments, R^4.Ais independently unsubstituted cyclopropyl. In embodiments, R^4.Ais independently hydrogen. In embodiments, R^4.ADis independently —OCH₃. In embodiments, R^4.ADis independently —OCH₂CH₃. In embodiments, R^4.ADis independently —OCH(CH₃)₂. In embodiments, R^4.ADis independently —OC(CH₃)₃. In embodiments, R^4.ADis independently —CH₃. In embodiments, R^4.Ais independently —CH₂CH₃. In embodiments, R^4.Ais independently —CH(CH₃)₂. In embodiments, R^4.ADis independently —C(CH₃)₃. In embodiments, R^4.ADis independently unsubstituted cyclopropyl. In embodiments, R^4.Ais independently unsubstituted cyclobutyl. In embodiments, R^4.Ais independently unsubstituted cyclopentyl. In embodiments, R^4.Ais independently unsubstituted cyclohexyl. In embodiments, R^4.Ais independently substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄). In embodiments, R^4.Ais independently substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered). In embodiments, R^4.Ais independently substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆). In embodiments, R^4.Ais independently substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered). In embodiments, R^4.Ais independently substituted or unsubstituted aryl (e.g., C₆-C₁₀, C₁₀, or phenyl). In embodiments, R^4.ADis independently substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R^4.Ais independently unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄). In embodiments, R^4.Ais independently unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered). In embodiments, R^4.Ais independently unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆). In embodiments, R^4.ADis independently unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered). In embodiments, R^4.Ais independently unsubstituted aryl (e.g., C₆-C₁₀, C₁₀, or phenyl). In embodiments, R^4.Ais independently unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, R^4.BDis independently hydrogen. In embodiments, R^4.BDis independently oxo. In embodiments, R^4.BDis independently —CF₃. In embodiments, R^4.BDis independently halogen. In embodiments, R^4.BDis independently —CCl₃. In embodiments, R^4.BDis independently —CBr₃. In embodiments, R^4.BDis independently —CF₃. In embodiments, R^4.BDis independently —CI₃. In embodiments, R^4.BDis independently —CHCl₂. In embodiments, R^4.BDis independently —CHBr₂. In embodiments, R^4.BDis independently —CHF₂. In embodiments, R^4.BDis independently —CHI₂. In embodiments, R^4.BDis independently —CH₂Cl. In embodiments, R^4.BDis independently —CH₂Br. In embodiments, R^4.BDis independently —CH₂F. In embodiments, R^4.BDis independently —CH₂I. In embodiments, R^4.BDis independently —CN. In embodiments, R^4.BDis independently —OH. In embodiments, R^4.BDis independently —NH₂. In embodiments, R^4.BDis independently —COOH. In embodiments, R^4.BDis independently —COOCH₃. In embodiments, R^4.BDis independently —CONH₂. In embodiments, R^4.BDis independently —NO₂. In embodiments, R^4.BDis independently —SH. In embodiments, R^4.BDis independently —SO₃H. In embodiments, R^4.BDis independently —SO₄H. In embodiments, R^4.BDis independently —SO₂NH₂. In embodiments, R^4.BDis independently —NHNH₂, —ONH₂. In embodiments, R^4.BDis independently —NHNH₂. In embodiments, R^4.BDis independently —ONH₂. In embodiments, R^4.BDis independently —NHC(O)NHNH₂. In embodiments, R^4.BDis independently —NHC(O)NH₂. In embodiments, R^4.BDis independently —NHSO₂H. In embodiments, R^4.BDis independently —NHC(O)H. In embodiments, R^4.BDis independently —NHC(O)OH. In embodiments, R^4.BDis independently —NHOH. In embodiments, R^4.BDis independently —OCCl₃. In embodiments, R^4.BDis independently —OCF₃. In embodiments, R^4.BDis independently —OCBr₃. In embodiments, R^4.BDis independently —OCI₃. In embodiments, R^4.BDis independently —OCHCl₂. In embodiments, R^4.BDis independently —OCHBr₂. In embodiments, R^4.BDis independently —OCHI₂. In embodiments, R^4.BDis independently —OCHF₂. In embodiments, R^4.BDis independently —OCH₂Cl. In embodiments, R^4.BDis independently —OCH₂Br. In embodiments, R^4.BDis independently —OCH₂I. In embodiments, R^4.BDis independently —OCH₂F. In embodiments, R^4.BDis independently —SF₅. In embodiments, R^4.BDis independently —N₃. In embodiments, R^4.BDis independently —F. In embodiments, R^4.BDis independently —Cl. In embodiments, R^4.BDis independently —Br. In embodiments, R^4.BDis independently —I. In embodiments, R^4.BDis independently —CH₂OCH₃. In embodiments, R^4.BDis independently —SCH₃. In embodiments, R^4.BDis independently —OCH₃. In embodiments, R^4.BDis independently —CH₂CH₂OCH₃. In embodiments, R^4.BDis independently —SCH₂CH₃. In embodiments, R^4.BDis independently —OCH₂CH₃. In embodiments, R^4.BDis independently —CH₂OCH₂CH₃. In embodiments, R^4.BDis independently unsubstituted C₁-C₄alkyl. In embodiments, R^4.BDis independently unsubstituted cyclopropyl. In embodiments, R^4.BDis independently hydrogen. In embodiments, R^4.BDis independently —OCH₃. In embodiments, R^4.BDis independently —OCH₂CH₃. In embodiments, R^4.BDis independently —OCH(CH₃)₂. In embodiments, R^4.BDis independently —OC(CH₃)₃. In embodiments, R^4.BDis independently —CH₃. In embodiments, R^4.BDis independently —CH₂CH₃. In embodiments, R^4.BDis independently —CH(CH₃)₂. In embodiments, R^4.BDis independently —C(CH₃)₃. In embodiments, R^4.BDis independently unsubstituted cyclopropyl. In embodiments, R^4.BDis independently unsubstituted cyclobutyl. In embodiments, R^4.BDis independently unsubstituted cyclopentyl. In embodiments, R^4.BDis independently unsubstituted cyclohexyl. In embodiments, R^4.BDis independently substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄). In embodiments, R^4.BDis independently substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered). In embodiments, R^4.BDis independently substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆). In embodiments, R^4.BDis independently substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered). In embodiments, R^4.BDis independently substituted or unsubstituted aryl (e.g., C₆-C₁₀, C₁₀, or phenyl). In embodiments, R^4.BDis independently substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R^4.BDis independently unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄). In embodiments, R^4.BDis independently unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered). In embodiments, R^4.BDis independently unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆). In embodiments, R^4.BDis independently unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered). In embodiments, R^4.BDis independently unsubstituted aryl (e.g., C₆-C₁₀, C₁₀, or phenyl). In embodiments, R^4.BDis independently unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, R^4.CDis independently hydrogen. In embodiments, R^4.CDis independently oxo. In embodiments, R^4.CDis independently —CF₃. In embodiments, R^4.CDis independently halogen. In embodiments, R^4.CDis independently —CCl₃. In embodiments, R^4.CDis independently —CBr₃. In embodiments, R^4.CDis independently —CF₃. In embodiments, R^4.CDis independently —CI₃. In embodiments, R^4.CDis independently —CHCl₂. In embodiments, R^4.CDis independently —CHBr₂. In embodiments, R^4.CDis independently —CHF₂. In embodiments, R^4.CDis independently —CHI₂. In embodiments, R^4.CDis independently —CH₂Cl. In embodiments, R^4.CDis independently —CH₂Br. In embodiments, R^4.CDis independently —CH₂F. In embodiments, R^4.CDis independently —CH₂I. In embodiments, R^4.CDis independently —CN. In embodiments, R^4.CDis independently —OH. In embodiments, R^4.CDis independently —NH₂. In embodiments, R^4.CDis independently —COOH. In embodiments, R^4.CDis independently —COOCH₃. In embodiments, R^4.CDis independently —CONH₂. In embodiments, R^4.CDis independently —NO₂. In embodiments, R^4.CDis independently —SH. In embodiments, R^4.CDis independently —SO₃H. In embodiments, R^4.CDis independently —SO₄H. In embodiments, R^4.CDis independently —SO₂NH₂. In embodiments, R^4.CDis independently —NHNH₂, —ONH₂. In embodiments, R^4.CDis independently —NHNH₂. In embodiments, R^4.CDis independently —ONH₂. In embodiments, R^4.CDis independently —NHC(O)NHNH₂. In embodiments, R^4.CDis independently —NHC(O)NH₂. In embodiments, R^4.CDis independently —NHSO₂H. In embodiments, R^4.CDis independently —NHC(O)H. In embodiments, R^4.CDis independently —NHC(O)OH. In embodiments, R^4.CDis independently —NHOH. In embodiments, R^4.CDis independently —OCCl₃. In embodiments, R^4.CDis independently —OCF₃. In embodiments, R^4.CDis independently —OCBr₃. In embodiments, R^4.CDis independently —OCI₃. In embodiments, R^4.CDis independently —OCHCl₂. In embodiments, R^4.CDis independently —OCHBr₂. In embodiments, R^4.CDis independently —OCHI₂. In embodiments, R^4.CDis independently —OCHF₂. In embodiments, R^4.CDis independently —OCH₂Cl. In embodiments, R^4.CDis independently —OCH₂Br. In embodiments, R^4.CDis independently —OCH₂I. In embodiments, R^4.CDis independently —OCH₂F. In embodiments, R^4.CDis independently —SF₅. In embodiments, R^4.CDis independently —N₃. In embodiments, R^4.CDis independently —F. In embodiments, R^4.CDis independently —Cl. In embodiments, R^4.CDis independently —Br. In embodiments, R^4.CDis independently —I. In embodiments, R^4.CDis independently —CH₂OCH₃. In embodiments, R^4.CDis independently —SCH₃. In embodiments, R^4.CDis independently —OCH₃. In embodiments, R^4.CDis independently —CH₂CH₂OCH₃. In embodiments, R^4.CDis independently —SCH₂CH₃. In embodiments, R^4.CDis independently —OCH₂CH₃. In embodiments, R^4.CDis independently —CH₂OCH₂CH₃. In embodiments, R^4.CDis independently unsubstituted C₁-C₄alkyl. In embodiments, R^4.CDis independently unsubstituted cyclopropyl. In embodiments, R^4.CDis independently hydrogen. In embodiments, R^4.CDis independently —OCH₃. In embodiments, R^4.CDis independently —OCH₂CH₃. In embodiments, R^4.CDis independently —OCH(CH₃)₂. In embodiments, R^4.CDis independently —OC(CH₃)₃. In embodiments, R^4.CDis independently —CH₃. In embodiments, R^4.CDis independently —CH₂CH₃. In embodiments, R^4.CDis independently —CH(CH₃)₂. In embodiments, R^4.CDis independently —C(CH₃)₃. In embodiments, R^4.CDis independently unsubstituted cyclopropyl. In embodiments, R^4.CDis independently unsubstituted cyclobutyl. In embodiments, R^4.CDis independently unsubstituted cyclopentyl. In embodiments, R^4.CDis independently unsubstituted cyclohexyl. In embodiments, R^4.CDis independently substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄). In embodiments, R^4.CDis independently substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered). In embodiments, R^4.CDis independently substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆). In embodiments, R^4.CDis independently substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered). In embodiments, R^4.CDis independently substituted or unsubstituted aryl (e.g., C₆-C₁₀, C₁₀, or phenyl). In embodiments, R^4.CDis independently substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R^4.CDis independently unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄). In embodiments, R^4.CDis independently unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered). In embodiments, R^4.CDis independently unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆). In embodiments, R^4.CDis independently unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered). In embodiments, R^4.CDis independently unsubstituted aryl (e.g., C₆-C₁₀, C₁₀, or phenyl). In embodiments, R^4.CDis independently unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, R^4.DDis independently hydrogen. In embodiments, R^4.DDis independently oxo. In embodiments, R^4.DDis independently —CF₃. In embodiments, R^4.DDis independently halogen. In embodiments, R^4.DDis independently —CCl₃. In embodiments, R^4.DDis independently —CBr₃. In embodiments, R^4.DDis independently —CF₃. In embodiments, R^4.DDis independently —CI₃. In embodiments, R^4.DDis independently —CHCl₂. In embodiments, R^4.DDis independently —CHBr₂. In embodiments, R^4.DDis independently —CHF₂. In embodiments, R^4.DDis independently —CHI₂. In embodiments, R^4.DDis independently —CH₂Cl. In embodiments, R^4.DDis independently —CH₂Br. In embodiments, R^4.DDis independently —CH₂F. In embodiments, R^4.DDis independently —CH₂I. In embodiments, R^4.DDis independently —CN. In embodiments, R^4.DDis independently —OH. In embodiments, R^4.DDis independently —NH₂. In embodiments, R^4.DDis independently —COOH. In embodiments, R^4.DDis independently —COOCH₃. In embodiments, R^4.DDis independently —CONH₂. In embodiments, R^4.DDis independently —NO₂. In embodiments, R^4.DDis independently —SH. In embodiments, R^4.DDis independently —SO₃H. In embodiments, R^4.DDis independently —SO₄H. In embodiments, R^4.DDis independently —SO₂NH₂. In embodiments, R^4.DDis independently —NHNH₂, —ONH₂. In embodiments, R^4.DDis independently —NHNH₂. In embodiments, R^4.DDis independently —ONH₂. In embodiments, R^4.DDis independently —NHC(O)NHNH₂. In embodiments, R^4.DDis independently —NHC(O)NH₂. In embodiments, R^4.DDis independently —NHSO₂H. In embodiments, R^4.DDis independently —NHC(O)H. In embodiments, R^4.DDis independently —NHC(O)OH. In embodiments, R^4.DDis independently —NHOH. In embodiments, R^4.DDis independently —OCCl₃. In embodiments, R^4.DDis independently —OCF₃. In embodiments, R^4.DDis independently —OCBr₃. In embodiments, R^4.DDis independently —OCI₃. In embodiments, R^4.DDis independently —OCHCl₂. In embodiments, R^4.DDis independently —OCHBr₂. In embodiments, R^4.DDis independently —OCHI₂. In embodiments, R^4.DDis independently —OCHF₂. In embodiments, R^4.DDis independently —OCH₂Cl. In embodiments, R^4.DDis independently —OCH₂Br. In embodiments, R^4.DDis independently —OCH₂I. In embodiments, R^4.DDis independently —OCH₂F. In embodiments, R^4.DDis independently —SF₅. In embodiments, R^4.DDis independently —N₃. In embodiments, R^4.DDis independently —F. In embodiments, R^4.DDis independently —Cl. In embodiments, R^4.DDis independently —Br. In embodiments, R^4.DDis independently —I. In embodiments, R^4.DDis independently —CH₂OCH₃. In embodiments, R^4.DDis independently —SCH₃. In embodiments, R^4.DDis independently —OCH₃. In embodiments, R^4.DDis independently —CH₂CH₂OCH₃. In embodiments, R^4.DDis independently —SCH₂CH₃. In embodiments, R^4.DDis independently —OCH₂CH₃. In embodiments, R^4.DDis independently —CH₂OCH₂CH₃. In embodiments, R^4.DDis independently unsubstituted C₁-C₄alkyl. In embodiments, R^4.DDis independently unsubstituted cyclopropyl. In embodiments, R^4.DDis independently hydrogen. In embodiments, R^4.DDis independently —OCH₃. In embodiments, R^4.DDis independently —OCH₂CH₃. In embodiments, R^4.DDis independently —OCH(CH₃)₂. In embodiments, R^4.DDis independently —OC(CH₃)₃. In embodiments, R^4.DDis independently —CH₃. In embodiments, R^4.DDis independently —CH₂CH₃. In embodiments, R^4.DDis independently —CH(CH₃)₂. In embodiments, R^4.DDis independently —C(CH₃)₃. In embodiments, R^4.DDis independently unsubstituted cyclopropyl. In embodiments, R^4.DDis independently unsubstituted cyclobutyl. In embodiments, R^4.DDis independently unsubstituted cyclopentyl. In embodiments, R^4.DDis independently unsubstituted cyclohexyl. In embodiments, R^4.DDis independently substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄). In embodiments, R^4.DDis independently substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered). In embodiments, R^4.DDis independently substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆). In embodiments, R^4.DDis independently substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered). In embodiments, R^4.DDis independently substituted or unsubstituted aryl (e.g., C₆-C₁₀, C₁₀, or phenyl). In embodiments, R^4.DDis independently substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R^4.DDis independently unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄). In embodiments, R^4.DDis independently unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered). In embodiments, R^4.DDis independently unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆). In embodiments, R^4.DDis independently unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered). In embodiments, R^4.DDis independently unsubstituted aryl (e.g., C₆-C₁₀, C₁₀, or phenyl). In embodiments, R^4.DDis independently unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, R⁵is independently oxo. In embodiments, R⁵is independently —CF₃. In embodiments, R⁵is independently halogen. In embodiments, R⁵is independently —CCl₃. In embodiments, R⁵is independently —CBr₃. In embodiments, R⁵is independently —CF₃. In embodiments, R⁵is independently —CI₃. In embodiments, R⁵is independently —CHCl₂. In embodiments, R⁵is independently —CHBr₂. In embodiments, R⁵is independently —CHF₂. In embodiments, R⁵is independently —CHI₂. In embodiments, R⁵is independently —CH₂Cl. In embodiments, R⁵is independently —CH₂Br. In embodiments, R⁵is independently —CH₂F. In embodiments, R⁵is independently —CH₂I. In embodiments, R⁵is independently —CN. In embodiments, R⁵is independently —OH. In embodiments, R⁵is independently —NH₂. In embodiments, R⁵is independently —COOH. In embodiments, R⁵is independently —CONH₂. In embodiments, R⁵is independently —NO₂. In embodiments, R⁵is independently —SH. In embodiments, R⁵is independently —SO₃H. In embodiments, R⁵is independently —SO₄H. In embodiments, R⁵is independently —SO₂NH₂. In embodiments, R⁵is independently —NHNH₂, —ONH₂. In embodiments, R⁵is independently —NHNH₂. In embodiments, R⁵is independently —ONH₂. In embodiments, R⁵is independently —NHC(O)NHNH₂. In embodiments, R⁵is independently —NHC(O)NH₂. In embodiments, R⁵is independently —NHSO₂H. In embodiments, R⁵is independently —NHC(O)H. In embodiments, R⁵is independently —NHC(O)OH. In embodiments, R⁵is independently —NHOH. In embodiments, R⁵is independently —OCCl₃. In embodiments, R⁵is independently —OCF₃. In embodiments, R⁵is independently —OCBr₃. In embodiments, R⁵is independently —OCI₃. In embodiments, R⁵is independently —OCHCl₂. In embodiments, R⁵is independently —OCHBr₂. In embodiments, R⁵is independently —OCHI₂. In embodiments, R⁵is independently —OCHF₂. In embodiments, R⁵is independently —OCH₂Cl. In embodiments, R⁵is independently —OCH₂Br. In embodiments, R⁵is independently —OCH₂I. In embodiments, R⁵is independently —OCH₂F. In embodiments, R⁵is independently —SF₅. In embodiments, R⁵is independently —N₃. In embodiments, R⁵is independently —F. In embodiments, R⁵is independently —Cl. In embodiments, R⁵is independently —Br. In embodiments, R⁵is independently —I. In embodiments, R⁵is independently —CH₂OCH₃. In embodiments, R⁵is independently —SCH₃. In embodiments, R⁵is independently —OCH₃. In embodiments, R⁵is independently —CH₂CH₂OCH₃. In embodiments, R⁵is independently —SCH₂CH₃. In embodiments, R⁵is independently —OCH₂CH₃. In embodiments, R⁵is independently —CH₂OCH₂CH₃. In embodiments, R⁵is independently unsubstituted C₁-C₄alkyl. In embodiments, R⁵is independently unsubstituted cyclopropyl. In embodiments, R⁵is independently hydrogen. In embodiments, R⁵is independently —OCH₃. In embodiments, R⁵is independently —OCH₂CH₃. In embodiments, R⁵is independently —OCH(CH₃)₂. In embodiments, R⁵is independently —OC(CH₃)₃. In embodiments, R⁵is independently —CH₃. In embodiments, R⁵is independently —CH₂CH₃. In embodiments, R⁵is independently —CH(CH₃)₂. In embodiments, R⁵is independently —C(CH₃)₃. In embodiments, R⁵is independently unsubstituted cyclopropyl. In embodiments, R⁵is independently unsubstituted cyclobutyl. In embodiments, R⁵is independently unsubstituted cyclopentyl. In embodiments, R⁵is independently unsubstituted cyclohexyl. In embodiments, R⁵is independently substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄). In embodiments, R⁵is independently substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered). In embodiments, R⁵is independently substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆). In embodiments, R⁵is independently substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered). In embodiments, R⁵is independently substituted or unsubstituted aryl (e.g., C₆-C₁₀, C₁₀, or phenyl). In embodiments, R⁵is independently substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R⁵is independently unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, or C₁-C₄). In embodiments, R⁵is independently unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered). In embodiments, R⁵is independently unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆). In embodiments, R⁵is independently unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered). In embodiments, R⁵is independently unsubstituted aryl (e.g., C₆-C₁₀, C₁₀, or phenyl). In embodiments, R⁵is independently unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, two adjacent R⁵substituents are joined to form a substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆). In embodiments, two adjacent R⁵substituents are joined to form a substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered). In embodiments, two adjacent R⁵substituents are joined to form a substituted or unsubstituted aryl (e.g., C₆-C₁₀, C₁₀, or phenyl). In embodiments, two adjacent R⁵substituents are joined to form a substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, two adjacent R⁵substituents are joined to form an unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, or C₅-C₆). In embodiments, two adjacent R⁵substituents are joined to form an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered). In embodiments, two adjacent R⁵substituents are joined to form an unsubstituted aryl (e.g., C₆-C₁₀, C₁₀, or phenyl). In embodiments, two adjacent R⁵substituents are joined to form an unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, z5 is independently 0. In embodiments, z5 is independently 1. In embodiments, z5 is independently 2. In embodiments, z5 is independently 3. In embodiments, z5 is independently 4.

In embodiments, L¹is substituted or unsubstituted heteroalkylene and R¹is independently substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

In embodiments, L¹is —(C₁-C₆alkyl)-C(O)N(R^L1)— or —(C₁-C₆alkyl)-SO₂N(R^L1)—; R¹is independently substituted phenyl or substituted 5 to 6 membered heteroaryl; and R^L1is independently hydrogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, unsubstituted alkyl, or unsubstituted cycloalkyl.

In embodiments, L¹is —(C₁-C₆alkyl)-C(O)N(R^L1)— or —(C₁-C₆alkyl)-SO₂N(R^L1)—; R¹is independently substituted phenyl or substituted 5 to 6 membered heteroaryl; and R¹is independently hydrogen, unsubstituted C₁-C₆alkyl, or unsubstituted C₃-C₆cycloalkyl.

In embodiments, L¹is —CH₂C(O)N(R^L1)— or —CH₂SO₂N(R^L1)—; R¹is independently substituted phenyl or substituted 5 to 6 membered heteroaryl; and R^L1is independently hydrogen, unsubstituted methyl, unsubstituted ethyl, unsubstituted isopropyl, or unsubstituted cyclopropyl.

In embodiments, L¹is —CH₂C(O)N(R^L1)—; R¹is independently substituted phenyl or substituted 5 to 6 membered heteroaryl; and R^L1is independently hydrogen.

In embodiments, R¹is independently R¹⁰-substituted phenyl or R¹⁰-substituted 5 to 6 membered heteroaryl; R¹⁰is independently halogen, —CX¹⁰₃, —CHX¹⁰₂, —CH₂X¹⁰, —OCX¹⁰₃, —OCH₂X¹⁰, —OCHX¹⁰₂, —CN, —SO₂R^10D, —SR^10D, —C(O)R^10C, —OR^10D, substituted or unsubstituted C₁-C₆alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C₃-C₆cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl; R^10A, R^10B, R^10C, and R^10Dare independently hydrogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, unsubstituted C₁-C₆alkyl, or unsubstituted C₃-C₆cycloalkyl; and X¹⁰is independently —F, —Cl, —Br, or —I.

In embodiments, R¹is independently R¹⁰-substituted phenyl or R¹⁰-substituted 5 to 6 membered heteroaryl; R¹⁰is independently halogen, —CX¹⁰₃, —CHX¹⁰₂, —CH₂X¹⁰, —OCX¹⁰₃, —OCH₂X¹⁰, —OCHX¹⁰₂, —CN, —SO₂R^10D, —SR^10D, —OR^10D, unsubstituted C₁-C₄alkyl, unsubstituted 2 to 6 membered heteroalkyl, unsubstituted C₃-C₄cycloalkyl, or unsubstituted phenyl; R^10A, R^10B, R^10C, and R^10Dare independently hydrogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, or unsubstituted methyl; and X¹⁰is independently —F, —Cl, —Br, or —I.

In embodiments, R¹is independently R¹⁰-substituted phenyl or R¹⁰-substituted 5 to 6 membered heteroaryl; and R¹⁰is independently halogen, —CF₃, —CIF₂, —CH₂F, —OCF₃, —OCH₂F, —OCHF₂, —OCH₃, —CH₂OCH₃, —CN, —SO₂CH₃, —SCH₃, —OCH₃, unsubstituted C₁-C₄alkyl, unsubstituted cyclopropyl, or unsubstituted phenyl.

In embodiments, R¹is independently

embedded image

and R^10.A, R^10.B, and R^10.Care independently halogen, —CF₃, —CIF₂, —CH₂F, —OCF₃, —OCH₂F, —OCHF₂, —OCH₃, —CH₂OCH₃, —CN, —SO₂CH₃, —SCH₃, —OCH₃, unsubstituted C₁-C₄alkyl, unsubstituted cyclopropyl, or unsubstituted phenyl.

In embodiments, L¹is a substituted or unsubstituted alkylene; R¹is independently —SO₂NR^1AR^1B, —NR^1AR^1B, or —C(O)NR^1AR^1B; and R^1Aand R^1Bare independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R^1Aand R^1Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl.

In embodiments, L¹is an unsubstituted C₁-C₆alkylene; R¹is independently —SO₂NR^1AR^1Bor —C(O)NR^1AR^1B; R^1Aand R^1Bare independently hydrogen, substituted or unsubstituted C₁-C₆alkyl, substituted or unsubstituted C₃-C₆cycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl; R^1Aand R^1Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted C₃-C₆heterocycloalkyl.

In embodiments, L¹is an unsubstituted methylene; R¹is independently —C(O)NR^1AR^1B; R^1Ais independently hydrogen, unsubstituted C₁-C₄alkyl, or unsubstituted cyclopropyl; R^1Bis independently R¹⁰-substituted phenyl or R¹⁰-substituted 5 to 6 membered heteroaryl; R¹⁰is independently halogen, —CX¹⁰₃, —CHX¹⁰₂, —CH₂X¹⁰, —OCX¹⁰₃, —OCH₂X¹⁰, —OCHX¹⁰₂, —CN, —SO₂R^10D, —SR^10D, —OR^10D, unsubstituted C₁-C₄alkyl, unsubstituted 2 to 6 membered heteroalkyl, unsubstituted C₃-C₄cycloalkyl, or unsubstituted phenyl; R^10A, R^10B, R^10C, and R^10Dare independently hydrogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, or unsubstituted methyl; and X¹⁰is independently —F, —Cl, —Br, or —I.

In embodiments, L¹is an unsubstituted methylene; R¹is independently —C(O)NR^1AR^1B; R^1Ais independently hydrogen, unsubstituted C₁-C₄alkyl, or unsubstituted cyclopropyl; R^1Bis independently

embedded image

R^10.A, R^10.B, and R^10.Care independently halogen, —CF₃, —CIF₂, —CH₂F, —OCF₃, —OCH₂F, —OCHF₂, —OCH₃, —CH₂OCH₃, —CN, —SO₂CH₃, —SCH₃, —OCH₃, unsubstituted C₁-C₄alkyl, unsubstituted cyclopropyl, or unsubstituted phenyl.

In embodiments, L¹is an unsubstituted C₁-C₆alkylene; R¹is independently —SO₂NR^1AR^1Bor —C(O)NR^1AR^1B; and R^1Aand R^1Bbonded to the same nitrogen atom are joined to form a substituted or unsubstituted C₃-C₆heterocycloalkyl.

In embodiments, L¹is an unsubstituted methylene; R¹is independently —C(O)NR^1AR^1B; and R^1Aand R^1Bbonded to the same nitrogen atom are joined to form a substituted or unsubstituted piperazinyl.

In embodiments, L¹is an unsubstituted methylene; R¹is independently —C(O)NR^1AR^1B; R^1Aand R^1Bbonded to the same nitrogen atom are joined to form

embedded image

and R^10.Cis unsubstituted C₁-C₄alkyl.

In embodiments, L¹is an unsubstituted methylene; R¹is independently —C(O)NR^1AR^1B; and R^1Aand R^1Bbonded to the same nitrogen atom are joined to form

embedded image

In embodiments, L¹is a substituted alkylene; R¹is independently —NR^1AR^1B; and R^1Aand R^1Bare independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R^1Aand R^1Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl.

In embodiments, L¹is a substituted C₁-C₆alkylene; R¹is independently —NR^1AR^1B; and R^1Aand R^1Bare independently hydrogen, substituted or unsubstituted C₁-C₆alkyl, substituted or unsubstituted C₃-C₆cycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl; R^1Aand R^1Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted C₃-C₆heterocycloalkyl.

In embodiments, L¹is —CH₂C(O)—; R¹is independently —NR^1AR^1B; R^1Ais independently hydrogen, unsubstituted C₁-C₄alkyl, or unsubstituted cyclopropyl; and R^1Bare independently substituted or unsubstituted phenyl or substituted or unsubstituted 5 to 6 membered heteroaryl.

In embodiments, L¹is —CH₂C(O)—; R¹is independently —NR^1AR^1B; R^1Ais independently hydrogen, unsubstituted C₁-C₄alkyl, or unsubstituted cyclopropyl; R^1Bis independently R¹⁰-substituted phenyl or R¹⁰-substituted 5 to 6 membered heteroaryl; R¹⁰is independently halogen, —CX¹⁰₃, —CHX¹⁰₂, —CH₂X¹⁰, —OCX¹⁰₃, —OCH₂X¹⁰, —OCHX¹⁰₂, —CN, —SO₂R^10D, —SR^10D, —OR^10D, unsubstituted C₁-C₄alkyl, unsubstituted 2 to 6 membered heteroalkyl, unsubstituted C₃-C₄cycloalkyl, or unsubstituted phenyl; R^10A, R^10B, R^10C, and R^10Dare independently hydrogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, or unsubstituted methyl; and X¹⁰is independently —F, —Cl, —Br, or —I.

In embodiments, L¹is —CH₂C(O)—; R¹is independently —NR^1AR^1B; R^1Ais independently hydrogen, unsubstituted C₁-C₄alkyl, or unsubstituted cyclopropyl; R^1Bis independently

embedded image

In embodiments, L¹is a substituted C₁-C₆alkylene; R¹is independently —NR^1AR^1B; and R^1Aand R^1Bbonded to the same nitrogen atom are joined to form a substituted or unsubstituted C₃-C₆heterocycloalkyl. In embodiments, L¹is —CH₂C(O)—; R¹is independently —NR^1AR^1B; and R^1Aand R^1Bbonded to the same nitrogen atom are joined to form a substituted or unsubstituted piperazinyl. In embodiments, L¹is —CH₂C(O)—; R¹is independently —NR^1AR^1B; R^1Aand R^1Bbonded to the same nitrogen atom are joined to form

embedded image

and R^10.Cis unsubstituted C₁-C₄alkyl. In embodiments, L¹is —CH₂C(O)—; R¹is independently —NR^1AR^1B; and R^1Aand R^1Bbonded to the same nitrogen atom are joined to form

embedded image

In embodiments, the compound has the formula:

embedded image

In embodiments, the salt (e.g., pharmaceutically acceptable salt) of the compound of formula VI is the HCl salt. In embodiments, the salt (e.g., pharmaceutically acceptable salt) of the compound of formula VI is the Cl⁻salt.

In embodiments, the compound has the formula:

embedded image

In embodiments, the salt (e.g., pharmaceutically acceptable salt) of the compound of formula VII is the HCl salt. In embodiments, the salt (e.g., pharmaceutically acceptable salt) of the compound of formula VII is the Cl⁻salt.

In embodiments, the compound has the formula:

embedded image

In embodiments, the compound has the formula:

embedded image

In embodiments, the compound has the formula:

embedded image

In embodiments, the compound has the formula:

embedded image

In embodiments, the compound has the formula:

embedded image

In embodiments, the compound has the formula:

embedded image

In embodiments, the compound has the formula:

embedded image

In embodiments, the compound has the formula:

embedded image

In embodiments, the compound has the formula:

embedded image

In embodiments, the compound has the formula:

embedded image

In embodiments, the compound has the formula:

embedded image

In embodiments, the compound has the formula:

embedded image

In embodiments, the compound has the formula:

embedded image

In embodiments, the compound has the formula:

embedded image

In embodiments, the compound has the formula:

embedded image

In embodiments, the compound has the formula:

embedded image

In embodiments, the compound has the formula:

embedded image

In embodiments, the compound has the formula:

embedded image

In embodiments, the compound has the formula:

embedded image

In embodiments, the compound has the formula:

embedded image

In embodiments, the compound has the formula:

embedded image

In embodiments, the compound has the formula:

embedded image

In embodiments, the compound has the formula:

embedded image

In embodiments, the compound has the formula:

embedded image

In embodiments, the compound has the formula:

embedded image

In embodiments, the compound has the formula:

embedded image

In embodiments, the compound has the formula:

embedded image

In embodiments, the compound has the formula:

embedded image

In embodiments, the compound has the formula:

embedded image

In embodiments, the compound has the formula:

embedded image

In embodiments, the compound has the formula:

embedded image

In embodiments, the compound has the formula:

embedded image

In embodiments, the compound has the formula:

embedded image

In embodiments, the compound has the formula:

embedded image

In embodiments, the compound has the formula:

embedded image

In embodiments, the compound has the formula:

embedded image

In embodiments, the compound has the formula:

embedded image

In embodiments, the compound has the formula:

embedded image

In embodiments, the compound has the formula:

embedded image

In embodiments, the compound has the formula:

embedded image

In embodiments, the compound has the formula:

embedded image

In embodiments, the compound has the formula:

embedded image

In embodiments, the compound has the formula:

embedded image

In embodiments, the compound has the formula:

embedded image

In embodiments, the compound has the formula:

embedded image

In embodiments, the compound has the formula:

embedded image

In embodiments, the compound has the formula:

embedded image

In embodiments, the compound has the formula:

embedded image

In embodiments, the compound has the formula:

embedded image

In embodiments, the compound has the formula:

embedded image

In embodiments, the compound has the formula:

embedded image

In embodiments, the compound has the formula:

embedded image

In embodiments, the compound has the formula:

embedded image

In embodiments, the compound has the formula:

embedded image

In embodiments, the compound has the formula:

embedded image

In embodiments, the compound has the formula:

embedded image

In embodiments, the compound has the formula:

embedded image

In embodiments, the compound has the formula:

embedded image

In embodiments, the compound has the formula:

embedded image

In embodiments, the compound has the formula:

embedded image

In embodiments, the compound has the formula:

embedded image

In embodiments, the compound has the formula:

embedded image

In embodiments, the compound has the formula:

embedded image

In embodiments, the compound has the formula:

embedded image

In embodiments, the compound has the formula:

embedded image

In embodiments, the compound has the formula:

embedded image

In embodiments, the compound has the formula:

embedded image

In embodiments, the compound has the formula:

embedded image

In embodiments, the compound has the formula:

embedded image

In embodiments, the compound has the formula:

embedded image

In embodiments, the compound has the formula:

embedded image

In embodiments, the compound has the formula:

embedded image

In embodiments, the compound has the formula:

embedded image

In embodiments, the compound has the formula:

embedded image

In embodiments, the compound has the formula:

embedded image

In embodiments, the compound has the formula:

embedded image

In embodiments, the compound has the formula:

embedded image

In embodiments, the compound has the formula:

embedded image

In embodiments, the compound has the formula:

embedded image

In embodiments, the compound has the formula:

embedded image

In embodiments, the compound has the formula:

embedded image

In embodiments, the compound has the formula:

embedded image

In embodiments, the compound has the formula:

embedded image

In embodiments, the compound has the formula:

embedded image

In embodiments, the compound has the formula:

embedded image

In embodiments, the compound has the formula:

embedded image

In embodiments, the salt (e.g., pharmaceutically acceptable salt) of the compound described above is the HCl salt. In embodiments, the salt (e.g., pharmaceutically acceptable salt) of the compound described above is the Cl⁻salt. In embodiments, the salt (e.g., pharmaceutically acceptable salt) of the compound described above is the HC(O)OH salt. In embodiments, the salt (e.g., pharmaceutically acceptable salt) of the compound described above is the HC(O)O— salt. In embodiments, the salt of the compound described above is a pharmaceutically acceptable salt.

In embodiments, when R¹is substituted, R¹is substituted with one or more first substituent groups denoted by R^1.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^1.1substituent group is substituted, the R^1.1substituent group is substituted with one or more second substituent groups denoted by R^1.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^1.2substituent group is substituted, the R^1.2substituent group is substituted with one or more third substituent groups denoted by R^1.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R¹, R^1.1, R^1.2, and R^1.3have values corresponding to the values of R^WW, R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW, R^WW.1, R^WW.2, and R^WW.3correspond to R¹, R^1.1, R^1.2, and R^1.3, respectively.

In embodiments, when R^1Ais substituted, R^1Ais substituted with one or more first substituent groups denoted by R^1A.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^1A.1substituent group is substituted, the R^1A.1substituent group is substituted with one or more second substituent groups denoted by R^1A.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^1A.2substituent group is substituted, the R^1A.2substituent group is substituted with one or more third substituent groups denoted by R^1A.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^1A, R^1A.1, R^1A.2, and R^1A.3have values corresponding to the values of R^WW, R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW, R^WW.1, R^WW.2, and R^WW.3correspond to R^1A, R^1A.1, R^1A.2, and R^1A.3, respectively.

In embodiments, when R^1Bis substituted, R^1Bis substituted with one or more first substituent groups denoted by R^1B.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^1B.1substituent group is substituted, the R^1B.1substituent group is substituted with one or more second substituent groups denoted by R^1B.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^1B.2substituent group is substituted, the R^1B.2substituent group is substituted with one or more third substituent groups denoted by R^1B.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^1B, R^1B.1, R^1B.2, and R^1B.3have values corresponding to the values of R^WW, R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW, R^WW.1, R^WW.2, and R^WW.3correspond to R^1B, R^1B.1, R^1B.2, and R^1B.3, respectively.

In embodiments, when R^1Aand R^1Bsubstituents 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 R^1A.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^1A.1substituent group is substituted, the R^1A.1substituent group is substituted with one or more second substituent groups denoted by R^1A.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^1A.2substituent group is substituted, the R^1A.2substituent group is substituted with one or more third substituent groups denoted by R^1A.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^1A, R^1A.1, R^1A.2, and R^1A.3have values corresponding to the values of R^WW, R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW, R^WW.1, R^WW.2, and R^WW.3correspond to R^1A, R^1A.1, R^1A.2, and R^1A.3, respectively.

In embodiments, when R^1Aand R^1Bsubstituents 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 R^1B.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^1B.1substituent group is substituted, the R^1B.1substituent group is substituted with one or more second substituent groups denoted by R^1B.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^1B.2substituent group is substituted, the R^1B.2substituent group is substituted with one or more third substituent groups denoted by R^1B.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^1B, R^1B.1, R^1B.2, and R^1B.3have values corresponding to the values of R^WW, R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW, R^WW.1, R^WW.2, and R^WW.3correspond to R^1B, R^1B.1, R^1B.2, and R^1B.3, respectively.

In embodiments, when R^1Cis substituted, R^1Cis substituted with one or more first substituent groups denoted by R^1C.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^1C.1substituent group is substituted, the R^1C.1substituent group is substituted with one or more second substituent groups denoted by R^1C.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^1C.2substituent group is substituted, the R^1C.2substituent group is substituted with one or more third substituent groups denoted by R^1C.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^1C, R^1C.1, R^1C.2, and R^1C.3have values corresponding to the values of R^WW, R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW, R^WW.1, R^WW.2, and R^WW.3correspond to R^1C, R^1C.1, R^1C.2, and R^1C.3, respectively.

In embodiments, when R^1Dis substituted, R^1Dis substituted with one or more first substituent groups denoted by R^1D.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^1D.1substituent group is substituted, the R^1D.1substituent group is substituted with one or more second substituent groups denoted by R^1D.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^1D.2substituent group is substituted, the R^1D.2substituent group is substituted with one or more third substituent groups denoted by R^1D.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^1D, R^1D.1, R^1D.2, and R^1D.3have values corresponding to the values of R^WW, R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW, R^WW.1, R^WW.2, and R^WW.3correspond to R^1D, R^1D.1, R^1D.2, and R^1D.3, respectively.

In embodiments, when R²is substituted, R²is substituted with one or more first substituent groups denoted by R^2.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^2.1substituent group is substituted, the R^2.1substituent group is substituted with one or more second substituent groups denoted by R^2.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^2.2substituent group is substituted, the R^2.2substituent group is substituted with one or more third substituent groups denoted by R^2.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R², R^2.1, R^2.2, and R^2.3have values corresponding to the values of R^WW, R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW, R^WW.1, R^WW.2, and R^WW.3correspond to R², R^2.1, R^2.2, and R^2.3, respectively.

In embodiments, when R³is substituted, R³is substituted with one or more first substituent groups denoted by R^3.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^3.1substituent group is substituted, the R^3.1substituent group is substituted with one or more second substituent groups denoted by R^3.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^3.2substituent group is substituted, the R^3.2substituent group is substituted with one or more third substituent groups denoted by R^3.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R³, R^3.1, R^3.2, and R^3.3have values corresponding to the values of R^WW, R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW, R^WW.1, R^WW.2, and R^WW.3correspond to R³, R^3.1, R^3.2, and R^3.3, respectively.

In embodiments, when two adjacent R³substituents are optionally joined 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 R^3.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^3.1substituent group is substituted, the R^3.1substituent group is substituted with one or more second substituent groups denoted by R^3.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^3.2substituent group is substituted, the R^3.2substituent group is substituted with one or more third substituent groups denoted by R^3.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R³, R^3.1, R^3.2, and R^3.3have values corresponding to the values of R^WW, R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW, R^WW.1, R^WW.2, and R^WW.3correspond to R³, R^3.1, R^3.2, and R^3.3, respectively.

In embodiments, when R⁴is substituted, R⁴is substituted with one or more first substituent groups denoted by R^4.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^4.1substituent group is substituted, the R^4.1substituent group is substituted with one or more second substituent groups denoted by R^4.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^4.2substituent group is substituted, the R^4.2substituent group is substituted with one or more third substituent groups denoted by R^4.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R⁴, R^4.1, R^4.2, and R^4.3have values corresponding to the values of R^WW, R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW, R^WW.1, R^WW.2, and R^WW.3correspond to R⁴, R^4.1, R^4.2, and R^4.3, respectively.

In embodiments, when two adjacent R⁴substituents are optionally joined 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 R^4.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^4.1substituent group is substituted, the R^4.1substituent group is substituted with one or more second substituent groups denoted by R^4.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^4.2substituent group is substituted, the R^4.2substituent group is substituted with one or more third substituent groups denoted by R^4.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R⁴, R^4.1, R^4.2, and R^4.3have values corresponding to the values of R^WW, R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW, R^WW.1, R^WW.2, and R^WW.3correspond to R⁴, R^4.1, R^4.2, and R^4.3, respectively.

In embodiments, when R^4.Ais substituted, R^4.Ais substituted with one or more first substituent groups denoted by R^4.A.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^4.A.1substituent group is substituted, the R^4.A.1substituent group is substituted with one or more second substituent groups denoted by R^4.A.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^4.A.2substituent group is substituted, the R^4.A.2substituent group is substituted with one or more third substituent groups denoted by R^4.A.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^4.A, R^4.A.1, R^4.A.2, and R^4.A.3have values corresponding to the values of R^WW, R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW, R^WW.1, R^WW.2, and R^WW.3correspond to R^4.A, R^4.A.1, R^4.A.2, and R^4.A.3, respectively.

In embodiments, when R^4.Bis substituted, R^4.Bis substituted with one or more first substituent groups denoted by R^4.B.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^4.B.1substituent group is substituted, the R^4.B.1substituent group is substituted with one or more second substituent groups denoted by R^4.B.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^4.B.2substituent group is substituted, the R^4.B.2substituent group is substituted with one or more third substituent groups denoted by R^4.B.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^4.B, R^4.B.1, R^4.B.2, and R^4.B.3have values corresponding to the values of R^WW, R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW, R^WW.1, R^WW.2, and R^WW.3correspond to R^4.B, R^4.B.1, R^4.B.2, and R^4.B.3, respectively.

In embodiments, when R^4.Cis substituted, R^4.Cis substituted with one or more first substituent groups denoted by R^4.C.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^4.C.1substituent group is substituted, the R^4.C.1substituent group is substituted with one or more second substituent groups denoted by R^4.C.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^4.C.2substituent group is substituted, the R^4.C.2substituent group is substituted with one or more third substituent groups denoted by R^4.C.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^4.C, R^4.C.1, R^4.C.2, and R^4.C.3have values corresponding to the values of R^WW, R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW, R^WW.1, R^WW.2, and R^WW.3correspond to R^4.C, R^4.C.1, R^4.C.2, and R^4.C.3, respectively.

In embodiments, when R^4.Dis substituted, R^4.Dis substituted with one or more first substituent groups denoted by R^4.D.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^4.D.1substituent group is substituted, the R^4.D.1substituent group is substituted with one or more second substituent groups denoted by R^4.D.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^4.D.2substituent group is substituted, the R^4.D.2substituent group is substituted with one or more third substituent groups denoted by R^4.D.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^4.D, R^4.D.1, R^4.D.2, and R^4.D.3have values corresponding to the values of R^WW, R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW, R^WW.1, R^WW.2, and R^WW.3correspond to R^4.D, R^4.D.1, R^4.D.2, and R^4.D.3, respectively.

In embodiments, when R^4.Eis substituted, R^4Eis substituted with one or more first substituent groups denoted by R^4.E.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^4.E.1substituent group is substituted, the R^4.E.1substituent group is substituted with one or more second substituent groups denoted by R^4.E.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^4.E.2substituent group is substituted, the R^4.E.2substituent group is substituted with one or more third substituent groups denoted by R^4.E.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^4.E, R^4.E.1, R^4.E.2, and R^4.E.3have values corresponding to the values of R^WW, R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW, R^WW.1, R^WW.2, and R^WW.3correspond to R^4.E, R^4.E.1, R^4.E.2, and R^4.E.3, respectively.

In embodiments, when R^4.ADis substituted, R^4.ADis substituted with one or more first substituent groups denoted by R^4.AD.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^4.AD.1substituent group is substituted, the R^4.AD.1substituent group is substituted with one or more second substituent groups denoted by R^4.AD.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^4.AD.2substituent group is substituted, the R^4.AD.2substituent group is substituted with one or more third substituent groups denoted by R^4.AD.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^4.AD, R^4.AD.1, R^4.AD.2, and R^4.AD.3have values corresponding to the values of R^WW, R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW, R^WW.1, R^WW.2, and R^WW.3correspond to R^4.AD, R^4.AD.1, R^4.AD.2, and R^4.AD.3, respectively.

In embodiments, when R^4.BDis substituted, R^4.BDis substituted with one or more first substituent groups denoted by R^4.BD.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^4.BD.1substituent group is substituted, the R^4.BD.1substituent group is substituted with one or more second substituent groups denoted by R^4.BD.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^4.BD.2substituent group is substituted, the R^4.BD.2substituent group is substituted with one or more third substituent groups denoted by R^4.BD.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^4.BD, R^4.BD.1, R^4.BD.2, and R^4.BD.3have values corresponding to the values of R^WW, R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW, RV-1, R^WW.2, and R^WW.3correspond to R^4.BD, R^4.BD.1, R^4.BD.2, and R^4.BD.3, respectively.

In embodiments, when R^4.CDis substituted, R^4.CDis substituted with one or more first substituent groups denoted by R^4.CD.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^4.CD.1substituent group is substituted, the R^4.CD.1substituent group is substituted with one or more second substituent groups denoted by R^4.CD.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^4.CD.2substituent group is substituted, the R^4.CD.2substituent group is substituted with one or more third substituent groups denoted by R^4.CD.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^4.CD, R^4.CD.1, R^4.CD.2, and R^4.CD.3have values corresponding to the values of R^WW, R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW, RV-1, R^WW.2, and R^WW.3correspond to R^4.CD, R^4.CD.1, R^4.CD.2, and R^4.CD.3, respectively.

In embodiments, when R^4.DDis substituted, R^4.DDis substituted with one or more first substituent groups denoted by R^4.DD.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^4.DD1substituent group is substituted, the R^4.DD1substituent group is substituted with one or more second substituent groups denoted by R^4.DD.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^4.DD.2substituent group is substituted, the R^4.DD.2substituent group is substituted with one or more third substituent groups denoted by R^4.DD.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^4.DD, R^4.DD.1, R^4.DD.2, and R^4.DD.3have values corresponding to the values of R^WW, R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW, R^WW.1, R^WW.2, and R^WW.3correspond to R^4.DD, R^4.DD.1, R^4.DD.2, and R^4.DD.3, respectively.

In embodiments, when R⁵is substituted, R⁵is substituted with one or more first substituent groups denoted by R^5.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^5.1substituent group is substituted, the R^5.1substituent group is substituted with one or more second substituent groups denoted by R^5.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^5.2substituent group is substituted, the R^5.2substituent group is substituted with one or more third substituent groups denoted by R^5.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R⁵, R^5.1, R^5.2, and R^5.3have values corresponding to the values of R^WW, R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW, R^WW.1, R^WW.2, and R^WW.3correspond to R⁵, R^5.1, R^5.2, and R^5.3, respectively.

In embodiments, when two adjacent R⁵substituents are optionally joined 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 R^5.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^5.1substituent group is substituted, the R^5.1substituent group is substituted with one or more second substituent groups denoted by R^5.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^5.2substituent group is substituted, the R^5.2substituent group is substituted with one or more third substituent groups denoted by R^5.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R⁵, R^5.1, R^5.2, and R^5.3have values corresponding to the values of R^WW, R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW, R^WW.1, R^WW.2, and R^WW.3correspond to R⁵, R^5.1, R^5.2, and R^5.3, respectively.

In embodiments, when R¹⁰is substituted, R¹⁰is substituted with one or more first substituent groups denoted by R^10.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^10.1substituent group is substituted, the R^10.1substituent group is substituted with one or more second substituent groups denoted by R^10.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^10.2substituent group is substituted, the R^10.2substituent group is substituted with one or more third substituent groups denoted by R^10.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R¹⁰, R^10.1, R^10.2, and R^10.3have values corresponding to the values of RWW, R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW, R^WW.1, R^WW.2, and R^WW.3correspond to R¹⁰, R^10.1, R^10.2, and R^10.3, respectively.

In embodiments, when two adjacent R¹⁰substituents are optionally joined 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 R^10.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^10.1substituent group is substituted, the R^10.1substituent group is substituted with one or more second substituent groups denoted by R^10.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^10.2substituent group is substituted, the R^10.2substituent group is substituted with one or more third substituent groups denoted by R^10.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R¹⁰, R^10.1, R^10.2, and R^10.3have values corresponding to the values of R^WW, R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW, R^WW.1, R^WW.2, and R^WW.3correspond to R¹⁰, R^10.1, R^10.2, and R^10.3, respectively.

In embodiments, when R^10Ais substituted, R^10Ais substituted with one or more first substituent groups denoted by R^10A.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^10A.1substituent group is substituted, the R^10A.1substituent group is substituted with one or more second substituent groups denoted by R^10A.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^10A.2substituent group is substituted, the R^10A.2substituent group is substituted with one or more third substituent groups denoted by R^10A.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^10A, R^10A.1, R^10A.2, and R^10A.3have values corresponding to the values of R^WW, R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW, R^WW.1, R^WW.2, and R^WW.3correspond to R^10A, R^10A.1, R^10A.2, and R^10A.3, respectively.

In embodiments, when R^10Bis substituted, R^10Bis substituted with one or more first substituent groups denoted by R^10B.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^10B.1substituent group is substituted, the R^10B.1substituent group is substituted with one or more second substituent groups denoted by R^10B.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^1B.2substituent group is substituted, the R^10B.2substituent group is substituted with one or more third substituent groups denoted by R^10B.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^10B, R^10B.1, R^10B.2, and R^10B.3have values corresponding to the values of R^WW, R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW, R^WW.1, R^WW.2, and R^WW.3correspond to R^10B, R^10B.1, R^10B.2, and R^10B.3, respectively.

In embodiments, when R^10Aand R^10Bsubstituents 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 R^10A.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^10A.1substituent group is substituted, the R^10A.1substituent group is substituted with one or more second substituent groups denoted by R^10A.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^10A.2substituent group is substituted, the R^10A.2substituent group is substituted with one or more third substituent groups denoted by R^10A.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^10A, R^10A.1, R^10A.2, and R^10A.3have values corresponding to the values of R^WW, R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW, R^WW.1, R^WW.2, and R^WW.3correspond to R^10A, R^10A.1, R^10A.2, and R^10A.3, respectively.

In embodiments, when R^10Aand R^10Bsubstituents 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 R^10B.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^10B.1substituent group is substituted, the R^10B.1substituent group is substituted with one or more second substituent groups denoted by R^10B.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^10B.2substituent group is substituted, the R^10B.2substituent group is substituted with one or more third substituent groups denoted by R^10B.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^10B, R^10B.1, R^10B.2, and R^10B.3have values corresponding to the values of R^WW, R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW, R^WW.1, R^WW.2, and R^WW.3correspond to R^10B, R^10B.1, R^10B.2, and R^10B.3, respectively.

In embodiments, when R^10Cis substituted, R^10Cis substituted with one or more first substituent groups denoted by R^10C.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^10C.1substituent group is substituted, the R^10C.1substituent group is substituted with one or more second substituent groups denoted by R^10C.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^10C.2substituent group is substituted, the R^10C.2substituent group is substituted with one or more third substituent groups denoted by R^10C.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^10C, R^10C.1, R^10C.2, and R^10C.3have values corresponding to the values of R^WW, R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW, R^WW.1, R^WW.2, and R^WW.3correspond to R^10C, R^10C.1, R^10C.2, and R^10C.3, respectively.

In embodiments, when R^10Dis substituted, R^10Dis substituted with one or more first substituent groups denoted by R^10D.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^10D.1substituent group is substituted, the R^10D.1substituent group is substituted with one or more second substituent groups denoted by R^10D.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^10D.2substituent group is substituted, the R^10D.2substituent group is substituted with one or more third substituent groups denoted by R^10D.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^10D, R^10D.1, R^10D.2, and R^10D.3have values corresponding to the values of R^WW, R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW, R^WW.1, R^WW.2, and R^WW.3correspond to R^10D, R^10D.1, R^10D.2, and R^10D.3, respectively.

In embodiments, when R^10.Ais substituted, R^10.Ais substituted with one or more first substituent groups denoted by R^10.A.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^10.A.1substituent group is substituted, the R^10.A.1substituent group is substituted with one or more second substituent groups denoted by R^10.A.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^10.A.2substituent group is substituted, the R^10.A.2substituent group is substituted with one or more third substituent groups denoted by R^10.A.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^10.A, R^10.A.1, R^10.A.2, and R^10.A.3have values corresponding to the values of R^WW, R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW, R^WW.1, R^WW.2, and R^WW.3correspond to R^10.A, R^10.A.1, R^10.A.2, and R^10A.3, respectively.

In embodiments, when R^10.Bis substituted, R^10.Bis substituted with one or more first substituent groups denoted by R^10B.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^10.B.1substituent group is substituted, the R^10.B.1substituent group is substituted with one or more second substituent groups denoted by R^10.B.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^10.B.2substituent group is substituted, the R^10.B.2substituent group is substituted with one or more third substituent groups denoted by R^10.B.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^10.B, R^10.B.1, R^10.B.2, and R^{10.B. 3}have values corresponding to the values of R^WW, R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW, R^WW.1, R^WW.2, and R^WW.3correspond to R^10.B, R^10.B.1, R^10.B.2, and R^10B.3, respectively.

In embodiments, when R^10.Cis substituted, R^10.Cis substituted with one or more first substituent groups denoted by R^10.C.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^10.C.1substituent group is substituted, the R^10.C.1substituent group is substituted with one or more second substituent groups denoted by R^10.C.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^10.C.2substituent group is substituted, the R^10.C.2substituent group is substituted with one or more third substituent groups denoted by R^10.C.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^10.C, R^10.C.1, R^10.C.2, and R^10.C.3have values corresponding to the values of R^WW, R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW, R^WW.1, R^WW.2, and R^WW.3correspond to R^10.C, R^10.C.1, R^10.C.2, and R^10.C.3, respectively.

In embodiments, when R^10.Dis substituted, R^10.Dis substituted with one or more first substituent groups denoted by R^10.D.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^10.D.1substituent group is substituted, the R^10.D.1substituent group is substituted with one or more second substituent groups denoted by R^10.D.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^10.D.2substituent group is substituted, the R^10.D.2substituent group is substituted with one or more third substituent groups denoted by R^10.D.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^10.D, R^10.D.1, R^10.D.2, and R^10.D.3have values corresponding to the values of R^WW, R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW, R^WW.1, R^WW.2, and R^WW.3correspond to R^10.D, R^10.D.1, R^10.D.2, and R^10D.3, respectively.

In embodiments, when L¹is substituted, L¹is substituted with one or more first substituent groups denoted by R^L1.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^L1.1substituent group is substituted, the R^L1.1substituent group is substituted with one or more second substituent groups denoted by R^L1.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^L1.2substituent group is substituted, the R^L1.2substituent group is substituted with one or more third substituent groups denoted by R^L1.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, L¹, R^L1.1, R^L1.2, and R^L1.3have values corresponding to the values of L^WW, R^LWW.1, R^LWW.2, and R^LWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein L^WW, R^LWW.1, R^LWW.2, and R^LWW.3are L¹, R^L1.1, R^L1.2, and R^L1.3, respectively.

In embodiments, when R^L1is substituted, R^L1is substituted with one or more first substituent groups denoted by R^L1.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^L1.1substituent group is substituted, the R^L1.1substituent group is substituted with one or more second substituent groups denoted by R^L1.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^L1.2substituent group is substituted, the R^L1.2substituent group is substituted with one or more third substituent groups denoted by R^L1.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^L1, R^L1.1, R^L1.2, and R^L1.3have values corresponding to the values of R^WW, R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW, R^WW.1, R^WW.2, and R^WW.3correspond to R^L1, R^L1.1, R^L1.2, and R^L1.3, respectively.

In embodiments, when L²is substituted, L²is substituted with one or more first substituent groups denoted by R^L2.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^L2.1substituent group is substituted, the R^L-1 substituent group is substituted with one or more second substituent groups denoted by R^L2.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^L2.2substituent group is substituted, the R^L2.2substituent group is substituted with one or more third substituent groups denoted by R^L2.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, L², R^L2.1, R^L2.2, and R^L2.3have values corresponding to the values of L^WW, R^LWW.1, R^LWW.2, and R^LWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein L^WW, R^LWW.1, R^LWW.2, and R^LWW.3are L², R^L2.1, R^L2.2, and R^L2.3, respectively.

In embodiments, when R^L2is substituted, R^L2is substituted with one or more first substituent groups denoted by R^L2.1as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^L2.1substituent group is substituted, the R^L2.1substituent group is substituted with one or more second substituent groups denoted by R^L2.2as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R^L2.2substituent group is substituted, the R^L2.2substituent group is substituted with one or more third substituent groups denoted by R^L2.3as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R^L2, R^L2.11, R^L2.2, and R^L2.3have values corresponding to the values of R^WW, R^WW.1, R^WW.2, and R^WW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R^WW, R^WW.1, R^WW.2, and R^WW.3correspond to R^L2, R^L2.1, R^L2.2, and R^L2.3, respectively.

In embodiments, a substituted R¹(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 R¹is 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 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.

In embodiments, a substituted R^1A(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 R^1Ais substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R^1Ais substituted, it is substituted with at least one substituent group. In embodiments, when R^1Ais substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^1Ais substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted R^1B(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 R^1Bis substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R^1Bis substituted, it is substituted with at least one substituent group. In embodiments, when R^1Bis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^1Bis substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted ring formed when R^1Aand R^1Bsubstituents 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 R^1Aand R^1Bsubstituents 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 R^1Aand R^1Bsubstituents 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 R^1Aand R^1Bsubstituents 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 R^1Aand R^1Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted R^1C(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 R^1Cis substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R^1Cis substituted, it is substituted with at least one substituent group. In embodiments, when R^1Cis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^1Cis substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted R^1D(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 R^1Dis substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R^1Dis substituted, it is substituted with at least one substituent group. In embodiments, when R^1Dis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^1Dis substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted R²(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 R²is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R²is substituted, it is substituted with at least one substituent group. In embodiments, when R²is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R²is substituted, it is substituted with at least one lower substituent group.

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.

In embodiments, a substituted ring formed when two R³substituents bonded to adjacent atoms 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 two R³substituents bonded to adjacent 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 two R³substituents bonded to adjacent atom are joined is substituted, it is substituted with at least one substituent group. In embodiments, when the substituted ring formed when two R³substituents bonded to adjacent atom are joined is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when the substituted ring formed when two R³substituents bonded to adjacent atom are joined is substituted, it is substituted with at least one lower substituent group.

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.

In embodiments, a substituted ring formed when two R⁴substituents bonded to adjacent atoms 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 two R⁴substituents bonded to adjacent 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 two R⁴substituents bonded to adjacent atom are joined is substituted, it is substituted with at least one substituent group. In embodiments, when the substituted ring formed when two R⁴substituents bonded to adjacent atom 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 bonded to adjacent atom are joined is substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted R^4.A(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 R^4.Ais substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R^4.Ais substituted, it is substituted with at least one substituent group. In embodiments, when R^4.Ais substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^4.Ais substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted R^4.B(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 R^4.Bis substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R^4.Bis substituted, it is substituted with at least one substituent group. In embodiments, when R^4.Bis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^4.Bis substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted R^4.C(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 R^4.Cis substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R^4.Cis substituted, it is substituted with at least one substituent group. In embodiments, when R^4.Cis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^4.Cis substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted R^4.D(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 R^4.Dis substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R^4.Dis substituted, it is substituted with at least one substituent group. In embodiments, when R^4.Dis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^4.Dis substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted R^4.E(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 R^4.Eis substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R^4.Eis substituted, it is substituted with at least one substituent group. In embodiments, when R^4.Eis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^4.Eis substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted R^4.AD(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 R^4.ADis substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R^4.ADis substituted, it is substituted with at least one substituent group. In embodiments, when R^4.ADis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^4.ADis substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted R^4.BD(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 R^4.BDis substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R^4.BDis substituted, it is substituted with at least one substituent group. In embodiments, when R^4.BDis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^4.BDis substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted R^4.CD(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 R^4.CDis substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R^4.CDis substituted, it is substituted with at least one substituent group. In embodiments, when R^4.CDis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^4.CDis substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted R^4.DD(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 R^4.DDis substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R^4.DDis substituted, it is substituted with at least one substituent group. In embodiments, when R^4.DDis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^4.DDis substituted, it is substituted with at least one lower substituent group.

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 at least one size-limited substituent group. In embodiments, when R⁵is substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted ring formed when two R⁵substituents bonded to adjacent atoms 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 two R⁵substituents bonded to adjacent 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 two R⁵substituents bonded to adjacent atom are joined is substituted, it is substituted with at least one substituent group. In embodiments, when the substituted ring formed when two R⁵substituents bonded to adjacent atom are joined is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when the substituted ring formed when two R⁵substituents bonded to adjacent atom are joined is substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted R¹⁰(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 R¹⁰is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R¹⁰is substituted, it is substituted with at least one substituent group. In embodiments, when R¹⁰is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R¹⁰is substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted ring formed when two R¹⁰substituents bonded to adjacent atoms 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 two R¹⁰substituents bonded to adjacent 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 two R¹⁰substituents bonded to adjacent atom are joined is substituted, it is substituted with at least one substituent group. In embodiments, when the substituted ring formed when two R¹⁰substituents bonded to adjacent atom are joined is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when the substituted ring formed when two R¹⁰substituents bonded to adjacent atom are joined is substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted R^10A(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 R^10Ais substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R^10Ais substituted, it is substituted with at least one substituent group. In embodiments, when R^10Ais substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^10Ais substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted R^10B(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 R^10Bis substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R^10Bis substituted, it is substituted with at least one substituent group. In embodiments, when R^10Bis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^10Bis substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted ring formed when R^10Aand R^10Bsubstituents 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 R^10Aand R^10Bsubstituents 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 R^10Aand R^10Bsubstituents 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 R^10Aand R^10Bsubstituents 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 R^10Aand R^10Bsubstituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted R^10C(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 R^10Cis substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R^10Cis substituted, it is substituted with at least one substituent group. In embodiments, when R^10Cis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^10Cis substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted R^10D(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 R^10Dis substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R^10Dis substituted, it is substituted with at least one substituent group. In embodiments, when R^10Dis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^10Dis substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted R^10.A(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 R^10.Ais substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R^10Ais substituted, it is substituted with at least one substituent group. In embodiments, when R^10Ais substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^10.Ais substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted R^10.B(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 R^10.Bis substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R^10.Bis substituted, it is substituted with at least one substituent group. In embodiments, when R^10.Bis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^10.Bis substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted R^10.C(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 R^10.Cis substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R^10.Cis substituted, it is substituted with at least one substituent group. In embodiments, when R^10.Cis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^10.Cis substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted R^10.D(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 R^10.Dis substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R^10.Dis substituted, it is substituted with at least one substituent group. In embodiments, when R^10.Dis substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^10.Dis substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted L¹(e.g., 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 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.

In embodiments, a substituted R^L(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 R^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 R^L1is substituted, it is substituted with at least one substituent group. In embodiments, when R^L1is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^L1is substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted L²(e.g., 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 L²is 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 L²is substituted, it is substituted with at least one substituent group. In embodiments, when L²is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when L²is substituted, it is substituted with at least one lower substituent group.

In embodiments, a substituted R^L2(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 R^L2is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R^L2is substituted, it is substituted with at least one substituent group. In embodiments, when R^L2is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R^L2is substituted, it is substituted with at least one lower substituent group.

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).

In embodiments, the compound is a compound described herein. In embodiments, the compound, or salt (e.g., pharmaceutically acceptable salt) thereof, is the compound. In embodiments, the compound, or a salt (e.g., pharmaceutically acceptable salt) thereof, is the salt (e.g., pharmaceutically acceptable salt) of the compound. In embodiments, the compound, or a salt (e.g., pharmaceutically acceptable salt) thereof, is the pharmaceutically acceptable salt of the compound.

In embodiments, L²is not unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered). In embodiments, L²is not —OCH₂—.

In embodiments, R¹is not

embedded image

and R^10.Cis as described herein, including in embodiments. In embodiments, R¹is not

embedded image

In embodiments, R²is not unsubstituted C₁-C₄alkyl. In embodiments, R¹is not unsubstituted methyl.

In embodiments, the compound does not have the formula:

embedded image

wherein R¹is

embedded image

and R³and R^L1is as described herein, including in embodiments.

In embodiments, the compound does not have the formula:

embedded image

wherein R¹is

embedded image

and L¹, R², L², R³, R^4.A, R^4.Band R^Lis as described herein, including in embodiments.

In embodiments, the compound does not have the formula:

embedded image

wherein R¹is

embedded image

and L¹, R², L², R³, R^4.A, and R^4.Bare as described herein, including in embodiments.

In embodiments, the compound does not have the formula:

embedded image

wherein R¹is

embedded image

and L¹, R², L², R³, R⁴, z3, and z4 are as described herein, including in embodiments.

In embodiments, the compound is not

embedded image

In embodiments, the compound is not

embedded image

In embodiments, the compound is not

embedded image

In embodiments, the compound is not

embedded image

In embodiments, the compound is not

embedded image

In embodiments, the compound is not

embedded image

In embodiments, the compound is not

embedded image

In embodiments, the compound is not

embedded image

In embodiments, the compound is not

embedded image

In embodiments, the compound is not

embedded image

In embodiments, the compound is not

embedded image

In embodiments, the compound is not

embedded image

In embodiments, the compound is not

embedded image

In embodiments, the compound is not

embedded image

In embodiments, compound is not

embedded image

In embodiments, the compound is not

embedded image

In embodiments, the compound is not

embedded image

In embodiments, the compound is not

embedded image

In embodiments, the compound is not

embedded image

In embodiments, the compound is not

embedded image

III. Pharmaceutical Compositions

In an aspect is provided a pharmaceutical composition including a compound described herein, or a salt (e.g., pharmaceutically acceptable salt) thereof, and a pharmaceutically acceptable excipient. In embodiments, the compound as described herein is included in a therapeutically effective amount. In embodiments, the compound as described herein is included in an effective amount.

In embodiments of the pharmaceutical compositions, the compound, or salt (e.g., pharmaceutically acceptable salt) thereof, is included in a therapeutically effective amount. In embodiments of the pharmaceutical compositions, the compound, or salt (e.g., pharmaceutically acceptable salt) thereof, is a compound. In embodiments of the pharmaceutical compositions, the compound, or salt (e.g., pharmaceutically acceptable salt) thereof, is a salt (e.g., pharmaceutically acceptable salt) of the compound. In embodiments of the pharmaceutical compositions, the compound, or salt (e.g., pharmaceutically acceptable salt) thereof, is a pharmaceutically acceptable salt of the compound.

In embodiments of the pharmaceutical compositions, the pharmaceutical composition includes a second agent (e.g., therapeutic agent). In embodiments of the pharmaceutical compositions, the pharmaceutical composition includes a second agent (e.g., therapeutic agent) in a therapeutically effective amount. In embodiments of the pharmaceutical compositions, the second agent is an agent for treating cancer. In embodiments of the pharmaceutical compositions, the second agent is an anti-cancer agent. In embodiments, the administering does not include administration of any active agent other than the recited active agent (e.g., a compound described herein). In embodiments, the second agent is included in an effective amount.

IV. Methods of Use

In an aspect is provided a method of decreasing the level of Notch (e.g., one or more of Notch 1, Notch 2, Notch 3, and/or Notch 4) protein activity in a subject, the method including administering a compound described herein, or a salt (e.g., pharmaceutically acceptable salt) thereof, to the subject. In embodiments, the compound is administered in a therapeutically effective amount. In embodiments, the compound as described herein is included in an effective amount. In embodiments, the Notch is Notch 1. In embodiments, the Notch is Notch 2. In embodiments, the Notch is Notch 3. In embodiments, the Notch is Notch 4. In embodiments, the Notch is Notch 1 and Notch 2. In embodiments, the Notch is Notch 1 and Notch 3. In embodiments, the Notch is Notch 1 and Notch 4. In embodiments, the Notch is Notch 2 and Notch 3. In embodiments, the Notch is Notch 2 and Notch 4. In embodiments, the Notch is Notch 3 and Notch 4. In embodiments, the Notch is Notch 1, Notch 2, and Notch 3. In embodiments, the Notch is Notch 1, Notch 2, and Notch 4. In embodiments, the Notch is Notch 1, Notch 3, and Notch 4. In embodiments, the Notch is Notch 2, Notch 3, and Notch 4. In embodiments, the Notch is Notch 1, Notch 2, Notch 3, and Notch 4.

In an aspect is provided a method of decreasing the level of Notch (e.g., one or more of Notch 1, Notch 2, Notch 3, and/or Notch 4) activity in a cell, the method including contacting the cell with a compound described herein, or a salt (e.g., pharmaceutically acceptable salt) thereof. In embodiments, the compound is administered in an effective amount. In embodiments, the compound as described herein is included in an effective amount. In embodiments, the Notch is Notch 1. In embodiments, the Notch is Notch 2. In embodiments, the Notch is Notch 3. In embodiments, the Notch is Notch 4. In embodiments, the Notch is Notch 1 and Notch 2. In embodiments, the Notch is Notch 1 and Notch 3. In embodiments, the Notch is Notch 1 and Notch 4. In embodiments, the Notch is Notch 2 and Notch 3. In embodiments, the Notch is Notch 2 and Notch 4. In embodiments, the Notch is Notch 3 and Notch 4. In embodiments, the Notch is Notch 1, Notch 2, and Notch 3. In embodiments, the Notch is Notch 1, Notch 2, and Notch 4. In embodiments, the Notch is Notch 1, Notch 3, and Notch 4. In embodiments, the Notch is Notch 2, Notch 3, and Notch 4. In embodiments, the Notch is Notch 1, Notch 2, Notch 3, and Notch 4.

In an aspect is provided a method of decreasing the level of CSL-Notch (e.g., one or more of Notch 1, Notch 2, Notch 3, and/or Notch 4)-Mastermind complex activity in a subject, the method including administering a compound described herein, or a salt (e.g., pharmaceutically acceptable salt) thereof, to the subject. In embodiments, the compound is administered in an effective amount. In embodiments, the compound as described herein is included in an effective amount. In embodiments, the Notch is Notch 1. In embodiments, the Notch is Notch 2. In embodiments, the Notch is Notch 3. In embodiments, the Notch is Notch 4. In embodiments, the Notch is Notch 1 and Notch 2. In embodiments, the Notch is Notch 1 and Notch 3. In embodiments, the Notch is Notch 1 and Notch 4. In embodiments, the Notch is Notch 2 and Notch 3. In embodiments, the Notch is Notch 2 and Notch 4. In embodiments, the Notch is Notch 3 and Notch 4. In embodiments, the Notch is Notch 1, Notch 2, and Notch 3. In embodiments, the Notch is Notch 1, Notch 2, and Notch 4. In embodiments, the Notch is Notch 1, Notch 3, and Notch 4. In embodiments, the Notch is Notch 2, Notch 3, and Notch 4. In embodiments, the Notch is Notch 1, Notch 2, Notch 3, and Notch 4.

In an aspect is provided a method of decreasing the level of CSL-Notch (e.g., one or more of Notch 1, Notch 2, Notch 3, and/or Notch 4)-Mastermind complex activity in a cell, the method including contacting the cell with a compound described herein, or a salt (e.g., pharmaceutically acceptable salt) thereof. In embodiments, the compound is administered in an effective amount. In embodiments, the compound as described herein is included in an effective amount. In embodiments, the Notch is Notch 1. In embodiments, the Notch is Notch 2. In embodiments, the Notch is Notch 3. In embodiments, the Notch is Notch 4. In embodiments, the Notch is Notch 1 and Notch 2. In embodiments, the Notch is Notch 1 and Notch 3. In embodiments, the Notch is Notch 1 and Notch 4. In embodiments, the Notch is Notch 2 and Notch 3. In embodiments, the Notch is Notch 2 and Notch 4. In embodiments, the Notch is Notch 3 and Notch 4. In embodiments, the Notch is Notch 1, Notch 2, and Notch 3. In embodiments, the Notch is Notch 1, Notch 2, and Notch 4. In embodiments, the Notch is Notch 1, Notch 3, and Notch 4. In embodiments, the Notch is Notch 2, Notch 3, and Notch 4. In embodiments, the Notch is Notch 1, Notch 2, Notch 3, and Notch 4.

In embodiments, the compound contacts Notch (e.g., one or more of Notch 1, Notch 2, Notch 3, and/or Notch 4) protein. In embodiments, the compound contacts both Notch (e.g., one or more of Notch 1, Notch 2, Notch 3, and/or Notch 4) protein and CSL protein at the interface between the two proteins. In embodiments, the Notch is Notch 1. In embodiments, the Notch is Notch 2. In embodiments, the Notch is Notch 3. In embodiments, the Notch is Notch 4. In embodiments, the Notch is Notch 1 and Notch 2. In embodiments, the Notch is Notch 1 and Notch 3. In embodiments, the Notch is Notch 1 and Notch 4. In embodiments, the Notch is Notch 2 and Notch 3. In embodiments, the Notch is Notch 2 and Notch 4. In embodiments, the Notch is Notch 3 and Notch 4. In embodiments, the Notch is Notch 1, Notch 2, and Notch 3. In embodiments, the Notch is Notch 1, Notch 2, and Notch 4. In embodiments, the Notch is Notch 1, Notch 3, and Notch 4. In embodiments, the Notch is Notch 2, Notch 3, and Notch 4. In embodiments, the Notch is Notch 1, Notch 2, Notch 3, and Notch 4.

In embodiments, the compound reduces Mastermind binding to Notch (e.g., one or more of Notch 1, Notch 2, Notch 3, and/or Notch 4). In embodiments, the Notch is Notch 1. In embodiments, the Notch is Notch 2. In embodiments, the Notch is Notch 3. In embodiments, the Notch is Notch 4. In embodiments, the Notch is Notch 1 and Notch 2. In embodiments, the Notch is Notch 1 and Notch 3. In embodiments, the Notch is Notch 1 and Notch 4. In embodiments, the Notch is Notch 2 and Notch 3. In embodiments, the Notch is Notch 2 and Notch 4. In embodiments, the Notch is Notch 3 and Notch 4. In embodiments, the Notch is Notch 1, Notch 2, and Notch 3. In embodiments, the Notch is Notch 1, Notch 2, and Notch 4. In embodiments, the Notch is Notch 1, Notch 3, and Notch 4. In embodiments, the Notch is Notch 2, Notch 3, and Notch 4. In embodiments, the Notch is Notch 1, Notch 2, Notch 3, and Notch 4.

In embodiments, the compound reduces CSL binding to Notch (e.g., one or more of Notch 1, Notch 2, Notch 3, and/or Notch 4). In embodiments, the Notch is Notch 1. In embodiments, the Notch is Notch 2. In embodiments, the Notch is Notch 3. In embodiments, the Notch is Notch 4. In embodiments, the Notch is Notch 1 and Notch 2. In embodiments, the Notch is Notch 1 and Notch 3. In embodiments, the Notch is Notch 1 and Notch 4. In embodiments, the Notch is Notch 2 and Notch 3. In embodiments, the Notch is Notch 2 and Notch 4. In embodiments, the Notch is Notch 3 and Notch 4. In embodiments, the Notch is Notch 1, Notch 2, and Notch 3. In embodiments, the Notch is Notch 1, Notch 2, and Notch 4. In embodiments, the Notch is Notch 1, Notch 3, and Notch 4. In embodiments, the Notch is Notch 2, Notch 3, and Notch 4. In embodiments, the Notch is Notch 1, Notch 2, Notch 3, and Notch 4.

In an aspect is provided a method of inhibiting cancer growth in a subject in need thereof, the method including administering to the subject in need thereof an effective amount of a compound described herein, or a salt (e.g., pharmaceutically acceptable salt) thereof. In embodiments, the compound is administered in a therapeutically effective amount. In embodiments, the compound as described herein is included in an effective amount.

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 an effective amount of a compound described herein, or a salt (e.g., pharmaceutically acceptable salt) thereof. In embodiments, the compound is administered in a therapeutically effective amount. In embodiments, the compound as described herein is included in an effective amount.

In embodiments, the cancer is breast cancer, esophageal cancer, leukemia, prostate cancer, colorectal cancer, lung cancer, central nervous system cancer. In embodiments, the cancer is T-cell acute lymphoblastic leukemia, B-cell acute lymphoblastic leukemia, chronic lymphocytic leukemia, myelomonocytic leukemia, breast cancer, medulloblastoma, colorectal cancer, non-small cell lung carcinoma, melanoma, cerebral autosomal-dominant ateriopathy with sub-cortical infarcts and leukoencephalophathy, hepatocellular carcinoma, pancreatic ductal adenocarcinoma, head and neck squamous cell carcinoma, renal cell adenocarcinoma, basal cell carcinoma, luminal A breast cancer, luminal B breast cancer, or fibrosarcoma.

In embodiments, the method further includes co-administering an anti-cancer agent to the subject in need. In embodiments, the anti-cancer agent is administered in a therapeutically effective amount.

In an aspect is provided a method of treating a disease associated with Notch (e.g., one or more of Notch 1, Notch 2, Notch 3, and/or Notch 4) activity in a subject in need thereof, the method including administering to the subject in need thereof an effective amount of a compound described herein, or a salt (e.g., pharmaceutically acceptable salt) thereof. In embodiments, the compound is administered in a therapeutically effective amount. In embodiments, the compound as described herein is included in an effective amount. In embodiments, the Notch is Notch 1. In embodiments, the Notch is Notch 2. In embodiments, the Notch is Notch 3. In embodiments, the Notch is Notch 4. In embodiments, the Notch is Notch 1 and Notch 2. In embodiments, the Notch is Notch 1 and Notch 3. In embodiments, the Notch is Notch 1 and Notch 4. In embodiments, the Notch is Notch 2 and Notch 3. In embodiments, the Notch is Notch 2 and Notch 4. In embodiments, the Notch is Notch 3 and Notch 4. In embodiments, the Notch is Notch 1, Notch 2, and Notch 3. In embodiments, the Notch is Notch 1, Notch 2, and Notch 4. In embodiments, the Notch is Notch 1, Notch 3, and Notch 4. In embodiments, the Notch is Notch 2, Notch 3, and Notch 4. In embodiments, the Notch is Notch 1, Notch 2, Notch 3, and Notch 4.

In embodiments, the disease is cancer. In embodiments, the disease is multiple sclerosis. In embodiments, the disease is Tetralogy of Fallot or Alagille syndrome or Hajdu-Cheney syndrome.

In embodiments, the compound reduces the level of Notch (e.g., one or more of Notch 1, Notch 2, Notch 3, and/or Notch 4) protein contacting a CSL protein (e.g., in a cell, in a subject, compared to a control such as absence of the compound under otherwise identical conditions). In embodiments, the compound reduces the level of Notch (e.g., one or more of Notch 1, Notch 2, Notch 3, and/or Notch 4) protein contacting a Mastermind protein (e.g., in a cell, in a subject, compared to a control such as absence of the compound under otherwise identical conditions).

V. Embodiments

Embodiment P1. A compound having the formula:

embedded image

wherein,

L¹is a bond, —N(R^L1)—, —O—, —S—, —SO₂—, —C(O)—, —C(O)N(R^L1)—, —N(R^L1)C(O)—, —N(R^L1)C(O)NH—, —NHC(O)N(R^L1)—, —C(O)O—, —OC(O)—, —SO₂N(R^L1)—, —N(R^L1)SO₂—, substituted or unsubstituted alkylene, or, substituted or unsubstituted heteroalkylene;

R¹is independently hydrogen, halogen, —CX¹³, —CHX¹², —CH₂X¹, —OCX¹³, —OCH₂X¹, —OCHX¹², —CN, —SO_n1R^1D, —SO_v1NR^1AR^1B, —NR^CNR^1AR^1B, —ONR^1AR^1B, —NHC(O)NR^1CNR^1AR^1B, —NHC(O)NR^1AR^1B, —N(O)_m1, —NR^1AR^1B, —C(O)R^1C, —C(O)—OR^1C, —C(O)NR^1AR^1B, —OR^1D, —NR^1ASO₂R^1D, —NR^1AC(O)R^1C, —NR^1AC(O)OR^1C, —NR^1AOR^1C, 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;

R²is independently hydrogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

Ring A is phenyl or 5 to 6 membered heteroaryl;

R³is independently halogen, oxo, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CIF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —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 adjacent 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 independently an integer from 0 to 4;

Ring B is phenyl or 5 to 6 membered heteroaryl;

R⁴is independently halogen, oxo, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CIF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —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 adjacent 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 4;

Ring C is C₃-C₆cycloalkyl, 3 to 6 membered heterocycloalkyl, phenyl, or 5 to 6 membered heteroaryl;

L²is a bond, —N(R²)—, —O—, —S—, —SO₂—, —C(O)—, —C(O)N(R^L)—, —N(R^L2)C(O)—, —N(R^L2)C(O)NH—, —NHC(O)N(R^L2)—, —C(O)O—, —OC(O)—, —SO₂N(R^L2)—, —N(R^L2)SO₂—, substituted or unsubstituted alkylene, or, substituted or unsubstituted heteroalkylene;

R⁵is independently halogen, oxo, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —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 adjacent R⁵substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

z5 is an integer from 0 to 5;

R^1A, R^1B, R^1C, R^1D, R^L1, and R^Lare independently hydrogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R^1Aand R^1Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;

X¹is independently —F, —Cl, —Br, or —I;

n1 is independently an integer from 0 to 4; and

m1 and v1 are independently 1 or 2;

or a salt thereof.

Embodiment P2. The compound of embodiment P1, wherein Ring A is phenyl.

Embodiment P3. The compound of embodiment P1, wherein Ring A is a 5 to 6 membered heteroaryl.

Embodiment P4. The compound of one of embodiments P1 to P3, wherein Ring B is phenyl.

Embodiment P5. The compound of one of embodiments P1 to P3, wherein Ring B is pyridyl, pyrazinyl, pyridazinyl, pyridonyl, or pyrimidinyl.

Embodiment P6. The compound of one of embodiments P1 to P5, wherein Ring C is 5 membered heteroaryl.

Embodiment P7. The compound of one of embodiments P1 to P5, wherein Ring C is triazolyl.

Embodiment P8. The compound of one of embodiments P1 to P5, wherein Ring C is 1,2,4-triazolyl.

Embodiment P9. The compound of one of embodiments P6 to P8, having the formula:

embedded image

Embodiment P10. The compound of one of embodiments P6 to P8, having the formula:

embedded image

and

R^4.Aand R^4.Bare independently halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —SF₅, —N₃, substituted or unsubstituted C₁-C₆alkyl, or substituted or unsubstituted 2 to 6 membered heteroalkyl.

Embodiment P11. The compound of embodiment P10, wherein R^4.Ais unsubstituted C₁-C₄alkoxy and R^4.Bis halogen.

Embodiment P12. The compound of embodiment P10, wherein R^4.Ais unsubstituted methoxy and R^4.Bis —F.

Embodiment P13. The compound of one of embodiments P1 to P12, wherein L²is an unsubstituted 2 to 6 membered heteroalkylene;

Embodiment P14. The compound of one of embodiments P1 to P12, wherein L²is an unsubstituted —O—(C₁-C₆alkyl)-.

Embodiment P15. The compound of one of embodiments P1 to P12, wherein L²is —OCH₂—.

Embodiment P16. The compound of one of embodiments P1 to P15, wherein R³is independently halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —NO₂, —SH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —CH₃, —CH₂CH₃, —OCH₃, or —OCH₂CH₃.

Embodiment P17. The compound of one of embodiments P1 to P15, wherein R³is independently halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, or —CH₂I.

Embodiment P18. The compound of one of embodiments P1 to P15, wherein R³is independently —F or —CF₃.

Embodiment P19. The compound of one of embodiments P1 to P15, wherein R³is independently —CF₃.

Embodiment P20. The compound of one of embodiments P1 to P19, wherein R²is independently substituted or unsubstituted C₁-C₄alkyl or substituted or unsubstituted C₃-C₆cycloalkyl.

Embodiment P21. The compound of one of embodiments P1 to P19, wherein R²is independently unsubstituted C₁-C₄alkyl or unsubstituted C₃-C₆cycloalkyl.

Embodiment P22. The compound of one of embodiments P1 to P19, wherein R²is independently unsubstituted methyl or unsubstituted cyclopropyl.

Embodiment P23. The compound of one of embodiments P1 to P19, wherein R²is independently unsubstituted methyl.

Embodiment P24. The compound of one of embodiments P1 to P23, wherein L¹is substituted or unsubstituted heteroalkylene; R¹is independently substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

Embodiment P25. The compound of one of embodiments P1 to P23, wherein

L¹is —(C₁-C₆alkyl)-C(O)N(R^L1)— or —(C₁-C₆alkyl)-SO₂N(R^L1)—;

R¹is independently substituted phenyl or substituted 5 to 6 membered heteroaryl;

R^L1is independently hydrogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, unsubstituted alkyl, or unsubstituted cycloalkyl.

Embodiment P26. The compound of one of embodiments P1 to P23, wherein

Embodiment P27. The compound of one of embodiments P1 to P23, wherein

L¹is —CH₂C(O)N(R^L1)— or —CH₂SO₂N(R^L1)—;

R¹is independently substituted phenyl or substituted 5 to 6 membered heteroaryl;

R^L1is independently hydrogen, unsubstituted methyl, unsubstituted ethyl, unsubstituted isopropyl, or unsubstituted cyclopropyl.

Embodiment P28. The compound of one of embodiments P1 to P23, wherein L¹is —CH₂C(O)N(R^L1)—; R¹is independently substituted phenyl or substituted 5 to 6 membered heteroaryl; RY is independently hydrogen.

Embodiment P29. The compound of one of embodiments P1 to P28, wherein;

R¹is independently R¹⁰-substituted phenyl or R¹⁰-substituted 5 to 6 membered heteroaryl;

R¹⁰is independently halogen, oxo, —CX¹⁰₃, —CHX¹⁰₂, —CH₂X¹⁰, —OCX¹⁰₃, —OCH₂X¹⁰, —OCHX¹⁰₂, —CN, —SO_n10R^10D, —SO_v10NR^10AR^10B, —NR^10CNR^10AR^10B, —ONR^10AR^10B, —NHC(O)NR^10CNR^10AR^10B, —NHC(O)NR^10AR^10B, —N(O)_m10, —NR^10AR^10B, —C(O)R^10C, —C(O)—OR^10C, —C(O)NR^10AR^10B, —OR^10D, —NR^10ASO₂R^10D, —NR^10AC(O)R^10C, —NR^10AC(O)OR^10C, —NR^10AOR^10C, —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;

R^10A, R^10B, R^10C, and R^10Dare independently hydrogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R^10Aand R^10Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;

X¹⁰is independently —F, —Cl, —Br, or —I;

n10 is independently an integer from 0 to 4; and

m10 and v10 are independently 1 or 2.

Embodiment P30. The compound of one of embodiments P1 to P28, wherein;

R¹is independently R¹⁰-substituted phenyl or R¹⁰-substituted 5 to 6 membered heteroaryl;

R¹⁰is independently halogen, —CX¹⁰₃, —CHX¹⁰₂, —CH₂X¹⁰, —OCX¹⁰₃, —OCH₂X¹⁰, —OCHX¹⁰₂, —CN, —SO₂R^10D, —SR^10D, —C(O)R^10C, —OR^10D, substituted or unsubstituted C₁-C₆alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C₃-C₆cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl;

R^10A, R^10B, R^10C, and R^10Dare independently hydrogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, unsubstituted C₁-C₆alkyl, or unsubstituted C₃-C₆cycloalkyl;

X¹⁰is independently —F, —Cl, —Br, or —I.

Embodiment P31. The compound of one of embodiments P1 to P28, wherein;

R¹is independently R¹⁰-substituted phenyl or R¹⁰-substituted 5 to 6 membered heteroaryl;

R¹⁰is independently halogen, —CX¹⁰₃, —CHX¹⁰₂, —CH₂X¹⁰, —OCX¹⁰₃, —OCH₂X¹⁰, —OCHX¹⁰₂, —CN, —SO₂R^10D, —SR^10D, —OR^10D, unsubstituted C₁-C₄alkyl, unsubstituted 2 to 6 membered heteroalkyl, unsubstituted C₃-C₄cycloalkyl, or unsubstituted phenyl;

R^10A, R^10B, R^10C, and R^10Dare independently hydrogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, or unsubstituted methyl;

X¹⁰is independently —F, —Cl, —Br, or —I.

Embodiment P32. The compound of one of embodiments P1 to P28, wherein;

R¹is independently R¹⁰-substituted phenyl or R¹⁰-substituted 5 to 6 membered heteroaryl;

R¹⁰is independently halogen, —CF₃, —CIF₂, —CH₂F, —OCF₃, —OCH₂F, —OCHF₂, —OCH₃, —CH₂OCH₃, —CN, —SO₂CH₃, —SCH₃, —OCH₃, unsubstituted C₁-C₄alkyl, unsubstituted cyclopropyl, or unsubstituted phenyl.

Embodiment P33. The compound of one of embodiments P1 to P28, wherein; R¹is independently

embedded image

R^10.A, R^10.B, and R^10.Care independently halogen, —CF₃, —CHF₂, —CH₂F, —OCF₃, —OCH₂F, —OCHF₂, —OCH₃, —CH₂OCH₃, —CN, —SO₂CH₃, —SCH₃, —OCH₃, unsubstituted C₁-C₄alkyl, unsubstituted cyclopropyl, or unsubstituted phenyl.

Embodiment P34. The compound of one of embodiments P1 to P23, wherein

L¹is a substituted or unsubstituted alkylene;

R¹is independently —SO₂NR^1AR^1B, —NR^1AR^1B, or —C(O)NR^1AR^1B;

R^1Aand R^1Bare independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R^1Aand R^1Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl.

Embodiment P35. The compound of one of embodiments P1 to P23, wherein

L¹is an unsubstituted C₁-C₆alkylene;

R¹is independently —SO₂NR^1AR^1Bor —C(O)NR^1AR^1B;

R^1Aand R^1Bare independently hydrogen, substituted or unsubstituted C₁-C₆alkyl, substituted or unsubstituted C₃-C₆cycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl; R^1Aand R^1Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted C₃-C₆heterocycloalkyl.

Embodiment P36. The compound of one of embodiments P1 to P23, wherein

L¹is an unsubstituted methylene;

R¹is independently —C(O)NR^1AR^1B;

R^1Ais independently hydrogen, unsubstituted C₁-C₄alkyl, or unsubstituted cyclopropyl;

R^1Bare independently substituted or unsubstituted phenyl or substituted or unsubstituted 5 to 6 membered heteroaryl.

Embodiment P37. The compound of one of embodiments P1 to P23, wherein

L¹is an unsubstituted methylene;

R¹is independently —C(O)NR^1AR^1B.

R^1Ais independently hydrogen, unsubstituted C₁-C₄alkyl, or unsubstituted cyclopropyl;

R^1Bis independently R¹⁰-substituted phenyl or R¹⁰-substituted 5 to 6 membered heteroaryl;

R¹⁰is independently halogen, —CX¹⁰₃, —CHX¹⁰₂, —CH₂X¹⁰, —OCX¹⁰₃, —OCH₂X¹⁰, —OCHX¹⁰₂, —CN, —SO₂R^10D, —SR^10D, —OR^10D, unsubstituted C₁-C₄alkyl, unsubstituted 2 to 6 membered heteroalkyl, unsubstituted C₃-C₄cycloalkyl, or unsubstituted phenyl;

R^10A, R^10B, R^10C, and R^10Dare independently hydrogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, or unsubstituted methyl; and X¹⁰is independently —F, —Cl, —Br, or —I.

Embodiment P38. The compound of one of embodiments P1 to P23, wherein

Embodiment P39. The compound of one of embodiments P1 to P23, wherein

L¹is an unsubstituted methylene;

R¹is independently —C(O)NR^1AR^1B.

R^1Ais independently hydrogen, unsubstituted C₁-C₄alkyl, or unsubstituted cyclopropyl; R^1Bis independently

embedded image

Embodiment P40. The compound of one of embodiments P1 to P23, wherein

L¹is an unsubstituted C₁-C₆alkylene;

R¹is independently —SO₂NR^1AR^1Bor —C(O)NR^1AR^1B;

R^1Aand R^1Bbonded to the same nitrogen atom are joined to form a substituted or unsubstituted C₃-C₆heterocycloalkyl.

Embodiment P41. The compound of one of embodiments P1 to P23, wherein

L¹is an unsubstituted methylene;

R¹is independently —C(O)NR^1AR^1B.

R^1Aand R^1Bbonded to the same nitrogen atom are joined to form a substituted or unsubstituted piperazinyl.

Embodiment P42. The compound of one of embodiments P1 to P23, wherein

L¹is an unsubstituted methylene;

R¹is independently —C(O)NR^1AR^1B.

R^1Aand R^1Bbonded to the same nitrogen atom are joined to form

embedded image

and

R^10.Cis unsubstituted C₁-C₄alkyl.

Embodiment P43. The compound of one of embodiments P1 to P23, wherein

L¹is an unsubstituted methylene;

R¹is independently —C(O)NR^1AR^1B; and

R^1Aand R^1Bbonded to the same nitrogen atom are joined to form

embedded image

Embodiment P44. The compound of one of embodiments P1 to P23, wherein

L¹is a substituted alkylene;

R¹is independently —NR^1AR^1B;

R^1Aand R^1Bare independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R^1Aand R^1Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl.

Embodiment P45. The compound of one of embodiments P1 to P23, wherein

L¹is a substituted C₁-C₆alkylene;

R¹is independently —NR^1AR^1B;

R^1Aand R^1Bare independently hydrogen, substituted or unsubstituted C₁-C₆alkyl, substituted or unsubstituted C₃-C₆cycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl; R^1Aand R^1Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted C₃-C₆heterocycloalkyl.

Embodiment P46. The compound of one of embodiments P1 to P23, wherein

L¹is —CH₂C(O)—;

R¹is independently —NR^1AR^1B;

R^1Ais independently hydrogen, unsubstituted C₁-C₄alkyl, or unsubstituted cyclopropyl; R^1Bare independently substituted or unsubstituted phenyl or substituted or unsubstituted 5 to 6 membered heteroaryl.

Embodiment P47. The compound of one of embodiments P1 to P23, wherein

L¹is —CH₂C(O)—;

R¹is independently —NR^1AR^1B;

R^1Ais independently hydrogen, unsubstituted C₁-C₄alkyl, or unsubstituted cyclopropyl;

R^1Bis independently R¹⁰-substituted phenyl or R¹⁰-substituted 5 to 6 membered heteroaryl;

R¹⁰is independently halogen, —CX¹⁰₃, —CHX¹⁰₂, —CH₂X¹⁰, —OCX¹⁰₃, —OCH₂X¹⁰, —OCHX¹⁰₂, —CN, —SO₂R^10D, —SR^10D, —OR^10D, unsubstituted C₁-C₄alkyl, unsubstituted 2 to 6 membered heteroalkyl, unsubstituted C₃-C₄cycloalkyl, or unsubstituted phenyl;

R^10A, R^10B, R^10C, and R^10Dare independently hydrogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, or unsubstituted methyl; and

X¹⁰is independently —F, —Cl, —Br, or —I.

Embodiment P48. The compound of one of embodiments P1 to P23, wherein

Embodiment P49. The compound of one of embodiments P1 to P23, wherein

L¹is —CH₂C(O)—;

R¹is independently —NR^1AR^1B;

R^1Ais independently hydrogen, unsubstituted C₁-C₄alkyl, or unsubstituted cyclopropyl;

R^1Bis independently

embedded image

Embodiment P50. The compound of one of embodiments P1 to P23, wherein

L¹is a substituted C₁-C₆alkylene;

R¹is independently —NR^1AR^1B;

R^1Aand R^1Bbonded to the same nitrogen atom are joined to form a substituted or unsubstituted C₃-C₆heterocycloalkyl.

Embodiment P51. The compound of one of embodiments P1 to P23, wherein

L¹is —CH₂C(O)—;

R¹is independently —NR^1AR^1B;

R^1Aand R^1Bbonded to the same nitrogen atom are joined to form a substituted or unsubstituted piperazinyl.

Embodiment P52. The compound of one of embodiments P1 to P23, wherein

L¹is —CH₂C(O)—;

R¹is independently —NR^1AR^1B;

R^1Aand R^1Bbonded to the same nitrogen atom are joined to form

embedded image

and R^10.Cis unsubstituted C₁-C₄alkyl.

Embodiment P53. The compound of one of embodiments P1 to P23, wherein

L¹is —CH₂C(O)—;

R¹is independently —NR^1AR^1B; and

R^1Aand R^1Bbonded to the same nitrogen atom are joined to form

embedded image

Embodiment P54. A pharmaceutical composition comprising the compound of any one of embodiments P1 to P53 and a pharmaceutically acceptable excipient.

Embodiment P55. A method of decreasing the level of Notch protein activity in a subject, said method comprising administering a compound of one of embodiments P1 to P53 to said subject.

Embodiment P56. A method of decreasing the level of Notch activity in a cell, said method comprising contacting said cell with a compound of one of embodiments P1 to P53.

Embodiment P57. A method of decreasing the level of CSL-Notch-Mastermind complex activity in a subject, said method comprising administering a compound of one of embodiments P1 to P53 to said subject.

Embodiment P58. A method of decreasing the level of CSL-Notch-Mastermind complex activity in a cell, said method comprising contacting said cell with a compound of one of embodiments P1 to P53.

Embodiment P59. The method of one of embodiments P55 to P58, wherein the compound contacts Notch protein.

Embodiment P60. The method of one of embodiments P55 to P59, wherein the compound reduces Mastermind binding to Notch.

Embodiment P61. The method of one of embodiments P55 to P60, wherein the compound reduces CSL binding to Notch.

Embodiment P62. A method of inhibiting cancer growth in a subject in need thereof, said method comprising administering to the subject in need thereof an effective amount of a compound of one of embodiments P1 to P53.

Embodiment P63. A method of treating a cancer in a subject in need thereof, said method comprising administering to the subject in need thereof an effective amount of a compound of one of embodiments P1 to P53.

Embodiment P64. The method of embodiment P63, wherein the cancer is breast cancer, esophageal cancer, leukemia, prostate cancer, colorectal cancer, lung cancer, central nervous system cancer.

Embodiment P65. The method of one of embodiments P63 to P64, further comprising co-administering an anti-cancer agent to said subject in need.

VI. Additional Embodiments

Embodiment 1. A compound having the formula:

embedded image

wherein

L¹is substituted or unsubstituted heteroalkylene, a bond, —N(R^L1)—, —O—, —S—, —SO₂—, —C(O)—, —C(O)N(R^L1)—, —N(R^L1)C(O)—, —N(R^L1)C(O)NH—, —NHC(O)N(R^L1)—, —C(O)O—, —OC(O)—, —SO₂N(R^L1)—, —N(R^L1)SO₂—, or substituted or unsubstituted alkylene;

R¹is substituted or unsubstituted aryl, hydrogen, halogen, —CX¹₃, —CHX¹₂, —CH₂X¹, —OCX¹₃, —OCH₂X¹, —OCHX¹₂, —CN, —SO_n1R^1D, —SO_v1NR^1AR^1B, —NR^1CNR^1AR^1B, —ONR^1AR^1B, —NHC(O)NR^1CNR^1AR^1B, —NHC(O)NR^1AR^1B, —N(O)_m1, —NR^1AR^1B, —C(O)R^1C, —C(O)—OR^1C, —C(O)NR^1AR^1B, —OR^1D, —NR^1ASO_2R^1D, —NR^1AC(O)R^1C, —NR^1AC(O)OR^1C, —NR^1AOR^1C, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted heteroaryl;

R²is unsubstituted alkyl, hydrogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, substituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

R³is independently —CF₃, halogen, —CCl₃, —CBr₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —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 adjacent R³substituents may optionally be joined to form substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

z3 is an integer from 0 to 3;

R⁴is independently halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —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 adjacent R⁴substituents may optionally be joined to form substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

z4 is an integer from 0 to 4;

L²is unsubstituted heteroalkylene, a bond, —N(R^L)—, —O—, —S—, —SO₂—, —C(O)—, —C(O)N(R^L2)—, —N(R^L2)C(O)—, —N(R^L2)C(O)NH—, —NHC(O)N(R^L2)—, —C(O)O—, —OC(O)—, —SO₂N(R^L2)—, —N(R^L)SO₂—, substituted or unsubstituted alkylene, or substituted heteroalkylene;

R⁵is independently halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —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 adjacent R⁵substituents may optionally be joined to form substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

z5 is an integer from 0 to 2;

R^1A, R^1B, R^1C, R^1D, R^L1, and R^L2are independently hydrogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CIF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R^1Aand R^1Bsubstituents bonded to the same nitrogen atom may optionally be joined to form substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;

X¹is independently —F, —Cl, —Br, or —I;

n1 is an integer from 0 to 4; and

m1 and v1 are independently 1 or 2;

or a pharmaceutically acceptable salt thereof.

Embodiment 2. A compound having the formula:

embedded image

wherein

L¹is a bond, —N(R^L1)—, —O—, —S—, —SO₂—, —C(O)—, —C(O)N(R^L1)—, —N(R^L1)C(O)—, —N(R^L1)C(O)NH—, —NHC(O)N(R^L1)—, —C(O)O—, —OC(O)—, —SO₂N(R^L1)—, —N(R^L1)SO₂—, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene;

R¹is hydrogen, halogen, —CX¹³, —CHX¹₂, —CH₂X¹, —OCX¹³, —OCH₂X¹, —OCHX¹₂, —CN, —SO_n1R^1D, —SO_v1NR^1AR^1B, —NR^1CNR^1AR^1B, —ONR^1AR^1B, —NHC(O)NR^1CNR^1AR^1B, —NHC(O)NR^1AR^1B, —N(O)_m1, —NR^1AR^1B, —C(O)R^1C, —C(O)—OR^1C, —C(O)NR^1AR^1B, —OR^1D, —NR^1ASO₂R^1D, —NR^1AC(O)R^1C, —NR^1AC(O)OR^1C, —NR^1AOR^1C, 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;

R²is hydrogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CIF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

Ring A is phenyl or 5 to 6 membered heteroaryl;

R³is independently halogen, oxo, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —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 adjacent 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 4;

Ring B is phenyl or 5 to 6 membered heteroaryl;

R⁴is independently halogen, oxo, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —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 adjacent 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 4;

Ring C is C₃-C₆cycloalkyl, 3 to 6 membered heterocycloalkyl, phenyl, or 5 to 6 membered heteroaryl;

L²is a bond, —N(R²)—, —O—, —S—, —SO₂—, —C(O)—, —C(O)N(R^L)—, —N(R^L2)C(O)—, —N(R^L2)C(O)NH—, —NHC(O)N(R^L2)—, —C(O)O—, —OC(O)—, —SO₂N(R^L2)—, —N(R^L2)SO₂—, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene;

R⁵is independently halogen, oxo, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —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 adjacent R⁵substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

z5 is an integer from 0 to 5;

R^1A, R^1B, R^1C, R^1D, R^L1, and R²are independently hydrogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CIF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R^1Aand R^1Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;

X¹is independently —F, —Cl, —Br, or —I;

n1 is an integer from 0 to 4; and

m1 and v1 are independently 1 or 2;

or a pharmaceutically acceptable salt thereof.

Embodiment 3. The compound of embodiment 2, wherein Ring A is phenyl.

Embodiment 4. The compound of embodiment 2, wherein Ring A is a 5 to 6 membered heteroaryl.

Embodiment 5. The compound of one of embodiments 2 to 4, wherein Ring B is phenyl.

Embodiment 6. The compound of one of embodiments 2 to 4, wherein Ring B is pyridyl, pyrazinyl, pyridazinyl, pyridonyl, or pyrimidinyl.

Embodiment 7. The compound of one of embodiments 2 to 6, wherein Ring C is 5 membered heteroaryl.

Embodiment 8. The compound of one of embodiments 2 to 6, wherein Ring C is triazolyl.

Embodiment 9. The compound of one of embodiments 2 to 6, wherein Ring C is 1,2,4-triazolyl.

Embodiment 10. The compound of one of embodiments 7 to 9, having the formula:

embedded image

Embodiment 11. The compound of one of embodiments 7 to 9, having the formula:

embedded image

wherein

R^4.Aand R^4.Bare independently halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH, —CONHl₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —SF₅, —N₃, substituted or unsubstituted C₁-C₆alkyl, or substituted or unsubstituted 2 to 6 membered heteroalkyl.

Embodiment 12. The compound of embodiment 11, wherein R^4.Ais unsubstituted C₁-C₄alkoxy and R^4.Bis halogen.

Embodiment 13. The compound of embodiment 11, wherein R^4.Ais unsubstituted methoxy and R^4.Bis —F.

Embodiment 14. The compound of one of embodiments 7 to 9, having the formula:

embedded image

wherein

R^4.Aand R^4.Bare independently halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —SF₅, —N₃, substituted or unsubstituted C₁-C₆alkyl, or substituted or unsubstituted 2 to 6 membered heteroalkyl.

Embodiment 15. The compound of embodiment 14, wherein R^4.Ais unsubstituted methoxy and R^4.Bis —F.

Embodiment 16. The compound of one of embodiments 7 to 9, having the formula:

embedded image

Embodiment 17. The compound of embodiment 16, wherein R^4.Ais —COOH and R^4.Bis unsubstituted methoxy.

Embodiment 18. The compound of embodiment 16, wherein R^4.Ais —F and R^4.Bis unsubstituted methoxy.

Embodiment 19. The compound of one of embodiments 7 to 9, having the formula:

embedded image

Embodiment 20. The compound of one of embodiments 1 to 19, wherein L²is an unsubstituted 2 to 6 membered heteroalkylene.

Embodiment 21. The compound of one of embodiments 1 to 19, wherein L²is an unsubstituted —O—(C₁-C₆alkyl)-.

Embodiment 2₂. The compound of one of embodiments 1 to 19, wherein L²is —OCH₂—.

Embodiment 2₃. The compound of one of embodiments 1 to 2₂, wherein R³is independently halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —NO₂, —SH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —CH₃, —CH₂CH₃, —OCH₃, or —OCH₂CH₃.

Embodiment 24. The compound of one of embodiments 1 to 2₂, wherein R³is independently halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, or —CH₂I.

Embodiment 25. The compound of one of embodiments 1 to 2₂, wherein R³is independently —F or —CF₃.

Embodiment 26. The compound of one of embodiments 1 to 2₂, wherein R³is independently —CF₃.

Embodiment 27. The compound of one of embodiments 1 to 26, wherein R²is substituted or unsubstituted C₁-C₄alkyl or substituted or unsubstituted C₃-C₆cycloalkyl.

Embodiment 28. The compound of one of embodiments 1 to 26, wherein R²is unsubstituted C₁-C₄alkyl or unsubstituted C₃-C₆cycloalkyl.

Embodiment 29. The compound of one of embodiments 1 to 26, wherein R²is unsubstituted methyl or unsubstituted cyclopropyl.

Embodiment 30. The compound of one of embodiments 1 to 26, wherein R²is unsubstituted methyl.

Embodiment 31. The compound of one of embodiments 1 to 30, wherein L¹is substituted or unsubstituted heteroalkylene; and R¹is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

Embodiment 32. The compound of one of embodiments 1 to 30, wherein

L¹is —(C₁-C₆alkyl)-C(O)N(R^L1)— or —(C₁-C₆alkyl)-SO₂N(R^L1)—;

R¹is substituted phenyl or substituted 5 to 6 membered heteroaryl; and

R^L1is hydrogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, unsubstituted alkyl, or unsubstituted cycloalkyl.

Embodiment 33. The compound of one of embodiments 1 to 30, wherein

L¹is —(C₁-C₆alkyl)-C(O)N(R^L1)— or —(C₁-C₆alkyl)-SO₂N(R^L1)—;

R¹is substituted phenyl or substituted 5 to 6 membered heteroaryl; and

R^L1is hydrogen, unsubstituted C₁-C₆alkyl, or unsubstituted C₃-C₆cycloalkyl.

Embodiment 34. The compound of one of embodiments 1 to 30, wherein

L¹is —CH₂C(O)N(R^L1)— or —CH₂SO₂N(R^L1)—;

R¹is substituted phenyl or substituted 5 to 6 membered heteroaryl; and

R^L1is hydrogen, unsubstituted methyl, unsubstituted ethyl, unsubstituted isopropyl, or unsubstituted cyclopropyl.

Embodiment 35. The compound of one of embodiments 1 to 30, wherein

L¹is —CH₂C(O)N(R^L1)—;

R¹is substituted phenyl or substituted 5 to 6 membered heteroaryl; and

R^L1is hydrogen.

Embodiment 36. The compound of one of embodiments 1 to 35, wherein;

R¹is R¹⁰-substituted phenyl or R¹⁰-substituted 5 to 6 membered heteroaryl;

R¹⁰is independently halogen, oxo, —CX¹⁰₃, —CHX¹⁰₂, —CH₂X¹⁰, —OCX¹⁰₃, —OCH₂X¹⁰, —OCHX¹⁰₂, —CN, —SO_n10R^10D, —SO_v10NR^10AR^10B, —NR^10CNR^10AR^10B, —ONR^10AR^10B, —NHC(O)NR^10CNR^10AR^10B, —NHC(O)NR^10AR^10B, —N(O)_m10, —NR^10AR^10B, —C(O)R^10C, —C(O)—OR^10C, —C(O)NR^10AR^10B, —OR^10D, —NR^10ASO₂R^10D, —NR^10AC(O)R^10C, —NR^10AC(O)OR^10C, —NR^10AOR^10C, —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;

R^10A, R^10B, R^10C, and R^10Dare independently hydrogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R^10Aand R^10Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;

X¹⁰is independently —F, —Cl, —Br, or —I;

n10 is an integer from 0 to 4; and

m10 and v10 are independently 1 or 2.

Embodiment 37. The compound of one of embodiments 1 to 35, wherein;

R¹is R¹⁰-substituted phenyl or R¹⁰-substituted 5 to 6 membered heteroaryl;

R¹⁰is independently halogen, —CX¹⁰₃, —CHX¹⁰₂, —CH₂X¹⁰, —OCX¹⁰₃, —OCH₂X¹⁰, —OCHX¹⁰₂, —CN, —SO₂R^10D, —SR^10D, —C(O)R^10C, —OR^10D, substituted or unsubstituted C₁-C₆alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C₃-C₆cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl;

R^10A, R^10B, R^10C, and R^10Dare independently hydrogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, unsubstituted C₁-C₆alkyl, or unsubstituted C₃-C₆cycloalkyl; and

X¹⁰is independently —F, —Cl, —Br, or —I.

Embodiment 38. The compound of one of embodiments 1 to 35, wherein;

R¹is R¹⁰-substituted phenyl or R¹⁰-substituted 5 to 6 membered heteroaryl;

R¹⁰is independently halogen, —CX¹⁰₃, —CHX¹⁰₂, —CH₂X¹⁰, —OCX¹⁰₃, —OCH₂X¹⁰, —OCHX¹⁰₂, —CN, —SO₂R^10D, —SR^10D, —OR^10D, unsubstituted C₁-C₄alkyl, unsubstituted 2 to 6 membered heteroalkyl, unsubstituted C₃-C₄cycloalkyl, or unsubstituted phenyl;

R^10A, R^10B, R^10C, and R^10Dare independently hydrogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, or unsubstituted methyl; and X¹⁰is independently —F, —Cl, —Br, or —I.

Embodiment 39. The compound of one of embodiments 1 to 35, wherein;

R¹is independently R¹⁰-substituted phenyl or R¹⁰-substituted 5 to 6 membered heteroaryl; and

R¹⁰is independently halogen, —CF₃, —CIF₂, —CH₂F, —OCF₃, —OCH₂F, —OCHF₂, —OCH₃, —CH₂OCH₃, —CN, —SO₂CH₃, —SCH₃, —OCH₃, unsubstituted C₁-C₄alkyl, unsubstituted cyclopropyl, or unsubstituted phenyl.

Embodiment 40. The compound of one of embodiments 1 to 35, wherein;

R¹is

embedded image

and

R^10.A, R^10.B, and R^10.Care independently halogen, —CF₃, —CIF₂, —CH₂F, —OCF₃, —OCH₂F, —OCHF₂, —OCH₃, —CH₂OCH₃, —CN, —SO₂CH₃, —SCH₃, —OCH₃, unsubstituted C₁-C₄alkyl, unsubstituted cyclopropyl, or unsubstituted phenyl.

Embodiment 41. The compound of one of embodiments 1 to 30, wherein

L¹is a substituted or unsubstituted alkylene;

R¹is-SO₂NR^1AR^1B, —NR^1AR^1B, or —C(O)NR^1AR^1B; and R^1Aand R^1Bare independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R^1Aand R^1Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl.

Embodiment 42. The compound of one of embodiments 1 to 30, wherein

L¹is an unsubstituted C₁-C₆alkylene;

R¹is-SO₂NR^1AR^1Bor —C(O)NR^1AR^1B; and

R^1Aand R^1Bare independently hydrogen, substituted or unsubstituted C₁-C₆alkyl, substituted or unsubstituted C₃-C₆cycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl; R^1Aand R^1Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted C₃-C₆heterocycloalkyl.

Embodiment 43. The compound of one of embodiments 1 to 30, wherein

L¹is an unsubstituted methylene;

R¹is —C(O)NR^1AR^1B;

R^1Ais hydrogen, unsubstituted C₁-C₄alkyl, or unsubstituted cyclopropyl; and

R^1Bis substituted or unsubstituted phenyl or substituted or unsubstituted 5 to 6 membered heteroaryl.

Embodiment 44. The compound of one of embodiments 1 to 30, wherein

L¹is an unsubstituted methylene;

R¹is —C(O)NR^1AR^1B;

R^1Ais hydrogen, unsubstituted C₁-C₄alkyl, or unsubstituted cyclopropyl;

R^1Bis R¹⁰-substituted phenyl or R¹⁰-substituted 5 to 6 membered heteroaryl;

R¹⁰is independently halogen, —CX¹⁰₃, —CHX¹⁰₂, —CH₂X¹⁰, —OCX¹⁰₃, —OCH₂X¹⁰, —OCHX¹⁰₂, —CN, —SO₂R^10D, —SR^10D, —OR^10D, unsubstituted C₁-C₄alkyl, unsubstituted 2 to 6 membered heteroalkyl, unsubstituted C₃-C₄cycloalkyl, or unsubstituted phenyl;

R^10A, R^10B, R^10C, and R^10Dare independently hydrogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, or unsubstituted methyl; and

X¹⁰is independently —F, —Cl, —Br, or —I.

Embodiment 45. The compound of one of embodiments 1 to 30, wherein

Embodiment 46. The compound of one of embodiments 1 to 30, wherein

L¹is an unsubstituted methylene;

R¹is —C(O)NR^1AR^1B;

R^1Ais hydrogen, unsubstituted C₁-C₄alkyl, or unsubstituted cyclopropyl;

R¹⁰is

embedded image

and

R^10.A, R^10.B, and R^10.Care independently halogen, —CF₃, —CIF₂, —CH₂F, —OCF₃, —OCH₂F, —OCHF₂, —OCH₃, —CH₂OCH₃, —CN, —SO₂CH₃, —SCH₃, —OCH₃, unsubstituted C₁-C₄alkyl, unsubstituted cyclopropyl, or unsubstituted phenyl.

Embodiment 47. The compound of one of embodiments 1 to 30, wherein

L¹is an unsubstituted C₁-C₆alkylene;

R¹is-SO₂NR^1AR^1Bor —C(O)NR^1AR^1B; and

R^1Aand R^1Bbonded to the same nitrogen atom are joined to form a substituted or unsubstituted C₃-C₆heterocycloalkyl.

Embodiment 48. The compound of one of embodiments 1 to 30, wherein

L¹is an unsubstituted methylene;

R¹is —C(O)NR^1AR^1B; and

R^1Aand R^1Bbonded to the same nitrogen atom are joined to form a substituted or unsubstituted piperazinyl.

Embodiment 49. The compound of one of embodiments 1 to 30, wherein

L¹is an unsubstituted methylene;

R¹is —C(O)NR^1AR^1B;

R^1Aand R^1Bbonded to the same nitrogen atom are joined to form

embedded image

and

R^10.Cis unsubstituted C₁-C₄alkyl.

Embodiment 50. The compound of one of embodiments 1 to 30, wherein

L¹is an unsubstituted methylene;

R¹is —C(O)NR^1AR^1B; and

R^1Aand R^1Bbonded to the same nitrogen atom are joined to form

embedded image

Embodiment 51. The compound of one of embodiments 1 to 30, wherein

L¹is a substituted alkylene;

R¹is —NR^1AR^1B; and

R^1Aand R^1Bare independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R^1Aand R^1Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl.

Embodiment 52. The compound of one of embodiments 1 to 30, wherein

L¹is a substituted C₁-C₆alkylene;

R¹is —NR^1AR^1B; and

R^1Aand R^1Bare independently hydrogen, substituted or unsubstituted C₁-C₆alkyl, substituted or unsubstituted C₃-C₆cycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl; R^1Aand R^1Bsubstituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted C₃-C₆heterocycloalkyl.

Embodiment 53. The compound of one of embodiments 1 to 30, wherein

L¹is —CH₂C(O)—;

R¹is —NR^1AR^1B;

R^1Ais hydrogen, unsubstituted C₁-C₄alkyl, or unsubstituted cyclopropyl; and

R^1Bis substituted or unsubstituted phenyl or substituted or unsubstituted 5 to 6 membered heteroaryl.

Embodiment 54. The compound of one of embodiments 1 to 30, wherein

L¹is —CH₂C(O)—;

R¹is —NR^1AR^1B;

R^1Ais hydrogen, unsubstituted C₁-C₄alkyl, or unsubstituted cyclopropyl;

R^1Bis R¹⁰-substituted phenyl or R¹⁰-substituted 5 to 6 membered heteroaryl;

R¹⁰is independently halogen, —CX¹⁰₃, —CHX¹⁰₂, —CH₂X¹⁰, —OCX¹⁰₃, —OCH₂X¹⁰, —OCHX¹⁰₂, —CN, —SO₂R^10D, —SR^10D, —OR^10D, unsubstituted C₁-C₄alkyl, unsubstituted 2 to 6 membered heteroalkyl, unsubstituted C₃-C₄cycloalkyl, or unsubstituted phenyl;

R^10A, R^10B, R^10C, and R^10Dare independently hydrogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, or unsubstituted methyl; and X¹⁰is independently —F, —Cl, —Br, or —I.

Embodiment 55. The compound of one of embodiments 1 to 30, wherein

L¹is —CH₂C(O)—;

R¹is —NR^1AR^1B;

R^1Ais hydrogen, unsubstituted C₁-C₄alkyl, or unsubstituted cyclopropyl;

R^1Bis R¹⁰-substituted phenyl or R¹⁰-substituted 5 to 6 membered heteroaryl; and

R¹⁰is independently halogen, —CF₃, —CIF₂, —CH₂F, —OCF₃, —OCH₂F, —OCHF₂, —OCH₃, —CH₂OCH₃, —CN, —SO₂CH₃, —SCH₃, —OCH₃, unsubstituted C₁-C₄alkyl, unsubstituted cyclopropyl, or unsubstituted phenyl.

Embodiment 56. The compound of one of embodiments 1 to 30, wherein

L¹is —CH₂C(O)—;

R¹is —NR^1AR^1B;

R^1Ais hydrogen, unsubstituted C₁-C₄alkyl, or unsubstituted cyclopropyl; R^1Bis

embedded image

and

R^10.A, R^10.B, and R^10.Care independently halogen, —CF₃, —CIF₂, —CH₂F, —OCF₃, —OCH₂F, —OCHF₂, —OCH₃, —CH₂OCH₃, —CN, —SO₂CH₃, —SCH₃, —OCH₃, unsubstituted C₁-C₄alkyl, unsubstituted cyclopropyl, or unsubstituted phenyl.

Embodiment 57. The compound of one of embodiments 1 to 30, wherein

L¹is a substituted C₁-C₆alkylene;

R¹is —NR^1AR^1B; and

R^1Aand R^1Bbonded to the same nitrogen atom are joined to form a substituted or unsubstituted C₃-C₆heterocycloalkyl.

Embodiment 58. The compound of one of embodiments 1 to 30, wherein

L¹is —CH₂C(O)—;

R¹is —NR^1AR^1B; and

R^1Aand R^1Bbonded to the same nitrogen atom are joined to form a substituted or unsubstituted piperazinyl.

Embodiment 59. The compound of one of embodiments 1 to 30, wherein

L¹is —CH₂C(O)—;

R¹is —NR^1AR^1B;

R^1Aand R^1Bbonded to the same nitrogen atom are joined to form

embedded image

and

R^10.Cis unsubstituted C₁-C₄alkyl.

Embodiment 60. The compound of one of embodiments 1 to 30, wherein

L¹is —CH₂C(O)—;

R¹is —NR^1AR^1B; and

R^1Aand R^1Bbonded to the same nitrogen atom are joined to form

embedded image

Embodiment 61. The compound of embodiment 2, having the formula:

embedded image

Embodiment 62. A pharmaceutical composition comprising the compound of any one of embodiments 1 to 61 and a pharmaceutically acceptable excipient.

Embodiment 63. A method of decreasing the level of Notch protein activity in a subject, said method comprising administering a compound of one of embodiments 1 to 61 to said subject.

Embodiment 64. A method of decreasing the level of Notch activity in a cell, said method comprising contacting said cell with a compound of one of embodiments 1 to 61.

Embodiment 65. A method of decreasing the level of CSL-Notch-Mastermind complex activity in a subject, said method comprising administering a compound of one of embodiments 1 to 61 to said subject.

Embodiment 66. A method of decreasing the level of CSL-Notch-Mastermind complex activity in a cell, said method comprising contacting said cell with a compound of one of embodiments 1 to 61.

Embodiment 67. The method of one of embodiments 63 to 66, wherein the compound contacts Notch protein.

Embodiment 68. The method of one of embodiments 63 to 67, wherein the compound reduces Mastermind binding to Notch.

Embodiment 69. The method of one of embodiments 63 to 68, wherein the compound reduces CSL binding to Notch.

Embodiment 70. A method of inhibiting cancer growth in a subject in need thereof, said method comprising administering to the subject in need thereof an effective amount of a compound of one of embodiments 1 to 61.

Embodiment 71. A method of treating a cancer in a subject in need thereof, said method comprising administering to the subject in need thereof an effective amount of a compound of one of embodiments 1 to 61.

Embodiment 72. The method of embodiment 71, wherein the cancer is breast cancer, esophageal cancer, leukemia, prostate cancer, colorectal cancer, lung cancer, central nervous system cancer.

Embodiment 73. The method of one of embodiments 71 to 72, further comprising co-administering an anti-cancer agent to said subject in need.

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.

EXAMPLES
Example 1: Experimental Procedures and Characterization Data

General Synthetic Procedures

embedded image

Method A. To a round bottom flask was added urea (1 eq), potassium carbonate (3 eq) and THE (0.1 M). Ethyl chloroacetate (1.05 eq) was added dropwise. The reaction was heated to 65° C. until full conversion. Upon completion, the reaction was cooled to room temperature and diluted with Et₂O. The mixture was filtered and concentrated. The crude material was purified by flash column chromatography (10-50% EtOAc/Hexanes) to afford the alkylated urea.

Method B. To a round bottom flask was added boronic ester (1 eq), aryl bromide (1 eq), palladium acetate (0.05 eq), RuPhos (0.1 eq), and potassium phosphate (3 eq). Toluene (0.1 M) and water (1 M) were added and degassed by bubbling argon for 15 minutes. The reaction was stirred at 85° C. until full conversion. Upon cooling, the aqueous layer was discarded. The organic layer was diluted with DCM and dried over sodium sulfate. The organic layer was filtered through celite and concentrated. The crude material was purified by flash column chromatography (MeOH/DCM, 0-5%) to yield the product.

Method C. To a round bottom flask was added benzyl alcohol (1 eq) and solvent (0.1 M; MeOH, toluene, THF, depending on solubility of SM). The vessel was purged by bubbling argon through the solution for 5 minutes. Then palladium on carbon was added (10% w/w). Hydrogen was then bubbled through the solution for 10 minutes, and then kept under a hydrogen atmosphere until full conversion was reached. Upon completion, the mixture was filtered through a pad of celite and concentrated to afford the product without any further purification.

Method D. To a round bottom flask was added phenol (1 eq), cesium carbonate (2 eq), chloromethyl triazole (1.05 eq), and DMF. The reaction was then stirred in an oil bath at 70° C. until full conversion. Upon completion, the reaction was diluted with Et₂O and transferred to a separatory funnel. The organic solution was washed twice with water and once with brine. The organic layer was separated, dried over anhydrous Na₂SO₄, filtered, and concentrated. The crude material was purified by flash column chromatography (0-5% MeOH/DCM) to afford the product.

Method E. To a round bottom flask was added ester (1 eq) and THF (0.1 M). An aqueous solution of LiOH (5 eq, 5 M) was added slowly. The reaction was stirred at room temperature until full conversion. Upon completion, the mixture was acidified with 1 M HCl to pH<3. The mixture was diluted with Et₂O and transferred to a separatory funnel and extracted three times. The combined organic extracts were dried over anhydrous Na₂SO₄, filtered, and concentrated to afford the product without further purification.

Method F. To a round bottom flask was added carboxylic acid (1 eq), HATU (1.6 eq), DMF, and ⁱPr₂NEt (5 eq) were added and stirred. Amine (1.05 eq) was added and stirred for 18 h at room temperature until completion. The reaction was diluted with Et₂O and transferred to a separatory funnel. The organic solution was washed with water and with brine. The combined aqueous washes were then extracted with Et₂O. The combined organic extracts were dried over anhydrous Na₂SO₄, filtered, and concentrated. The crude material was purified by flash column chromatography (0-5% MeOH/DCM) to afford the product.

Method G. To a round bottom flask was added trityl triazole (1 eq) and anhydrous THF (0.1 M). Anhydrous HCl (5 eq, 2 M in Et₂O) was then added dropwise. Upon full conversion as determined by LCMS, the mixture was concentrated and then purified by flash column chromatography (MeOH/DCM, 0-20%) to afford the final target.

Preparation of Boronate Ester (1)

embedded image

2-(benzyloxy)-5-bromo-3-fluorobenzaldehyde (3)

To a stirred solution of 5-bromo-3-fluoro-2-hydroxybenzaldehyde (1, 10.0 g, 45.66 mmol) in ACN (250 mL), K₂CO₃(10.1 g, 73.05 mmol) was added at 0° C. followed by benzyl bromide (15.6 g, 91.32 mmol) and the reaction mixture was stirred at room temperature for 8 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was diluted with ice cold water and extracted with ethyl acetate. The organic layer was dried over anhydrous Na₂SO₄and concentrated under reduced pressure. The crude compound was purified by flash column chromatography (10% EtOAc/hexane) to afford compound 3 (10.0 g, 71.0%) as a white solid. ¹H NMR (400 MHz, DMSO-d6): δ 10.03 (s, 1H), 8.015 (d, J=10.8 Hz, 1H), 7.59 (s, 1H), 7.45-7.38 (m, 5H), 5.26 (s, 2H).

2-(benzyloxy)-5-bromo-3-fluorophenol (4)

To a stirred solution of compound 3 (10.0 g, 32.46 mmol) in DCM (150 mL), KH₂PO₄(35.3 g, 259.68 mmol) was added at 0° C. To the resulting reaction mixture, H₂O₂(30%, 40 mL) was added followed by TFAA (60 mL) drop wise at 0° C. and the reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. After completion of reaction, DCM layer was separated. The aqueous layer was extracted with DCM. Combined organic layer was washed with brine, dried over anhydrous Na₂SO₄and concentrated under reduced pressure. The crude compound was purified by flash column chromatography (2% EtOAc/hexane) to afford compound 4 (5.8 g, 60.0%) as colorless viscous oil. ¹H NMR (400 MHz, DMSO-d6): δ 10.40 (s, 1H), 7.43-7.30 (m, 5H), 6.94 (d, J=11.6 Hz, 1H), 6.86 (s, 1H), 5.03 (s, 2H).

2-(benzyloxy)-5-bromo-1-fluoro-3-methoxybenzene (5)

To a stirred solution of compound 4 (10.5 g, 35.47 mmol) in ACN (150 mL), K₂CO₃(12.2 g, 88.68 mmol) was added, followed by methyl iodide (3.3 mL, 53.20 mmol) at room temperature and the reaction mixture was heated at 60° C. for 2 h in a sealed tube. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was cooled, filtered through celite bed and washed thoroughly with ethyl acetate. The organic layer was dried over anhydrous Na₂SO₄and concentrated under reduced pressure. The crude compound was purified by flash column chromatography (5% EtOAc/hexane) to afford compound 5 (9.0 g, 82.0%) as a white solid. ¹H NMR (400 MHz, DMSO-d6): δ 7.43-7.32 (m, 5H), 7.15-7.11 (m, 2H), 5.02 (s, 2H), 3.86 (s, 3H).

2-(4-(benzyloxy)-3-fluoro-5-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1)

A stirred solution of compound 5 (5.0 g, 16.12 mmol) in 1,4 dioxane (200 mL) was purged with argon for 15 min. To the reaction mixture, PdCl₂(dppf) (0.58 g, 0.81 mmol), bispinacolato diboron (5.32 g, 20.96 mmol) and KOAc (4.74 g, 48.038 mmol) were added and the reaction mixture was again purged with argon for 15 min. The reaction mixture was stirred at 80° C. for 4 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was cooled to room temperature, filtered through celite. The filtrate was dried over anhydrous Na₂SO₄and concentrated under reduced pressure. The crude compound was purified by flash column chromatography (2% EtOAc/hexane) to afford compound 1 (4.2 g, 73.0%) as an off-white semi solid. ¹H NMR (400 MHz, DMSO-d6): δ 7.42-7.32 (m, 5H), 7.06 (s, 1H), 7.00 (d, J=10.4 Hz, 1H), 5.08 (s, 2H), 3.86 (s, 3H), 1.29 (s, 12H).

Preparation of Trityl Triazole (2)

embedded image

5-(chloromethyl)-1-trityl-1H-1,2,4-triazole (2)

To a stirred solution of 5-(chloromethyl)-1H-1,2,4-triazole hydrochloride (1 g, 6.53 mmol) in DCM (100 mL), trityl chloride (908 mg, 3.26 mmol) was added at 0° C. Then TEA (1.4 mL, 9.80 mmol) was added dropwise over a period of 10 min. The reaction mixture was stirred at rt for 1 h. The progress of the reaction was monitored by TLC (30% EtOAc:Hexane). After completion, the reaction mixture was diluted with DCM and wash with water and brine. Organic layer was dried over anhydrous Na₂SO₄and concentrated under reduced pressure. The crude compound was purified by flash column chromatography (30% EtOAc/hexane) to afford 2 (1.0 g, 42%) as white solid. ¹H NMR (400 MHz, DMSO-d6): δ 8.00 (s, 1H), 7-7.5 (m, 15H), 4.7 (s, 2H).

Preparation of Carboxylic Acid (12)

embedded image

Ethyl 2-(4-bromo-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)acetate (8)

7-bromo-1-methyl-5-(trifluoromethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (5.00 g, 16.9 mmol) was treated with potassium carbonate (3 eq) Ethyl chloroacetate (1.05 eq) according to Method A. The crude material was purified by flash column chromatography (EtOAc/Hexanes, 10-50%) to afford compound 8 as an off white solid (5.55 g, 86%). ¹H NMR (400 MHz, DMSO) δ 7.76-7.71 (m, 1H), 7.62-7.57 (m, 1H), 4.83 (s, 2H), 4.15 (q, J=7.1 Hz, 2H), 3.66 (d, J=1.0 Hz, 3H), 1.20 (t, J=7.1 Hz, 3H); LCMS: m/z 382.6 [M+H]⁺.

Ethyl 2-(4-(4-(benzyloxy)-3-fluoro-5-methoxyphenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)acetate (9)

Compound 8 (4.79 g, 12.56 mmol) was treated with boronic ester 1 (4.50 g, 12.56 mmol), palladium acetate (141 mg, 0.628 mmol, 0.05 eq.), RuPhos (586 mg, 1.26 mmol, 0.1 eq.) and potassium phosphate (8.00 g, 37.7 mmol, 3 eq.) according to Method B. The crude material was purified by flash column chromatography (EtOAc/Hexanes, 10-50%) to yield 9 as an off white solid (4.56 g, 68%). ¹H NMR (400 MHz, DMSO) δ 7.71 (d, J=1.7 Hz, 1H), 7.46-7.28 (m, 5H), 7.23 (dd, J=1.8, 0.8 Hz, 1H), 7.03-6.93 (m, 2H), 5.11 (s, 2H), 4.86 (s, 2H), 4.17 (q, J=7.1 Hz, 2H), 3.87 (s, 3H), 2.88 (s, 3H), 1.22 (t, J=7.1 Hz, 3H); LCMS: m/z 532.6 [M+H]+.

Ethyl 2-(4-(3-fluoro-4-hydroxy-5-methoxyphenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)acetate (10)

Compound 9 (4.56 g, 8.56 mmol) was treated with Pd/C (450 mg) and hydrogen (1 atm) according to Method C to afford 10 as an off white solid (3.79 g, 99%) and was used in subsequent reactions without further purification. LCMS: m/z 442.6 [M+H]⁺.

Ethyl 2-(4-(3-fluoro-5-methoxy-4-((4-trityl-4H-1,2,4-triazol-3-yl)methoxy)phenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)acetate (11)

Phenol 10 (3.79 g, 8.56 mmol) was treated with 5-(chloromethyl)-1-trityl-1H-1,2,4-triazole (2, 3.24 g, 8.99 mmol) and cesium carbonate (5.58 g, 17.1 mmol) according to Method D. The crude material was purified by flash column chromatography (MeOH/DCM, 0-5%) to yield 11 as an off white solid (1.65 g, 25%). ¹H NMR (400 MHz, DMSO) δ 8.10 (s, 1H), 7.72 (d, J=1.7 Hz, 1H), 7.38-7.32 (m, 10H), 7.18-7.13 (m, 1H), 7.01-6.97 (m, 7H), 5.11 (s, 2H), 4.86 (s, 2H), 4.17 (q, J=7.1 Hz, 2H), 3.84-3.78 (m, 3H), 2.84 (s, 3H), 1.23 (t, J=7.1 Hz, 3H); LCMS: m/z 523.5 [M-CPh₃]⁺.

2-(4-(3-fluoro-5-methoxy-4-((4-trityl-4H-1,2,4-triazol-3-yl)methoxy)phenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)acetic acid (12)

Compound 11 (1.65 g, 2.16 mmol) was treated with LiOH (450 mg, 10.8 mmol) according to Method E to afford acid 12 as an off white solid (1.51 g, 95%)) and was used in subsequent reactions without further purification. ¹H NMR (400 MHz, DMSO) δ 8.10 (s, 1H), 7.71 (d, J=1.8 Hz, 1H), 7.38-7.34 (m, 9H), 7.22-7.17 (m, 1H), 7.14 (dd, J=1.8, 0.8 Hz, 1H), 6.99 (dt, J=5.6, 1.9 Hz, 6H), 5.11 (s, 2H), 4.76 (s, 2H), 3.82 (s, 3H), 2.84 (s, 3H); LCMS: m/z 495.5 [M−CPh₃]⁺.

Synthesis of Final Targets

embedded image

Example 1
2-(4-(4-((1H-1,2,4-triazol-3-yl)methoxy)-3-fluoro-5-methoxyphenyl)-6-fluoro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-chlorophenyl)-N-methylacetamide hydrochloride (SSTN-384)

N-(4-chlorophenyl)-2-(6-fluoro-4-(3-fluoro-5-methoxy-4-((1-trityl-1H-1,2,4-triazol-3-yl)methoxy)phenyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-methylacetamide (145 mg, 0.18 mmol) was treated with HCl (460 μL, 0.92 mmol) according to Method G. The residue was purified using flash chromatography eluting with 0-20% MeOH in DCM to give the title compound as an off white solid (42 mg, 39%). ¹H NMR (400 MHz, DMSO): δ 8.37 (s, 1H), 7.59 (s, 3H), 7.20-7.09 (m, 1H), 6.95 (t, J=1.7 Hz, 1H), 6.91 (dd, J=10.4, 1.9 Hz, 1H), 6.75 (dd, J=10.4, 2.5 Hz, 1H), 5.13-5.09 (m, 2H), 4.40 (s, 2H), 3.84 (s, 3H), 3.18 (s, 3H), 2.86 (s, 3H); LCMS: m/z 569.2 [M+H]⁺.

embedded image

Example 2
2-(4-(4-((4H-1,2,4-triazol-3-yl)methoxy)-3-fluoro-5-methoxyphenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-chlorophenyl)-N-methylacetamide hydrochloride (SSTN-424)

N-(4-chlorophenyl)-2-(4-(3-fluoro-5-methoxy-4-((1-trityl-1H-1,2,4-triazol-3-yl)methoxy)phenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-methylacetamide (85 mg, 0.10 mmol) was treated with HCl (250 μL, 0.5 mmol) according to Method G. The residue was purified using flash chromatography eluting with 0-20% MeOH in DCM to give the title compound as an off white solid (31 mg, 48%). ¹H NMR (600 MHz, DMSO) δ 8.53 (s, 1H), 7.96 (s, 1H), 7.68-7.54 (m, 4H), 7.24-7.20 (m, 1H), 7.05-6.90 (m, 2H), 5.11 (s, 2H), 4.54 (s, 2H), 3.86 (s, 3H), 2.90 (s, 3H), 2.75-2.72 (m, 3H); LCMS: m/z 618.5 [M+H]⁺.

embedded image

Example 3
2-(4-(4-((4H-1,2,4-triazol-3-yl)methoxy)-3-fluoro-5-methoxyphenyl)-6-fluoro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)-N-methylacetamide hydrochloride (SSTN-425)

2-(6-fluoro-4-(3-fluoro-5-methoxy-4-((1-trityl-1H-1,2,4-triazol-3-yl)methoxy)phenyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)-N-methylacetamide (99 mg, 0.125 mmol) was treated with HCl (310 μL, 0.63 mmol) according to Method G. The residue was purified using flash chromatography eluting with 0-20% MeOH in DCM to give the title compound as an off white solid (60 mg, 82%). ¹H NMR (400 MHz, DMSO) δ 8.40 (s, 1H), 7.63 (s, 1H), 7.37 (t, J=8.5 Hz, 2H), 7.17 (d, J=8.8 Hz, 1H), 6.95 (t, J=1.7 Hz, 1H), 6.91 (dd, J=10.4, 1.9 Hz, 1H), 6.75 (dd, J=10.4, 2.5 Hz, 1H), 5.11 (s, 2H), 4.36 (s, 2H), 3.84 (s, 3H), 3.16 (s, 3H), 2.85 (s, 3H). LCMS: m/z 552.6 [M+H]⁺.

embedded image

Example 4
2-(4-(4-((4H-1,2,4-triazol-3-yl)methoxy)-3-fluoro-5-methoxyphenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-methyl-N-(4-(trifluoromethyl)phenyl)acetamide hydrochloride (SSTN-439)

2-(4-(3-fluoro-5-methoxy-4-((1-trityl-1H-1,2,4-triazol-3-yl)methoxy)phenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-methyl-N-(4-(trifluoromethyl)phenyl)acetamide (146 mg, 0.16 mmol) was treated with HCl (410 μL, 0.82 mmol) according to Method G. The residue was purified using flash chromatography eluting with 0-20% MeOH in DCM to give the title compound as an off white solid (74 mg, 66%). ¹H NMR (600 MHz, DMSO) δ 8.53 (s, 1H), 7.94-7.59 (m, 5H), 7.22 (d, J=1.7 Hz, 1H), 6.98 (d, J=13.1 Hz, 2H), 5.13 (s, 2H), 4.65 (s, 2H), 3.86 (s, 3H), 2.91 (d, J=11.1 Hz, 3H). LCMS: m/z 652.5 [M+H]⁺.

embedded image

Example 5
2-(4-(4-((4H-1,2,4-triazol-3-yl)methoxy)-3-fluoro-5-methoxyphenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)-N-methylacetamide hydrochloride (SSTN-440)

2-(4-(3-fluoro-5-methoxy-4-((1-trityl-1H-1,2,4-triazol-3-yl)methoxy)phenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)-N-methylacetamide (191 mg, 0.23 mmol) was treated with HCl (570 μL, 1.1 mmol) according to Method G. The residue was purified using flash chromatography eluting with 0-20% MeOH in DCM to give the title compound as an off white solid (72 mg, 50%). ¹H NMR (400 MHz, DMSO) δ 8.51 (s, 1H), 7.65-7.60 (m, 2H), 7.38 (t, J=8.9 Hz, 2H), 7.20 (s, 1H), 7.03-6.90 (m, 2H), 5.09 (s, 2H), 4.49 (s, 2H), 3.84 (s, 3H), 3.18 (s, 3H), 2.89 (s, 3H); LCMS: m/z 602.5 [M+H]⁺.

embedded image

Example 6
2-(4-(4-((4H-1,2,4-triazol-3-yl)methoxy)-3-fluoro-5-methoxyphenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(2,4-difluorophenyl)-N-methylacetamide hydrochloride (SSTN-447)

N-(2,4-difluorophenyl)-2-(4-(3-fluoro-5-methoxy-4-((1-trityl-1H-1,2,4-triazol-3-yl)methoxy)phenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)acetamide (38 mg, 0.04 mmol) was treated with HCl (110 μL, 0.22 mmol) according to Method G. The residue was purified using flash chromatography eluting with 0-20% MeOH in DCM to give the title compound as an off white solid (15 mg, 52%). ¹H NMR (400 MHz, DMSO) δ 8.41 (s, 1H), 7.82 (td, J=9.1, 6.1 Hz, 1H), 7.64-7.52 (m, 1H), 7.50 (s, 1H), 7.36-7.23 (m, 1H), 7.21 (s, 1H), 7.01-6.92 (m, 2H), 5.14 (d, J=17.6 Hz, 2H), 4.61 (d, J=16.9 Hz, 1H), 4.39 (d, J=17.3 Hz, 1H), 3.84 (s, 3H), 3.14 (s, 3H), 2.92 (s, 3H); LCMS: m/z 620.5 [M+H]⁺.

embedded image

Example 7
2-(4-(4-((4H-1,2,4-triazol-3-yl)methoxy)-3-fluoro-5-methoxyphenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(3-chlorophenyl)-N-methylacetamide hydrochloride (SSTN-448)

N-(3-chlorophenyl)-2-(4-(3-fluoro-5-methoxy-4-((1-trityl-1H-1,2,4-triazol-3-yl)methoxy)phenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-methylacetamide (114 mg, 0.132 mmol) was treated with HCl (330 μL, 0.66 mmol) according to Method G. The residue was purified using flash chromatography eluting with 0-20% MeOH in DCM to give the title compound as an off white solid (67 mg, 77%)¹H NMR (400 MHz, DMSO) δ 8.40 (s, 1H), 7.80-7.61 (m, 2H), 7.60-7.36 (m, 3H), 7.21 (s, 1H), 6.98 (t, J=1.6 Hz, 1H), 6.96 (dd, J=10.3, 1.9 Hz, 1H), 5.13 (s, 2H), 4.56 (s, 2H), 3.84 (s, 3H), 3.21 (s, 3H), 2.90 (s, 3H); LCMS: m/z 618.5 [M+H]⁺.

embedded image

Example 8
2-(4-(4-((4H-1,2,4-triazol-3-yl)methoxy)-3-fluoro-5-methoxyphenyl)-3-cyclopropyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)-N-methylacetamide hydrochloride (SSTN-464)

2-(3-cyclopropyl-4-(3-fluoro-5-methoxy-4-((1-trityl-1H-1,2,4-triazol-3-yl)methoxy)phenyl)-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)-N-methylacetamide (69 mg, 0.08 mmol) was treated with HCl (200 μL, 0.40 mmol) according to Method G. The residue was purified using flash chromatography eluting with 0-20% MeOH in DCM to give the title compound as an off white solid (36 mg, 68%). ¹H NMR (400 MHz, DMSO) δ 8.49 (s, 1H), 7.70-7.50 (m, 3H), 7.40-7.32 (m, 2H), 7.25-7.20 (m, 1H), 7.06-6.93 (m, 2H), 5.13 (s, 2H), 4.44 (s, 2H), 3.83 (s, 3H), 3.18 (s, 3H), 2.57 (s, 1H), 0.42 (s, 4H); LCMS: m/z 628.5 [M+H]⁺.

embedded image

Example 9
2-(4-(4-((4H-1,2,4-triazol-3-yl)methoxy)-3-fluoro-5-methoxyphenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)acetamide hydrochloride (SSTN-465)

2-(4-(3-fluoro-5-methoxy-4-((1-trityl-1H-1,2,4-triazol-3-yl)methoxy)phenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)acetamide (693 mg, 0.834 mmol) was treated with HCl (2.1 mL, 4.2 mmol) according to Method G. The residue was purified using flash chromatography eluting with 0-20% MeOH in DCM to give the title compound as an off white solid (317 mg, 61%). ¹H NMR (400 MHz, DMSO) δ 10.48 (s, 1H), 8.43 (s, 1H), 7.70 (d, J=1.7 Hz, 1H), 7.60 (dd, J=8.5, 5.1 Hz, 2H), 7.23 (d, J=1.7 Hz, 1H), 7.16 (t, J=8.9 Hz, 2H), 7.03-6.94 (m, 2H), 5.14 (s, 2H), 4.85 (s, 2H), 3.85 (s, 3H), 2.94 (s, 3H); LCMS: m/z 588.5 [M+H]⁺.

embedded image

Example 10
2-(4-(4-((4H-1,2,4-triazol-3-yl)methoxy)-3-fluoro-5-methoxyphenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-chlorophenyl)acetamide hydrochloride (SSTN-489)

N-(4-chlorophenyl)-2-(4-(3-fluoro-5-methoxy-4-((1-trityl-1H-1,2,4-triazol-3-yl)methoxy)phenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)acetamide (125 mg, 0.15 mmol) was treated with HCl (370 μL, 0.74 mmol) according to Method G. The residue was purified using flash chromatography eluting with 0-20% MeOH in DCM to give the title compound as an off white solid (76 mg, 80%). ¹H NMR (400 MHz, DMSO) δ 10.57 (s, 1H), 8.42 (s, 1H), 7.71 (d, J=1.8 Hz, 1H), 7.65-7.57 (m, 2H), 7.42-7.33 (m, 2H), 7.23 (d, J=1.7 Hz, 1H), 7.01-6.94 (m, 2H), 5.14 (s, 2H), 4.87 (s, 2H), 3.85 (s, 3H), 2.94 (s, 3H); LCMS: m/z 604.5 [M+H]⁺.

embedded image

Example 11
2-(4-(4-((4H-1,2,4-triazol-3-yl)methoxy)-3-fluoro-5-methoxyphenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(3-chlorophenyl)acetamide hydrochloride (SSTN-490)

N-(3-chlorophenyl)-2-(4-(3-fluoro-5-methoxy-4-((1-trityl-1H-1,2,4-triazol-3-yl)methoxy)phenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)acetamide (104 mg, 0.12 mmol) was treated with HCl (310 μL, 0.61 mmol) according to Method G. The residue was purified using flash chromatography eluting with 0-20% MeOH in DCM to give the title compound as an off white solid (58 mg, 74%). ¹H NMR (400 MHz, DMSO) δ 10.68 (s, 1H), 8.45 (s, 1H), 7.78 (t, J=2.1 Hz, 1H), 7.72 (d, J=1.7 Hz, 1H), 7.46 (d, J=7.8 Hz, 1H), 7.35 (t, J=8.1 Hz, 1H), 7.24 (d, J=1.7 Hz, 1H), 7.16-7.09 (m, 1H), 7.03-6.94 (m, 2H), 5.14 (s, 2H), 4.88 (s, 2H), 3.85 (s, 3H), 2.94 (s, 3H); LCMS: m/z 604.5 [M+H]⁺.

embedded image

Example 12
2-(4-(4-((4H-1,2,4-triazol-3-yl)methoxy)-3-fluoro-5-methoxyphenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(2-chlorophenyl)acetamide hydrochloride (SSTN-491)

N-(2-chlorophenyl)-2-(4-(3-fluoro-5-methoxy-4-((1-trityl-1H-1,2,4-triazol-3-yl)methoxy)phenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)acetamide (49 mg, 0.06 mmol) was treated with HCl (150 μL, 0.29 mmol) according to Method G. The residue was purified using flash chromatography eluting with 0-20% MeOH in DCM to give the title compound as an off white solid (29 mg, 78%). ¹H NMR (400 MHz, DMSO) δ 10.00 (s, 1H), 8.44 (s, 1H), 7.71 (dd, J=8.0, 1.5 Hz, 1H), 7.66 (d, J=1.8 Hz, 1H), 7.52 (dd, J=8.0, 1.4 Hz, 1H), 7.33 (td, J=7.7, 1.5 Hz, 1H), 7.26-7.16 (m, 2H), 7.03-6.93 (m, 2H), 5.14 (s, 2H), 4.96 (s, 2H), 3.84 (s, 3H), 2.94 (s, 3H); LCMS: m/z 604.5 [M+H]⁺.

embedded image

Example 13
2-(4-(4-((4H-1,2,4-triazol-3-yl)methoxy)-3-fluoro-5-methoxyphenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(3-methoxyphenyl)acetamide hydrochloride (SSTN-492)

2-(4-(3-fluoro-5-methoxy-4-((1-trityl-1H-1,2,4-triazol-3-yl)methoxy)phenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(3-methoxyphenyl)acetamide (69 mg, 0.08 mmol) was treated with HCl (210 μL, 0.41 mmol) according to Method G. The residue was purified using flash chromatography eluting with 0-20% MeOH in DCM to give the title compound as an off white solid (24 mg, 46%). ¹H NMR (400 MHz, DMSO) δ 10.39 (s, 1H), 8.37 (s, 1H), 7.71 (d, J=1.7 Hz, 1H), 7.30 (t, J=2.2 Hz, 1H), 7.26-7.18 (m, 2H), 7.09 (dd, J=7.8, 1.9 Hz, 1H), 7.03-6.93 (m, 2H), 6.65 (dd, J=8.3, 2.5 Hz, 1H), 5.13 (s, 2H), 4.85 (s, 2H), 3.85 (s, 3H), 3.70 (s, 3H), 2.94 (s, 3H); LCMS: m/z 600.5 [M+H]⁺.

embedded image

Example 14
2-(4-(4-((4H-1,2,4-triazol-3-yl)methoxy)-3-fluoro-5-methoxyphenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(2-methoxyphenyl)acetamide hydrochloride (SSTN-493)

2-(4-(3-fluoro-5-methoxy-4-((1-trityl-1H-1,2,4-triazol-3-yl)methoxy)phenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(2-methoxyphenyl)acetamide (89 mg, 0.11 mmol) was treated with HCl (260 μL, 0.53 mmol) according to Method G. The residue was purified using flash chromatography eluting with 0-20% MeOH in DCM to give the title compound as an off white solid (43 mg, 64%). ¹H NMR (400 MHz, DMSO) δ 9.64 (s, 1H), 8.52 (s, 1H), 7.91 (d, J=8.2 Hz, 1H), 7.66 (s, 1H), 7.23 (s, 1H), 7.08 (d, J=2.9 Hz, 2H), 6.98 (q, J=10.9, 10.3 Hz, 2H), 6.88 (t, J=8.4 Hz, 1H), 5.14 (d, J=36.9 Hz, 2H), 4.96 (s, 2H), 3.87 (s, 3H), 3.85 (s, 3H), 2.94 (s, 3H); LCMS: m/z 600.5 [M+H]⁺.

embedded image

Example 15
2-(4-(4-((4H-1,2,4-triazol-3-yl)methoxy)-3-fluoro-5-methoxyphenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(2,4-difluorophenyl)acetamide hydrochloride (SSTN-494)

N-(2,4-difluorophenyl)-2-(4-(3-fluoro-5-methoxy-4-((1-trityl-1H-1,2,4-triazol-3-yl)methoxy)phenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)acetamide (69 mg, 0.08 mmol) was treated with HCl (200 μL, 0.41 mmol) according to Method G. The residue was purified using flash chromatography eluting with 0-20% MeOH in DCM to give the title compound as an off white solid (36 mg, 69%). ¹H NMR (400 MHz, DMSO) δ 10.22 (s, 1H), 8.39 (s, 1H), 7.82 (td, J=9.0, 6.1 Hz, 1H), 7.67 (d, J=1.7 Hz, 1H), 7.35 (ddd, J=11.4, 9.0, 2.9 Hz, 1H), 7.23 (d, J=1.1 Hz, 1H), 7.06 (t, J=8.9 Hz, 1H), 7.00 (t, J=1.7 Hz, 1H), 6.97 (dd, J=10.4, 2.0 Hz, 1H), 5.13 (s, 2H), 4.92 (s, 2H), 3.85 (s, 3H), 2.94 (s, 3H); LCMS: m/z 606.5 [M+H]⁺.

embedded image

Example 16
2-(4-(4-((4H-1,2,4-triazol-3-yl)methoxy)-3-fluoro-5-methoxyphenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(3-(trifluoromethyl)phenyl)acetamide hydrochloride (SSTN-495)

2-(4-(3-fluoro-5-methoxy-4-((1-trityl-1H-1,2,4-triazol-3-yl)methoxy)phenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(3-(trifluoromethyl)phenyl)acetamide (74 mg, 0.08 mmol) was treated with HCl (210 μL, 0.42 mmol) according to Method G. The residue was purified using flash chromatography eluting with 0-20% MeOH in DCM to give the title compound as an off white solid (44 mg, 78%). ¹H NMR (400 MHz, DMSO) δ 10.74 (s, 1H), 8.52 (s, 1H), 8.08 (t, J=2.1 Hz, 1H), 7.79-7.70 (m, 2H), 7.58 (t, J=8.0 Hz, 1H), 7.43 (d, J=7.8 Hz, 1H), 7.24 (d, J=1.7 Hz, 1H), 7.05-6.92 (m, 2H), 5.15 (s, 2H), 4.90 (s, 2H), 3.86 (s, 3H), 2.95 (s, 3H); LCMS: m/z 638.5 [M+H]⁺.

embedded image

Example 17
2-(4-(4-((4H-1,2,4-triazol-3-yl)methoxy)-3-fluoro-5-methoxyphenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(3-fluorophenyl)acetamide hydrochloride (SSTN-496)

2-(4-(3-fluoro-5-methoxy-4-((1-trityl-1H-1,2,4-triazol-3-yl)methoxy)phenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(3-fluorophenyl)acetamide (77 mg, 0.09 mmol) was treated with HCl (230 μL, 0.46 mmol) according to Method G. The residue was purified using flash chromatography eluting with 0-20% MeOH in DCM to give the title compound as an off white solid (43 mg, 74%). ¹H NMR (400 MHz, DMSO) δ 10.61 (s, 1H), 8.52 (s, 1H), 7.72 (d, J=2.0 Hz, 1H), 7.55 (dt, J=11.6, 2.3 Hz, 1H), 7.37 (td, J=8.1, 6.6 Hz, 1H), 7.30 (dt, J=8.4, 1.3 Hz, 1H), 7.24 (d, J=1.7 Hz, 1H), 7.06-6.85 (m, 3H), 5.14 (s, 2H), 4.87 (s, 2H), 3.85 (s, 3H), 2.95 (d, J=5.2 Hz, 3H); LCMS: m/z 588.5 [M+H]+.

embedded image

Example 18
2-(4-(4-((4H-1,2,4-triazol-3-yl)methoxy)-3-fluoro-5-methoxyphenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-(difluoromethoxy)phenyl)acetamide hydrochloride (SSTN-497)

2-(4-(4-((4H-1,2,4-triazol-3-yl)methoxy)-3-fluoro-5-methoxyphenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-(difluoromethoxy)phenyl)acetamide (85 mg, 0.10 mmol) was treated with HCl (240 μL, 0.48 mmol) according to Method G. The residue was purified using flash chromatography eluting with 0-20% MeOH in DCM to give the title compound as an off white solid (44 mg, 68%). ¹H NMR (400 MHz, DMSO) δ 10.50 (s, 1H), 8.41 (s, 1H), 7.70 (d, J=1.7 Hz, 1H), 7.61 (d, J=4.5 Hz, 2H), 7.23 (d, J=1.7 Hz, 1H), 7.18-7.11 (m, 3H), 7.02-6.94 (m, 2H), 5.13 (s, 2H), 4.86 (s, 2H), 3.85 (s, 3H), 2.94 (s, 3H); LCMS: m/z 636.5 [M+H]⁺.

embedded image

Example 19
2-(4-(4-((4H-1,2,4-triazol-3-yl)methoxy)-3-fluoro-5-methoxyphenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-(methylthio)phenyl)acetamide hydrochloride (SSTN-498)

2-(4-(3-fluoro-5-methoxy-4-((1-trityl-1H-1,2,4-triazol-3-yl)methoxy)phenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-(methylthio)phenyl)acetamide (91 mg, 0.11 mmol) was treated with HCl (270 μL, 0.53 mmol) according to Method G. The residue was purified using flash chromatography eluting with 0-20% MeOH in DCM to give the title compound as an off white solid (53 mg, 77%). ¹H NMR (400 MHz, DMSO) δ 10.40 (s, 1H), 8.37 (s, 1H), 7.70 (s, 1H), 7.54 (d, J=8.7 Hz, 2H), 7.27-7.20 (m, 3H), 7.02-6.94 (m, 2H), 5.13 (s, 2H), 4.85 (s, 2H), 3.85 (s, 3H), 2.94 (s, 3H), 2.43 (s, 3H); LCMS: m/z 616.5 [M+H]⁺.

embedded image

Example 20
2-(4-(4-((4H-1,2,4-triazol-3-yl)methoxy)-3-fluoro-5-methoxyphenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-(methylthio)phenyl)acetamide hydrochloride (SSTN-499)

2-(4-(3-fluoro-5-methoxy-4-((1-trityl-1H-1,2,4-triazol-3-yl)methoxy)phenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-(methylthio)phenyl)acetamide (91 mg, 0.11 mmol) was treated with HCl (270 μL, 0.53 mmol) according to Method G. The residue was purified using flash chromatography eluting with 0-20% MeOH in DCM to give the title compound as an off white solid (53 mg, 77%). ¹H NMR (400 MHz, DMSO) δ 10.17 (s, 1H), 8.52 (s, 1H), 7.78 (t, J=8.4 Hz, 1H), 7.68 (s, 1H), 7.27-7.19 (m, 2H), 7.09-6.92 (m, 3H), 5.14 (s, 2H), 4.92 (s, 2H), 3.85 (s, 3H), 2.94 (d, J=4.3 Hz, 3H), 2.47 (s, 3H); LCMS: m/z 617.4 [M+H]⁺.

embedded image

Example 21
2-(4-(4-((4H-1,2,4-triazol-3-yl)methoxy)-3-fluoro-5-methoxyphenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(2-fluoro-4-(methylthio)phenyl)acetamide hydrochloride (SSTN-500)

N-(2-fluoro-4-(methylthio)phenyl)-2-(4-(3-fluoro-5-methoxy-4-((1-trityl-1H-1,2,4-triazol-3-yl)methoxy)phenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)acetamide (73 mg, 0.08 mmol) was treated with HCl (210 μL, 0.42 mmol) according to Method G. The residue was purified using flash chromatography eluting with 0-20% MeOH in DCM to give the title compound as an off white solid (55 mg, 99%). ¹H NMR (400 MHz, DMSO) δ 10.46 (s, 1H), 8.40 (s, 1H), 7.71 (d, J=1.7 Hz, 1H), 7.59 (s, 1H), 7.33-7.21 (m, 3H), 6.97 (dd, J=16.5, 6.2 Hz, 3H), 5.13 (s, 2H), 4.86 (s, 2H), 3.85 (s, 3H), 2.94 (s, 3H), 2.43 (s, 3H); LCMS: m/z 635.4 [M+H]+.

embedded image

Example 22
2-(4-(4-((4H-1,2,4-triazol-3-yl)methoxy)-3-fluoro-5-methoxyphenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(3-(methylsulfonyl)phenyl)acetamide hydrochloride (SSTN-501)

2-(4-(3-fluoro-5-methoxy-4-((1-trityl-1H-1,2,4-triazol-3-yl)methoxy)phenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(3-(methylsulfonyl)phenyl)acetamide (80 mg, 0.09 mmol) was treated with HCl (230 μL, 0.45 mmol) according to Method G. The residue was purified using flash chromatography eluting with 0-20% MeOH in DCM to give the title compound as an off white solid (34 mg, 55%). ¹H NMR (400 MHz, DMSO) δ 10.80 (s, 1H), 8.52 (s, 1H), 8.27-8.22 (m, 1H), 7.83 (dt, J=5.4, 2.6 Hz, 1H), 7.73 (s, 1H), 7.67-7.57 (m, 2H), 7.24 (d, J=1.7 Hz, 1H), 7.05-6.92 (m, 2H), 5.14 (s, 2H), 4.90 (s, 2H), 3.86 (s, 3H), 3.17 (s, 3H), 2.95 (s, 3H); LCMS: m/z 648.5 [M+H]⁺.

embedded image

Example 23
2-(4-(4-((4H-1,2,4-triazol-3-yl)methoxy)-3-fluoro-5-methoxyphenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(5-methylpyridin-3-yl)acetamide hydrochloride (SSTN-502)

2-(4-(3-fluoro-5-methoxy-4-((1-trityl-1H-1,2,4-triazol-3-yl)methoxy)phenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(5-methylpyridin-3-yl)acetamide (65 mg, 0.08 mmol) was treated with HCl (200 μL, 0.39 mmol) according to Method G. The residue was purified using flash chromatography eluting with 0-20% MeOH in DCM to give the title compound as an off white solid (29 mg, 56%). ¹H NMR (400 MHz, DMSO) δ 11.35 (s, OH), 8.91 (s, 1H), 8.41 (s, 2H), 8.24 (s, 1H), 7.73 (s, 1H), 7.25 (d, J=1.7 Hz, 1H), 7.02-6.93 (m, 2H), 5.13 (s, 2H), 4.97 (s, 2H), 3.86 (s, 3H), 2.95 (s, 3H), 2.42 (s, 3H); LCMS: m/z 585.5 [M+H]⁺.

embedded image

Example 24
2-(4-(4-((4H-1,2,4-triazol-3-yl)methoxy)-3-fluoro-5-methoxyphenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-(methylsulfonyl)phenyl)acetamide hydrochloride (SSTN-503)

2-(4-(3-fluoro-5-methoxy-4-((1-trityl-1H-1,2,4-triazol-3-yl)methoxy)phenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-(methylsulfonyl)phenyl)acetamide (70 mg, 0.08 mmol) was treated with HCl (200 μL, 0.39 mmol) according to Method G. The residue was purified using flash chromatography eluting with 0-20% MeOH in DCM to give the title compound as an off white solid (2₂mg, 41%)¹H NMR (400 MHz, DMSO) δ 10.85 (s, 1H), 8.52 (s, 1H), 7.91-7.84 (m, 2H), 7.84-7.78 (m, 2H), 7.73 (d, J=1.8 Hz, 1H), 7.24 (d, J=1.7 Hz, 1H), 6.97 (d, J=19.2 Hz, 2H), 5.10 (s, 2H), 4.92 (s, 2H), 3.85 (s, 3H), 3.16 (s, 3H), 2.94 (s, 3H); LCMS: m/z 648.5 [M+H]⁺.

embedded image

Example 25
2-(4-(4-((4H-1,2,4-triazol-3-yl)methoxy)-3-fluoro-5-methoxyphenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(1-methyl-1H-pyrazol-3-yl)acetamide hydrochloride (SSTN-509)

2-(4-(3-fluoro-5-methoxy-4-((1-trityl-1H-1,2,4-triazol-3-yl)methoxy)phenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)acetic acid (75 mg, 0.10 mmol) was dissolved in DCM (2.0 mL, 0.05 M), cooled to 0° C., and treated with oxalyl chloride (10 μL, 0.12 mmol) and a catalytic amount of DMF. The reaction was stirred for 1 hour before NEt₃(40 μL, 0.31 mmol) and 1-methyl-1H-pyrazol-3-amine (10 mg, 0.11 mmol) were added. The reaction was stirred for one hour before dilution with Et₂O and water. The layers were separated, and the aqueous was extracted with Et₂O. The combined organic extracts were dried over anhydrous Na₂SO₄, filtered, and concentrated. The crude material was purified by flash chromatography eluting with 0-20% MeOH in DCM to give the title compound as an off white solid (19 mg, 31%). ¹H NMR (400 MHz, DMSO) δ 10.83 (s, 1H), 8.53 (s, 1H), 7.67 (d, J=2.0 Hz, 1H), 7.55 (d, J=2.2 Hz, 1H), 7.22 (d, J=1.7 Hz, 1H), 7.04-6.92 (m, 2H), 6.35 (d, J=2.2 Hz, 1H), 5.14 (s, 2H), 4.82 (s, 2H), 3.85 (s, 3H), 3.74 (s, 3H), 2.93 (s, 3H); LCMS: m/z 574.5 [M+H]+.

embedded image

Example 26
2-(4-(4-((4H-1,2,4-triazol-3-yl)methoxy)-3-fluoro-5-methoxyphenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)-N-isopropylacetamide (SSTN-542)

2-(4-(3-fluoro-5-methoxy-4-((1-trityl-1H-1,2,4-triazol-3-yl)methoxy)phenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)-N-isopropylacetamide (134 mg, 0.15 mmol) was treated with HCl (380 μL, 0.77 mmol) according to Method G. The residue was purified using flash chromatography eluting with 0-20% MeOH in DCM to give the title compound as an off white solid (30 mg, 29%). ¹H NMR (400 MHz, DMSO) δ 8.37 (s, 1H), 7.55 (d, J=1.7 Hz, 1H), 7.53-7.45 (m, 2H), 7.39 (t, J=8.7 Hz, 2H), 7.20 (d, J=1.6 Hz, 1H), 7.00-6.91 (m, 2H), 5.12 (s, 2H), 4.74 (p, J=6.8 Hz, 1H), 4.31 (s, 2H), 3.84 (s, 3H), 2.89 (s, 3H), 1.00 (d, J=6.8 Hz, 6H); LCMS: m/z 630.5 [M+H]⁺.

embedded image

Example 27
2-(4-(4-((4H-1,2,4-triazol-3-yl)methoxy)-3-fluoro-5-methoxyphenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-cyclopropyl-N-(4-fluorophenyl)acetamide (SSTN-543)

N-cyclopropyl-2-(4-(3-fluoro-5-methoxy-4-((1-trityl-1H-1,2,4-triazol-3-yl)methoxy)phenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)acetamide (178 mg, 0.20 mmol) was treated with HCl (510 μL, 1.0 mmol) according to Method G. The residue was purified using flash chromatography eluting with 0-20% MeOH in DCM to give the title compound as an off white solid (53 mg, 39%). ¹H NMR (500 MHz, DMSO, 80° C.) δ 8.30 (s, 1H), 7.52 (s, 1H), 7.33 (dd, J=8.7, 5.0 Hz, 2H), 7.25-7.16 (m, 3H), 6.96 (t, J=1.7 Hz, 1H), 6.91 (dd, J=10.6, 1.9 Hz, 1H), 6.13 (br s, 2H), 5.17 (s, 2H), 4.85 (s, 1H), 3.85 (s, 3H), 2.94 (s, 3H), 0.88 (d, J=6.9 Hz, 2H), 0.62 (s, 2H); LCMS: m/z 628.5 [M+H]⁺.

embedded image

Example 28
4-(4-((4H-1,2,4-triazol-3-yl)methoxy)-3-fluoro-5-methoxyphenyl)-3-methyl-1-(2-(4-methylpiperazin-1-yl)-2-oxoethyl)-6-(trifluoromethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (SSTN-544)

4-(3-fluoro-5-methoxy-4-((4-trityl-4H-1,2,4-triazol-3-yl)methoxy)phenyl)-3-methyl-1-(2-(4-methylpiperazin-1-yl)-2-oxoethyl)-6-(trifluoromethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (83 mg, 0.10 mmol) was treated with HCl (250 μL, 0.51 mmol) according to Method G. The residue was purified using flash chromatography eluting with 0-20% MeOH in DCM to give the title compound as an off white solid (44 mg, 67%). ¹H NMR (400 MHz, DMSO) δ 11.02 (s, 1H), 8.39 (s, 1H), 7.59 (d, J=1.8 Hz, 1H), 7.22 (d, J=1.8 Hz, 1H), 7.00 (t, J=1.7 Hz, 1H), 6.97 (dd, J=10.3, 1.9 Hz, 1H), 5.15-5.04 (m, 3H), 4.92 (d, 1H), 4.35 (d, J=13.9 Hz, 1H), 4.18 (d, J=14.4 Hz, 1H), 3.85 (s, 3H), 3.61 (t, J=13.1 Hz, 1H), 3.50 (d, J=12.3 Hz, 1H), 3.42 (d, J=12.0 Hz, 1H), 3.22-3.06 (m, 2H), 2.99 (d, J=11.4 Hz, 1H), 2.93 (s, 3H), 2.80 (d, J=4.3 Hz, 3H); LCMS: m/z 578.6 [M+H]⁺.

embedded image

Example 29
2-(4-(4-((4H-1,2,4-triazol-3-yl)methoxy)-3-fluoro-5-methoxyphenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(3-cyanophenyl)acetamide (SSTN-545)

N-(3-cyanophenyl)-2-(4-(3-fluoro-5-methoxy-4-((4-trityl-4H-1,2,4-triazol-3-yl)methoxy)phenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)acetamide (69 mg, 0.08 mmol) was treated with HCl (210 μL, 0.41 mmol) according to Method G. The residue was purified using flash chromatography eluting with 0-20% MeOH in DCM to give the title compound as an off white solid (30 mg, 58%). ¹H NMR (400 MHz, DMSO) δ 10.75 (s, 1H), 8.52 (s, 1H), 8.05 (q, J=1.3 Hz, 1H), 7.81 (dq, J=7.8, 2.6 Hz, 1H), 7.73 (d, J=1.7 Hz, 1H), 7.60-7.51 (m, 2H), 7.24 (d, J=1.7 Hz, 1H), 7.00 (s, 1H), 6.96 (d, J=9.7 Hz, 1H), 5.23-5.08 (m, 2H), 4.90 (s, 2H), 3.86 (s, 3H), 2.94 (s, 3H); LCMS: m/z 595.5 [M+H]⁺.

embedded image

Example 30
2-(4-(4-((4H-1,2,4-triazol-3-yl)methoxy)-3-fluoro-5-methoxyphenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-([1,1′-biphenyl]-3-yl)acetamide (SSTN-546)

N-([1,1′-biphenyl]-3-yl)-2-(4-(3-fluoro-5-methoxy-4-((4-trityl-4H-1,2,4-triazol-3-yl)methoxy)phenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)acetamide (85 mg, 0.10 mmol) was treated with HCl (240 μL, 0.48 mmol) according to Method G. The residue was purified using flash chromatography eluting with 0-20% MeOH in DCM to give the title compound as an off white solid (58 mg, 89%). ¹H NMR (400 MHz, DMSO) δ 10.56 (s, 1H), 8.42 (s, 1H), 7.96 (d, J=1.9 Hz, 1H), 7.73 (d, J=1.8 Hz, 1H), 7.62-7.56 (m, 2H), 7.56-7.51 (m, 1H), 7.50-7.32 (m, 5H), 7.24 (d, J=1.7 Hz, 1H), 7.00 (t, J=1.6 Hz, 1H), 6.98 (dd, J=10.2, 1.9 Hz, 1H), 5.14 (s, 2H), 4.90 (s, 2H), 3.85 (s, 3H), 2.95 (s, 3H); LCMS: m/z 646.5 [M+H]⁺.

embedded image

Example 31
2-(4-(4-((4H-1,2,4-triazol-3-yl)methoxy)-3-fluoro-5-methoxyphenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(3-cyclopropylphenyl)acetamide (SSTN-547)

N-(3-cyclopropylphenyl)-2-(4-(3-fluoro-5-methoxy-4-((4-trityl-4H-1,2,4-triazol-3-yl)methoxy)phenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)acetamide (86 mg, 0.10 mmol) was treated with HCl (250 μL, 0.50 mmol) according to Method G. The residue was purified using flash chromatography eluting with 0-20% MeOH in DCM to give the title compound as an off white solid (54 mg, 83%). ¹H NMR (400 MHz, DMSO) δ 10.33 (s, 1H), 8.40 (s, 1H), 7.70 (d, J=1.7 Hz, 1H), 7.31 (d, J=6.6 Hz, 2H), 7.23 (d, J=1.7 Hz, 1H), 7.17 (t, J=8.1 Hz, 1H), 7.03-6.93 (m, 2H), 6.80 (d, J=7.5 Hz, 1H), 5.13 (s, 2H), 4.84 (s, 2H), 3.85 (s, 3H), 2.94 (s, 3H), 1.86 (tt, J=8.5, 5.0 Hz, 1H), 0.97-0.88 (m, 2H), 0.63-0.55 (m, 2H); LCMS: m/z 610.7 [M+H]⁺.

embedded image

Example 32
2-(4-(4-((4H-1,2,4-triazol-3-yl)methoxy)-3-fluoro-5-methoxyphenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(3-(methoxymethyl)phenyl)acetamide (SSTN-548)

2-(4-(3-fluoro-5-methoxy-4-((4-trityl-4H-1,2,4-triazol-3-yl)methoxy)phenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(3-(methoxymethyl)phenyl)acetamide (65 mg, 0.08 mmol) was treated with HCl (190 μL, 0.38 mmol) according to Method G. The residue was purified using flash chromatography eluting with 0-20% MeOH in DCM to give the title compound as an off white solid (44 mg, 89%). ¹H NMR (400 MHz, DMSO) δ 10.39 (s, 1H), 8.52 (s, 1H), 7.70 (d, J=1.7 Hz, 1H), 7.59 (s, 1H), 7.51-7.44 (m, 1H), 7.29 (t, J=7.8 Hz, 1H), 7.23 (d, J=1.4 Hz, 1H), 6.98 (dd, J=17.3, 9.0 Hz, 3H), 5.23-5.08 (m, 2H), 4.86 (s, 2H), 4.37 (s, 2H), 3.85 (s, 3H), 3.27 (s, 3H), 2.94 (s, 3H); LCMS: m/z 614.6 [M+H]⁺.

embedded image

Example 33
2-(4-(4-((4H-1,2,4-triazol-3-yl)methoxy)-3-fluoro-5-methoxyphenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(3-(tert-butyl)phenyl)acetamide (SSTN-555)

N-(3-(tert-butyl)phenyl)-2-(4-(3-fluoro-5-methoxy-4-((4-trityl-4H-1,2,4-triazol-3-yl)methoxy)phenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)acetamide (90 mg, 0.10 mmol) was treated with HCl (260 μL, 0.52 mmol) according to Method G. The residue was purified using flash chromatography eluting with 0-20% MeOH in DCM to give the title compound as an off white solid (39 mg, 57%). ¹H NMR (400 MHz, DMSO) δ 10.33 (s, 1H), 8.52 (s, 1H), 7.70 (d, J=1.8 Hz, 1H), 7.65 (t, J=2.0 Hz, 1H), 7.41-7.34 (m, 1H), 7.28-7.19 (m, 2H), 7.10 (dt, J=8.0, 1.4 Hz, 1H), 7.00 (s, 1H), 6.96 (d, J=9.8 Hz, 1H), 5.10 (s, 2H), 4.85 (s, 2H), 3.85 (s, 3H), 2.94 (s, 3H), 1.25 (s, 9H); LCMS: m/z 626.6 [M+H]⁺.

embedded image

Example 34
2-(4-(4-((4H-1,2,4-triazol-3-yl)methoxy)-3-fluoro-5-methoxyphenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(3-morpholinophenyl)acetamide (SSTN-558)

2-(4-(3-fluoro-5-methoxy-4-((4-trityl-4H-1,2,4-triazol-3-yl)methoxy)phenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(3-morpholinophenyl)acetamide (58 mg, 0.07 mmol) was treated with HCl (160 μL, 0.32 mmol) according to Method G. The residue was purified using flash chromatography eluting with 0-20% MeOH in DCM to give the title compound as an off white solid (15 mg, 35%). ¹H NMR (400 MHz, DMSO) δ 10.46-10.41 (m, 1H), 8.46 (s, 1H), 7.70 (d, J=1.7 Hz, 1H), 7.39 (s, 1H), 7.23 (d, J=1.7 Hz, 1H), 7.18 (t, J=8.1 Hz, 1H), 7.06-6.94 (m, 3H), 6.77-6.70 (m, 1H), 5.14 (s, 2H), 4.86 (s, 2H), 3.85 (s, 3H), 3.77-3.70 (m, 4H), 3.08 (d, J=9.4 Hz, 4H), 2.94 (s, 3H); LCMS: m/z 656.5 [M+H]⁺.

embedded image

Example 35
2-(4-(4-((4H-1,2,4-triazol-3-yl)methoxy)-3-fluoro-5-methoxyphenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(3-(4-methylpiperazin-1-yl)phenyl)acetamide (SSTN-559)

2-(4-(3-fluoro-5-methoxy-4-((4-trityl-4H-1,2,4-triazol-3-yl)methoxy)phenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(3-(4-methylpiperazin-1-yl)phenyl)acetamide (78 mg, 0.09 mmol) was treated with HCl (210 μL, 0.43 mmol) according to Method G. The residue was purified using flash chromatography eluting with 0-20% MeOH in DCM to give the title compound as an off white solid (26 mg, 45%). ¹H NMR (400 MHz, DMSO) δ 11.19 (s, 1H), 10.50 (s, 1H), 8.49 (s, 1H), 7.70 (d, J=1.8 Hz, 1H), 7.37 (s, 1H), 7.23 (d, J=1.7 Hz, 1H), 7.16 (t, J=8.1 Hz, 1H), 7.02-6.93 (m, 3H), 6.69 (d, J=8.7 Hz, 1H), 5.12 (s, 2H), 4.87 (s, 2H), 3.85 (s, 3H), 3.22 (s, 4H), 3.05-2.68 (m, 6H), 2.68-2.52 (m, 2H); LCMS: m/z 668.5 [M+H]⁺.

embedded image

Example 36
2-(4-(4-((4H-1,2,4-triazol-3-yl)methoxy)-3-fluoro-5-methoxyphenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(3-(morpholinomethyl)phenyl)acetamide (SSTN-575)

2-(4-(3-fluoro-5-methoxy-4-((4-trityl-4H-1,2,4-triazol-3-yl)methoxy)phenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(3-(morpholinomethyl)phenyl)acetamide (74 mg, 0.08 mmol) was treated with HCl (200 μL, 0.41 mmol) according to Method G. The residue was purified using flash chromatography eluting with 0-20% MeOH in DCM to give the title compound as an off white solid (51 mg, 94%). ¹H NMR (400 MHz, DMSO) δ 11.30 (s, 1H), 10.78 (s, 1H), 8.42 (s, 1H), 7.84 (s, 1H), 7.72 (d, J=1.7 Hz, 1H), 7.60 (t, J=4.9 Hz, 1H), 7.41 (d, J=4.6 Hz, 2H), 7.23 (d, J=1.7 Hz, 1H), 7.02-6.93 (m, 2H), 5.13 (s, 2H), 4.92 (s, 2H), 4.27 (d, J=4.5 Hz, 2H), 3.90 (d, J=13.1 Hz, 2H), 3.85 (s, 3H), 3.78 (t, J=12.1 Hz, 2H), 3.18 (d, J=12.0 Hz, 2H), 3.12-2.98 (m, 2H), 2.94 (s, 3H); LCMS: m/z 669.7 [M+H]⁺.

embedded image

Example 37
2-(4-(4-((4H-1,2,4-triazol-3-yl)methoxy)-3-fluorophenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-((4H-1,2,4-triazol-3-yl)methyl)-N-(4-fluorophenyl)acetamide (SSTN-592)
Step-1: 2-(4-(4-(benzyloxy)-3-fluorophenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)acetamide (2)

To a stirred mixture of 2-(4-bromo-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)acetamide (200 mg, 0.448 mmol, 1 eq) and 2-(4-(benzyloxy)-3-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1) (110 mg, 0.448 mmol, 1 eq) in dioxane:water (10:2 mL) was added potassium carbonate (182 mg, 1.344 mmol, 3 eq) followed by catalyst Pd(PPh₃)₄(25 mg, 0.022 mmol, 0.05 eq) at room temperature and degassed with argon for 15 min. The reaction was further heated at 90° C. for 12 h. The progress of the reaction was monitored by TLC (M.Ph: 50% ethyl acetate in n-hexane). The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo up to dryness resulting in the crude compound. The crude compound was purified by Combiflash column chromatography (elution: 50-60% ethyl acetate in n-hexane) to afford 2 (85 mg, 34.1%) as an off white solid. ¹H NMR (DMSO-d₆, 400 MHz): δ ppm 10.44 (br. s, 1H), 7.70 (br. s, 1H), 7.59 (d, J=4.40 Hz, 2H), 7.33-7.53 (m, 7H), 7.26 (d, J=8.31 Hz, 1H), 7.12-7.22 (m, 3H), 5.26 (s, 2H), 4.85 (br. s, 2H), 2.94 (s, 3H); LC-MS: m/z 590.20 [M+Na]⁺.

Step-2: 2-(4-(3-fluoro-4-hydroxyphenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)acetamide (3)

To a stirred solution of 2-(4-(4-(benzyloxy)-3-fluorophenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)acetamide (2) (80 mg, 0.140 mmol, 1 eqv) in methanol (10 mL) was added 20% Pd/C (20 mg) into a hydrogenator. The mixture was degassed for 15 min with the help of alternative vacuum and nitrogen. The reaction was stirred under hydrogen atmosphere (5 bar pressure) at room temperature for 2 h. The progress of the reaction was monitored by TLC (M.Ph: 60% EtOAc in n-hexane). The reaction mixture was filtered through a Celite bed and washed with methanol (3×15 mL). The filtrate was concentrated in vacuo up to dryness to afford 3 (62 mg, 93.9%) as an off white solid. Crude compound obtained was used as such in the next step without further purification. ¹H NMR (DMSO-d₆, 400 MHz): δ ppm 10.45 (br. s, 1H), 7.66 (br. s, 1H), 7.56-7.63 (m, 2H), 7.31 (d, J=10.76 Hz, 1H), 7.13-7.22 (m, 3H), 6.98-7.10 (m, 3H), 4.85 (br. s, 2H), 2.95 (br. s, 3H); LC-MS: m/z 478.15 [M+H]⁺.

Step-3: 2-(4-(3-fluoro-4-((4-trityl-4H-1,2,4-triazol-3-yl)methoxy)phenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)-N-((4-trityl-4H-1,2,4-triazol-3-yl)methyl)acetamide (5A)

To a stirred solution of 2-(4-(3-fluoro-4-hydroxyphenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)acetamide (3) (62 mg, 0.129 mmol, 1 eq) in DMF (5 mL) was added cesium carbonate (19 mg, 0.324 mmol, 2.5 eq) followed by 3-(chloromethyl)-4-trityl-4H-1,2,4-triazole (4) (92 mg, 0.259 mmol, 2 eqv) at room temperature. The reaction mixture was further heated at 80° C. for 12 h. The progress of the reaction was monitored by TLC (M.Ph: 60% ethyl acetate in n-hexane). The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to dryness resulting in the crude compound. The crude compound was purified by Combiflash column chromatography (elution: 40-50% ethyl acetate in n-hexane) to afford compound 5A (80 mg, 54.8%) as a yellow solid. ¹H NMR (DMSO-d₆, 400 MHz): δ ppm 8.19 (br. s, 1H), 8.04 (br. s, 1H), 7.95 (br. s, 1H), 7.59 (br. s, 1H), 7.45 (d, J=10.27 Hz, 3H), 7.24-7.42 (m, 20H), 7.19 (d, J=8.31 Hz, 1H), 7.15 (br. s, 1H), 7.05 (d, J=3.42 Hz, 7H), 6.93 (d, J=5.87 Hz, 5H), 5.31 (br. s, 2H), 4.94 (br. s, 2H), 4.52 (br. s, 2H), 2.69 (br. s, 3H).

Step-4: 2-(4-(4-((4H-1,2,4-triazol-3-yl)methoxy)-3-fluorophenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-((4H-1,2,4-triazol-3-yl)methyl)-N-(4-fluorophenyl)acetamide hydrochloride salt (SSTN-592)

To a solution of 2-(4-(3-fluoro-4-((4-trityl-4H-1,2,4-triazol-3-yl)methoxy)phenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)-N-((4-trityl-4H-1,2,4-triazol-3-yl)methyl)acetamide (5A) (80 mg, 0.071 mmol, 1 eq) in DCM (5 mL) at 0° C. was added 4M HCl in ethyl acetate (1 mL). The reaction mixture was allowed to attain room temperature and stirred for 1 h. The progress of the reaction was monitored by TLC (M.Ph: 5% methanol in DCM). The reaction mixture was concentrated in vacuo resulting in the crude compound. The crude compound was triturated with n-hexane:DCM (1:1; 5 mL×2), filtered and dried under vacuum. Compound obtained after trituration was purified by preparative HPLC to afford SSTN-592 (35 mg, 69.1%) as an off white solid. ¹H NMR (DMSO-d₆, 400 MHz): δ ppm 14.13 (br. s, 1H), 13.85 (br. s, 1H), 8.29-8.64 (m, 2H), 7.55-7.75 (m, 3H), 7.42 (d, J=8.31 Hz, 2H), 7.33 (br. s, 2H), 7.24 (d, J=7.34 Hz, 1H), 7.18 (br. s, 2H), 5.28 (br. s, 2H), 4.91 (br. s, 2H), 4.54 (br. s, 2H), 2.89 (br. s, 3H). LC-MS: m/z 640.15 [M+H]⁺; HPLC: 98.94%.

embedded image

Example 38
2-(4-(4-((4H-1,2,4-triazol-3-yl)methoxy)-3,5-dichlorophenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-((4H-1,2,4-triazol-3-yl)methyl)-N-(4-fluorophenyl)acetamide (SSTN-594)
Step-1: 2-(4-(4-(benzyloxy)-3,5-dichlorophenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)acetamide (3)

To a stirred mixture of 2-(4-bromo-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)acetamide (1) (200 mg, 0.448 mmol, 1 eq) and (4-(benzyloxy)-3,5-dichlorophenyl)boronic acid (2) (146 mg, 0.493 mmol, 1.1 eq) in dioxane (10 mL) was added solution of potassium carbonate (185 mg, 1.340 mmol, 3 eq) in water (2 mL) and degassed with argon for 30 min. To the resulting solution was added catalyst Pd(PPh₃)₄(25.8 mg, 0.022 mmol, 0.05 eq) at room temperature and degassed with argon for 15 min. The reaction was further heated at 90° C. for 8 h in a sealed tube. The progress of the reaction was monitored by TLC (M.Ph: 40% ethyl acetate in n-hexane). The reaction mixture was cooled to room temperature and concentrated in vacuo up to dryness. Crude residue obtained was dissolved in ethyl acetate (100 mL). The organic layer was washed with water (20 mL) followed by brine (20 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated to dryness resulting in the crude compound. The crude compound was purified through 100-200 mesh size silica gel column chromatography (elution: 20-80% ethyl acetate in n-hexane) to afford 3 (175 mg, 63.1%) as an off white solid. ¹H NMR (DMSO-d₆, 400 MHz): δ ppm 10.45 (br. s, 1H), 7.70-7.76 (m, 3H), 7.58-7.64 (m, 2H), 7.56 (d, J=6.36 Hz, 2H), 7.37-7.49 (m, 3H), 7.31 (br. s, 1H), 7.17 (t, J=8.56 Hz, 2H), 5.13 (s, 2H), 4.87 (br. s, 2H), 2.96 (s, 3H); LC-MS: m/z 640.20 [M+Na]⁺.

Step-2: 2-(4-(3,5-dichloro-4-hydroxyphenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)acetamide (4)

To a stirred solution of 2-(4-(4-(benzyloxy)-3,5-dichlorophenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)acetamide (3) (170 mg, 0.274 mmol, 1 eq) in DCM:MeOH (4:6 mL) was added 10% Pd/C (50 mg) into a hydrogenator. The mixture was degassed for 15 min with the help of alternative vacuum and nitrogen. The reaction was stirred under hydrogen atmosphere (5 bar pressure) in a seal tube at room temperature for 1 h. The progress of the reaction was monitored by TLC (M.Ph: 50% ethyl acetate in n-hexane). The reaction mixture was filtered through a Celite bed and the filtrate was concentrated up to dryness resulting in the crude compound. The crude compound was purified through 100-200 mesh size silica gel column chromatography (elution: 40-60% ethyl acetate in n-hexane) to afford 4 (140 mg, 96.5%) as an off white solid. ¹H NMR (DMSO-d₆, 400 MHz): δ ppm 10.45 (br. s, 1H), 7.69 (br. s, 1H), 7.56-7.65 (m, 3H), 7.53 (s, 2H), 7.24 (br. s, 1H), 7.17 (t, J=8.56 Hz, 2H), 4.85 (br. s, 2H), 2.98 (s, 3H); LC-MS: m/z 527.90 [M+H]⁺.

Step-3: 2-(4-(3,5-dichloro-4-((4-trityl-4H-1,2,4-triazol-3-yl)methoxy)phenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)-N-((4-trityl-4H-1,2,4-triazol-3-yl)methyl)acetamide (6A)

To a stirred solution of 2-(4-(3,5-dichloro-4-hydroxyphenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)acetamide (4) (130 mg, 0.246 mmol, 1 eqv) in DMF (5 mL) was added cesium carbonate (240 mg, 0.738 mmol, 3 eq) at room temperature and stirred for 10 min. To the resulting solution was added 3-(chloromethyl)-4-trityl-4H-1,2,4-triazole (5) (177 mg, 0.492 mmol, 2 eq). The reaction mixture was further heated at 80° C. for 5 h. The reaction was monitored by TLC (M.Ph: 5% methanol in DCM). The reaction mixture was quenched with chilled water (100 mL) and extracted with ethyl acetate (2×200 mL). The combined organic layers was washed with water (100 mL×2) followed by brine (50 mL). The organic layer was separated was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo resulting in the crude compound. The crude compound was purified through 100-200 mesh size silica gel column chromatography (elution: 3-7% methanol in DCM) to afford 6A (175 mg, 83.7%) as white solid. ¹H NMR (DMSO-d₆, 400 MHz): δ ppm 8.17 (br. s, 1H), 8.04 (br. s, 1H), 7.62-7.68 (m, 2H), 7.46 (br. s, 2H), 7.25-7.42 (m, 22H), 7.18 (br. s, 1H), 7.04 (d, J=5.87 Hz, 7H), 6.93 (d, J=5.87 Hz, 4H), 5.21 (br. s, 2H), 4.94 (br. s, 2H), 4.52 (br. s, 2H), 2.78-2.86 (m, 3H).

Step-4: 2-(4-(4-((4H-1,2,4-triazol-3-yl)methoxy)-3,5-dichlorophenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-((4H-1,2,4-triazol-3-yl)methyl)-N-(4-fluorophenyl)acetamide hydrochloride salt (SSTN-594)

To a solution of 2-(4-(3,5-dichloro-4-((4-trityl-4H-1,2,4-triazol-3-yl)methoxy)phenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)-N-((4-trityl-4H-1,2,4-triazol-3-yl)methyl)acetamide (6A) (110 mg, 0.129 mmol, 1 eqv) in DCM (5 mL) at 0° C. was added 4M HCl in dioxane (2 mL). The reaction mixture was allowed to attain room temperature and stirred for 1 h. The progress of the reaction was monitored by TLC (M.Ph: 5% methanol in DCM). The reaction mixture was concentrated in vacuo resulting in the crude compound. The crude compound was washed with diethyl ether and DCM and further purified by preparative HPLC to afford SSTN-594 (30 mg, 30.4%) as an off white solid. ¹H NMR (DMSO-d₆, 400 MHz): δ ppm 14.07 (br. s, 1H), 13.90 (br. s, 1H), 13.82 (br. s, 1H), 8.56 (br. s, 1H), 8.39-8.49 (m, 1H), 7.64 (d, J=17.61 Hz, 4H), 7.12-7.45 (m, 4H), 5.17 (br. s, 2H), 4.90 (br. s, 2H), 4.55 (br. s, 2H), 2.92 (br. s, 3H). LC-MS: m/z 691.75 free base [M+H]⁺; HPLC: 97.97%.

embedded image

Example 39
Synthesis of 2-(4-(4-((4H-1,2,4-triazol-3-yl)methoxy)-3-fluoro-5-methoxyphenyl)-6-methoxy-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)acetamide (SSTN-596)
Step-1: 2-bromo-4-methoxy-N-methyl-6-nitroaniline (2)

To a stirred solution of 2-bromo-4-methoxy-6-nitroaniline (1) (4.00 g, 16.19 mmol, 1 eq) in DMF (40 mL) at 0° C. was added sodium hydride (60% dispersion in oil, 830 mg, 19.42 mmol, 1.2 eq) and methyl iodide (1.51 mL, 24.28 mmol, 1.5 eq) and stirred at same temperature for 1 h. The reaction was monitored by TLC (M.Ph: 10% ethyl acetate in n-hexane). The reaction mixture was diluted with ice cold water (100 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to dryness resulting in the crude compound. The crude compound was purified through Combiflash column chromatography (elution: 2-5% ethyl acetate in n-hexane) to afford 2 (3 g, 72.1%) as an off white solid. ¹H NMR (DMSO-d₆, 400 MHz): δ ppm 7.53 (s, 1H), 7.38 (s, 1H), 5.74 (br. s, 1H), 3.76 (s, 3H), 2.69 (d, J=4.40 Hz, 3H); LC-MS: m/z 260.95 [M+H]⁺.

Step-2: 6-bromo-4-methoxy-N1-methylbenzene-1,2-diamine (3)

To a stirred solution of 2-bromo-4-methoxy-N-methyl-6-nitroaniline (2) (3 g, 11.49 mmol, 1 eq) in THF:H₂O (30:3 mL) was added Fe powder (3.86 g, 68.94 mmol, 6 eq) and acetic acid (3.94 mL, 68.94 mmol, 6 eq) at room temperature. The reaction was further heated at 70° C. for 2 h. The reaction was monitored by TLC (M.Ph: 10% ethyl acetate in n-hexane). The reaction mixture was diluted with ice cold water (100 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to dryness resulting in the crude compound. The crude compound was purified through Combiflash column chromatography (elution: 10-20% ethyl acetate in n-hexane) to afford 3 (1.50 g, 57.6%) as brown liquid. LC-MS: m/z 231.00 [M+H]⁺.

Step-3: 7-bromo-5-methoxy-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (4)

To a stirred solution of 6-bromo-4-methoxy-N1-methylbenzene-1,2-diamine (3) (200 mg, 0.865 mmol, 1 eq) in DMF (10 mL) at 0° C. was added CDI (420 mg, 2.596 mmol, 3 eq). The reaction was further heated at 70° C. for 16 h. The reaction was monitored by TLC (M.Ph: 20% ethyl acetate in n-hexane). The reaction mixture was diluted with water (200 mL) and the solid precipitated was filtered and dried under vacuum to afford 4 (80 mg, 36.6%) as an off white solid. Crude compound obtained was used as such in the next step without further purification. ¹H NMR (DMSO-d₆, 400 MHz): δ ppm 11.08 (br. s, 1H), 6.74 (s, 1H), 6.57 (s, 1H), 3.73 (s, 3H), 3.50 (s, 3H).

Step-4: 2-(4-bromo-6-methoxy-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)acetamide (6)

To a stirred solution of 7-bromo-5-methoxy-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (4) (250 mg, 0.972 mmol, 1 eq) in acetronitrile (50 mL) at 0° C. was added potassium carbonate (403 mg, 2.917 mmol, 3 eq) and 2-chloro-N-(4-fluorophenyl)acetamide (5) (200 mg, 1.069 mmol, 1.1 eq) at room temperature. The reaction was further heated at 70° C. for 16 h. The reaction was monitored by TLC (M.Ph: 5% methanol in DCM). The reaction mixture was concentrated in vacuo up to dryness. Crude residue obtained was dissolved in ethyl acetate (50 mL) and washed with water (50 mL) followed by brine (50 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated to dryness resulting in the crude compound. The crude compound was purified through 100-200 mesh size silica gel column chromatography (elution: 0-5% methanol in DCM) to afford 6 (260 mg, 65.4%) as an off white solid. ¹H NMR (DMSO-d₆, 400 MHz): δ ppm 10.34 (br. s, 1H), 7.54-7.61 (m, 2H), 7.12-7.20 (m, 2H), 6.92 (s, 1H), 6.81 (s, 1H), 4.69 (s, 2H), 3.74 (s, 3H), 3.59 (s, 3H); LC-MS: m/z 409.90 [M+H]⁺.

Step-5: 2-(4-(4-(benzyloxy)-3-fluoro-5-methoxyphenyl)-6-methoxy-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)acetamide (8)

To a stirred mixture of 2-(4-bromo-6-methoxy-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)acetamide (6) (500 mg, 1.224 mmol, 1 eq) and 2-(4-(benzyloxy)-3-fluoro-5-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (482 mg, 1.347 mmol, 1.1 eq) in dioxane (50 mL) was added solution of potassium carbonate (508 mg, 3.674 mmol, 3 eq) in water (5 mL) and degassed with argon for 30 min. To the resulting solution was added catalyst Pd(PPh₃)₄(70.7 mg, 0.061 mmol, 0.05 eq) at room temperature and degassed with argon for 15 min. The reaction was further heated at 90° C. for 8 h. The reaction was monitored by TLC (M.Ph: 40% ethyl acetate in n-hexane). The reaction mixture was filtered through a Celite bed and washed with ethyl acetate (200 mL). The filtrate was concentrated in vacuo up to dryness. Crude residue was dissolved in ethyl acetate and washed with water (50 mL) followed by brine (50 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated to dryness resulting in the crude compound. The crude compound was purified through 100-200 mesh size silica gel column chromatography (elution: 0-40% ethyl acetate in n-hexane) to afford 8 (510 mg, 74.5%) as an off white solid. ¹H NMR (DMSO-d₆, 400 MHz): δ ppm 10.38 (s, 1H), 7.60 (dd, J=4.89, 8.80 Hz, 2H), 7.42-7.46 (m, 2H), 7.33-7.40 (m, 3H), 7.17 (t, J=8.80 Hz, 2H), 6.90-6.95 (m, 3H), 6.48 (d, J=1.96 Hz, 1H), 5.11 (s, 2H), 4.71 (s, 2H), 3.88 (s, 3H), 3.75 (s, 3H), 2.85 (s, 3H); LC-MS: m/z 560.15 [M+H]⁺.

Step-6: 2-(4-(3-fluoro-4-hydroxy-5-methoxyphenyl)-6-methoxy-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)acetamide (9)

To a stirred solution of 2-(4-(4-(benzyloxy)-3-fluoro-5-methoxyphenyl)-6-methoxy-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)acetamide (8) (300 mg, 0.536 mmol, 1 eqv) in DCM:MeOH (8:12 mL) was added 10% Pd/C (70 mg) into a hydrogenator. The mixture was degassed for 15 min with the help of alternative vacuum and nitrogen. The reaction was further stirred under hydrogen atmosphere (5 bar pressure) at room temperature for 2 h. The reaction was monitored by TLC (M.Ph: 60% ethyl acetate in n-hexane). The reaction mixture was filtered through a Celite bed and the filtrate was concentrated up to dryness resulting in the crude compound. The crude compound was purified through 100-200 mesh size silica gel column chromatography (elution: 2-8% methanol in DCM) to afford 9 (238 mg, 94.5%) as an off white solid. ¹H NMR (DMSO-d₆, 400 MHz): δ ppm 10.38 (s, 1H), 9.36 (s, 1H), 7.60 (dd, J=4.89, 8.80 Hz, 2H), 7.17 (t, J=8.80 Hz, 2H), 6.86 (d, J=14.67 Hz, 3H), 6.47 (d, J=1.96 Hz, 1H), 4.71 (s, 2H), 3.84 (s, 3H), 3.75 (s, 3H), 2.91 (s, 3H); LC-MS: m/z 469.90 [M+H]⁺.

Step-7: 2-(4-(3-fluoro-5-methoxy-4-((4-trityl-4H-1,2,4-triazol-3-yl)methoxy)phenyl)-6-methoxy-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)acetamide (11)

To a stirred solution of 2-(4-(3-fluoro-4-hydroxy-5-methoxyphenyl)-6-methoxy-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)acetamide (9) (232 mg, 0.494 mmol, 1 eq) in anhydrous DMF (5 mL) at 0° C. was added cesium carbonate (482 mg, 1.482 mmol, 3 eq) under nitrogen atmosphere and stirred for 10 min. To the resulting solution was added 3-(chloromethyl)-4-trityl-4H-1,2,4-triazole (10) (213 mg, 0.592 mmol, 1.2 eq). The reaction mixture was allowed to attain room temperature and stirred for 16 h. The reaction was monitored by TLC (M.Ph: 5% methanol in DCM). The reaction mixture was quenched with chilled water (50 mL) and extracted with ethyl acetate (2×100 mL). The combined organic layers was washed with water (3×50 mL) followed by brine (20 mL). The organic layer was separated was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo resulting in the crude compound. The crude compound was purified through 100-200 mesh size silica gel column chromatography (elution: 2-8% methanol in DCM) to afford 11 (248 mg, 63.4%) as an off white solid. LC-MS: m/z 791.85 [M]⁺.

Step-8: 2-(4-(4-((4H-1,2,4-triazol-3-yl)methoxy)-3-fluoro-5-methoxyphenyl)-6-methoxy-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)acetamide hydrochloride salt (SSTN-596)

To a solution of 2-(4-(3-fluoro-5-methoxy-4-((4-trityl-4H-1,2,4-triazol-3-yl)methoxy)phenyl)-6-methoxy-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)acetamide (11) (480 mg, 0.605 mmol, 1 eq) in DCM (20 mL) at 0° C. was added 4 M HCl in dioxane (5 mL). The reaction mixture was allowed to attain room temperature and stirred for 1 h. The progress of the reaction was monitored by TLC (M.Ph: 5% Methanol in DCM). The reaction mixture was concentrated in vacuo resulting in the crude compound. The crude compound was purified by trituration using diethyl ether (3×5 mL) followed by n-hexane (5 mL). Compound obtained after trituration was repurified using preparative HPLC to afford SSTN-596 (285 mg, 80.2%) as an off white solid. ¹H NMR (DMSO-d₆, 400 MHz): δ ppm 13.98 (br. s, 1H), 10.38 (br. s, 1H), 8.52 (br. s, 1H), 7.55-7.65 (m, 3H), 7.16 (t, J=7.58 Hz, 2H), 6.92 (d, J=9.29 Hz, 3H), 6.49 (br. s, 1H), 5.11 (br. s, 2H), 4.71 (s, 2H), 3.86 (s, 3H), 3.75 (s, 3H), 2.89 (s, 3H); LC-MS: m/z 551.00 [M+H]⁺; HPLC: 99.87%.

embedded image

Example 40
Synthesis of 2-(4-(4-((4H-1,2,4-triazol-3-yl)methoxy)-3-fluorophenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)acetamide (SSTN-597)
Step-1: 2-(4-(4-(benzyloxy)-3-fluorophenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)acetamide (2)

To a stirred mixture of 2-(4-bromo-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)acetamide (MK-682) (300 mg, 0.672 mmol, 1 eq) and 2-(4-(benzyloxy)-3-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1) (165 mg, 0.672 mmol, 1 eq) in dioxane:water (10:2 mL) was added potassium carbonate (278 mg, 2.017 mmol, 3 eq) followed by catalyst Pd(PPh₃)₄(38 mg, 0.033 mmol, 0.05 eq) at room temperature and degassed with argon for 15 min. The reaction was further heated at 90° C. for 12 h. The progress of the reaction was monitored by TLC (M.Ph: 50% ethyl acetate in n-hexane). The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo up to dryness resulting in the crude compound. The crude compound was purified by Combiflash column chromatography (elution: 50-60% ethyl acetate in n-hexane) to afford 3 (150 mg, 39.3%) as an off white solid. ¹H NMR (DMSO-d₆, 400 MHz): δ ppm 10.43 (br. s, 1H), 7.69 (br. s, 1H), 7.55-7.65 (m, 3H), 7.34-7.52 (m, 6H), 7.13-7.29 (m, 4H), 5.26 (s, 2H), 4.85 (s, 2H), 2.94 (s, 3H); LC-MS: m/z 568.00 [M+H]⁺.

Step-2: 2-(4-(3-fluoro-4-hydroxyphenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)acetamide (3)

To a stirred solution of 2-(4-(4-(benzyloxy)-3-fluorophenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)acetamide (2) (150 mg, 0.264 mmol, 1 eqv) in methanol (15 mL) was added 20% Pd/C (40 mg) into a hydrogenator. The mixture was degassed for 15 min with the help of alternative vacuum and nitrogen. The reaction was stirred under hydrogen atmosphere (5 bar pressure) at room temperature for 2 h. The progress of the reaction was monitored by TLC (M.Ph: 50% EtOAc in n-hexane). The reaction mixture was filtered through a Celite bed and washed with methanol (3×15 mL). The filtrate was concentrated in vacuo up to dryness to afford 3 (110 mg, 87.3%) as an off white solid. Crude compound obtained was used as such in the next step without further purification. LC-MS: m/z 478.10 [M+H]⁺.

Step-3: 2-(4-(3-fluoro-4-((4-trityl-4H-1,2,4-triazol-3-yl)methoxy)phenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)acetamide (5)

To a stirred solution of 2-(4-(3-fluoro-4-hydroxyphenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)acetamide (3) (20 mg, 0.041 mmol, 1 eq) in DMF (5 mL) was added potassium carbonate (17 mg, 0.125 mmol, 3 eq) followed by 3-(chloromethyl)-4-trityl-4H-1,2,4-triazole (4) (18 mg, 0.050 mmol, 1 eqv) at room temperature. The reaction mixture was further heated at 80° C. for 12 h. The progress of the reaction was monitored by TLC (M.Ph: 60% ethyl acetate in n-hexane). The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to dryness resulting in the crude compound. The crude compound was purified by Combiflash column chromatography (elution: 40-50% ethyl acetate in n-hexane) to afford 5 (13 mg, 39.4%) as a yellow solid. LC-MS: m/z 799.10 [M−H]⁺.

Step-4: 2-(4-(4-((4H-1,2,4-triazol-3-yl)methoxy)-3-fluorophenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)acetamide hydrochloride salt (SSTN-597)

To a solution of 2-(4-(3-fluoro-4-((4-trityl-4H-1,2,4-triazol-3-yl)methoxy)phenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)acetamide (5) (30 mg, 0.037 mmol, 1 eqv) in DCM (5 mL) at 0° C. was added 4 M HCl in ethyl acetate (0.6 mL). The reaction mixture was allowed to attain room temperature and stirred for 1 h. The progress of the reaction was monitored by TLC (M.Ph: 80% ethyl acetate in n-hexane). The reaction mixture was concentrated in vacuo resulting in the crude compound. The crude compound was triturated with diethyl ether followed by DCM, filtered and dried under vacuum. Compound obtained after trituration was purified by preparative HPLC to afford SSTN-597 (4 mg, 20%) as an off white solid. ¹H NMR (DMSO-d₆, 400 MHz): δ ppm 14.16 (br. s, 1H), 10.43 (br. s, 1H), 8.37-8.60 (m, 1H), 7.69-7.74 (m, 1H), 7.60 (br. s, 2H), 7.44 (d, J=8.31 Hz, 2H), 7.04-7.31 (m, 4H), 5.29 (s, 2H), 4.85 (s, 2H), 2.94 (s, 3H); LC-MS: m/z 559.00 [M+H]⁺; HPLC: 97.29%.

embedded image

Example 41
Synthesis of 2-(4-(4-((4H-1,2,4-triazol-3-yl)methoxy)-3-methoxyphenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)acetamide hydrochloride salt (SSTN-598)
Step-1: 2-(4-(4-(benzyloxy)-3-methoxyphenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)acetamide (2)

To a stirred mixture of 2-(4-bromo-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)acetamide (MK-682) (300 mg, 0.672 mmol, 1 eq) and 2-(4-(benzyloxy)-3-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1) (173 mg, 0.672 mmol, 1 eq) in dioxane:water (10:2 mL) was added potassium carbonate (278 mg, 2.017 mmol, 3 eq) followed by catalyst Pd(PPh₃)₄(38 mg, 0.033 mmol, 0.05 eq) at room temperature and degassed with argon for 15 min. The reaction was further heated at 90° C. for 12 h. The progress of the reaction was monitored by TLC (M.Ph: 50% ethyl acetate in n-hexane). The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to dryness resulting in the crude compound. The crude compound was purified by Combiflash column chromatography (elution: 50-60% ethyl acetate in n-hexane) to afford 2 (167 mg, 42.9%) as an off white solid. ¹H NMR (DMSO-d₆, 400 MHz): δ ppm 10.43 (br. s, 1H), 7.33-7.70 (m, 9H), 7.06-7.24 (m, 4H), 6.98 (d, J=6.85 Hz, 1H), 5.15 (s, 2H), 4.85 (s, 2H), 3.82 (s, 3H), 2.95 (s, 3H); LC-MS: m/z 580.10 [M+H]⁺.

Step-2: N-(4-fluorophenyl)-2-(4-(4-hydroxy-3-methoxyphenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)acetamide (3)

To a stirred solution of 2-(4-(4-(benzyloxy)-3-methoxyphenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)acetamide (2) (160 mg, 0.276 mmol, 1 eq) in methanol (15 mL) was added 20% Pd/C (50 mg) into a hydrogenator. The mixture was degassed for 15 min with the help of alternative vacuum and nitrogen. The reaction mixture was stirred under hydrogen atmosphere (5 bar pressure) at room temperature for 2 h. The progress of the reaction was monitored by TLC (M.Ph: 50% ethyl acetate in n-hexane). The reaction mixture was filtered through a Celite bed and washed with methanol (3×15 mL). The filtrate was concentrated in vacuo up to dryness to afford 3 (115 mg, 85.2%) as an off white solid. Crude compound obtained was used as such in the next step without further purification. LC-MS: m/z 490.10 [M+H]⁺.

Step-3: N-(4-fluorophenyl)-2-(4-(3-methoxy-4-((4-trityl-4H-1,2,4-triazol-3-yl)methoxy)phenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)acetamide (5)

To a stirred solution of N-(4-fluorophenyl)-2-(4-(4-hydroxy-3-methoxyphenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)acetamide (3) (110 mg, 0.224 mmol, 1 eqv) in DMF (5 mL) was added cesium carbonate (215 mg, 0.674 mmol, 3 eq) followed by 3-(chloromethyl)-4-trityl-4H-1,2,4-triazole (4) (97 mg, 0.269 mmol, 1.2 eqv) at room temperature and stirred for 16 h. The progress of the reaction was monitored by TLC (M.Ph: 60% ethyl acetate in n-hexane). The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to dryness resulting in the crude compound. The crude compound was purified by Combiflash column chromatography (elution: 40-50% ethyl acetate in n-hexane) to afford 5 (137 mg, 76.9%) as a yellow solid. LC-MS: m/z 811.55 [M−H]⁺.

Step-4: 2-(4-(4-((4H-1,2,4-triazol-3-yl)methoxy)-3-methoxyphenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)acetamide hydrochloride salt (SSTN-598)

To a solution of N-(4-fluorophenyl)-2-(4-(3-methoxy-4-((4-trityl-4H-1,2,4-triazol-3-yl)methoxy)phenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)acetamide (5) (137 mg, 0.168 mmol, 1 eqv) in DCM (5 mL) at 0° C. was added 4M HCl in ethyl acetate (2 mL). The reaction mixture was allowed to attain room temperature and stirred for 1 h. The progress of the reaction was monitored by TLC (M.Ph: 70% ethyl acetate in n-hexane). The reaction mixture was concentrated in vacuo resulting in the crude compound. The crude compound was triturated with diethyl ether followed by DCM, filtered and dried under vacuum. Compound obtained after trituration was purified by preparative HPLC to afford SSTN-598 (35 mg, 36.4%) as an off white solid. ¹H NMR (DMSO-d₆, 400 MHz): δ ppm 14.11 (br. s, 1H), 10.43 (s, 1H), 8.33-8.53 (m, 1H), 7.67 (s, 1H), 7.60 (dd, J=5.14, 7.58 Hz, 2H), 7.13-7.26 (m, 5H), 7.09 (s, 1H), 6.98 (d, J=7.82 Hz, 1H), 5.17 (s, 2H), 4.85 (s, 2H), 3.80 (s, 3H), 2.94 (s, 3H); LC-MS: m/z 571.10 [M+H]⁺; HPLC: 99.82%.

embedded image

Example 42
Synthesis of 2-(4-(4-((4H-1,2,4-triazol-3-yl)methoxy)-3,5-dichlorophenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)acetamide (SSTN-599)
Step-1: 2-(4-(4-(benzyloxy)-3,5-dichlorophenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)acetamide (3)

To a stirred mixture of 2-(4-bromo-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)acetamide (1) (300 mg, 0.672 mmol, 1 eq) and (4-(benzyloxy)-3,5-dichlorophenyl)boronic acid (2) (219 mg, 0.739 mmol, 1.1 eq) in dioxane (10 mL) was added solution of potassium carbonate (278 mg, 2.016 mmol, 3 eq) in water (2 mL) and degassed with argon for 30 min. To the resulting solution was added catalyst Pd(PPh₃)₄(38.8 mg, 0.033 mmol, 0.05 eq) at room temperature and degassed with argon for 15 min. The reaction was further heated at 90° C. for 8 h in a sealed tube. The progress of the reaction was monitored by TLC (M.Ph: 40% ethyl acetate in n-hexane). The reaction mixture was cooled to room temperature and diluted with ethyl acetate (200 mL). The organic layer was washed with water (2×50 mL) followed by brine (20 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated to dryness resulting in the crude compound. The crude compound was purified through 100-200 mesh size silica gel column chromatography (elution: 30-70% ethyl acetate in n-hexane) to afford 3 (200 mg, 48.1%) as an off white solid. LC-MS: m/z 616.00 [M−H]⁺.

Step-2: 2-(4-(3,5-dichloro-4-hydroxyphenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)acetamide (4)

To a stirred solution of 2-(4-(4-(benzyloxy)-3,5-dichlorophenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)acetamide (3) (190 mg, 0.307 mmol, 1 eqv) in DCM:MeOH (4:6 mL) was added 10% Pd/C (60 mg) into a hydrogenator. The mixture was degassed for 15 min with the help of alternative vacuum and nitrogen. The reaction was stirred under hydrogen atmosphere (5 bar pressure) for 1 h. The progress of the reaction was monitored by TLC (M.Ph: 50% ethyl acetate in n-hexane). The reaction mixture was filtered through a Celite bed and the filtrate was concentrated up to dryness resulting in the crude compound. The crude compound was purified through 100-200 mesh size silica gel column chromatography (elution: 40-60% ethyl acetate in n-hexane) to afford 4 (135 mg, 83.3%) as an off white solid. LC-MS: m/z 527.90 [M+H]⁺.

Step-3: 2-(4-(3,5-dichloro-4-((4-trityl-4H-1,2,4-triazol-3-yl)methoxy)phenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)acetamide (6)

To a stirred solution of 2-(4-(3,5-dichloro-4-hydroxyphenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)acetamide (4) (130 mg, 0.246 mmol, 1 eq) in DMF (5 mL) at 0° C. was added cesium carbonate (240 mg, 0.738 mmol, 3 eq) under nitrogen atmosphere and stirred for 10 min. To the resulting solution was added 3-(chloromethyl)-4-trityl-4H-1,2,4-triazole (5) (97.4 mg, 0.270 mmol, 1.1 eq). The reaction mixture was allowed to attain room temperature and stirred for 16 h. The reaction was monitored by TLC (M.Ph: 5% methanol in DCM). The reaction mixture was quenched with chilled water (50 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layers was washed with water (50 mL) followed by brine (50 mL). The organic layer was separated was dried over anhydrous sodium sulfate, filtered and concentrated to dryness to afford 5 (150 mg, crude) as a pale yellow semi solid. LC-MS: m/z 849.55 [M−H]⁺.

Step-4: 2-(4-(4-((4H-1,2,4-triazol-3-yl)methoxy)-3,5-dichlorophenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)acetamide formate salt (SSTN-599)

To a solution of 2-(4-(3,5-dichloro-4-((4-trityl-4H-1,2,4-triazol-3-yl)methoxy)phenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)acetamide (6) (140 mg, 0.164 mmol, 1 eqv) in DCM (5 mL) at 10° C. was added 4M HCl in dioxane (2 mL). The reaction mixture was allowed to attain room temperature and stirred for 1 h. The progress of the reaction was monitored by TLC (M.Ph: 5% methanol in DCM). The reaction mixture was concentrated in vacuo resulting in the crude compound. The crude compound was purified by preparative HPLC to afford SSTN-599 (7 mg, 6.5%) as an off white solid. ¹H NMR (DMSO-d₆, 400 MHz): δ ppm 13.82 (br. s, 1H), 10.44 (br. s, 1H), 8.45 (br. s, 1H), 7.55-7.73 (m, 3H), 7.51 (br. s, 2H), 7.33 (br. s, 2H), 7.29-7.38 (m, 2H), 4.90 (br. s, 2H), 4.53 (br. s, 2H), 2.93 (br. s, 3H); LC-MS: m/z 608.90 [M+H]⁺; HPLC: 99.33%.

embedded image

Example 43
Synthesis of 2-(4-(4-((4H-1,2,4-triazol-3-yl)methoxy)-3-fluoro-5-methoxyphenyl)-3-methyl-2-oxo-6-(trifluoromethoxy)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)acetamide hydrochloride salt (SSTN-600)
Step-1: 2-bromo-N-methyl-6-nitro-4-(trifluoromethoxy)aniline (2)

To a stirred mixture of 2-bromo-6-nitro-4-(trifluoromethoxy)aniline (1) (1.00 g, 3.333 mmol, 1 eq) in DMF (20 mL) at 0° C. was added sodium hydride (60% dispersion in oil, 133 mg, 3.333 mmol, 1 eq) and methyl iodide (0.304 mL, 4.900 mmol, 1.5 eq). The reaction was allowed to attain room temperature and stirred for 1 h. The reaction was monitored by TLC (M.Ph: 10% ethyl acetate in n-hexane). The reaction mixture was diluted with ice cold water and extracted with ethyl acetate (100 mL). The organic layer was washed with water (50 mL) followed by brine (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to dryness resulting in the crude compound. The crude compound was purified through 100-200 mesh size silica gel column chromatography (elution: 0-10% ethyl acetate in n-hexane) to afford 2 (448 mg, 42.6%) as an off white solid. ¹H NMR (DMSO-d₆, 400 MHz): δ ppm 7.95 (s, 1H), 7.88 (s, 1H), 6.54 (s, 1H), 2.71 (s, 3H); LC-MS: m/z 316.90 [M+H]⁺.

Step-2: 6-bromo-N1-methyl-4-(trifluoromethoxy)benzene-1,2-diamine (3)

To a stirred mixture of 2-bromo-N-methyl-6-nitro-4-(trifluoromethoxy)aniline (2) (445 mg, 1.415 mmol, 1 eq) in THF:H₂O (20:5 mL) was added Fe powder (473 mg, 8.474 mmol) and acetic acid (0.48 mL) at room temperature. The reaction was further heated at 75° C. for 3 h. The reaction was monitored by TLC (M.Ph: 10% ethyl acetate in n-hexane). The reaction mixture was diluted with ethyl acetate (100 mL) and filtered through a Celite bed. The filtrate was concentrated in vacuo up to dryness. The crude residue was dissolved in ethyl acetate and washed with water (20 mL) followed by NaHCO₃solution (20 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated to dryness resulting in the crude compound. The crude compound was purified through 100-200 mesh size silica gel column chromatography (elution: 0-10% ethyl acetate in n-hexane) to afford 3 (240 mg, 59.7%) as an off white solid. ¹H NMR (DMSO-d₆, 400 MHz): δ ppm 6.61 (s, 1H), 6.54 (s, 1H), 5.42 (br. s, 2H), 3.69 (d, J=3.42 Hz, 1H), 2.51 (d, J=4.89 Hz, 3H); LC-MS: m/z 284.90 [M+H]⁺.

Step-3: 7-bromo-1-methyl-5-(trifluoromethoxy)-1,3-dihydro-2H-benzo[d]imidazol-2-one (4)

To a stirred solution of 6-bromo-N1-methyl-4-(trifluoromethoxy)benzene-1,2-diamine (3) (240 mg, 0.842 mmol, 1 eq) in DMF (10 mL) was added CDI (546 mg, 3.367 mmol, 4 eq) at room temperature. The reaction was further heated at 70° C. for 8 h. The reaction was monitored by TLC (M.Ph: 40% ethyl acetate in n-hexane). The reaction mixture was cooled to room temperature and diluted with ice cold water (50 mL). Solid precipitated was filtered, washed with n-hexane and dried under vacuum to afford 4 (220 mg, 84.2%) as an off white solid. Crude compound obtained was used as such in the next step without further purification. ¹H NMR (DMSO-d₆, 400 MHz): δ ppm 11.43 (br. s, 1H), 7.23 (s, 1H), 6.99 (s, 1H), 3.56 (s, 3H); LC-MS: m/z 312.90 [M+H]⁺.

Step-4: 2-(4-bromo-3-methyl-2-oxo-6-(trifluoromethoxy)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)acetamide (6)

To a stirred mixture of 7-bromo-1-methyl-5-(trifluoromethoxy)-1,3-dihydro-2H-benzo[d]imidazol-2-one (4) (215 mg, 0.691 mmol, 1 eq) and 2-chloro-N-(4-fluorophenyl)acetamide (5) (142 mg, 0.760 mmol, 1.1 eq) in acetronitrile (20 mL) was added potassium carbonate (286 mg, 2.078 mmol, 3 eq) at room temperature and degassed with argon for 15 min. The reaction was further heated to reflux at 85° C. for 16 h. The reaction was monitored by TLC (M.Ph: 40% ethyl acetate in n-hexane). The reaction mixture was concentrated to dryness resulting in the crude compound. The crude compound was purified through 100-200 mesh size silica gel column chromatography (elution: 0-40% ethyl acetate in n-hexane) to afford 6 (189 mg, 59.2%) as an off white solid. ¹H NMR (DMSO-d₆, 400 MHz): δ ppm 10.38 (br. s, 1H), 7.53-7.62 (m, 2H), 7.45 (s, 1H), 7.31 (s, 1H), 7.17 (d, J=7.34 Hz, 2H), 4.76 (br. s, 2H), 3.65 (s, 3H); LC-MS: m/z 459.90 [M−H]⁺.

Step-5: 2-(4-(4-(benzyloxy)-3-fluoro-5-methoxyphenyl)-3-methyl-2-oxo-6-(trifluoromethoxy)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)acetamide (8)

To a stirred mixture of 2-(4-bromo-3-methyl-2-oxo-6-(trifluoromethoxy)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)acetamide (6) (185 mg, 0.400 mmol, 1 eq) and 2-(4-(benzyloxy)-3-fluoro-5-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (157 mg, 0.440 mmol, 1.1 eq) in dioxane (15 mL) was added solution of potassium carbonate (166 mg, 1.200 mmol, 3 eq) in water (2 mL) and degassed with argon for 30 min. To the resulting solution was added catalyst Pd(PPh₃)₄(23.1 mg, 0.020 mmol, 0.05 eq) at room temperature and degassed with argon for 15 min. The reaction was further heated at 90° C. for 8 h in a sealed tube. The reaction was monitored by TLC (M.Ph: 50% ethyl acetate in n-hexane). The reaction mixture was filtered through a Celite bed and the filtrate was concentrated to dryness resulting in the crude compound. The crude compound was purified through 100-200 mesh size silica gel column chromatography (elution: 0-50% ethyl acetate in n-hexane) to afford 8 (215 mg, 87.6%) as an off white solid. ¹H NMR (DMSO-d₆, 400 MHz): δ ppm 10.41 (br. s, 1H), 7.56-7.64 (m, 2H), 7.33-7.47 (m, 6H), 7.18 (d, J=7.83 Hz, 2H), 6.89-7.02 (m, 3H), 5.12 (s, 2H), 4.79 (s, 2H), 3.88 (s, 3H), 2.88 (s, 3H); LC-MS: m/z 614.02 [M+H]⁺.

Step-6: 2-(4-(3-fluoro-4-hydroxy-5-methoxyphenyl)-3-methyl-2-oxo-6-(trifluoromethoxy)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)acetamide (9)

To a stirred solution of 2-(4-(4-(benzyloxy)-3-fluoro-5-methoxyphenyl)-3-methyl-2-oxo-6-(trifluoromethoxy)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)acetamide (8) (215 mg, 0.350 mmol, 1 eqv) in methanol (15 mL) was added 10% Pd/C (100 mg) into a hydrogenator. The mixture was degassed for 15 min with the help of alternative vacuum and nitrogen. The reaction was stirred under hydrogen atmosphere (5 bar pressure) for 1 h. The reaction was monitored by TLC (M.Ph: 40% ethyl acetate in n-hexane). The reaction mixture was filtered through a Celite bed and washed with methanol. The filtrate was concentrated up to dryness to afford 9 (170 mg, 92.8%) as an off white solid. Crude compound obtained was used as such in the next step without further purification. ¹H NMR (DMSO-d₆, 400 MHz): δ ppm 10.42 (s, 1H), 9.45 (br. s, 1H), 7.60 (dd, J=4.89, 8.31 Hz, 2H), 7.38 (s, 1H), 7.17 (t, J=8.56 Hz, 2H), 6.87-6.94 (m, 3H), 4.78 (s, 2H), 3.85 (s, 3H), 2.96 (s, 3H); LC-MS: m/z 523.97 [M+H]⁺.

Step-7: 2-(4-(3-fluoro-5-methoxy-4-((4-trityl-4H-1,2,4-triazol-3-yl)methoxy)phenyl)-3-methyl-2-oxo-6-(trifluoromethoxy)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)acetamide (11)

To a stirred solution of 2-(4-(3-fluoro-4-hydroxy-5-methoxyphenyl)-3-methyl-2-oxo-6-(trifluoromethoxy)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)acetamide (9) (170 mg, 0.324 mmol, 1 eq) in anhydrous DMF (10 mL) at 0° C. was added cesium carbonate (317 mg, 0.974 mmol, 3 eq) under nitrogen atmosphere and stirred for 10 min. To the resulting solution was added 3-(chloromethyl)-4-trityl-4H-1,2,4-triazole (10) (128 mg, 0.357 mmol, 1.1 eq). The reaction mixture was allowed to attain room temperature and stirred for 16 h. The reaction was monitored by TLC (M.Ph: 5% methanol in DCM). The reaction mixture was quenched with chilled water (50 mL) and extracted with ethyl acetate (2×100 mL). The combined organic layers was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo resulting in the crude compound. The crude compound was purified through 100-200 mesh size silica gel column chromatography (elution: 0-5% methanol in DCM) to afford 11 (222 mg, 80.7%) as an off white solid. LC-MS: m/z 845.30 [M−H]⁺.

Step-8: 2-(4-(4-((4H-1,2,4-triazol-3-yl)methoxy)-3-fluoro-5-methoxyphenyl)-3-methyl-2-oxo-6-(trifluoromethoxy)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)acetamide hydrochloride salt (SSTN-600)

To a solution of 2-(4-(3-fluoro-5-methoxy-4-((4-trityl-4H-1,2,4-triazol-3-yl)methoxy)phenyl)-3-methyl-2-oxo-6-(trifluoromethoxy)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)acetamide (11) (220 mg, 0.259 mmol, 1 eqv) in DCM (10 mL) at 0° C. was added 4M HCl in dioxane (2.5 mL). The reaction mixture was allowed to attain room temperature and stirred for 1 h. The progress of the reaction was monitored by TLC (M.Ph: 5% methanol in DCM). The reaction mixture was concentrated in vacuo resulting in the crude compound. The crude compound was purified by preparative HPLC to afford SSTN-600 (75 mg, 47.7%) as an off white solid. ¹H NMR (DMSO-d₆, 400 MHz): δ ppm 14.01 (br. s, 1H), 10.40 (br. s, 1H), 8.42 (br. s, 1H), 7.55-7.63 (m, 2H), 7.41 (br. s, 1H), 7.17 (t, J=7.82 Hz, 2H), 6.87-7.03 (m, 3H), 5.13 (br. s, 2H), 4.79 (br. s, 2H), 3.86 (s, 3H), 2.93 (s, 3H). LC-MS: m/z 605.00 [M+H]⁺; HPLC: 99.81%.

embedded image

Example 44
Synthesis of 2-(4-(4-((4H-1,2,4-triazol-3-yl)methoxy)-3-fluoro-5-methoxyphenyl)-6-chloro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)acetamide (SSTN-601)
Step-1: 2-bromo-4-chloro-N-methyl-6-nitroaniline (2)

To a stirred solution of 2-bromo-4-chloro-6-nitroaniline (1) (1.00 g, 3.976 mmol, 1 eq) in DMF (20 mL) at 0° C. was added sodium hydride (60% dispersion in oil, 159 mg, 3.976 mmol, 1 eq) and methyl iodide (0.37 mL, 5.964 mmol, 1.5 eq). The progress of the reaction was allowed to attain room temperature and stirred for 1 h. The reaction was monitored by TLC (M.Ph: 5% methanol in DCM). The reaction mixture was quenched with ice cold water and diluted with ethyl acetate (200 mL). The organic layer was separated and washed with water (2×50 mL) followed by brine (20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to dryness resulting in the crude compound. The crude compound was purified through 100-200 mesh size silica gel column chromatography (elution: 0-5% methanol in DCM) to afford 2 (505 mg, 47.8%) as an off white solid. ¹H NMR (DMSO-d₆, 400 MHz): δ ppm 7.92 (d, J=1.96 Hz, 1H), 7.87 (d, J=2.45 Hz, 1H), 6.46 (br. s, 1H), 2.68 (s, 3H); LC-MS: m/z 266.99 [M+H]⁺.

Step-2: 6-bromo-4-chloro-N1-methylbenzene-1,2-diamine (3)

To a stirred solution of 2-bromo-4-chloro-N-methyl-6-nitroaniline (2) (500 mg, 1.883 mmol, 1 eq) in THF:H₂O (10:2 mL) was added Fe powder (631 mg, 11.29 mmol, 6 eq) and acetic acid (0.644 mL, 11.29 mmol, 6 eq) at room temperature. The reaction was further heated at 70° C. for 3 h. The reaction was monitored by TLC (M.Ph: 20% ethyl acetate in n-hexane). The reaction mixture was diluted with ethyl acetate (100 mL) and filtered through a Celite bed. The filtrate was washed with water (50 mL) followed by brine (50 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo resulting in the crude compound. The crude compound was purified through 100-200 mesh size silica gel column chromatography (elution: 0-10% ethyl acetate in n-hexane) to afford 3 (255 mg, 57.5%) as brown liquid. ¹H NMR (DMSO-d₆, 400 MHz): δ ppm 6.73 (d, J=2.45 Hz, 1H), 6.64 (d, J=2.45 Hz, 1H), 5.36 (s, 2H), 3.68-3.74 (m, 1H), 2.55 (d, J=5.87 Hz, 3H); LC-MS: m/z 236.80 [M+H]⁺.

Step-3: 7-bromo-5-chloro-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (4)

To a stirred solution of 6-bromo-4-chloro-N1-methylbenzene-1,2-diamine (3) (250 mg, 1.061 mmol, 1 eq) in DMF (15 mL) was added CDI (515 mg, 3.184 mmol, 3 eq) at room temperature. The reaction was further heated at 85° C. for 12 h. The progress of the reaction was monitored by TLC (M.Ph: 40% ethyl acetate in n-hexane). The reaction mixture was diluted with ethyl acetate (200 mL) and washed with water (50 mL) followed by brine (50 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated to dryness resulting in the crude compound. The crude compound was purified through 100-200 mesh size silica gel column chromatography (elution: 0-40% ethyl acetate in n-hexane) to afford 4 (260 mg, 93.8%) as an off white solid. ¹H NMR (DMSO-d₆, 400 MHz): δ ppm 11.34 (br. s, 1H), 7.25 (s, 1H), 7.02 (s, 1H), 3.54 (s, 3H); LC-MS: m/z 260.94 [M+H]⁺.

Step-4: 2-(4-bromo-6-chloro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)acetamide (6)

To a stirred mixture of 7-bromo-5-chloro-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (4) (260 mg, 0.994 mmol, 1 eq) and 2-chloro-N-(4-fluorophenyl)acetamide (5) (205 mg, 1.093 mmol, 1.1 eq) in acetronitrile (20 mL) was added potassium carbonate (412 mg, 2.982 mmol, 3 eq) at room temperature and degassed with argon for 15 min. The reaction was further heated at 70° C. for 8 h in a sealed tube. The progress of the reaction was monitored by TLC (M.Ph: 40% ethyl acetate in n-hexane). The reaction mixture was concentrated in vacuo up to dryness. Crude residue obtained was dissolved in ethyl acetate (200 mL) and washed with water (50 mL) followed by brine (50 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo resulting in the crude compound. The crude compound was purified through 100-200 mesh size silica gel column chromatography (elution: 0-40% ethyl acetate in n-hexane) to afford 6 (356 mg, 86.8%) as an off white solid. ¹H NMR (DMSO-d₆, 400 MHz): δ ppm 10.39 (s, 1H), 7.58 (dd, J=5.14, 8.56 Hz, 2H), 7.45 (d, J=0.98 Hz, 1H), 7.34 (s, 1H), 7.16 (t, J=8.80 Hz, 2H), 4.74 (s, 2H), 3.63 (s, 3H); LC-MS: m/z 411.93 [M+H]⁺.

Step-5: 2-(4-(4-(benzyloxy)-3-fluoro-5-methoxyphenyl)-6-chloro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)acetamide (8)

To a stirred mixture of 2-(4-bromo-6-chloro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)acetamide (6) (350 mg, 0.848 mmol, 1 eq) and 2-(4-(benzyloxy)-3-fluoro-5-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.334 mg, 0.933 mmol, 1.1 eq) in dioxane (16 mL) was added solution of potassium carbonate (351 mg, 2.544 mmol, 3 eq) in water (2 mL) and degassed with argon for 30 min. To the resulting solution was added catalyst Pd(PPh₃)₄(47.9 mg, 0.042 mmol, 0.05 eq) at room temperature and degassed with argon for 15 min. The reaction was further heated at 90° C. for 8 h. The reaction was monitored by TLC (M.Ph: 60% ethyl acetate in n-hexane). The reaction mixture was filtered through a Celite bed and washed with ethyl acetate (200 mL). The filtrate was concentrated in vacuo up to dryness to afford 8 (310 mg, 64.8%) as an off white solid. ¹H NMR (DMSO-d₆, 400 MHz): δ ppm 10.42 (s, 1H), 7.60 (dd, J=4.89, 8.80 Hz, 2H), 7.41-7.46 (m, 3H), 7.31-7.40 (m, 3H), 7.17 (t, J=8.80 Hz, 2H), 6.92-6.99 (m, 3H), 5.11 (s, 2H), 4.76 (s, 2H), 3.88 (s, 3H), 2.86 (s, 3H); LC-MS: m/z 564.10 [M+H]⁺.

Step-6: 2-(6-chloro-4-(3-fluoro-4-hydroxy-5-methoxyphenyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)acetamide (9)

To a stirred solution of 2-(4-(4-(benzyloxy)-3-fluoro-5-methoxyphenyl)-6-chloro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)acetamide (8) (305 mg, 0.541 mmol, 1 eq) in DCM:MeOH (10:10 mL) was added 10% Pd/C (150 mg) into a hydrogenator. The mixture was degassed for 15 min with the help of alternative vacuum and nitrogen. The reaction was stirred under hydrogen atmosphere (5 bar pressure) at room temperature for 15 min. The progress of the reaction was monitored by TLC (M.Ph: 60% ethyl acetate in n-hexane). The reaction mixture was filtered through a Celite bed and washed with DCM:MeOH mixture. The filtrate was concentrated in vacuo up to dryness to afford 9 (230 mg, 89.8%) as an off white solid. ¹H NMR (DMSO-d₆, 400 MHz): δ ppm 10.44 (s, 1H), 9.41 (br. s, 1H), 7.60 (dd, J=4.65, 8.56 Hz, 2H), 7.40 (s, 1H), 7.17 (t, J=8.80 Hz, 2H), 6.86-6.95 (m, 3H), 4.76 (s, 2H), 3.84 (s, 3H), 2.94 (s, 3H); LC-MS: m/z 473.99 [M+H]⁺.

Step-7: 2-(6-chloro-4-(3-fluoro-5-methoxy-4-((4-trityl-4H-1,2,4-triazol-3-yl)methoxy)phenyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)acetamide (11)

To a stirred solution of 2-(6-chloro-4-(3-fluoro-4-hydroxy-5-methoxyphenyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)acetamide (9) (230 mg, 0.485 mmol, 1 eqv) in anhydrous DMF (10 mL) at 0° C. was added cesium carbonate (192 mg, 0.533 mmol, 1.1 eq) under nitrogen atmosphere and stirred for 10 min. To the resulting solution was added 3-(chloromethyl)-4-trityl-4H-1,2,4-triazole (10) (475 mg, 1.456 mmol, 3 eq) at the same temperature. The reaction mixture was allowed to attain room temperature and stirred for 16 h. The progress of the reaction was monitored by TLC (M.Ph: 5% methanol in DCM). The reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (3×50 mL) followed by brine (20 mL). The organic layer was separated was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo resulting in the crude compound. The crude compound was purified through 100-200 mesh size silica gel column chromatography (elution: 0-5% methanol in DCM) to afford 11 (210 mg, 57%) as an off white solid. LC-MS: m/z 797.04 [M+H]⁺.

Step-8: 2-(4-(4-((4H-1,2,4-triazol-3-yl)methoxy)-3-fluoro-5-methoxyphenyl)-6-chloro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)acetamide hydrochloride salt (SSTN-601)

To a solution of 2-(6-chloro-4-(3-fluoro-5-methoxy-4-((4-trityl-4H-1,2,4-triazol-3-yl)methoxy)phenyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)acetamide (11) (205 mg, 0.257 mmol, 1 eqv) in DCM (20 mL) at 0° C. was added 4M HCl in dioxane (5 mL). The reaction mixture was allowed to attain room temperature and stirred for 1 h. The progress of the reaction was monitored by TLC (M.Ph: 5% methanol in DCM). The reaction mixture was concentrated in vacuo resulting in the crude compound. The crude compound was purified by trituration using diethyl ether (10 mL) followed by n-hexane (10 mL). Compound obtained after trituration was repurified using preparative HPLC to afford SSTN-601 (87 mg, 57.1%) as an off white solid. ¹H NMR (DMSO-d₆, 400 MHz): δ ppm 13.99 (br. s, 1H), 10.42 (s, 1H), 8.36 (br. s, 1H), 7.60 (d, J=4.89, 8.80 Hz, 2H), 7.43 (s, 1H), 7.17 (t, J=8.80 Hz, 2H), 6.92-6.99 (m, 3H), 5.13 (s, 2H), 4.76 (s, 2H), 3.86 (s, 3H), 2.91 (s, 3H); LC-MS: m/z 555.00 [M+H]⁺; HPLC: 99.33%.

embedded image

Example 45
Synthesis of 2-(4-(4-((4H-1,2,4-triazol-3-yl)methoxy)-3-fluoro-5-methoxyphenyl)-5-fluoro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)acetamide (SSTN-602)
Step-1: 2-bromo-3-fluoro-N-methyl-6-nitroaniline (2)

To a stirred solution of 2-bromo-3-fluoro-6-nitroaniline (1) (1.5 g, 6.382 mmol, 1 eq) in DMF (20 mL) at 0° C. was added sodium hydride (60% dispersion in oil, 255 mg, 6.382 mmol, 1 eq) and methyl iodide (0.596 mL, 9.574 mmol, 1.5 eq). The reaction was allowed to attain room temperature and stirred for 1 h. The reaction was monitored by TLC (M.Ph: 10% ethyl acetate in n-hexane). The reaction mixture was quenched with ice cold water (100 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layer was washed with water (2×50 mL) followed by brine (20 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated to dryness resulting in the crude compound. The crude compound was purified through 100-200 mesh size silica gel column chromatography (elution: 0-10% ethyl acetate in n-hexane) to afford 2 (1.1 g, 63.2%) as brown oil. ¹H NMR (DMSO-d₆, 400 MHz): δ ppm 7.90 (d, J=5.87 Hz, 1H), 7.29 (t, J=8.31 Hz, 1H), 6.69-6.83 (m, 1H), 2.78 (s, 3H).

Step-2: 6-bromo-5-fluoro-N1-methylbenzene-1,2-diamine (3) (E20209-020-02)

To a stirred solution of 2-bromo-3-fluoro-N-methyl-6-nitroaniline (2) (1.00 g, 4.015 mmol, 1 eq) in THF:H₂O (50:5 mL) was added Fe powder (1.34 g, 24.09 mmol, 6 eq) and acetic acid (1.37 mL, 24.09 mmol, 6 eq) at room temperature. The reaction was further heated at 70° C. for 3 h. The reaction was monitored by TLC (M.Ph: 10% ethyl acetate in n-hexane). The reaction mixture was cooled to room temperature and diluted with ethyl acetate (100 mL). The resulting solution was filtered through a Celite bed and the filtrate was concentrated in vacuo up to dryness. Crude residue obtained was dissolved in ethyl acetate (100 m) and washed with saturated NaHCO₃solution (50 mL) followed by brine (20 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated to dryness resulting in the crude compound. The crude compound was purified through 100-200 mesh size silica gel column chromatography (elution: 0-10% ethyl acetate in n-hexane) to afford 3 (430 mg, 48.9%) as brown liquid. ¹H NMR (DMSO-d₆, 400 MHz): δ ppm 6.55-6.64 (m, 1H), 6.44-6.53 (m, 1H), 4.69 (br. s, 2H), 3.79 (d, J=3.91 Hz, 1H), 3.19 (br. s, 3H); LC-MS: m/z 218.80 [M+H]⁺

Step-3: 7-bromo-6-fluoro-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (4) (E20227-004-01)

To a stirred solution of 6-bromo-5-fluoro-N1-methylbenzene-1,2-diamine (3) (430 mg, 1.962 mmol, 1 eq) in DMF (10 mL) was added CDI (954 mg, 5.888 mmol, 3 eq) at room temperature. The reaction was further heated at 70° C. for 8 h. The reaction was monitored by TLC (M.Ph: 40% ethyl acetate in n-hexane). The reaction mixture was cooled to room temperature and diluted with ice cold water. The solid precipitated was filtered, washed with n-hexane (10 mL) and dried under vacuum to afford 4 (450 mg, 93.7%) as an off white solid. Crude compound obtained was used as such in the next step without further purification. ¹H NMR (DMSO-d₆, 400 MHz): δ ppm 11.18 (br. s, 1H), 6.90-7.01 (m, 2H), 3.57 (s, 3H); LC-MS: m/z 285.90 [M+ACN]⁺

Step-4: 2-(4-bromo-5-fluoro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)acetamide (6) (E20227-008-01)

To a stirred solution of 7-bromo-6-fluoro-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (4) (448 mg, 1.824 mmol, 1 eq) and 2-chloro-N-(4-fluorophenyl)acetamide (5) (376 mg, 2.007 mmol, 1.1 eq) in acetronitrile (50 mL) was added potassium carbonate (756 mg, 5.474 mmol, 3 eq) at room temperature and degassed with argon for 15 min. The reaction was further heated at 70° C. for 8 h. The reaction was monitored by TLC (M.Ph: 40% ethyl acetate in n-hexane). The reaction mixture was concentrated in vacuo up to dryness. Crude residue obtained was dissolved in ethyl acetate (200 mL) and washed with water (50 mL) followed by brine (50 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo resulting in the crude compound. The crude compound was purified through 100-200 mesh size silica gel column chromatography (elution: 0-40% ethyl acetate in n-hexane) to afford 6 (300 mg, 41.5%) as an off white solid. ¹H NMR (DMSO-d₆, 400 MHz): δ ppm 10.39 (br. s, 1H), 7.52-7.62 (m, 2H), 7.04-7.25 (m, 4H), 4.72 (s, 2H), 3.66 (s, 3H); LC-MS: m/z 397.90 [M+H]+

Step-5: 2-(4-(4-(benzyloxy)-3-fluoro-5-methoxyphenyl)-5-fluoro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)acetamide (8) (E20227-010-01)

To a stirred mixture of 2-(4-bromo-5-fluoro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)acetamide (6) (300 mg, 0.757 mmol, 1 eq) and 2-(4-(benzyloxy)-3-fluoro-5-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (298 mg, 0.832 mmol, 1.1 eq) in dioxane (15 mL) was added solution of potassium carbonate (314 mg, 2.271 mmol, 3 eq) in water (3 mL) and degassed with argon for 30 min. To the resulting solution was added catalyst Pd(PPh₃)₄(43.7 mg, 0.037 mmol, 0.05 eq) at room temperature and degassed with argon for 15 min. The reaction was further heated at 90° C. for 8 h. The reaction was monitored by TLC (M.Ph: 70% ethyl acetate in n-hexane). The reaction mixture was filtered through a Celite bed and washed with ethyl acetate (200 mL). The filtrate was concentrated in vacuo up to dryness resulting in the crude compound. The crude compound was purified through 100-200 mesh size silica gel column chromatography (elution: 40-50% ethyl acetate in n-hexane) to afford 8 (220 mg, 53.1%) as an off white solid. LC-MS: m/z 548.07 [M+H]+

Step-6: 2-(5-fluoro-4-(3-fluoro-4-hydroxy-5-methoxyphenyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)acetamide (9) (E20227-013-01)

To a stirred solution of 2-(4-(4-(benzyloxy)-3-fluoro-5-methoxyphenyl)-5-fluoro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)acetamide (8) (220 mg, 0.401 mmol, 1 eq) in DCM:MeOH (15:15 mL) was added 10% Pd/C (120 mg) into a hydrogenator. The mixture was degassed for 15 min with the help of alternative vacuum and nitrogen. The reaction was stirred under hydrogen atmosphere (5 bar pressure) for 1 h. The reaction was monitored by TLC (M.Ph: 5% methanol in DCM). The reaction mixture was filtered through a Celite bed and the filtrate was concentrated in vacuo up to dryness to afford 9 (103 mg, 56.2%) as an off white solid. Crude compound was used as such in the next step without further purification. ¹H NMR (DMSO-d₆, 400 MHz): δ ppm 10.39 (br. s, 1H), 9.46 (br. s, 1H), 7.59 (br. s, 2H), 7.17 (d, J=5.87 Hz, 3H), 6.82-7.00 (m, 3H), 4.73 (s, 2H), 3.83 (s, 3H), 2.88 (s, 3H); LC-MS: m/z 458.00 [M+H]+

Step-7: 2-(5-fluoro-4-(3-fluoro-5-methoxy-4-((4-trityl-4H-1,2,4-triazol-3-yl)methoxy)phenyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)acetamide (11) (E20227-015-01)

To a stirred solution of 2-(5-fluoro-4-(3-fluoro-4-hydroxy-5-methoxyphenyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)acetamide (9) (100 mg, 0.218 mmol, 1 eq) in anhydrous DMF (10 mL) at 0° C. was added cesium carbonate (213 mg, 0.655 mmol, 3 eq) under nitrogen atmosphere and stirred for 10 min. To the resulting solution was added 3-(chloromethyl)-4-trityl-4H-1,2,4-triazole (10) (86.5 mg, 0.240 mmol, 1.1 eq). The reaction mixture was allowed to attain room temperature and stirred for 16 h. The reaction was monitored by TLC (M.Ph: 5% methanol in DCM). The reaction mixture was quenched with chilled water (50 mL) and extracted with ethyl acetate (2×100 mL). The combined organic layers was washed with water (3×50 mL) followed by brine (20 mL). The organic layer was separated was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo resulting in the crude compound. The crude compound was purified through 100-200 mesh size silica gel column chromatography (elution: 0-5% methanol in DCM) to afford 11 (150 mg, 88.2%) as an off white solid. LC-MS: m/z 803.10 [M+Na]⁺

Step-8: 2-(4-(4-((4H-1,2,4-triazol-3-yl)methoxy)-3-fluoro-5-methoxyphenyl)-5-fluoro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)acetamide hydrochloride salt (E20227-016-02)

To a solution of 2-(5-fluoro-4-(3-fluoro-5-methoxy-4-((4-trityl-4H-1,2,4-triazol-3-yl)methoxy)phenyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)acetamide (11) (150 mg, 0.192 mmol, 1 eq) in DCM (15 mL) at 0° C. was added 4 M HCl in dioxane (3 mL). The reaction mixture was allowed to attain room temperature and stirred for 1 h. The progress of the reaction was monitored by TLC (M.Ph: 5% Methanol in DCM). The reaction mixture was concentrated in vacuo resulting in the crude compound. The crude compound was purified by trituration with n-hexane (5 mL). Compound obtained after trituration was repurified using preparative HPLC to afford 2-(4-(4-((4H-1,2,4-triazol-3-yl)methoxy)-3-fluoro-5-methoxyphenyl)-5-fluoro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)acetamide hydrochloride salt (35 mg, 33.9%) as an off white solid. ¹H NMR (DMSO-d₆, 400 MHz): δ ppm 10.40 (br. s, 1H), 8.37 (br. s, 1H), 7.60 (br. s, 2H), 7.17 (d, J=7.34 Hz, 3H), 6.88-7.04 (m, 3H), 5.16 (d, J=4.89 Hz, 2H), 4.73 (br. s, 2H), 3.84 (s, 3H), 2.85 (s, 3H); LC-MS: m/z 539.00 [M+H]⁺; HPLC: 99.79%

embedded image

Example 46
Synthesis of 2-(4-(4-((4H-1,2,4-triazol-3-yl)methoxy)-2-fluoro-5-methoxyphenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)acetamide (SSTN-603)
Step-1: 1-(benzyloxy)-4-bromo-5-fluoro-2-methoxybenzene (2)

To a stirred solution of 4-bromo-5-fluoro-2-methoxyphenol (1) (500 mg, 2.262 mmol, 1 eq) in acetonitrile (10 mL) at 0° C. was added anhydrous potassium carbonate (468 mg, 3.393 mmol, 1.5 eq) and stirred for 10 min. To the resulting solution was added benzyl bromide (0.402 mL, 3.393 mmol, 1.5 eq) at the same temperature. The reaction mixture was allowed to attain room temperature and stirred for 16 h. The progress of the reaction was monitored by TLC (M.Ph: 10% ethyl acetate in n-hexane). The reaction mixture was concentrated in vacuo up to dryness resulting in the crude compound. The crude compound was purified through 100-200 mesh size silica gel column chromatography (elution: 0-10% ethyl acetate in n-hexane) to afford 2 (480 mg, 68.2%) as an off white solid. ¹H NMR (DMSO-d₆, 400 MHz): δ ppm 7.33-7.48 (m, 5H), 7.16-7.25 (m, 2H), 5.10 (s, 2H), 3.77 (s, 3H).

Step-2: 2-(4-(benzyloxy)-2-fluoro-5-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3)

To a stirred solution of 1-(benzyloxy)-4-bromo-5-fluoro-2-methoxybenzene (2) (470 mg, 1.510 mmol, 1 eq) and bis(pinacolato)diboron (421 mg, 1.661 mmol, 1.1 eq) in dioxane (15 mL) was added potassium acetate (444 mg, 4.531 mmol, 3 eq) and degassed with argon at room temperature for 30 min. To the resulting solution was added catalyst PdCl₂(dppf) (55.2 g, 0.075 mmol, 0.05 eq) at room temperature and degassed with argon at room temperature for 15 min. The reaction mixture was further heated at 80° C. for 6 h. The progress of the reaction was monitored by TLC (M.Ph: 10% ethyl acetate in n-hexane). The reaction mixture was diluted with ethyl acetate (200 mL) and washed with water (2×50 mL) followed by brine (20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to dryness resulting in the crude compound. The crude compound was purified through 100-200 mesh size silica gel column chromatography (elution: 0-5% ethyl acetate in n-hexane) to afford 3 (280 mg, 51.7%) as an off white solid. ¹H NMR (DMSO-d₆, 400 MHz): δ ppm 7.32-7.49 (m, 4H), 7.14-7.26 (m, 1H), 6.90-7.08 (m, 2H), 5.13 (br. s, 1H), 5.10 (br. s, 1H), 3.77 (s, 1H), 3.75 (s, 2H), 1.28 (br. s, 4H), 1.17 (br. s, 8H); LC-MS: m/z 381.05 [M+Na]⁺.

Step-3: 2-(4-(4-(benzyloxy)-2-fluoro-5-methoxyphenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)acetamide (4)

To a stirred mixture of 2-(4-bromo-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)acetamide (MK-682) (548 mg, 0.672 mmol, 1.1 eq) and 2-(4-(benzyloxy)-2-fluoro-5-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3) (400 mg, 1.116 mmol, 1 eq) in dioxane (8 mL) was added solution of potassium carbonate (463 mg, 3.349 mmol, 3 eq) in water (2 mL) and degassed with argon for 30 min. To the resulting solution was added catalyst Pd(PPh₃)₄(64.1 mg, 0.555 mmol, 0.05 eq) at room temperature and degassed with argon for 15 min. The reaction was further heated at 90° C. for 8 h. The progress of the reaction was monitored by TLC (M.Ph: 40% ethyl acetate in n-hexane). The reaction mixture was diluted with ethyl acetate (200 mL) and washed with water (2×50 mL) followed by brine (20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to dryness resulting in the crude compound. The crude compound was purified through 100-200 mesh size silica gel column chromatography (elution: 0-40% ethyl acetate in n-hexane) to afford 4 (169 mg, 31.5%) as an off white solid. ¹H NMR (DMSO-d₆, 400 MHz): δ ppm 10.43 (br. s, 1H), 7.71 (br. s, 1H), 7.60 (br. s, 2H), 7.34-7.53 (m, 5H), 7.05-7.29 (m, 5H), 5.17 (br. s, 2H), 4.86 (br. s, 2H), 3.80 (br. s, 3H), 2.98 (br. s, 3H); LC-MS: m/z 598.20 [M+H]⁺.

Step-4: 2-(4-(2-fluoro-4-hydroxy-5-methoxyphenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)acetamide (5)

To a stirred solution of 2-(4-(4-(benzyloxy)-2-fluoro-5-methoxyphenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)acetamide (4) (165 mg, 0.276 mmol, 1 eq) in DCM:MeOH (5:10 mL) was added 10% Pd/C (100 mg) into a hydrogenator. The mixture was degassed for 15 min with the help of alternative vacuum and nitrogen. The reaction was stirred under hydrogen atmosphere (5 bar pressure) for 1 h. The progress of the reaction was monitored by TLC (M.Ph: 40% ethyl acetate in n-hexane). The reaction mixture was filtered through a Celite bed and the filtrate was concentrated up to dryness resulting in the crude compound. The crude compound was purified through 100-200 mesh size silica gel column chromatography (elution: 0-40% ethyl acetate in n-hexane) to afford 5 (135 mg, 96.4%) as an off white solid. ¹H NMR (DMSO-d₆, 400 MHz): δ ppm 10.46 (s, 1H), 9.81 (s, 1H), 7.70 (s, 1H), 7.60 (dd, J=4.89, 8.80 Hz, 2H), 7.24 (s, 1H), 7.17 (t, J=8.80 Hz, 2H), 7.02 (d, J=7.34 Hz, 1H), 6.77 (d, J=10.76 Hz, 1H), 4.85 (s, 2H), 3.80 (s, 3H), 2.99 (s, 3H); LC-MS: m/z 507.95 [M+H]⁺.

Step-5: 2-(4-(2-fluoro-5-methoxy-4-((4-trityl-4H-1,2,4-triazol-3-yl)methoxy)phenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)acetamide (7)

To a stirred solution of 2-(4-(2-fluoro-4-hydroxy-5-methoxyphenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)acetamide (5) (135 mg, 0.266 mmol, 1 eqv) in DMF (10 mL) at 0° C. was added cesium carbonate (260 mg, 0.798 mmol, 3 eq) under nitrogen atmosphere and stirred for 10 min. To the resulting solution was added 3-(chloromethyl)-4-trityl-4H-1,2,4-triazole (6) (95.7 mg, 0.266 mmol, 1 eq). The reaction mixture was allowed to attain room temperature and stirred for 16 h. The reaction was monitored by TLC (M.Ph: 5% methanol in DCM). The reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (50 mL) followed by brine (50 mL). The organic layer was separated was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo resulting in the crude compound. The crude compound was purified through 100-200 mesh size silica gel column chromatography (elution: 0-5% methanol in DCM) to afford 7 (156 mg, 70.5%) as a yellow solid. ¹H NMR (DMSO-d₆, 400 MHz): δ ppm 10.46 (br. s, 1H), 8.21 (s, 1H), 7.72 (d, J=10.76 Hz, 2H), 7.57-7.64 (m, 3H), 7.34-7.43 (m, 9H), 7.12-7.22 (m, 3H), 7.02-7.11 (m, 7H), 5.24 (s, 1H), 4.86 (br. s, 2H), 3.72-3.82 (m, 3H), 2.99 (s, 1H), 2.93 (s, 2H); LC-MS: m/z 853.00 [M+Na]⁺.

Step-6: 2-(4-(4-((4H-1,2,4-triazol-3-yl)methoxy)-2-fluoro-5-methoxyphenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)acetamide hydrochloride salt (SSTN-603)

To a solution of 2-(4-(2-fluoro-5-methoxy-4-((4-trityl-4H-1,2,4-triazol-3-yl)methoxy)phenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)acetamide (7) (150 mg, 0.180 mmol, 1 eq) in DCM (20 mL) at 10° C. was added 4 M HCl in dioxane (3 mL). The reaction mixture was allowed to attain room temperature and stirred for 1 h. The progress of the reaction was monitored by TLC (M.Ph: 5% methanol in DCM). The reaction mixture was concentrated in vacuo up to dryness resulting in the crude compound. The crude compound was purified by preparative HPLC to afford SSTN-603 (40 mg, 38%) as an off white solid. ¹H NMR (DMSO-d₆, 400 MHz): δ ppm 14.15 (br. s, 1H), 10.46 (s, 1H), 8.40-8.56 (m, 1H), 7.73 (s, 1H), 7.60 (dd, J=4.89, 8.80 Hz, 2H), 7.26-7.32 (m, 2H), 7.17 (t, J=8.80 Hz, 2H), 7.09 (d, J=6.85 Hz, 1H), 5.20 (s, 2H), 4.86 (s, 2H), 3.78 (s, 3H), 2.98 (s, 3H); LC-MS: m/z 589.00 [M+H]⁺; HPLC: 99.15%.

embedded image

Examples 47 and 48
Synthesis of Methyl 5-((4H-1,2,4-triazol-3-yl)methoxy)-2-(1-(2-((4-fluorophenyl)amino)-2-oxoethyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-4-methoxybenzoate hydrochloride salt (SSTN-604, 10.4 μM) and 5-((4H-1,2,4-triazol-3-yl)methoxy)-2-(1-(2-((4-fluorophenyl)amino)-2-oxoethyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-4-methoxybenzoic acid hydrochloride salt (SSTN-605)
Step-1: Methyl 5-(benzyloxy)-2-bromo-4-methoxybenzoate (2)

To a stirred mixture of 5-(benzyloxy)-2-bromo-4-methoxybenzoic acid (1) (500 mg, 1.482 mmol, 1 eq) in methanol (5 mL) at 0° C. was added SOCl₂(1.07 mL, 14.82 mmol) under nitrogen atmosphere at room temperature. The reaction was further heated at 65° C. for 5 h. The progress of the reaction was monitored by TLC (M.Ph: 70% ethyl acetate in n-hexane). The reaction mixture was concentrated in vacuo up to dryness and the crude residue treated with saturated aqueous NaHCO₃solution (30 mL) and extracted with ethyl acetate (2×60 mL). The combined organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to dryness resulting in the crude compound. The crude compound was purified through 100-200 mesh size silica gel column chromatography (elution: 10-90% ethyl acetate in n-hexane) to afford 2 (501 mg, 96.3%) as an off white solid. ¹H NMR (DMSO-d₆, 400 MHz): δ ppm 7.49 (s, 1H), 7.33-7.47 (m, 5H), 7.28 (s, 1H), 5.12 (s, 2H), 3.86 (s, 3H), 3.82 (s, 3H); LC-MS: m/z 351.10 [M+H]⁺.

Step-2: Methyl 5-(benzyloxy)-4-methoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (4)

To a stirred mixture of methyl 5-(benzyloxy)-2-bromo-4-methoxybenzoate (2) (500 mg, 1.420 mmol, 1 eq), bispinacolato diboron (3) (723 mg, 2.840 mmol, 1.2 eq) and potassium acetate (418 mg, 4.260 mmol, 3 eq) in dioxane (20 mL) was degassed with argon for 30 min. To the resulting solution was added catalyst PdCl₂(dppf) (51.9 mg, 0.071 mmol, 0.05 eq) at room temperature and degassed with argon for 10 min. The reaction was further heated at 80° C. for 8 h in a sealed tube. The progress of the reaction was monitored by TLC (M.Ph: 50% ethyl acetate in n-hexane). The reaction mixture was concentrated in vacuo up to dryness and the crude residue obtained was dissolved in ethyl acetate (200 mL). The organic layer was washed with water (2×50 mL) followed by brine (20 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated to dryness resulting in the crude compound. The crude compound was purified through 100-200 mesh size silica gel column chromatography (elution: 10-90% ethyl acetate in n-hexane) to afford 4 (180 mg, 31.8%) as an off white solid. ¹H NMR (DMSO-d₆, 400 MHz): δ ppm 7.49 (s, 1H), 7.43-7.47 (m, 2H), 7.40 (t, J=7.34 Hz, 2H), 7.30-7.37 (m, 1H), 6.94 (s, 1H), 5.14 (s, 2H), 3.85 (s, 3H), 3.80 (s, 3H), 1.32 (s, 9H), 1.17 (s, 3H); LC-MS: m/z 399.00 [M+H]⁺.

Step-3: methyl 5-(benzyloxy)-2-(1-(2-((4-fluorophenyl)amino)-2-oxoethyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-4-methoxybenzoate (5)

To a stirred mixture of 2-(4-bromo-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)acetamide (MK-682) (310 mg, 0.778 mmol, 1 eq) and methyl 5-(benzyloxy)-4-methoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (4) (347 mg, 0.778 mmol, 1 eq) in dioxane (10 mL) was added solution of potassium carbonate (322 mg, 2.330 mmol, 3 eq) in water (2 mL) and degassed with argon for 30 min. To the resulting solution was added catalyst Pd(PPh₃)₄(45 mg, 0.038 mmol, 0.05 eq) at room temperature and degassed with argon for 15 min. The reaction was further heated at 90° C. for 8 h. The progress of the reaction was monitored by TLC (M.Ph: 50% ethyl acetate in n-hexane). The reaction mixture was cooled to room temperature and diluted with ethyl acetate (100 mL) and washed with water (50 mL) followed by brine (20 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo resulting in the crude compound. The crude compound was purified through 100-200 mesh size silica gel column chromatography (elution: 0-50% ethyl acetate in n-hexane) to afford 5 (405 mg, 81.6%) as an off white solid. ¹H NMR (DMSO-d₆, 400 MHz): δ ppm 10.47 (br. s, 1H), 7.65 (br. s, 1H), 7.60 (d, J=5.38 Hz, 2H), 7.51 (d, J=6.85 Hz, 2H), 7.32-7.46 (m, 4H), 7.17 (t, J=8.07 Hz, 2H), 7.07 (d, J=10.27 Hz, 2H), 5.21 (s, 2H), 4.86 (d, J=7.34 Hz, 2H), 3.86 (s, 3H), 3.56 (s, 3H), 2.81 (s, 3H); LC-MS: m/z 637.90 [M+H]⁺.

Step-4: methyl 2-(1-(2-((4-fluorophenyl)amino)-2-oxoethyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-5-hydroxy-4-methoxybenzoate (6)

To a stirred solution of methyl 5-(benzyloxy)-2-(1-(2-((4-fluorophenyl)amino)-2-oxoethyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-4-methoxybenzoate (5) (400 mg, 0.629 mmol, 1 eq) in DCM (5 mL) was added trifluoroacetic acid (5 mL) at room temperature and stirred for 16 h. The reaction was further heated at 40° C. for 8 h. The progress of the reaction was monitored by TLC (M.Ph: 50% ethyl acetate in n-hexane). The reaction mixture was filtered through a Celite bed and the filtrate was concentrated up to dryness resulting in the crude compound. The crude compound was purified through 100-200 mesh size silica gel column chromatography (elution: 40-60% ethyl acetate in n-hexane) to afford 6 (275 mg, 80.1%) as an off white solid. ¹H NMR (DMSO-d₆, 400 MHz): δ ppm 10.46 (s, 1H), 9.76 (s, 1H), 7.63 (s, 1H), 7.57-7.63 (m, 2H), 7.46 (s, 1H), 7.17 (t, J=8.80 Hz, 2H), 7.06 (s, 1H), 6.96 (s, 1H), 4.78-4.91 (m, 2H), 3.84 (s, 3H), 3.54 (s, 3H), 2.80 (s, 3H); LC-MS: m/z 547.90 [M+H]⁺.

Step-5: methyl 2-(1-(2-((4-fluorophenyl)amino)-2-oxoethyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-4-methoxy-5-((4-trityl-4H-1,2,4-triazol-3-yl)methoxy)benzoate (8)

To a stirred solution of methyl 2-(1-(2-((4-fluorophenyl)amino)-2-oxoethyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-5-hydroxy-4-methoxybenzoate (6) (270 mg, 0.493 mmol, 1 eq) in anhydrous DMF (10 mL) at 0° C. was added cesium carbonate (321 mg, 0.986 mmol, 2 eq) under nitrogen atmosphere and stirred for 10 min. To the resulting solution was added 3-(chloromethyl)-4-trityl-4H-1,2,4-triazole (7) (186 mg, 0.517 mmol, 1.05 eq). The reaction mixture was allowed to attain room temperature and stirred for 16 h. The progress of the reaction was monitored by TLC (M.Ph: 5% methanol in DCM). The reaction mixture was poured into chilled water (50 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layer was washed with water (2×50 mL) followed by brine (20 mL). The organic layer was separated was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo resulting in the crude compound. The crude compound was purified through 100-200 mesh size silica gel column chromatography (elution: 0-5% methanol in DCM) to afford 8 (200 mg, 46.6%) as an off white solid. LC-MS: m/z 869.95 [M−H]⁺.

Step-6: Methyl 5-((4H-1,2,4-triazol-3-yl)methoxy)-2-(1-(2-((4-fluorophenyl)amino)-2-oxoethyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-4-methoxybenzoate hydrochloride salt (SSTN-604)

To a solution of methyl 2-(1-(2-((4-fluorophenyl)amino)-2-oxoethyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-4-methoxy-5-((4-trityl-4H-1,2,4-triazol-3-yl)methoxy)benzoate (8) (100 mg, 0.114 mmol, 1 eq) in DCM (10 mL) at 10° C. was added 4M HCl in ethyl acetate (5 mL). The reaction mixture was allowed to attain room temperature and stirred for 1 h. The progress of the reaction was monitored by TLC (M.Ph: 5% methanol in DCM). The reaction mixture was concentrated in vacuo up to dryness and the crude residue obtained was triturated with mixture of DCM:n-hexane (1:1; 20 mL) to afford SSTN-604 (70 mg, crude) as an off white solid. Crude compound was used as such in the next step without further purification. LC-MS: m/z 629.00 [M+H]⁺.

Step-7: 5-((4H-1,2,4-triazol-3-yl)methoxy)-2-(1-(2-((4-fluorophenyl)amino)-2-oxoethyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-4-methoxybenzoic acid hydrochloride salt (SSTN-605)

To a solution of methyl 5-((4H-1,2,4-triazol-3-yl)methoxy)-2-(1-(2-((4-fluorophenyl)amino)-2-oxoethyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-4-methoxybenzoate (SSTN-604) (70 mg, 0.105 mmol, 1 eq) in THF:MeOH (2:1 mL) at 0° C. was added solution of lithium hydroxide monohydrate (22.1 mg, 0.526 mmol, 5 eq) in water (1 mL). The reaction mixture was allowed to attain room temperature and stirred for 16 h. The progress of the reaction was monitored by TLC (M.Ph: 10% methanol in DCM). The reaction mixture was concentrated in vacuo up to dryness. Crude residue obtained was diluted with water (3 mL) and acidified up to pH=3 using dilute HCl solution and stirred for 5 min. Solid precipitated was filtered and dried under vacuum resulting in the crude compound. The crude compound from batch no. E20209-064 (25 mg scale) and E20209-067 (70 mg scale) were combined together for purification by preparative HPLC to afford SSTN-605 (61 mg, 65.6%) as an off white solid. ¹H NMR (DMSO-d₆, 400 MHz): δ ppm 13.97 (s, 1H), 12.55 (br. s, 1H), 10.47 (br. s, 1H), 8.52-8.67 (m, 1H), 7.72 (s, 1H), 7.59-7.65 (m, 4H), 7.17 (t, J=8.80 Hz, 2H), 7.08 (s, 1H), 6.97 (s, 1H), 5.23 (br. s, 2H), 4.78-4.91 (m, 2H), 3.83 (s, 3H), 2.83 (s, 3H); LC-MS: m/z 615.05 [M+H]⁺; HPLC: 99.38%.

embedded image

Example 49
Synthesis of 2-(4-(4-((4H-1,2,4-triazol-3-yl)methoxy)-3-fluoro-5-methoxyphenyl)-3,6-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)acetamide hydrochloride salt (SSTN-606)
Step-1: 2-bromo-N,4-dimethyl-6-nitroaniline (2)

To a stirred solution of 2-bromo-4-methyl-6-nitroaniline (1) (1.50 g, 6.493 mmol, 1 eq) in DMF (10 mL) at 0° C. was added sodium hydride (60% dispersion in oil, 144 mg, 6.493 mmol, 1 eq) and methyl iodide (0.603 mL, 9.740 mmol, 1.5 eq). The reaction was further stirred at 0° C. for 2 h. The reaction was monitored by TLC (M.Ph: 5% ethyl acetate in n-hexane). The reaction mixture was diluted with ice cold water (50 mL) and ethyl acetate (50 mL). The organic layer was separated and washed with water (50 mL) followed by brine (50 mL) and dried over anhydrous sodium sulfate, filtered and concentrated in vacuo resulting in the crude compound. The crude compound was purified through Combiflash column chromatography (elution: 0-5% ethyl acetate in n-hexane) to afford 2 (600 mg, 40.8%) as yellow solid. ¹H NMR (DMSO-d₆, 400 MHz): δ ppm 7.65 (s, 1H), 7.59 (s, 1H), 6.07-6.12 (m, 1H), 2.69 (d, J=4.89 Hz, 3H), 2.22 (s, 3H); LC-MS: m/z 244.98 [M+H]⁺.

Step-2: 6-bromo-N1,4-dimethylbenzene-1,2-diamine (3)

To a stirred solution of 2-bromo-N,4-dimethyl-6-nitroaniline (2) (600 mg, 2.448 mmol, 1 eq) in EtOAc:H₂O (10:1 mL) was added acetic acid (0.700 mL, 12.24 mmol, 6 eq) and stirred at 40° C. for 10 min. To the resulting solution was added Fe powder (683 mg, 12.24 mmol, 5 eq) at same temperature. The reaction was further heated at 70° C. for 3 h. The reaction was monitored by TLC (M.Ph: 20% ethyl acetate in n-hexane). The reaction mixture was diluted with ethyl acetate (100 mL) and filtered through a Celite bed. The filtrate was concentrated in vacuo up to dryness resulting in the crude compound. The crude compound was purified through 100-200 mesh size silica gel column chromatography (elution: 0-20% ethyl acetate in n-hexane) to afford 3 (300 mg, 57.2%) as brown liquid. ¹H NMR (DMSO-d₆, 400 MHz): δ ppm 6.53 (s, 1H), 6.41 (s, 1H), 4.95 (s, 2H), 3.43-3.49 (m, 1H), 2.50-2.53 (m, 3H), 2.08 (s, 3H); LC-MS: m/z 214.90 [M+H]⁺.

Step-3: 7-bromo-1,5-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (4)

To a stirred solution of 6-bromo-N1,4-dimethylbenzene-1,2-diamine (3) (300 mg, 1.394 mmol, 1 eq) in DMF (5 mL) was added CDI (678 mg, 4.184 mmol, 3 eq) at room temperature and stirred for 16 h. The reaction was monitored by TLC (M.Ph: 40% EtOAc in n-hexane). The reaction mixture was diluted with water (50 mL), the solid precipitated was filtered and dried under vacuum to afford 6 (250 mg, 74.6%) as an off white solid. ¹H NMR (DMSO-d₆, 400 MHz): δ ppm 11.07 (br. s, 1H), 6.98 (s, 1H), 6.79 (s, 1H), 3.52 (s, 3H), 2.27 (s, 3H); LC-MS: m/z 241.02 [M+H]⁺.

Step-4: 2-(4-bromo-3,6-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)acetamide (6)

To a stirred mixture of 7-bromo-1,5-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (4) (250 mg, 1.037 mmol, 1 eq) and 2-chloro-N-(4-fluorophenyl)acetamide (5) (204 mg, 1.089 mmol, 1.05 eq) in acetronitrile (10 mL) was added potassium carbonate (429 mg, 3.111 mmol, 3 eq) at room temperature. The reaction was further heated at 70° C. for 8 h in a sealed tube. The reaction was monitored by TLC (M.Ph: 40% ethyl acetate in n-hexane). The reaction mixture was diluted with water (50 mL), the solid precipitated was filtered and dried under vacuum to afford 6 (350 mg, 86.4%) as an off white solid. ¹H NMR (DMSO-d₆, 400 MHz): δ ppm 10.38 (s, 1H), 7.58 (dd, J=5.14, 8.56 Hz, 2H), 7.16 (t, J=8.56 Hz, 2H), 7.07 (s, 1H), 7.03 (s, 1H), 4.68 (s, 2H), 3.61 (s, 3H), 2.29 (s, 3H); LC-MS: m/z 391.80 [M+H]⁺.

Step-5: 2-(4-(4-(benzyloxy)-3-fluoro-5-methoxyphenyl)-3,6-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)acetamide (8)

To a stirred mixture of 2-(4-bromo-3,6-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)acetamide (6) (350 mg, 0.895 mmol, 1 eq) and 2-(4-(benzyloxy)-3-fluoro-5-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.352 mg, 0.984 mmol, 1.1 eq) in dioxane:water (15:5 mL) was added potassium carbonate (371 mg, 2.685 mmol, 3 eq) and degassed with argon for 15 min. To the resulting solution was added catalyst Pd(PPh₃)₄(51.7 mg, 0.044 mmol, 0.05 eq) at room temperature and degassed with argon for 30 min. The reaction was further heated at 90° C. for 8 h. The reaction was monitored by TLC (M.Ph: 5% methanol in DCM). The reaction mixture was filtered through a Celite bed and the filtrate was concentrated in vacuo up to dryness to afford 8 (378 mg, 77.9%) as an off white solid. ¹H NMR (DMSO-d₆, 400 MHz): δ ppm 10.40 (s, 1H), 7.60 (dd, J=4.89, 8.31 Hz, 2H), 7.42-7.46 (m, 2H), 7.33-7.39 (m, 3H), 7.17 (t, J=8.56 Hz, 2H), 7.02 (s, 1H), 6.85-6.92 (m, 2H), 6.74 (s, 1H), 5.10 (s, 2H), 4.70 (s, 2H), 3.87 (s, 3H), 2.87 (s, 3H), 2.33 (s, 3H); LC-MS: m/z 544.70 [M+H]⁺.

Step-6: 2-(4-(3-fluoro-4-hydroxy-5-methoxyphenyl)-3,6-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)acetamide (9)

To a stirred solution of 2-(4-(4-(benzyloxy)-3-fluoro-5-methoxyphenyl)-3,6-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)acetamide (8) (370 mg, 0.680 mmol, 1 eq) in DCM:MeOH (10:10 mL) was added 10% Pd/C (200 mg) into a hydrogenator. The mixture was degassed for 15 min with the help of alternative vacuum and nitrogen. The reaction was stirred under hydrogen atmosphere (5 bar pressure) for 1 h. The reaction was monitored by TLC (M.Ph: 5% methanol in DCM). The reaction mixture was filtered through a Celite bed and washed with DCM:MeOH mixture. The filtrate was concentrated in vacuo up to dryness to afford 9 (206 mg, 66.8%) as an off white solid. Crude compound was used in the next step without further purification. ¹H NMR (DMSO-d₆, 400 MHz): δ ppm 10.41 (s, 1H), 9.36 (br. s, 1H), 7.54-7.65 (m, 3H), 7.17 (t, J=8.80 Hz, 2H), 7.00 (s, 1H), 6.82 (s, 1H), 6.72 (s, 1H), 4.70 (s, 2H), 3.84 (s, 3H), 2.93 (s, 3H), 2.33 (s, 3H); LC-MS: m/z 453.94 [M+H]⁺.

Step-7: 2-(4-(3-fluoro-5-methoxy-4-((4-trityl-4H-1,2,4-triazol-3-yl)methoxy)phenyl)-3,6-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)acetamide (11)

To a stirred solution of 2-(4-(3-fluoro-4-hydroxy-5-methoxyphenyl)-3,6-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)acetamide (9) (200 mg, 0.441 mmol, 1 eq) in anhydrous DMF (20 mL) at 0° C. was added cesium carbonate (430 mg, 1.323 mmol, 3 eq) under nitrogen atmosphere and stirred for 10 min. To the resulting solution was added 3-(chloromethyl)-4-trityl-4H-1,2,4-triazole (10) (158 mg, 0.441 mmol, 1 eq). The reaction mixture was allowed to attain room temperature and stirred for 16 h. The reaction was monitored by TLC (M.Ph: 5% methanol in DCM). The reaction mixture was diluted with ethyl acetate (100 mL) and washed with ice cold water (3×50 mL) followed by brine (20 mL). The organic layer was separated was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo resulting in the crude compound. The crude compound was purified through 100-200 mesh size silica gel column chromatography (elution: 0-5% methanol in DCM) to afford 11 (257 mg, 74.9%) as an off white solid. LC-MS: m/z 775.65 [M−H]⁺.

Step-8: 2-(4-(4-((4H-1,2,4-triazol-3-yl)methoxy)-3-fluoro-5-methoxyphenyl)-3,6-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)acetamide hydrochloride salt (SSTN-606)

To a solution of 2-(4-(3-fluoro-5-methoxy-4-((4-trityl-4H-1,2,4-triazol-3-yl)methoxy)phenyl)-3,6-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(4-fluorophenyl)acetamide (11) (250 mg, 0.321 mmol, 1 eq) in DCM (15 mL) at 0° C. was added 4 M HCl in dioxane (5 mL). The reaction mixture was allowed to attain room temperature and stirred for 1 h. The progress of the reaction was monitored by TLC (M.Ph: 5% methanol in DCM). The reaction mixture was concentrated in vacuo resulting in the crude compound. The crude compound was purified by trituration with n-hexane (10 mL), filtered and dried under vacuum. Compound obtained after trituration was repurified using preparative HPLC to afford SSTN-606 (41 mg, 23.8%) as an off white solid. ¹H NMR (DMSO-d₆, 400 MHz): δ ppm 14.01 (br. s, 11H), 10.41 (s, 1H), 8.24-8.46 (m, 1H), 7.60 (dd, J=4.89, 8.31 Hz, 2H), 7.17 (t, J=8.56 Hz, 2H), 7.03 (s, 1H), 6.91 (s, 1H), 6.87 (d, J=10.27 Hz, 1H), 6.75 (s, 1H), 5.12 (s, 2H), 4.70 (s, 2H), 3.85 (s, 3H), 2.91 (s, 3H), 2.33 (s, 3H); LC-MS: m/z 535.60 [M+H]⁺; HPLC: 96.68%.

embedded image

Example 50
Synthesis of 2-(7-(4-((4H-1,2,4-triazol-3-yl)methoxy)-3-fluoro-5-methoxyphenyl)-1-methyl-2-oxo-1,2-dihydro-3H-imidazo[4,5-c]pyridin-3-yl)-N-(4-fluorophenyl)acetamide hydrochloride salt (SSTN-608)
Step-1a: 2-(benzyloxy)-5-bromo-3-fluorobenzaldehyde (3a)

To a stirred solution of 5-bromo-3-fluoro-2-hydroxybenzaldehyde (1a) (30 g, 136.98 mmol, 1 eq) in acetonitrile (300 mL) at 0° C. was added benzyl bromide (2a) (24.4 mL, 205.45 mmol, 1.5 eq) followed by potassium carbonate (28.4 g, 205.45 mmol, 1.5 eq) slowly. To the resulting solution was added TFAA (174 mL) dropwise at the same temperature. The reaction mixture was allowed to attain room temperature and stirred for 16 h. The progress of the reaction was monitored by TLC (M.Ph: 10% EtOAc in n-hexane). The reaction mixture was concentrated in vacuo up to dryness resulting in the crude compound. The crude compound was purified through 100-200 mesh size silica gel column chromatography (elution: 0-10% EtOAc in n-hexane) to afford 3a (29.1 g, 68.7%) as an off white solid. ¹H NMR (DMSO-d₆, 400 MHz): δ ppm 10.03 (s, 1H), 8.01 (d, J=11.25 Hz, 1H), 7.60 (s, 1H), 7.35-7.46 (m, 5H), 5.26 (s, 2H).

Step-2a: 2-(benzyloxy)-5-bromo-3-fluorophenol (4a)

To a stirred solution of 2-(benzyloxy)-5-bromo-3-fluorobenzaldehyde (3a) (29 g, 93.81 mmol, 1 eq) in DCM (300 mL) at 0° C. was added KH₂PO₄(102.7 g, 750.49 mmol, 8 eq) followed by 30% H₂O₂(116 mL, 1017.5 mmol, 10.8 eq) slowly. To the resulting solution was added TFAA (174 mL) dropwise at the same temperature. The reaction mixture was allowed to attain room temperature and stirred for 16 h. The progress of the reaction was monitored by TLC (M.Ph: 20% ethyl acetate in n-hexane). The reaction mixture was diluted with water (300 mL) and DCM (300 mL). The organic layer was separated and washed with water (200 mL) followed by brine (200 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to dryness resulting in the crude compound. The crude compound was purified through 100-200 mesh size silica gel column chromatography (elution: 0-20% ethyl acetate in n-hexane) to afford 4a (18 g, 64.7%) as an off white solid. ¹H NMR (DMSO-d₆, 400 MHz): δ ppm 10.40 (s, 1H), 7.30-7.48 (m, 5H), 6.93 (d, J=10.08 Hz, 1H), 6.86 (s, 1H), 5.03 (s, 2H).

Step-3a: 2-(benzyloxy)-5-bromo-1-fluoro-3-methoxybenzene (5a)

To a stirred solution of 2-(benzyloxy)-5-bromo-3-fluorophenol (4a) (18 g, 60.83 mmol, 1 eq) in acetonitrile (300 mL) was added methyl iodide (5.67 mL, 91.24 mmol, 1.5 eq) followed by potassium carbonate (21 g, 152.07 mmol, 2.5 eq) at room temperature. The reaction mixture was further heated at 60° C. for 3 h. The progress of the reaction was monitored by TLC (M.Ph: 20% ethyl acetate in n-hexane). The reaction mixture was concentrated in vacuo up to dryness. Crude residue obtained was dissolved in ethyl acetate (100 mL) and washed with water (100 mL) followed by brine (100 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated to dryness resulting in the crude compound. The crude compound was purified through 100-200 mesh size silica gel column chromatography (elution: 0-20% ethyl acetate in n-hexane) to afford 5a (18.1 g, 95.6%) as an off white solid. ¹H NMR (DMSO-d₆, 400 MHz): δ ppm 7.30-7.45 (m, 5H), 7.08-7.17 (m, 2H), 5.02 (s, 2H), 3.86 (s, 3H).

Step-4a: 2-(4-(benzyloxy)-3-fluoro-5-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (7a)

To a stirred solution of 2-(benzyloxy)-5-bromo-1-fluoro-3-methoxybenzene (5a) (18 g, 57.78 mmol, 1 eq) in dioxane (200 mL) was added potassium acetate (17.01 g, 173.35 mmol, 3 eq) and bis(pinacolato)diboron (6a) (19.07 g, 75.12 mmol, 1.3 eq) and degassed with argon at room temperature for 15 min. To the resulting solution was added catalyst PdCl₂(dppf) (2.11 g, 2.889 mmol, 0.05 eq) at room temperature. The reaction mixture was further heated at 80° C. for 4 h. The reaction was monitored by TLC (M.Ph: 40% ethyl acetate in n-hexane). The reaction mixture was filtered through a Celite bed and washed with ethyl acetate (200 mL). The filtrate was concentrated in vacuo resulting in the crude compound. The crude compound was purified through 100-200 mesh size silica gel column chromatography (elution: 0-20% ethyl acetate in n-hexane) to afford 8 (16 g, 77.6%) as an off white solid. ¹H NMR (DMSO-d₆, 400 MHz): δ ppm 7.29-7.45 (m, 5H), 7.06 (s, 1H), 7.00 (d, J=10.27 Hz, 1H), 5.08 (s, 2H), 3.86 (s, 3H), 1.29 (s, 12H).

Step-1: 3-bromo-N-methyl-5-nitropyridin-4-amine (2)

To a stirred solution of 3-bromo-5-nitropyridin-4-amine (1) (3 g, 12.71 mmol, 1 eq) in THF (10 mL) was added methyl amine (2.4 mL, 50.86 mmol, 4 eq) at room temperature. The reaction was further heated at 90° C. for 8 h in a sealed tube. The progress of the reaction was monitored by TLC (M.Ph: 20% ethyl acetate in n-hexane). The reaction mixture was cooled to room temperature and diluted with water and extracted with ethyl acetate (3×200 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to dryness resulting in the crude compound. The crude compound was purified through 100-200 mesh size silica gel column chromatography (elution: 0-20% ethyl acetate in n-hexane) to afford 2 (2.70 g, 92.1%) as a yellow solid. ¹H NMR (DMSO-d₆, 400 MHz): δ ppm 8.67 (s, 1H), 8.48 (s, 1H), 7.34 (br. s, 1H), 2.77 (d, J=4.89 Hz, 3H); LC-MS: m/z 231.86 [M+H]⁺.

Step-2: 5-bromo-N4-methylpyridine-3,4-diamine (3)

To a stirred mixture of 3-bromo-N-methyl-5-nitropyridin-4-amine (2) (2.70 g, 11.69 mmol, 1 eq) in THF:H₂O (30:10 mL) was added Fe powder (3.91 g, 70.14 mmol, 6 eq) and acetic acid (4 mL, 70.14 mmol, 6 eq) at room temperature. The reaction was further heated at 50° C. for 8 h. The reaction was monitored by TLC (M.Ph: 5% methanol in DCM). The reaction mixture was concentrated in vacuo up to dryness. Crude residue was diluted with water (100 mL) and pH was adjusted to basic using NaHCO₃solution and extracted with ethyl acetate (3×200 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to dryness resulting in the crude compound. The crude compound was purified through 100-200 mesh size silica gel column chromatography (elution: 5% methanol in DCM) to afford 3 (1.60 g, 68.3%) as an off white solid. LC-MS: m/z 203.75 [M+H]⁺.

Step-3: 7-bromo-1-methyl-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (4)

To a stirred mixture of 5-bromo-N4-methylpyridine-3,4-diamine (3) (1.50 g, 7.463 mmol, 1 eq) in DMF (7 mL) was added CDI (4.85 g, 29.85 mmol, 4 eq) at room temperature. The reaction was further heated at 85° C. for 12 h. The progress of the reaction was monitored by TLC (M.Ph: 5% methanol in DCM). The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3×300 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to dryness resulting in the crude compound. The crude compound was purified through 100-200 mesh size silica gel column chromatography (elution: 5% methanol in DCM) to afford 4 (1.00 g, 59%) as an off white solid. ¹H NMR (DMSO-d₆, 400 MHz): δ ppm 11.46 (br. s, 1H), 8.22 (s, 1H), 8.14 (s, 1H), 3.54 (s, 3H); LC-MS: m/z 229.70 [M+H]⁺.

Step-4: 2-(7-bromo-1-methyl-2-oxo-1,2-dihydro-3H-imidazo[4,5-c]pyridin-3-yl)-N-(4-fluorophenyl)acetamide (6)

To a stirred mixture of 7-bromo-1-methyl-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (4) (1.00 g, 4.405 mmol, 1 eq) and 2-chloro-N-(4-fluorophenyl)acetamide (5) (910 mg, 4.846 mmol, 1.1 eq) in acetronitrile (10 mL) was added potassium carbonate (1.82 g, 13.21 mmol, 3 eq) at room temperature and degassed with argon for 15 min. The reaction was further heated at 70° C. for 8 h. The progress of the reaction was monitored by TLC (M.Ph: 5% methanol in DCM). The reaction mixture was concentrated in vacuo, diluted with water (100 mL) and extracted with ethyl acetate (3×300 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to dryness resulting in the crude compound. The crude compound was purified through 100-200 mesh size silica gel column chromatography (elution: 5% methanol in DCM) to afford 6 (1.1 g, 66.2%) as an off white solid. ¹H NMR (DMSO-d₆, 400 MHz): δ ppm 10.42 (s, 1H), 8.41 (s, 1H), 8.31 (s, 1H), 7.58 (dd, J=5.14, 8.56 Hz, 2H), 7.16 (t, J=8.80 Hz, 2H), 4.79 (s, 2H), 3.64 (s, 3H); LC-MS: m/z 378.93 [M+H]⁺.

Step-5: 2-(7-(4-(benzyloxy)-3-fluoro-5-methoxyphenyl)-1-methyl-2-oxo-1,2-dihydro-3H-imidazo[4,5-c]pyridin-3-yl)-N-(4-fluorophenyl)acetamide (8)

To a stirred mixture of 2-(7-bromo-1-methyl-2-oxo-1,2-dihydro-3H-imidazo[4,5-c]pyridin-3-yl)-N-(4-fluorophenyl)acetamide (6) (1.00 g, 2.645 mmol, 1 eq) and 2-(4-(benzyloxy)-3-fluoro-5-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (7a) (947 mg, 2.645 mmol, 1 eq) in dioxane (20 mL) was added solution of potassium carbonate (1.09 g, 7.936 mmol, 3 eq) in water (5 mL) and degassed with argon for 30 min. To the resulting solution was added catalyst Pd(PPh₃)₄(0.152 mg, 0.132 mmol, 0.05 eq) at room temperature and degassed with argon for 15 min. The reaction was further heated at 90° C. for 8 h in a sealed tube. The progress of the reaction was monitored by TLC (M.Ph: 40% ethyl acetate in n-hexane). The reaction mixture was diluted with ethyl acetate (100 mL) and filtered through a Celite bed. The filtrate was diluted with water and extracted with ethyl acetate (3×300 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude compound was triturated with diethyl ether, filtered and dried under vacuum to afford 8 (1.00 g, crude) as an off white solid. ¹H NMR (DMSO-d₆, 400 MHz): δ ppm 10.46 (s, 1H), 8.44 (s, 1H), 8.10 (s, 1H), 7.95 (s, 1H), 7.60 (dd, J=4.65, 8.56 Hz, 2H), 7.42-7.47 (m, 2H), 7.34-7.41 (m, 2H), 7.17 (t, J=8.56 Hz, 2H), 6.98-7.05 (m, 2H), 5.12 (s, 2H), 4.82 (s, 2H), 3.89 (s, 3H), 2.73 (s, 3H); LC-MS: m/z 530.88 [M+H]⁺.

Step-6: 2-(7-(3-fluoro-4-hydroxy-5-methoxyphenyl)-1-methyl-2-oxo-1,2-dihydro-3H-imidazo[4,5-c]pyridin-3-yl)-N-(4-fluorophenyl)acetamide (9)

To a stirred solution of 2-(7-(4-(benzyloxy)-3-fluoro-5-methoxyphenyl)-1-methyl-2-oxo-1,2-dihydro-3H-imidazo[4,5-c]pyridin-3-yl)-N-(4-fluorophenyl)acetamide (8) (500 mg, 0.942 mmol, 1 eq) in DCM:MeOH (10:8 mL) was added 10% Pd/C (20 mg) into a hydrogenator. The mixture was degassed for 15 min with the help of alternative vacuum and nitrogen. The reaction was stirred under hydrogen atmosphere (5 bar pressure) for 4 h. The progress of the reaction was monitored by TLC (M.Ph: 5% methanol in DCM). The reaction mixture was filtered through a Celite bed and washed with methanol. The filtrate was concentrated in vacuo, triturated with diethyl ether, filtered and dried under vacuum to afford 9 (170 mg, crude) as an off white solid. ¹H NMR (DMSO-d₆, 400 MHz): δ ppm 10.45 (s, 1H), 9.47 (s, 1H), 8.41 (s, 1H), 8.08 (s, 1H), 7.55-7.65 (m, 2H), 7.17 (t, J=8.56 Hz, 2H), 6.91-6.98 (m, 2H), 4.81 (s, 2H), 3.85 (s, 3H), 3.02 (s, 3H); LC-MS: m/z 441.02 [M+H]⁺.

Step-7: 2-(7-(3-fluoro-5-methoxy-4-((4-trityl-4H-1,2,4-triazol-3-yl)methoxy)phenyl)-1-methyl-2-oxo-1,2-dihydro-3H-imidazo[4,5-c]pyridin-3-yl)-N-(4-fluorophenyl)acetamide (11)

To a stirred solution of 2-(7-(3-fluoro-4-hydroxy-5-methoxyphenyl)-1-methyl-2-oxo-1,2-dihydro-3H-imidazo[4,5-c]pyridin-3-yl)-N-(4-fluorophenyl)acetamide (9) (160 mg, 0.363 mmol, 1 eq) in anhydrous DMF (4 mL) at 0° C. was added cesium carbonate (296 mg, 0.908 mmol, 2.5 eq) under nitrogen atmosphere and stirred for 10 min. To the resulting solution was added 3-(chloromethyl)-4-trityl-4H-1,2,4-triazole (10) (123 mg, 0.363 mmol, 1 eq). The reaction mixture was allowed to attain room temperature and stirred for 16 h. The progress of the reaction was monitored by TLC (M.Ph: 5% methanol in DCM). The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layers was washed with water (3×50 mL) followed by brine (20 mL). The organic layer was separated was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, triturated with diethyl ether, filtered and dried under vacuum to afford 11 (300 mg, crude) as an off white solid. LC-MS: m/z 763.97 [M+H]⁺.

Step-8: 2-(7-(4-((4H-1,2,4-triazol-3-yl)methoxy)-3-fluoro-5-methoxyphenyl)-1-methyl-2-oxo-1,2-dihydro-3H-imidazo[4,5-c]pyridin-3-yl)-N-(4-fluorophenyl)acetamidehydrochloride salt (SSTN-608)

To a solution of 2-(7-(3-fluoro-5-methoxy-4-((4-trityl-4H-1,2,4-triazol-3-yl)methoxy)phenyl)-1-methyl-2-oxo-1,2-dihydro-3H-imidazo[4,5-c]pyridin-3-yl)-N-(4-fluorophenyl)acetamide (11) (300 mg, 0.392 mmol, 1 eq) in DCM (15 mL) at 0° C. was added 4 M HCl in dioxane (5 mL). The reaction mixture was allowed to attain room temperature and stirred for 2 h. The progress of the reaction was monitored by TLC (M.Ph: 5% methanol in DCM). The reaction mixture was concentrated in vacuo up to dryness resulting in the crude compound. The crude compound was purified by preparative HPLC to afford SSTN-608 (40 mg, 19.5%) as an off white solid. ¹H NMR (DMSO-d₆, 400 MHz): δ ppm 14.02 (br. s, 1H), 10.46 (s, 1H), 8.48-8.58 (m, 1H), 8.44 (s, 1H), 8.10 (s, 1H), 7.60 (dd, J=4.89, 8.31 Hz, 2H), 7.17 (t, J=8.56 Hz, 2H), 6.95-7.06 (m, 2H), 5.13 (br. s, 2H), 4.82 (s, 2H), 3.87 (s, 3H), 3.00 (s, 3H); LC-MS: m/z 522.10 [M+H]⁺; HPLC: 98.45%.

embedded image

Example 51
2-(4-(4-((4H-1,2,4-triazol-3-yl)methoxy)-3-fluoro-5-methoxyphenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(6-fluoropyridin-3-yl)acetamide (SSTN-609)

2-(4-(3-fluoro-5-methoxy-4-((4-trityl-4H-1,2,4-triazol-3-yl)methoxy)phenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(6-fluoropyridin-3-yl)acetamide (79 mg, 0.10 mmol) was treated with HCl (240 μL, 0.48 mmol) according to Method G. The residue was purified using flash chromatography eluting with 0-20% MeOH in DCM to give the title compound as an off white solid (35 mg, 59%). ¹H NMR (400 MHz, DMSO) δ 10.82 (s, 1H), 8.46-8.41 (m, 1H), 8.39 (s, 1H), 8.19-8.10 (m, 1H), 7.72 (d, J=1.7 Hz, 1H), 7.23 (d, J=1.7 Hz, 1H), 7.17 (dd, J=8.9, 3.1 Hz, 1H), 7.02-6.93 (m, 2H), 5.13 (s, 2H), 4.90 (s, 2H), 3.85 (s, 3H), 2.94 (s, 3H); LCMS: m/z 589.5 [M+H]⁺.

embedded image

Example 52
2-(4-(4-((4H-1,2,4-triazol-3-yl)methoxy)-3-fluoro-5-methoxyphenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(5-methoxypyridin-3-yl)acetamide (SSTN-611)

2-(4-(3-fluoro-5-methoxy-4-((4-trityl-4H-1,2,4-triazol-3-yl)methoxy)phenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(5-methoxypyridin-3-yl)acetamide (39 mg, 0.05 mmol) was treated with HCl (120 μL, 0.23 mmol) according to Method G. The residue was purified using flash chromatography eluting with 0-20% MeOH in DCM to give the title compound as an off white solid (25 mg, 85%). ¹H NMR (400 MHz, DMSO) δ 10.80 (s, 1H), 8.37 (s, 1H), 8.07 (s, 1H), 7.75 (dd, J=14.1, 2.0 Hz, 2H), 7.24 (d, J=1.7 Hz, 1H), 7.03-6.93 (m, 2H), 5.13 (s, 2H), 4.91 (s, 2H), 3.85 (s, 3H), 3.80 (s, 3H), 3.67 (s, 1H), 2.94 (s, 3H); LCMS: m/z 601.5 [M+H]⁺.

embedded image

Example 53
2-(4-(4-((4H-1,2,4-triazol-3-yl)methoxy)-3-fluoro-5-methoxyphenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(2-fluoropyridin-3-yl)acetamide (SSTN-612)

2-(4-(3-fluoro-5-methoxy-4-((4-trityl-4H-1,2,4-triazol-3-yl)methoxy)phenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(2-fluoropyridin-3-yl)acetamide (39 mg, 0.05 mmol) was treated with HCl (120 μL, 0.23 mmol) according to Method G. The residue was purified using flash chromatography eluting with 0-20% MeOH in DCM to give the title compound as an off white solid (29 mg, 99%). ¹H NMR (400 MHz, DMSO) δ 10.44 (s, 1H), 8.52 (s, 1H), 8.47-8.38 (m, 1H), 7.95 (dt, J=5.0, 1.6 Hz, 1H), 7.71 (d, J=1.7 Hz, 1H), 7.33 (dd, J=7.9, 4.9 Hz, 1H), 7.23 (d, J=1.7 Hz, 1H), 7.05-6.92 (m, 2H), 5.22-5.07 (m, 2H), 4.97 (s, 2H), 3.85 (s, 3H), 2.94 (s, 3H); LCMS: m/z 589.5 [M+H]⁺.

embedded image

Example 54
2-(4-(4-((4H-1,2,4-triazol-3-yl)methoxy)-3-fluoro-5-methoxyphenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(6-methoxypyridin-3-yl)acetamide (SSTN-613)

2-(4-(3-fluoro-5-methoxy-4-((4-trityl-4H-1,2,4-triazol-3-yl)methoxy)phenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)acetic acid (12) (75 mg, 0.10 mmol) in DCM (1.0 mL, 0.1 M) was treated with oxalyl chloride (10 μL, 0.11 mmol) and DMF (1 μL, 0.01 mmol). The reaction was stirred at room temperature for 1 hour and then was concentrated. The residue was dissolved in THF (1.0 mL, 0.1 M), followed by addition of 6-methoxypyridin-3-amine (13 mg, 0.10 mmol) and triethylamine (70 μL, 0.51 mmol). The solution was stirred at 50° C. for 18 h and then concentrated. The residue was purified using flash chromatography eluting with 0-20% MeOH in DCM to give the title compound as an off white solid (8.0 mg, 13%). ¹H NMR (400 MHz, DMSO) δ 10.50 (s, 1H), 8.42-8.35 (m, 2H), 7.88 (dd, J=8.9, 2.7 Hz, 1H), 7.69 (dd, J=11.8, 1.8 Hz, 1H), 7.26-7.21 (m, 1H), 7.03-6.94 (m, 2H), 6.81 (d, J=8.9 Hz, 1H), 5.13 (s, 2H), 4.86 (s, 2H), 3.85 (s, 3H), 3.81 (s, 3H), 2.93 (s, 3H), 1.22 (s, OH); LCMS: m/z 601.5 [M+H]⁺.

embedded image

Example 55
2-(4-(4-((4H-1,2,4-triazol-3-yl)methoxy)-3-fluoro-5-methoxyphenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(5-(trifluoromethyl)pyridin-3-yl)acetamide (SSTN-614)

2-(4-(3-fluoro-5-methoxy-4-((4-trityl-4H-1,2,4-triazol-3-yl)methoxy)phenyl)-3-methyl-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)acetic acid (12) (75 mg, 0.10 mmol) in DCM (1.0 mL, 0.1 M) was treated with oxalyl chloride (10 μL, 0.11 mmol) and DMF (1 μL, 0.01 mmol). The reaction was stirred at room temperature for 1 hour and then was concentrated. The residue was dissolved in THF (1.0 mL, 0.1 M), followed by addition of 5-(trifluoromethyl)pyridin-3-amine (17 mg, 0.10 mmol) and triethylamine (70 μL, 0.51 mmol). The solution was stirred at 50° C. for 18 h and then concentrated. The residue was purified using flash chromatography eluting with 0-20% MeOH in DCM to give the title compound as an off white solid (7.9 mg, 12%). ¹H NMR (600 MHz, DMSO) δ 11.05 (s, 1H), 8.96 (d, J=2.4 Hz, 1H), 8.71 (dd, J=2.1, 0.9 Hz, 1H), 8.54 (s, 1H), 8.47 (t, J=2.3 Hz, 1H), 7.76 (d, J=1.9 Hz, 1H), 7.27 (d, J=1.8 Hz, 1H), 7.07-6.95 (m, 3H), 5.12 (s, 2H), 4.96 (s, 2H), 3.87 (s, 3H), 2.97 (d, J=6.4 Hz, 3H); LCMS: m/z 639.3 [M+H]⁺.

TABLE 1

Additional compounds

embedded image

SSTN-426

SSTN-427

SSTN-428

SSTN-431

SSTN-434

SSTN-504

SSTN-505

SSTN-506

SSTN-507

SSTN-508

SSTN-520

SSTN-556

SSTN-557

SSTN-573

SSTN-574

SSTN-610

Example 2: Biological Assay Procedures and Activity Data

Notch11-3 Reporter Assay

293A cells expressing 1) pCMV-Tet-On 3G, 2) pLV[Tet]-Puro-TRE3G>Notch1-ICD, 3) pLV[Tet]-Puro-TRE3G>Notch2-ICD, 4) pLV[Tet]-Puro-TRE3G>Notch3-ICD, and 5) pCSL-RElement-Luc were used. When Doxycycline is added, the Tet-ON gene activates expression of hNotch1ICD, which together with endogenous NTC components binds to CSL responsive elements (pCSL-RElement-Luc) and expresses luciferase. 1×10⁴cells are plated in 100 μL (96-well format). 24 h later, compounds (10 mM stock in DMSO) are diluted in DMSO to 200×, then added (5 ul into 1 mL) to cell culture media containing 50 ng/mL Dox. This is then added 1:1 to cells. Final DMSO=0.25%, Dox=25 ng/mL. After 24 h, media is discarded, and cells are lysed in passive lysis buffer (Promega). Cells are rocked at room temperature for 15 min and then lysate is divided for luciferase assay (Luciferase Assay System, Promega) and cell viability (CellTiter Glo 2.0, Promega). Raw luciferase is normalized to cell viability, and then scaled to DMSO wells. Results are analyzed and IC₅₀'s are determined in GraphPad by nonlinear regression curve fitting (4 parameter) of dose response curves.

OE33 Colony Formation Assay:

The OE33 Esophageal Adenocarcinoma cell line was cultured and plated into 96-well tissue culture plates under sparse conditions (200 cells/well). Test compounds were serially diluted in DMSO and then into culture media (final DMSO concentration=0.1%). Compound/media was then added to cells every 48 hours for a total of 7 days. Clonogenic growth was assessed using the CellTiter-Glo reagent, according to manufacturer (Promega) specifications. Percent inhibition was calculated as the percent of luminescence normalized to control (0.1% DMSO) wells. Nonlinear regression curve fitting was performed using GraphPad Prism software to determine EC₅₀'s.

TABLE 2

Biological data

Notch1
OE33 Colony

Compound
Reporter Assay
Formation Assay

(SSTN-XXX)
IC₅₀, μM
EC₅₀, μM

384
14.2
N.T.

424
3.6
1.4

425
33.5
N.T.

426
n/a
N.T.

427
n/a
N.T.

428
n/a
N.T.

431
n/a
N.T.

434
n/a
N.T.

439
3.5
1.2

440
3.1
4.6

447
3.3
2.8

448
2.4
2.1

464
1.7
1.3

465
8.6
5.2

489
7.9
2.1

490
5.5
1.7

491
11.1
4.6

492
6.3
6.6

493
8.5
2.4

494
12.1
7.1

495
4.3
1.5

496
6.0
3.7

497
6.9
2.9

498
8.5
3

499
8.1
3

500
7.4
2.7

501
13.0
N.T.

502
12.0
8

503
12.5
8.4

504
n/a
N.T.

505
n/a
N.T.

506
n/a
N.T.

507
n/a
N.T.

508
n/a
N.T.

509
16.1
N.T.

520
n/a
N.T.

542
3.8
1.7

543
4.7
2.9

544
51.1
N.T.

545
5.8
N.T.

546
4.2
3.6

547
5.9
1.7

548
8.7
2.3

555
4.1
1.7

556
n/a
N.T.

557
n/a
N.T.

558
9.4
4.7

559
19.9
4.3

573
n/a
N.T.

574
n/a
N.T.

575
12.5
N.T.

592
14.8
N.T.

594
4.5
N.T.

596
n/a
N.T.

597
8.1
N.T.

598
6.4
11.6

599
13.9
N.T.

600
5.8
6.6

601
10.2
7.1

602
n/a
N.T.

603
7.4
3.8

604
10.4
18.9

605
n/a
N.T.

606
15.3
N.T.

608
n/a
N.T.

609
10.3
18.8

610
n/a
N.T.

611
20.9
N.T.

612
13.2
17.1

613
9.2
N.T.

614
3.4
N.T.

N.T. = not tested

Notch Inhibitors and Uses Thereof

Information

Publication Number

Date Filed

Date Published

Inventors

Original Assignees

CPC

International Classifications

Abstract

Description

Claims

CROSS-REFERENCES TO RELATED APPLICATIONS

PCT Information

Provisional Applications (1)