Methods for preparing trans isomeric forms of G protein-coupled receptor modulators - Patents.com

Abstract

Disclosed herein, inter alia, are methods for synthesizing trans isomeric forms of G protein coupled receptor modulators with high trans isomeric purity.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 144,878, filed February 2, 2021, which is incorporated by reference in its entirety and for all purposes.

[0002] The present disclosure relates to methods for preparing trans isomeric forms of G protein coupled receptor modulators with high trans isomeric purity. [Background technology]

[0003] Processes for preparing G protein-coupled receptor modulators, including C-C chemokine receptor type 4 (CCR4) inhibitors and antagonists, have been previously described. See, for example, U.S. Patent Application Publication No. 2019 / 0233397, published August 1, 2019, which discloses C-C chemokine receptor 4 (CCR4) inhibitors / antagonists having a trans isomeric configuration in which the carboxylic acid moiety and the amine moiety are attached to a cycloalkyl (e.g., cyclobutane) ring in a trans isomeric configuration. In compounds such as these, where the desired modulator has a trans isomeric chemical structure, known synthetic processes tend to produce racemic mixtures of the desired and undesired isomers / diastereomers (e.g., racemic mixtures of cis and trans isomers), making such processes uneconomical for preparing commercial quantities of the desired trans isomer or trans diastereomer. It would therefore be desirable to have a method for synthesizing trans isomeric / diastereomeric G protein coupled receptor modulators that has relatively low levels of any undesired cis isomers / diastereomers and is economically efficient for commercial scale-up. These and other needs in the art are addressed herein. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] US Patent Application Publication No. 2019 / 0233397 Summary of the Invention

[0005] Provided herein, inter alia, are methods for synthesizing trans isomeric forms of C-C chemokine receptor type 4 (CCR4) modulators, or salts or esters thereof. In some embodiments, the methods relate to synthesizing trans isomeric forms of G protein coupled receptor modulators, or salts or esters thereof, having a 3-8 membered cycloalkyl ring with at least an amine moiety substitution and a carboxylic acid or carboxylic acid derived moiety substitution, where the amine moiety and the carboxylic acid or carboxylic acid derived moiety substitution can be in a cis or trans isomeric configuration. In some embodiments, the methods include using 1,4-dihydropyridine as a carboxylic acid directed reducing agent of an imine or eneamine to prepare a modulator or precursor thereof comprising an amine moiety and a 3-8 membered cycloalkyl ring with a carboxylic acid or carboxylic acid derived moiety substitution in a predominantly trans isomerically pure form.

[0006] In one aspect, provided herein is a method of synthesizing a trans isomeric form of a C-C chemokine receptor type 4 (CCR4) modulator, or a salt or ester thereof. In some embodiments, the method comprises preparing a trans isomeric compound of formula (III) by reacting a compound of formula (I) with a compound of formula (II) in the presence of a carboxylic acid directing reducing agent, wherein the compound of formula (III) is primarily in trans isomerically pure form.

[0007] In one aspect, provided herein is a method of synthesizing a trans isomeric form of a C-C chemokine receptor type 4 (CCR4) modulator, or a salt or ester thereof. In some embodiments, the method comprises preparing a trans isomeric compound of formula (III) by reacting a compound of formula (I) with a compound of formula (II) in the presence of a carboxylic acid directing reducing agent, wherein the compound of formula (III) is in at least 80% trans isomerically pure form:

[0008] [ka] During the ceremony, n1' and n2' each independently represent an integer of 0 to 5, and the sum of n1' and n2' is at least 1 and not more than 6; L 1’ is C(R 4’ )2, L 2’ is C(R 5’ )2, R 1’ is hydrogen, halogen, -CX 1’ 3. -CHX 1’ 2, -CH2X 1’ , -OCX 1’ 3. -OCHX 1’ 2, -OCH2X 1’ , -CN, -S(O)2R 1’A , -SR 1’A , -S(O)R 1’A , -SO2NR 1’A R 1’B , -NHC(O)NR 1’A R 1’B , -N(O)2, -NR 1’A R 1’B , -NHNR 1’A R 1’B , -C(O)R 1’A , -C(O)-OR 1’A , -C(O)NR 1’A R 1’B , -C(O)NHNR 1’A R 1’B , -OR 1’A , -NR 1’A SO2R 1’B , -NR1’A C(O)R 1’B , -NR 1’A C(O)OR 1’B , -NR 1’A OR 1’B , -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 2’ is hydrogen, -CX 2’ 3. -CHX 2’ 2, -CH2X 2’ , -OCX 2’ 3. -OCHX 2’ 2, -OCH2X 2’ , -SR 2’A , -NR 2’A R 2’B , -NHNR 2’A R 2’B , -OR 2’A , -NR 2’A SO2R 2’B , -NR 2’A C(O)R 2’B , -NR 2’A C(O)OR 2’B , -NR 2’A OR 2’B , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R 2’ and R 3’ can be optionally linked to form a substituted or unsubstituted heterocycloalkyl; R 3’ is hydrogen, -CX 3’ 3. -CHX 3’ 2, -CH2X 3’ , -OCX 3’ 3. -OCHX 3’ 2, -OCH2X 3’ , -SR 3’A , -NR 3’A R 3’B , -NHNR 3’A R 3’B , -OR 3’A, -NR 3’A SO2R 3’B , -NR 3’A C(O)R 3’B , -NR 3’A C(O)OR 3’B , -NR 3’A OR 3’B , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R 2’ and R 3’ can be optionally linked to form a substituted or unsubstituted heterocycloalkyl; R 4’ is hydrogen, halogen, -CX 4’ 3. -CHX 4’ 2, -CH2X 4’ , -OCX 4’ 3. -OCHX 4’ 2, -OCH2X 4’ , -CN, -S(O)2R 4’A , -SR 4’A , -S(O)R 4’A , -SO2NR 4’A R 4’B , -NHC(O)NR 4’A R 4’B , -N(O)2, -NR 4’A R 4’B , -NHNR 4’A R 4’B , -C(O)R 4’A , -C(O)-OR 4’A , -C(O)NR 4’A R 4’B , -C(O)NHNR 4’A R 4’B , -OR 4’A , -NR 4’A SO2R 4’B , -NR 4’A C(O)R 4’B , -NR 4’A C(O)OR 4’B , -NR 4’A OR 4’B, -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 5’ is hydrogen, halogen, -CX 5’ 3. -CHX 5’ 2, -CH2X 5’ , -OCX 5’ 3. -OCHX 5’ 2, -OCH2X 5’ , -CN, -S(O)2R 5’A , -SR 5’A , -S(O)R 5’A , -SO2NR 5’A R 5’B , -NHC(O)NR 5’A R 5’B , -N(O)2, -NR 5’A R 5’B , -NHNR 5’A R 5’B , -C(O)R 5’A , -C(O)-OR 5’A , -C(O)NR 5’A R 5’B , -C(O)NHNR 5’A R 5’B , -OR 5’A , -NR 5’A SO2R 5’B , -NR 5’A C(O)R 5’B , -NR 5’A C(O)OR 5’B , -NR 5’A OR 5’B , -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 12’ are independently -OH or NHR 12” and R 12’’ is hydrogen, or substituted or unsubstituted alkyl; R 1’A , R 1’B , R2’A , R 2’B , R 3’A , R 3’B , R 4’A , R 4’B , R 5’A , and R 5’B are independently hydrogen, -F, -Cl, -Br, -I, -CF3, -CHF2, -CH2F, -CCl3, -CHCl2, -CH2Cl, -CBr3, -CHBr2, -CH2Br, -CI3, -CHI2, -CH2I, -OCF3, -OCCl3, -OCBr3, -OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -C(O)OH, -C(O)NH2, -OH, -NH2, -COOH, -CO NH2, -SH, -SO3H, -SO4H, -SON2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)OH, -NHOH, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or R bonded to the same nitrogen atom 2’A and R 2’B The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl, or may be linked together ... 3’A and R 3’B The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; X 1’ , X 2’ , X 3’ , X 4’ , and X 5’ are independently halogen.

[0009] In some embodiments, the compound of formula (III) is in at least 80% trans isomerically pure form. In some embodiments, the compound of formula (III) is in at least 85% trans isomerically pure form. In some embodiments, the compound of formula (III) is in at least 90% trans isomerically pure form. In some embodiments, the compound of formula (III) is in at least 95% trans isomerically pure form. In some embodiments, the compound of formula (III) is in at least 98% trans isomerically pure form. In some embodiments, the compound of formula (III) is in at least 99% trans isomerically pure form. In some embodiments, the compound of formula (III) is in 100% trans isomerically pure form.

[0010] In some embodiments, reacting the compound of Formula (I) with the compound of Formula (II) is carried out in the absence of a separate catalyst.

[0011] In some embodiments, R 2’ and R 3’ are linked to form a substituted or unsubstituted piperidinyl ring. In some embodiments, the piperidinyl is substituted with a substituted or unsubstituted heterocycloalkyl. In some embodiments, the substituted or unsubstituted heterocycloalkyl is a nitrogen-containing 3- to 6-membered heterocycloalkyl.

[0012] In some embodiments, the compound of formula (I) is

[0013] [ka] and During the ceremony, R 11’is -CF3, -CHF2, -CH2F, -CCl3, -CHCl2, -CH2Cl, -CBr3, -CHBr2, -CH2Br, -CI3, -CHI2, -CH2I, -NH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In some embodiments, R 11’ is substituted or unsubstituted alkyl.

[0014] The compound of formula III is

[0015] [ka] and In the formula, R 11’ is a substituted or unsubstituted alkyl, and each of n1′ and n2′ is 1 or 2. R 1’ , L 1’ , L 2’ , and R 12’’ As described above, including several embodiments.

[0016] In some embodiments, the carboxylic acid-directed reducing agent is a 1,4-dihydropyridine. In some embodiments, the 1,4-dihydropyridine has the formula (IV):

[0017] [ka] is a compound of During the ceremony, L 3’ and L 4’ are independently O or NR 20’ and R 20’ is hydrogen or R 21’ and R 21’ is hydrogen, -CX 21’ 3. -CHX 21’ 2, -CH2X 21’, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; R 6’ is hydrogen, -CX 6’ 3. -CHX 6’ 2, -CH2X 6’ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a bond attaching 1,4-dihydropyridine to a polymeric support; R 7’ is hydrogen, -CX 7’ 3. -CHX 7’ 2, -CH2X 7’ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a bond attaching 1,4-dihydropyridine to a polymeric support; R 8’ are independently hydrogen, halogen, -CX 8’ 3. -CHX 8’ 2, -CH2X 8’ , -OCX 8’ 3. -OCHX 8’ 2, -OCH2X 8’ , -CN, -S(O)2R 8’A , -SR 8’A , -S(O)R 8’A , -SO2NR 8’A R 8’B , -NHC(O)NR 8’A R 8’B , -N(O)2, -NR 8’A R 8’B , -NHNR 8’A R 8’B , -C(O)R 8’A , -C(O)-OR 8’A , -C(O)NR 8’A R 8’B , -C(O)NHNR 8’AR 8’B , -OR 8’A , -NR 8’A SO2R 8’B , -NR 8’A C(O)R 8’B , -NR 8’A C(O)OR 8’B , -NR 8’A OR 8’B , -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 9’ are independently hydrogen, halogen, -CX 9’ 3. -CHX 9’ 2, -CH2X 9’ , -OCX 9’ 3. -OCHX 9’ 2, -OCH2X 9’ , -CN, -S(O)2R 9’A , -SR 9’A , -S(O)R 9’A , -SO2NR 9’A R 9’B , -NHC(O)NR 9’A R 9’B , -N(O)2, -NR 9’A R 9’B , -NHNR 9’A R 9’B , -C(O)R 9’A , -C(O)-OR 9’A , -C(O)NR 9’A R 9’B , -C(O)NHNR 9’A R 9’B , -OR 9’A , -NR 9’A SO2R 9’B , -NR 9’A C(O)R 9’B , -NR 9’A C(O)OR 9’B , -NR 9’A OR 9’B, -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 10’ are independently hydrogen, halogen, -CX 10’ 3. -CHX 10’ 2, -CH2X 10’ , -OCX 10’ 3. -OCHX 10’ 2, -OCH2X 10’ , -CN, -S(O)2R 10’A , -SR 10’A , -S(O)R 10’A , -SO2NR 10’A R 10’B , -NHC(O)NR 10’A R 10’B , -N(O)2, -NR 10’A R 10’B , -NHNR 10’A R 10’B , -C(O)R 10’A , -C(O)-OR 10’A , -C(O)NR 10’A R 10’B , -C(O)NHNR 10’A R 10’B , -OR 10’A , -NR 10’A SO2R 10’B , -NR 10’A C(O)R 10’B , -NR 10’A C(O)OR 10’B , -NR 10’A OR 10’B , -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 8’A , R 8’B , R 9’A , R 9’B , R 10’A , and R 10’Bare independently hydrogen, -F, -Cl, -Br, -I, -CF3, -CHF2, -CH2F, -CCl3, -CHCl2, -CH2Cl, -CBr3, -CHBr2, -CH2Br, -CI3, -CHI2, -CH2I, -OCF3, -OCCl3, -OCBr3, -OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -C(O)OH, -C(O)NH2, -OH, -NH2, -C OOH, -CONH2, -SH, -SO3H, -SO4H, -SON2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)OH, -NHOH, 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; X 6’ , X 7’ , X 8’ , X 9’ , and X 10’ are independently halogen.

[0018] These and other aspects of the present disclosure will become apparent from the following description of the preferred embodiments, but are susceptible to variation and modification thereof without departing from the spirit and scope of the novel concepts of the disclosure. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0019] Provided herein is a method for synthesizing a trans isomeric form of a G protein coupled receptor modulator, or a salt or ester thereof, the method relates to synthesizing a trans isomeric form of a G protein coupled receptor modulator, or a salt or ester thereof, having a 3-8 membered cycloalkyl ring having at least an amine moiety substitution and a carboxylic acid or carboxylic acid derived moiety substitution, wherein the amine moiety and the carboxylic acid or carboxylic acid derived moiety substitution can be in a cis or trans isomeric configuration.

[0020] definition The abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulas set forth herein are constructed according to the standard rules of chemical valency known to the chemical arts.

[0021] Substituents, when specified by their conventional chemical formula written from left to right, equally encompass the chemically identical substituents that would result from writing the structure from right to left, e.g., -CH2O- is equivalent to -OCH2-.

[0022] The term "alkyl," by itself or as part of another substituent, means, unless otherwise stated, a straight-chain (i.e., unbranched) or branched carbon chain (or carbons), or combinations thereof, which may be fully saturated, mono- or polyunsaturated, and can include monovalent, divalent, and polyvalent radicals. An alkyl may contain the specified number of carbons (e.g., C1-C 10 means 1-10 carbons). An alkyl is a non-cyclized chain. Examples of saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl. Unsaturated alkyl groups are those having one or more double or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologs and isomers. An alkoxy is an alkyl attached to the remainder of the molecule via an oxygen linker (-O-). The alkyl moiety can be an alkenyl moiety. The alkyl moiety can be an alkynyl moiety. The alkyl moiety can be fully saturated. An alkenyl may contain, in addition to one or more double bonds, more than one double bond and / or one or more triple bonds. An alkynyl may contain, in addition to one or more triple bonds, more than one triple bond and / or one or more double bonds.

[0023] The term "alkylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkyl, exemplified by, but not limited to, -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 8 or fewer carbon atoms. The term "alkenylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkene.

[0024] The term "heteroalkyl," alone or in combination with another term, means, unless otherwise specified, a stable linear or branched chain, or combination thereof, containing at least one carbon atom and at least one heteroatom (e.g., O, N, P, Si, and S), wherein the nitrogen and sulfur atoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized. The heteroatom (e.g., N, S, Si, or P) may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. Heteroalkyl is a non-cyclizing chain. Examples include, but are not limited to, -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2, -S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, -O-CH3, -O-CH-2-CH3, and -CN. Up to two or three heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. The heteroalkyl moiety may contain one heteroatom (e.g., O, N, S, Si, or P). The heteroalkyl moiety may contain two optionally different heteroatoms (e.g., O, N, S, Si, or P). The heteroalkyl moiety may contain three optionally different heteroatoms (e.g., O, N, S, Si, or P). The heteroalkyl moiety may contain four optionally different heteroatoms (e.g., O, N, S, Si, or P). The heteroalkyl moiety may contain five optionally different heteroatoms (e.g., O, N, S, Si, or P). The heteroalkyl moiety may contain up to eight optionally different heteroatoms (e.g., O, N, S, Si, or P). The term "heteroalkenyl", alone or in combination with another term, means a heteroalkyl containing at least one double bond, unless otherwise stated. The heteroalkenyl may optionally contain, in addition to one or more double bonds, two or more double bonds and / or one or more triple bonds.The term "heteroalkynyl," alone or in combination with another term, means, unless otherwise stated, a heteroalkyl containing at least one triple bond. Heteroalkynyl can optionally contain, in addition to one or more triple bonds, two or more triple bonds and / or one or more double bonds.

[0025] Similarly, the term "heteroalkylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from a heteroalkyl, exemplified by, but not limited to, -CH-CH-S-CH-CH- and -CH-S-CH-CH-NH-CH-. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, etc.). Still further, in the case of alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula -C(O)R'- represents both C(O)R'- and -R'C(O)-. As noted above, heteroalkyl groups as used herein include groups attached to the remainder of the molecule via a heteroatom, such as -C(O)R', -C(O)NR', ​​-NR'R'', -OR', -SR', and / or -SOR'. When "heteroalkyl" is recited followed by a specific heteroalkyl group, such as -NR'R'', it will be understood that the terms heteroalkyl and -NR'R'' are not redundant or mutually exclusive. Rather, the specific heteroalkyl group is recited for clarity. Thus, the term "heteroalkyl" should not be construed herein as excluding specific heteroalkyl groups, such as -NR'R''.

[0026] The terms "cycloalkyl" and "heterocycloalkyl", by themselves or in combination with other terms, mean cyclic versions of "alkyl" and "heteroalkyl", respectively, unless otherwise stated. Cycloalkyl and heterocycloalkyl are not aromatic. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkyl include, but are not limited to, 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like. A "cycloalkylene" and a "heterocycloalkylene," alone or as part of another substituent, mean a divalent radical derived from a cycloalkyl and heterocycloalkyl, respectively.

[0027] In embodiments, the term "cycloalkyl" refers to a monocyclic, bicyclic or polycyclic cycloalkyl ring system. In embodiments, a monocyclic ring system is a cyclic hydrocarbon group containing 3 to 8 carbon atoms, and such groups may be saturated or unsaturated, but are not aromatic. In embodiments, a cycloalkyl group is fully saturated. Examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. A bicyclic cycloalkyl ring system is a bridged monocyclic ring or a fused bicyclic ring. In embodiments, a bridged monocyclic ring is one in which two non-adjacent carbon atoms of a monocyclic ring are joined by an alkylene bridge of 1 to 3 additional carbon atoms (i.e., of the form (CH2) wwhere w is 1, 2, or 3). Representative examples of bicyclic ring systems include, but are not limited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, and bicyclo[4.2.1]nonane. In embodiments, the fused bicyclic cycloalkyl ring system comprises a monocyclic cycloalkyl ring fused to either a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocyclyl, or a monocyclic heteroaryl. In embodiments, the bridged or fused bicyclic cycloalkyl is attached to the parent molecular moiety through any carbon atom contained within the monocyclic cycloalkyl ring. In embodiments, the cycloalkyl group is optionally substituted with one or two groups, 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, optionally substituted by one or two groups, independently oxo or thia. In some embodiments, the polycyclic cycloalkyl ring system is a monocyclic cycloalkyl ring (base ring) fused to either (i) one ring system selected from the group consisting of bicyclic aryl, bicyclic heteroaryl, bicyclic cycloalkyl, bicyclic cycloalkenyl, and bicyclic heterocyclyl, or (ii) two other ring systems independently selected from the group consisting of phenyl, bicyclic aryl, monocyclic or bicyclic heteroaryl, monocyclic or bicyclic cycloalkyl, monocyclic or bicyclic cycloalkenyl, and monocyclic or bicyclic heterocyclyl. In embodiments, a polycyclic cycloalkyl is attached to the parent molecular moiety through any carbon atom contained within the base ring.In some embodiments, the polycyclic cycloalkyl ring system is a monocyclic cycloalkyl ring (base ring) fused to either (i) one ring system selected from the group consisting of bicyclic aryl, bicyclic heteroaryl, bicyclic cycloalkyl, bicyclic cycloalkenyl, and bicyclic heterocyclyl, or (ii) two other ring systems independently selected from the group consisting of phenyl, monocyclic heteroaryl, monocyclic cycloalkyl, monocyclic cycloalkenyl, and monocyclic heterocyclyl. Examples of polycyclic cycloalkyl groups include, but are not limited to, tetradecahydrophenanthrenyl, perhydrophenothiazin-1-yl, and perhydrophenoxazin-1-yl.

[0028] In embodiments, cycloalkyl is cycloalkenyl. The term "cycloalkenyl" is used according to its plain and ordinary meaning. In embodiments, cycloalkenyl is a monocyclic, bicyclic or polycyclic cycloalkenyl ring system. In embodiments, a monocyclic cycloalkenyl ring system is a cyclic hydrocarbon group containing 3 to 8 carbon atoms, such group being unsaturated (i.e., containing at least one cyclic carbon-carbon double bond) but not aromatic. Examples of monocyclic cycloalkenyl ring systems include cyclopentenyl and cyclohexenyl. In embodiments, a bicyclic cycloalkenyl ring is a bridged monocyclic ring, or a fused bicyclic ring. In embodiments, a bridged monocyclic ring is a ring in which two non-adjacent carbon atoms of a monocyclic ring are joined by an alkylene bridge (i.e., of the form (CH2)) between 1 to 3 additional carbon atoms. wwhere w is 1, 2 or 3). Representative examples of bicyclic cycloalkenyls include, but are not limited to, norbornenyl and bicyclo[2.2.2]oct2enyl. In embodiments, the fused bicyclic cycloalkenyl ring system comprises a monocyclic cycloalkenyl ring fused to either a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocyclyl, or a monocyclic heteroaryl. In embodiments, the bridged or fused bicyclic cycloalkenyl is attached to the parent molecular moiety through any carbon atom contained within the monocyclic cycloalkenyl ring. In embodiments, the cycloalkenyl group is optionally substituted with one or two groups, which are independently oxo or thia. In some embodiments, the polycyclic cycloalkenyl ring comprises a monocyclic cycloalkenyl ring (base ring) fused to either (i) one ring system selected from the group consisting of bicyclic aryl, bicyclic heteroaryl, bicyclic cycloalkyl, bicyclic cycloalkenyl, and bicyclic heterocyclyl, or (ii) two ring systems independently selected from the group consisting of phenyl, bicyclic aryl, monocyclic or bicyclic heteroaryl, monocyclic or bicyclic cycloalkyl, monocyclic or bicyclic cycloalkenyl, and monocyclic or bicyclic heterocyclyl. In embodiments, the polycyclic cycloalkenyl is attached to the parent molecular moiety through any carbon atom contained within the base ring. In some embodiments, the polycyclic cycloalkenyl ring comprises a monocyclic cycloalkenyl ring (base ring) fused to either (i) one ring system selected from the group consisting of bicyclic aryl, bicyclic heteroaryl, bicyclic cycloalkyl, bicyclic cycloalkenyl, and bicyclic heterocyclyl, or (ii) two ring systems independently selected from the group consisting of phenyl, monocyclic heteroaryl, monocyclic cycloalkyl, monocyclic cycloalkenyl, and monocyclic heterocyclyl.

[0029] In an embodiment, the heterocycloalkyl is heterocyclyl. As used herein, the term "heterocyclyl" refers to a monocyclic, bicyclic or polycyclic heterocycle. A heterocyclyl monocyclic heterocycle is a 3-, 4-, 5-, 6-, or 7-membered ring, the ring being saturated or unsaturated but not aromatic, containing at least one heteroatom independently selected from the group consisting of O, N, and S. A 3- or 4-membered ring contains one heteroatom selected from the group consisting of O, N, and S. A 5-membered ring can contain zero or one double bond and one, two, or three heteroatoms selected from the group consisting of O, N, and S. A 6- or 7-membered ring can contain zero, one, or two double bonds and one, two, or three heteroatoms selected from the group consisting of O, N, and S. A heterocyclyl monocyclic heterocycle is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the heterocyclyl monocyclic heterocycle. Representative examples of heterocyclyl monocyclic heterocycles include azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, and oxazolinyl. Heterocyclyl bicyclic heterocycles include, but are not limited to, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, tyrazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxidethiomorpholinyl (thiomorpholine sulfone), thiopyranyl, and trithianyl. Heterocyclyl bicyclic heterocycles are monocyclic heterocycles fused to either phenyl, monocyclic cycloalkyl, monocyclic cycloalkenyl, monocyclic heterocycle, or monocyclic heteroaryl. Heterocyclyl bicyclic heterocycles are connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the monocyclic heterocycle portion of the bicyclic ring system.Representative examples of bicyclic heterocyclyls include, but are not limited to, 2,3-dihydrobenzofuran-2-yl, 2,3-dihydrobenzofuran-3-yl, indolin-1-yl, indolin-2-yl, indolin-3-yl, 2,3-dihydrobenzothien-2-yl, decahydroquinolinyl, decahydroisoquinolinyl, octahydro-1H-indolyl, and octahydrobenzofuranyl. In embodiments, the heterocyclyl group is optionally substituted with one or two groups that 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, optionally substituted by one or two groups that are independently oxo or thia. A polycyclic heterocyclyl ring system is a monocyclic heterocyclyl ring (base ring) fused to either (i) one ring system selected from the group consisting of bicyclic aryl, bicyclic heteroaryl, bicyclic cycloalkyl, bicyclic cycloalkenyl, and bicyclic heterocyclyl, or (ii) two other ring systems independently selected from the group consisting of phenyl, bicyclic aryl, monocyclic or bicyclic heteroaryl, monocyclic or bicyclic cycloalkyl, monocyclic or bicyclic cycloalkenyl, and monocyclic or bicyclic heterocyclyl. The polycyclic heterocyclyl is attached to the parent molecular moiety through any carbon or nitrogen atom contained within the base ring. In some embodiments, the polycyclic cyclocyclyl ring system is a monocyclic heterocyclyl ring (base ring) fused to either (i) one ring system selected from the group consisting of bicyclic aryl, bicyclic heteroaryl, bicyclic cycloalkyl, bicyclic cycloalkenyl, and bicyclic heterocyclyl, or (ii) two other ring systems independently selected from the group consisting of phenyl, monocyclic heteroaryl, monocyclic cycloalkyl, monocyclic cycloalkenyl, and monocyclic heterocyclyl.Examples of polycyclic heterocyclyl groups include, but are not limited to, 10H-phenothiazin-10-yl, 9,10-dihydroacridin-9-yl, 9,10-dihydroacridin-10-yl, 10H-phenoxazin-10-yl, 10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl, 1,2,3,4-tetrahydropyrido[4,3-g]isoquinolin-2-yl, 12H-benzo[b]phenoxazin-12-yl, and dodecahydro-1H-carbazol-9-yl.

[0030] 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, and 3-bromopropyl.

[0031] The term "acyl," unless otherwise specified, means -C(O)R, where R is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0032] The term "aryl", unless otherwise specified, refers to a polyunsaturated, aromatic, hydrocarbon substituent, which may be a single ring or multiple rings (preferably 1-3 rings) fused together (i.e., fused-ring aryl) or covalently linked together. Fused-ring aryl refers to multiple rings fused together, where at least one of the fused rings is an aryl ring. The term "heteroaryl" refers to an aryl group (or ring) containing at least one heteroatom, such as N, O, or S, where the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom is optionally quaternized. Thus, the term "heteroaryl" includes fused-ring heteroaryl groups (i.e., multiple rings fused together, where at least one of the fused rings is an aromatic heterocycle). 5,6-fused-ring heteroarylene refers to two rings fused together, where one ring has 5 members and the other ring has 6 members, and where at least one ring is a heteroaryl ring. Similarly, a 6,6-fused ring heteroarylene refers to two rings fused together, one having 6 members and the other having 6 members, with at least one ring being a heteroaryl ring. Also, a 6,5-fused ring heteroarylene refers to two rings fused together, one having 6 members and the other having 5 members, with at least one ring being a heteroaryl ring. The heteroaryl group can be attached to the remainder of the molecule through a carbon atom or a heteroatom.Non-limiting examples of aryl and heteroaryl groups include phenyl, naphthyl, pyrrolyl, pyrazolyl, pyridazinyl, triazinyl, pyrimidinyl, imidazolyl, pyrazinyl, purinyl, oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzofuran, isobenzofuranyl, indolyl, isoindolyl, benzothiophenyl, isoquinolyl, quinoxalinyl, quinolyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, aryl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl. Substituents for each of the above noted aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below. An "arylene" and a "heteroarylene," alone or as part of another substituent, mean a divalent radical derived from an aryl and heteroaryl, respectively. The heteroaryl group substituent may be -O-bonded to a ring heteroatom nitrogen.

[0033] A spirocyclic ring is two or more rings in which adjacent rings are linked through a single atom. The individual rings in a spirocyclic ring may be the same or different. The individual rings in a spirocyclic ring may be substituted or unsubstituted and may have different substituents than the other individual rings in a set of spirocyclic rings. The possible substituents of the individual rings in a spirocyclic ring are the possible substituents of the same ring (e.g., the substituents of a cycloalkyl ring or a heterocycloalkyl ring) when they are not part of a spirocyclic ring. The spirocyclic ring may be a substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted heterocycloalkylene, and the individual rings in a spirocyclic ring group may be any of the previous lists, including all rings of one kind (e.g., all rings are substituted heterocycloalkylene, and each ring may be the same or different substituted heterocycloalkylene). When referring to a spirocyclic ring system, a heterocyclic spirocyclic ring means a spirocyclic ring in which at least one ring is a heterocyclic ring, and each ring may be a different ring. When referring to a spirocyclic ring system, a substituted spirocyclic ring means that at least one ring is substituted, and each substituent may optionally be different.

[0034] symbol

[0035] [ka] indicates the point of attachment of the chemical moiety to the remainder of the molecule or chemical formula.

[0036] The term "oxo" as used herein means an oxygen that is double bonded to a carbon atom.

[0037] The term "alkylarylene" as an arylene moiety covalently linked to an alkylene moiety (also referred to herein as an alkylene linker). In embodiments, the alkylarylene group has the formula:

[0038] [ka] has.

[0039] The alkylarylene moiety may be substituted (e.g., with a substituent) on the alkylene portion or on 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, -SON2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, substituted or unsubstituted C1-C5 alkyl, or substituted or unsubstituted 2-5 membered heteroalkyl). In embodiments, the alkylarylene is unsubstituted.

[0040] 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.

[0041] Substituents for alkyl and heteroalkyl radicals (including groups often referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) range in number from zero to (2m'+1), where m' is the total number of carbon atoms in such radical, and include the following: -OR', =O, =NR', =N-OR', -NR'R'', -SR', -halogen, -SiR'R''R''', -OC(O)R', -C(O)R', -COR', -CONR'R'', -OC(O)NR'R The aryl group may be one or more of a variety of groups selected from, but not limited to, -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'S02R'', -NR'C(O)R'', -NR'C(O)-OR'', -NR'OR''. R, R', R'', R''', and R'''' each preferably independently refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1-3 halogens), substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, alkoxy, or thioalkoxy groups, or arylalkyl groups. When the compounds described herein contain 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. 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 intended to include groups that contain carbon atoms bonded to groups other than hydrogen groups, such as haloalkyl (e.g., -CF and -CHCF) and acyl (e.g., -C(O)CH, -C(O)CF, -C(O)CHOCH, etc.).

[0042] Similar to the substituents described for the alkyl radical, substituents for the aryl and heteroaryl groups are varied and include, for example, -OR', -NR'R'', -SR', -halogen, -SiR'R''R''', -OC(O)R', -C(O)R', -COR', -CONR'R'', -OC(O)NR'R'', -NR''C(O)R', -NR'-C(O)NR''R''', -NR''C(O)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'SOR'', -NR'C(O)R'', -NR'C(O)-OR'', -NR'OR'', 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 the compounds described herein include 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.

[0043] Substituents for a ring (e.g., cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene) may be shown as substituents on the ring (commonly referred to as floating substituents) rather than on a specific atom of the ring. In such cases, the substituent may be attached to any of the ring atoms (according to the rules of chemical valence), and in the case of a fused or spirocyclic ring, a substituent shown as attached to one member of the fused or spirocyclic ring (floating substituents on a single ring) may also be a substituent on either the fused or spirocyclic ring (floating substituents on a polycyclic ring). When a substituent is attached to a ring rather than to a specific atom (floating substituents) and the substituent subscript is an integer greater than 1, the multiple substituents may be on the same atom, the same ring, different atoms, different fused rings, different spirocyclic rings, and each substituent may optionally be different. If the point of attachment of a ring to the remainder of the molecule is not limited to a single atom (floating substituent), the point of attachment may be any atom of the ring, or, in the case of a fused or spirocyclic ring, any atom of either of the fused or spirocyclic rings, according to the rules of chemical valence. If a ring, fused or spirocyclic ring contains one or more ring heteroatoms and the ring, fused or spirocyclic ring is shown with another floating substituent (including, but not limited to, the point of attachment to the remainder of the molecule), the floating substituent may be attached to the heteroatom. If a ring heteroatom is shown to be attached to one or more hydrogens in a structure or formula with a floating substituent (e.g., a ring nitrogen with two bonds to a ring atom and a third bond to a hydrogen), it will be understood that when the heteroatom is attached to the floating substituent, the substituent replaces the hydrogen, according to the rules of chemical valence.

[0044] Two or more substituents may be optionally linked to form an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group. Such so-called ring-forming substituents are typically, but not necessarily, found attached to a cyclic base structure. In one embodiment, the ring-forming substituents are attached to adjacent members of the base structure. For example, two ring-forming substituents attached to adjacent members of a cyclic base structure form a fused ring structure. In another embodiment, the ring-forming substituents are attached to a single member of the base structure. For example, two ring-forming substituents attached to a single member of a cyclic base structure create a spirocyclic structure. In yet another embodiment, the ring-forming substituents are attached to non-adjacent members of the base structure.

[0045] Two of the substituents on adjacent atoms of the aryl or heteroaryl ring are optionally represented by the formula -TC(O)-(CRR') q -U-, where T and U are independently -NR-, -O-, -CRR'-, or a single bond, and q is an integer from 0 to 3. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally form a ring of the formula -A-(CH2) r A and B are independently -CRR'-, -O-, -NR-, -S-, -S(O)-, -S(O)2-, -S(O)2NR'-, or a single bond, and r is an integer from 1 to 4. One of the single bonds 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'') dwhere s and d are independently integers from 0 to 3 and X' is -O-, -NR'-, -S-, -S(O)-, -S(O)2-, or -S(O)2NR'-. The substituents R, R', R'', and R''' are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0046] As used herein, the term "heteroatom" or "ring heteroatom" is meant to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).

[0047] As used herein, "substituent" means a group selected from the following moieties: (A) oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -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, unsubstituted alkyl (e.g. , C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3-8 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, or 5-6 membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5-10 membered heteroaryl, 5-9 membered heteroaryl, or 5-6 membered heteroaryl), and (B) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, substituted with at least one substituent selected from the following: (i) oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -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, unsubstituted alkyl (e.g. , C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3-8 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, or 5-6 membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5-10 membered heteroaryl, 5-9 membered heteroaryl, or 5-6 membered heteroaryl), and (ii) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, substituted with at least one substituent selected from the following: (a) oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -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, -OCHCl 2、-OCHBr2, -OCHI2, -OCHF2, unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3-8 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, or 5-6 membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5-10 membered heteroaryl, 5-9 membered heteroaryl, or 5-6 membered heteroaryl), and (b) oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -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, unsubstituted alkyl (e.g. , C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3-8 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, or 5-6 membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5-10 membered heteroaryl, 5-9 membered heteroaryl, or 5-6 membered heteroaryl).

[0048] As used herein, "size-limited substituent" or "size-limited substituent" refers to a group selected from all of the substituents described above for "substituent", and each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C 20 each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2-20 membered heteroalkyl; each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C8 cycloalkyl; each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3-8 membered heterocycloalkyl; and each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C8 10 aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5-10 membered heteroaryl.

[0049] As used herein, a "lower substituent" or "lower substituent group" refers to a group selected from all of the substituents described above for "substituent", wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C8 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2-8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C7 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3-7 membered heterocycloalkyl, and each substituted or unsubstituted aryl is a substituted or unsubstituted C6 ... 2-8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted 2-8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted 2-8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted 2-8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted 2-8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted 2-8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted 2-8 membered heteroalkyl, each substituted or unsubstituted 2-8 membered heteroalkyl, each substituted or unsubstituted 2-8 membered heteroalkyl, each substituted or unsubstituted 2-8 membered heteroalkyl, each substituted or unsubstituted 2-8 membered hetero 10 aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5- to 9-membered heteroaryl.

[0050] In some embodiments, each of the substituents described in the compounds herein is substituted with at least one substituent. More specifically, in some embodiments, each of the substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene described in the compounds herein is substituted with at least one substituent. In other embodiments, at least one or all of these groups are substituted with at least one size-limited substituent. In other embodiments, at least one or all of these groups are substituted with at least one lower substituent.

[0051] In other embodiments of the compounds herein, each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C 20 each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2-20 membered heteroalkyl; each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C8 cycloalkyl; each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3-8 membered heterocycloalkyl; and each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C8 10 aryl, and / or each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5-10 membered heteroaryl. In some embodiments of the compounds herein, each substituted or unsubstituted alkylene is a substituted or unsubstituted C1-C 20 each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2-20 membered heteroalkylene; each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C3-C8 cycloalkylene; each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3-8 membered heterocycloalkylene; and each substituted or unsubstituted arylene is a substituted or unsubstituted C6-C 10 arylene, and / or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5- to 10-membered heteroarylene.

[0052] In some embodiments, each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C8 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2-8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C7 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3-7 membered heterocycloalkyl, and each substituted or unsubstituted aryl is a substituted or unsubstituted C6 ... 10 In some embodiments, each substituted or unsubstituted alkylene is a substituted or unsubstituted C1-C8 alkylene, each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2-8 membered heteroalkylene, each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C3-C7 cycloalkylene, each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3-7 membered heterocycloalkylene, and each substituted or unsubstituted arylene is a substituted or unsubstituted C6-C8 alkylene, each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5-9 membered heteroaryl, and each substituted or unsubstituted aryl is a substituted or unsubstituted 5-9 membered heteroaryl. 10 and / or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5- to 9-membered heteroarylene. In some embodiments, the compound is a species described in the Examples section, Figures, or Tables below.

[0053] In embodiments, a substituted or unsubstituted moiety (e.g., substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, and / or substituted or unsubstituted heteroarylene) is unsubstituted (e.g., unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted alkylene, unsubstituted heteroalkylene, unsubstituted cycloalkylene, unsubstituted heterocycloalkylene, unsubstituted arylene, and / or unsubstituted heteroarylene, respectively). In embodiments, a substituted or unsubstituted moiety (e.g., substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, and / or substituted or unsubstituted heteroarylene) is substituted (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene, respectively).

[0054] In embodiments, a substituted moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene) is substituted with at least one substituent, and when a substituted moiety is substituted with multiple substituents, each substituent can optionally be different. In embodiments, when a substituted moiety is substituted with multiple substituents, each substituent is different.

[0055] In embodiments, a substituted moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene) is substituted with at least one size-limiting substituent, and when a substituted moiety is substituted with multiple substituents, each size-limiting substituent can optionally be different. In embodiments, when a substituted moiety is substituted with multiple size-limiting substituents, each size-limiting substituent is different.

[0056] In embodiments, a substituted moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene) is substituted with at least one lower substituent, and when a substituted moiety is substituted with multiple lower substituents, each lower substituent may optionally be different. In embodiments, when a substituted moiety is substituted with multiple lower substituents, each lower substituent is different.

[0057] In embodiments, a substituted moiety (e.g., a substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene) is substituted with at least one substituent, size-limiting substituent, or lower substituent, and when a substituted moiety is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent can optionally be different. In embodiments, when a substituted moiety is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent is different.

[0058] Certain compounds of the present disclosure have asymmetric carbon atoms (optical or chiral centers) or double bonds, and enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisomeric forms, and individual isomers, which may be defined in terms of absolute stereochemistry as (R)- or (S)- or (D)- or (L) for amino acids, are encompassed within the scope of the present disclosure. The compounds of the present disclosure do not include compounds known in the art to be too unstable to synthesize and / or isolate. The present disclosure is intended to include compounds in racemic and optically pure form. Optically active (R)- and (S)- or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents or resolved using conventional techniques. When the compounds described herein contain olefinic bonds or other geometric asymmetric centers, it is intended that the compounds include both E and Z geometric isomers, unless otherwise specified.

[0059] As used herein, the term "isomers" refers to compounds that have the same number and kinds of atoms, and therefore the same molecular weight, but differ with regard to the structural or stereochemical arrangement of the atoms.

[0060] The term "tautomer," as used herein, refers to one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another.

[0061] It will be apparent to one of ordinary skill in the art that certain compounds may exist in tautomeric forms, with all such tautomeric forms of the compounds being within their scope.

[0062] Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms of the structure, i.e., 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 their scope.

[0063] 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, the replacement of hydrogen by deuterium or tritium, or 13 C or 14 Compounds having this structure except for the replacement of a carbon with a C-enriched carbon are within the scope.

[0064] The compounds of the present disclosure may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may contain, for example, tritium ( 3 H), iodine-125( 125 I), or carbon-14 ( 14 C). All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present invention.

[0065] It should be noted that throughout this application, options, e.g., each amino acid position that contains more than one possible amino acid, are described in Markush groups. It is specifically contemplated that each member of a Markush group should be considered separately, thereby including alternative embodiments, and that a Markush group should not be read as a single unit.

[0066] "Analog" or "analogue" is used according to its plain and ordinary meaning within Chemistry and Biology to refer to a compound that is structurally similar to another compound (i.e., a so-called "reference" compound) but differs in composition, e.g., the replacement of one atom by an atom of a different element, or 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. Thus, an analog is a compound that is similar or equivalent in function and appearance to the reference compound, but differs in structure or origin.

[0067] As used herein, the terms "a" or "an" mean one or more. Additionally, the phrase "substituted with a[n]" as used herein means that the particular group may be substituted with one or more of any or all of the specified substituents. For example, when a group such as an alkyl group or a heteroaryl group is an "unsubstituted C1-C 20 When "substituted with alkyl or unsubstituted 2-20 membered heteroalkyl," the group is selected from the group consisting of one or more unsubstituted C1-C 20 It may contain alkyl and / or one or more unsubstituted 2-20 membered heteroalkyl.

[0068] Additionally, when a moiety is substituted with an R substituent, the group may be referred to as "R-substituted." When a moiety is R-substituted, the moiety is substituted with at least one R substituent, and each R substituent is optionally different. When a particular R group is present in a description of a chemical species (such as formula (I)), the Roman alphabet symbols may be used to distinguish between each occurrence of that particular R group. For example, multiple R 13 When substituents are present, each R 13 The substituent is R 13A , R 13B , R 13C , R 13D etc., and R 13A , R 13B , R 13C , R 13D etc. are R13 are defined within the definition of and may vary arbitrarily.

[0069] As used herein, the term "detectable moiety" refers to a moiety that can be covalently or non-covalently bound to a compound or biomolecule that can be detected, for example, using techniques known in the art. In some embodiments, the detectable moiety is covalently bound. The detectable moiety can provide imaging of the bound compound or biomolecule. The detectable moiety can indicate contact between two compounds. Exemplary detectable moieties are fluorophores, antibodies, reactive dyes, radiolabeled moieties, magnetic contrast agents, and quantum dots. Exemplary fluorophores include fluorescein, rhodamine, GFP, coumarin, FITC, Alexa fluor, Cy3, Cy5, BODIPY, and cyanine dyes. Exemplary radionuclides include fluorine-18, gallium-68, and copper-64. Exemplary magnetic contrast agents include gadolinium, iron oxide and iron platinum, and manganese.

[0070] The description of the compounds of the present disclosure is limited by the principles of chemical bonding known to those skilled in the art.Therefore, when a group can be substituted with one or more of several substituents, such substitutions are selected to comply with the principles of chemical bonding and to result in compounds known to those skilled in the art that are not inherently unstable and / or are likely to be unstable under ambient conditions, such as aqueous, neutral, and some known physiological conditions.For example, heterocycloalkyl or heteroaryl are bonded to the rest of the molecule through ring heteroatoms according to the principles of chemical bonding known to those skilled in the art, thereby avoiding inherently unstable compounds.

[0071] The term "pharmaceutically acceptable salts" is meant to include salts of active compounds prepared using relatively non-toxic acids or bases, depending on the specific substituents found in the compounds described herein.When a compound of the present disclosure contains a relatively acidic functional group, a base addition salt can be obtained by contacting a neutral form of such a compound 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 salts, or similar salts.When a compound of the present disclosure contains a relatively basic functional group, an acid addition salt can be obtained by contacting a neutral form of such a compound with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharma- ceutically acceptable acid addition salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphate, dihydrogenphosphate, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, or phosphorous acid, as well as salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, oxalic acid, methanesulfonic acid, etc. Also included are salts of amino acids such as arginate, and salts of organic acids such as glucuronic acid or galactunoric acid (see, for example, Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present disclosure contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

[0072] Therefore, the compounds of the present disclosure may exist as salts with pharma- ceutically acceptable acids and the like. The present disclosure includes such salts. Non-limiting examples of such salts include hydrochloride, hydrobromide, phosphate, sulfate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, propionate, tartrate (e.g., (+)-tartrate, (-)-tartrate, or mixtures thereof, including racemic mixtures), succinate, benzoate, and salts with amino acids, such as glutamic acid, and quaternary ammonium salts (e.g., methyl iodide, ethyl iodide, etc.). These salts can be prepared by methods known to those skilled in the art.

[0073] The neutral form of the compound is preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in a 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 some embodiments, the compounds of the present disclosure contain both basic and acidic functional groups that allow the compounds to be converted into either base or acid addition salts. The neutral form of the compound may be regenerated by contacting the salt with a base or acid and isolating the parent compound in a conventional manner. Although the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, the salts disclosed herein are equivalent to the parent form of the compound for the purposes of the present disclosure, unless otherwise indicated.

[0074] In addition to salt forms, the present disclosure provides compounds in prodrug form. Prodrugs of the compounds described herein are compounds that easily undergo chemical changes under physiological conditions to produce the compounds of the present disclosure. Prodrugs of the compounds described herein can be converted in vivo after administration. Furthermore, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment, for example, when contacted with a suitable enzyme or chemical reagent.

[0075] Certain compounds of the present disclosure may exist in unsolvated and solvated forms, including hydrated forms. In general, solvated forms are equivalent to unsolvated forms and are included within the scope of the present disclosure. Certain compounds of the present disclosure may exist in polycrystalline 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.

[0076] "Pharmaceutically acceptable excipient" and "Pharmaceutically acceptable carrier" refer to substances that aid in the administration and absorption of a compound by a subject and may be included in the compositions of the present disclosure without causing significant adverse toxic effects to the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline, lactated Ringer's solution, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coating agents, sweeteners, flavoring agents, saline (such as Ringer's solution), alcohol, oils, gelatin, carbohydrates such as lactose, amylose, or starch, fatty acid esters, hydroxymethylcellulose, polyvinylpyrrolidine, and coloring agents. Such preparations may be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring agents, and / or aromatic substances that do not adversely react with the compounds of the present disclosure. Those of skill in the art will recognize that other pharmaceutical excipients are useful in the present disclosure.

[0077] The term "preparation" is intended to include the formulation of the active compound with an encapsulating material as a carrier to provide a capsule in which the active ingredient, with or without other carriers, is surrounded by the carrier and is therefore associated with the carrier. Also included are cachets and lozenges. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.

[0078] "CCR4 inhibitor" refers to a compound (e.g., a compound described herein) that can reduce the activity of CCR4 (e.g., by binding to CCR4) compared to a control, such as no compound or a compound with known inactivity.

[0079] The term "CCR4-mediated disease or disorder" refers to a disease or disorder characterized by the involvement of CCR4 activity and / or function through a CCR4-mediated pathway in the body.

[0080] "Contacting" is used according to its plain and ordinary meaning to refer to a process that allows at least two different species (e.g., chemical compounds, including biological molecules or cells) to come into sufficient proximity to react, interact, or come into physical contact. However, it should be understood that the resulting reaction product may be produced directly from the reaction between the added reagents, or from an intermediate from one or more of the added reagents that may be produced in the reaction mixture.

[0081] The term "contacting" can include allowing two species to react, interact, or come into physical contact, and the two species can be a compound described herein and a protein or enzyme. In some embodiments, contacting includes allowing a compound described herein to interact with a protein or enzyme involved in a signal transduction pathway (e.g., the USP7, p53, or Foxp3 pathway).

[0082] As defined herein, the terms "activation," "activate," "activating," and the like, with respect to a protein, refer to the conversion of a protein from an initial inactive or inactivated state to a biologically active derivative. These terms refer to activating, or activating, sensitizing, or upregulating signal transduction or enzymatic activity or the amount of a protein (e.g., decreased in a disease).

[0083] The terms "agonist", "activator", "up-regulator" and the like refer to a substance capable of detectably increasing the expression or activity of a given gene or protein. An agonist can increase expression or activity by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more compared to a control in the absence of the agonist. In certain instances, the expression or activity is 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold or more higher than the expression or activity in the absence of the agonist. In embodiments, an agonist is a molecule that interacts with a target to cause or promote increased activation of the target. In embodiments, an activator is a molecule that increases, activates, promotes, enhances activation, sensitizes, or upregulates, for example, a gene, protein, ligand, receptor, or cell.

[0084] As defined herein, the terms "inhibit," "inhibit," "inhibiting," and the like, with respect to protein-inhibitor interactions, refer to adversely affecting (e.g., reducing) the activity or function of a protein compared to the activity or function of the protein in the absence of the inhibitor. In some embodiments, inhibition refers to adversely affecting (e.g., reducing) the protein concentration or level compared to the protein concentration or level in the absence of the inhibitor. In embodiments, inhibition refers to a reduction in a disease or disease symptom. In embodiments, inhibition refers to a reduction in the activity of a particular protein target. Thus, inhibition includes at least in part, partially or completely blocking a stimulus, reducing, preventing, or delaying activation, or inactivating, desensitizing, or downregulating a signaling or enzyme activity or amount of a protein. In some embodiments, inhibition refers to a reduction in the activity of a target protein due to a direct interaction (e.g., an inhibitor binds to the target protein). In embodiments, inhibition refers to a reduction in the activity of a target protein due to an indirect interaction (e.g., an inhibitor binds to a protein that activates the target protein, thereby preventing activation of the target protein).

[0085] The terms "inhibitor", "suppressor", or "antagonist", or "down-regulator" refer interchangeably to a substance that can detectably reduce the expression or activity of a given gene or protein. An antagonist can reduce expression or activity by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more compared to a control in the absence of the antagonist. In certain instances, the expression or activity is 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold or more lower than the expression or activity in the absence of the antagonist. An antagonist prevents, reduces, inhibits, or neutralizes the activity of an agonist, and an antagonist can also prevent, inhibit, or reduce the constitutive activity of a target, e.g., a target receptor, even in the absence of a recognized agonist. In embodiments, an inhibitor is a molecule that decreases, blocks, prevents, delays activation, inactivates, desensitizes, or downregulates, for example, a gene, protein, ligand, receptor, or cell. An inhibitor may also be defined as a molecule that reduces, blocks, or inactivates a constitutive activity. An "antagonist" is a molecule that opposes the action of an agonist.

[0086] The terms "C-C chemokine receptor type 4" and "CCR4" refer to the protein (including homologs, isoforms, and functional fragments thereof) that is a high affinity receptor for C-C type chemokines (e.g., CCL2 (MCP-1), CCL4 (MIP-1), CCL5 (RANTES), CCL17 (TARC), and CCL22 (MDC)). It is referred to by several different names in the scientific literature, including "CC-C CKR-4", "C-C CKR-4", "K5-5", "CD194", "CMKBR4", "ChemR13", "HGCN", and "14099". The term includes any recombinant or natural form of CCR4 and / or variants thereof that maintain CCR4 activity (e.g., within at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% activity compared to wild-type CCR4). The term includes any mutant form of CCR4 or variants thereof (e.g., frameshift mutations) that maintain CCR4 activity (e.g., within at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% activity compared to wild-type CCR4). In some embodiments, the CCR4 protein encoded by the CCR4 gene has an amino acid sequence set forth in or corresponding to Entrez 1233, UniProt P51679, or RefSeq(protein)NP_005499.1. In embodiments, the CCR4 gene has a nucleic acid sequence set forth in RefSeq(mRNA) NM_005508. In embodiments, the amino acid sequence or nucleic acid sequence is a sequence known at the time of filing of this application. In embodiments, the sequence corresponds to GI:5031627. In some embodiments, the sequence corresponds to NP_005499.1. In some embodiments, the sequence corresponds to NM_005508.4. In some embodiments, the sequence corresponds to GI:48762930. In embodiments, the CCR4 is human CCR4, such as in human cancers that cause CCR4. Although frequently found on dendritic cells, macrophages, NK cells, platelets, and basophils, CCR4 is primarily associated with T cells.It plays a role in the progression of multiple inflammation-related disorders and is also implicated in several other conditions, as described herein. The genomic sequence of CCR4 is present on chromosome 3 (NC_000003.12), and the CCR4 gene is conserved in several species, including chimpanzee, rhesus monkey, dog, cow, mouse, rat, chicken, and zebrafish. The CCR4 polypeptide contains 360 amino acid residues (NP_005499.1), and like other chemokine receptors, CCR4 is a G protein-coupled receptor found on the surface of leukocytes (see, e.g., Horuk (1994) Trends Pharm. Sci. 15:159-165).

[0087] The term "substantially pure" indicates that a component constitutes more than about 50% of the total content of the composition, typically more than about 60% of the total content. More typically, "substantially pure" refers to a composition in which at least 75%, at least 85%, at least 90% or more of the total composition is the component of interest. In some cases, the polypeptide constitutes more than about 90% or more than about 95% of the total content of the composition (percentage on a weight / weight basis).

[0088] The term "trans isomerically pure form" refers to a compound in which greater than about 50% of the total compound content, typically greater than about 60% of the total compound content, is the trans isomer form. More typically, a "trans isomerically pure form" refers to a compound in which at least 75%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99% or more of the total compound is the trans isomer form (percentage on a weight / weight basis).

[0089] The terms "specifically bind" and "selectively bind", when referring to a ligand / receptor, antibody / antigen, or other binding pair, refer to a binding reaction that determines the presence of a protein in a heterogeneous population of proteins and other biologics. Thus, under specified conditions, a particular ligand binds to a particular receptor and does not bind in significant amounts to other proteins present in a sample. The antibody or binding composition derived from an antigen-binding site of an antibody of the contemplated method binds to its antigen or variant or mutein thereof with an affinity that is at least 2-fold greater, at least 10-fold greater, at least 20-fold greater, or at least 100-fold greater than the affinity of any other antibody or binding composition derived therefrom. In some embodiments, the antibody ... 9 The solubility of the solubility-dependent agonist will have an affinity that is greater than liters / mole.

[0090] The term "protecting group" refers to a reversibly formed derivative of an existing functional group in a molecule that is temporarily attached to reduce reactivity such that the protected functional group does not react under the synthetic conditions under which the molecule is subjected to one or more subsequent steps.

[0091] The term "carboxylic acid-directed reducing agent" refers to a compound that binds to the carboxylic acid moiety of a substrate compound and reduces the substrate compound via hydride transfer. One embodiment of a carboxylic acid direct reducing agent is a 1,4-dihydropyridine, amide or mixed ester-amide, or chemical analogues thereof, all of which are referred to herein as "1,4-dihydropyridines". 1,4-dihydropyridines are a class of reducing agents that have been used in thermal catalytic hydrogenation reactions. Hantzsch esters are products of the Hantzsch dihydropyridine synthesis. Hantzsch esters are mild reducing agents that are often used in the transfer hydrogenation of activated C=C bonds, C=O bonds in carbonyl compounds, and C=N bonds in imines. A summary of these agents is given in Wang et al., Hantzsch esters: an emerging versatile class of reagents in photoredox catalyzed organic synthesis; Org. Biomol. Chem., 2019, 17, 6936-6951. In certain embodiments, the carboxylic acid-directed reducing agent has one of the following two formulas, the first of which is commonly referred to as a Hantzsch ester.

[0092] [ka]

[0093] II.Synthesis method In one aspect, provided herein is a method of synthesizing a trans isomeric form of a C-C chemokine receptor type 4 (CCR4) modulator, or a salt or ester thereof, the method comprising reacting a compound of formula (I) with a compound of formula (II) in the presence of a carboxylic acid directing reducing agent to prepare a trans isomeric compound of formula (III), wherein the compound of formula (III) is in at least 80% trans isomerically pure form:

[0094] [ka] n1' and n2' are each independently an integer of 0 to 5, the sum of n1' and n2' is at least 1 and not more than 6, and L 1’ is C(R 4’ )2, and L 2’ is C(R 5’ )2, and R 1’ is hydrogen, halogen, -CX 1’ 3. -CHX 1’ 2, -CH2X 1’ , -OCX 1’ 3. -OCHX 1’ 2, -OCH2X 1’ , -CN, -S(O)2R 1’A , -SR 1’A , -S(O)R 1’A , -SO2NR 1’A R 1’B , -NHC(O)NR 1’A R 1’B , -N(O)2, -NR 1’A R 1’B , -NHNR 1’A R 1’B , -C(O)R 1’A , -C(O)-OR 1’A , -C(O)NR 1’A R 1’B , -C(O)NHNR 1’A R 1’B , -OR 1’A , -NR 1’A SO2R 1’B , -NR 1’A C(O)R 1’B , -NR 1’A C(O)OR 1’B , -NR 1’A OR 1’B , -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 2’ is hydrogen, -CX 2’ 3. -CHX 2’ 2, -CH2X 2’ , -OCX 2’ 3. -OCHX 2’ 2, -OCH2X 2’ , -SR2’A , -NR 2’A R 2’B , -NHNR 2’A R 2’B , -OR 2’A , -NR 2’A SO2R 2’B , -NR 2’A C(O)R 2’B , -NR 2’A C(O)OR 2’B , -NR 2’A OR 2’B , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R 2’ and R 3’ can be optionally linked to form a substituted or unsubstituted heterocycloalkyl; R 3’ is hydrogen, -CX 3’ 3. -CHX 3’ 2, -CH2X 3’ , -OCX 3’ 3. -OCHX 3’ 2, -OCH2X 3’ , -SR 3’A , -NR 3’A R 3’B , -NHNR 3’A R 3’B , -OR 3’A , -NR 3’A SO2R 3’B , -NR 3’A C(O)R 3’B , -NR 3’A C(O)OR 3’B , -NR 3’A OR 3’B , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R 2’ and R 3’ can be optionally linked to form a substituted or unsubstituted heterocycloalkyl; R 4’ is hydrogen, halogen, -CX 4’ 3. -CHX 4’2, -CH2X 4’ , -OCX 4’ 3. -OCHX 4’ 2, -OCH2X 4’ , -CN, -S(O)2R 4’A , -SR 4’A , -S(O)R 4’A , -SO2NR 4’A R 4’B , -NHC(O)NR 4’A R 4’B , -N(O)2, -NR 4’A R 4’B , -NHNR 4’A R 4’B , -C(O)R 4’A , -C(O)-OR 4’A , -C(O)NR 4’A R 4’B , -C(O)NHNR 4’A R 4’B , -OR 4’A , -NR 4’A SO2R 4’B , -NR 4’A C(O)R 4’B , -NR 4’A C(O)OR 4’B , -NR 4’A OR 4’B , -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 5’ are independently hydrogen, halogen, -CX 5’ 3. -CHX 5’ 2, -CH2X 5’ , -OCX 5’ 3. -OCHX 5’ 2, -OCH2X 5’ , -CN, -S(O)2R 5’A , -SR 5’A , -S(O)R 5’A , -SO2NR 5’A R 5’B , -NHC(O)NR 5’A R 5’B , -N(O)2, -NR 5’A R 5’B , -NHNR 5’A R5’B , -C(O)R 5’A , -C(O)-OR 5’A , -C(O)NR 5’A R 5’B , -C(O)NHNR 5’A R 5’B , -OR 5’A , -NR 5’A SO2R 5’B , -NR 5’A C(O)R 5’B , -NR 5’A C(O)OR 5’B , -NR 5’A OR 5’B , -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 12’ are independently -OH or NHR 12” and R 12’’ is hydrogen or substituted or unsubstituted alkyl; R 1’A , R 1’B , R 2’A , R 2’B , R 3’A , R 3’B , R 4’A , R 4’B , R 5’A , and R 5’Bare independently hydrogen, -F, -Cl, -Br, -I, -CF3, -CHF2, -CH2F, -CCl3, -CHCl2, -CH2Cl, -CBr3, -CHBr2, -CH2Br, -CI3, -CHI2, -CH2I, -OCF3, -OCCl3, -OCBr3, -OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -C(O)OH, -C(O)NH2, -OH, -NH2, -COOH, -CO NH2, -SH, -SO3H, -SO4H, -SON2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)OH, -NHOH, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or R bonded to the same nitrogen atom 2’A and R 2’B The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl, or R 3’A and R 3’B The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; X 1’ , X 2’ , X 3’ , X 4’ , and X 5’ are independently halogen.

[0095] In some embodiments, the compound of formula (III) is in at least 85% trans isomerically pure form. In some embodiments, the compound of formula (III) is in at least 90% trans isomerically pure form. In some embodiments, the compound of formula (III) is in at least 95% trans isomerically pure form. In some embodiments, the compound of formula (III) is in at least 98% trans isomerically pure form. In some embodiments, the compound of formula (III) is in at least 99% trans isomerically pure form. In some embodiments, the compound of formula (III) is in 100% trans isomerically pure form.

[0096] In some embodiments, n1' and n2' are each independently an integer from 0 to 5, and the sum of n1' and n2' is at least 1 and no greater than 6.

[0097] In some embodiments, L 1 is C(R 4’ )2.

[0098] R 4’ are independently hydrogen, halogen, -CX 4’ 3. -CHX 4’ 2, -CH2X 4’ , -OCX 4’ 3. -OCHX 4’ 2, -OCH2X 4’ , -CN, -S(O)2R 4’A , -SR 4’A , -S(O)R 4’A , -SO2NR 4’A R 4’B , -NHC(O)NR 4’A R 4’B , -N(O)2, -NR 4’A R 4’B , -NHNR 4’A R 4’B , -C(O)R 4’A , -C(O)-OR 4’A , -C(O)NR 4’A R 4’B , -C(O)NHNR 4’A R 4’B , -OR4’A , -NR 4’A SO2R 4’B , -NR 4’A C(O)R 4’B , -NR 4’A C(O)OR 4’B , -NR 4’A OR 4’B , -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;

[0099] In some embodiments, R 4’ is hydrogen, halogen (e.g., -F, -Cl, Br, -I), -CX 4’ 3. -CX 4’ 2, -CH2X 4’ , -OCX 4’ 3. -OCHX 4’ 2, -OCH2X 4’ , -CN, -S(O)2R 4’A , -SR 4’A , -S(O)R 4’A , -SO2NR 4’A R 4’B , -NHC(O)NR 4’A R 4’B , -N(O)2, -NR 4’A R 4’B , -NHNR 4’A R 4’B , -C(O)R 4’A , -C(O)-OR 4’A , -C(O)NR 4’A R 4’B , -C(O)NHNR 4’A R 4’B , -OR 4’A , -NR 4’A SO2R 4’B , -NR 4’A C(O)R 4’B , -NR 4’A C(O)OR 4’B , -NR 4’A OR 4’B, -N3, (e.g. -CF3, -CHF2, -CH2F, -CCl3, -CHCl2, -CH2Cl, -CBr3, -CHBr2, -CH2Br, -CI3, -CHI2, -CH2I, -OCF3, -OCCl3, -OCBr3, -OCI3, -OCHF2, -OCHCl2, -OCH Br2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -N3, -CN, -SH, -SCH3, -SO2H, -SO2CH3, -SO2NH2, -SO2NHCH3, -NHC(O)NH2, -NHC(O)NHCH3, -NO2, -NH2, -NHCH 3、 -C(O)H, -C(O)CH 3、 -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -OH, -OCH3, -NHSO2H, -NHSO2CH3, -NHC(O)H, -NCH3C(O)H, -NHC(O)OH, -NCH3C(O)OH, -NHOH, -NCH3OH, or -NCH3OCH3), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent), ) or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, or 2-4 membered), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, or 5-6 membered), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted aryl (e.g., C6-C 10 , C6, or phenyl), or substituted (e.g., substituted, size-limited, or lower substituted) or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered). X 4’ is independently -F, -Cl, -Br, or -I.

[0100] In some embodiments, R 4’is hydrogen, -F, -Cl, Br, -I, -CF3, -CHF2, -CH2F, -CCl3, -CHCl2, -CH2Cl, -CBr3, -CHBr2, -CH2Br, -CI3, -CHI2, -CH2I, -OCF3, -OCCl3, -OCBr3, -OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -N3, -CN, -SH, -SCH3, -SO2H, -SO2CH3, -SO2NH2, -SO2NHCH3, -NHC(O)NH 2、 -NHC(O)NHCH 3、 -NO 2、 -NH2, -NHCH 3、 -C(O)H, -C(O)CH 3、 -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -OH, -OCH3, -NHSO2H, -NHSO2CH3, -NHC(O)H, -NCH3C(O)H, -NHC(O)OH, -NCH3C(O)OH, -NHOH, -NCH3OH, -NCH3OCH3, substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), ... or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, or 2-4 membered), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, or 5-6 membered), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted aryl (e.g., C6-C 10 , C, or phenyl), or substituted (e.g., substituted, size-limited, or lower substituted) or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered). 4’ If is replaced, R 4’ is substituted with a substituent. In some embodiments, R4’ If is replaced, R 4’ is substituted with size-limited substituents. In some embodiments, R 4’ If is replaced, R 4’ is substituted with a lower substituent.

[0101] In some embodiments, R 4’ is hydrogen, -F, -Cl, Br, -I, -CF3, -CHF2, -CH2F, -CCl3, -CHCl2, -CH2Cl, -CBr3, -CHBr2, -CH2Br, -CI3, -CHI2, -CH2I, -OCF3, -OCCl3, -OCBr3, -OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -N3, -CN, -SH, -SCH3, -SO2H, -SO2CH3, -SO2NH2, -SO2NHCH3, -NHC(O)NH 2、 -NHC(O)NHCH 3、 -NO 2、 -NH2, -NHCH 3、 -C(O)H, -C(O)CH3, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -OH, -OCH3, -NHSO2H, -NHSO2CH3, -NHC(O)H, -NCH3C(O)H, -NHC(O)OH, -NCH3C(O)OH, -NHOH, -NCH3OH, -NCH3OCH3, unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1C4), unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, or 2-4 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, or 5-6 membered), unsubstituted aryl (e.g., C6-C8, C3-C6, or C5-C6), 10 , C6, or phenyl), or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered).

[0102] In some embodiments, L 2’ is C(R 5’ )2.

[0103] R 5’are independently hydrogen, halogen, -CX 5’ 3. -CHX 5’ 2, -CH2X 5’ , -OCX 5’ 3. -OCHX 5’ 2, -OCH2X 5’ , -CN, -S(O)2R 5’A , -SR 5’A , -S(O)R 5’A , -SO2NR 5’A R 5’B , -NHC(O)NR 5’A R 5’B , -N(O)2, -NR 5’A R 5’B , -NHNR 5’A R 5’B , -C(O)R 5’A , -C(O)-OR 5’A , -C(O)NR 5’A R 5’B , -C(O)NHNR 5’A R 5’B , -OR 5’A , -NR 5’A SO2R 5’B , -NR 5’A C(O)R 5’B , -NR 5’A C(O)OR 5’B , -NR 5’A OR 5’B , -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.

[0104] In some embodiments, R 5’ is hydrogen, halogen (e.g., -F, -Cl, Br, -I), -CX 5’ 3. -CHX 5’ 2, -CH2X 5’ , -OCX 5’ 3. -OCHX 5’ 2, -OCH2X 5’ , -CN, -S(O)2R 5’A , -SR 5’A , -S(O)R 5’A , -SO2NR 5’A R5’B 、-NHC(O)NR 5’A R 5’B 、-N(O) 2、 -NR 5’A R 5’B 、-NHNR 5’A R 5’B 、-C(O)R 5’A 、-C(O)-OR 5’A 、-C(O)NR 5’A R 5’B 、-C(O)NHNR 5’A R 5’B 、-OR 5’A 、-NR 5’A SO2R 5’B 、-NR 5’A C(O)R 5’B 、-NR 5’A C(O)OR 5’B 、-NR 5’A OR 5’B, -N3, (e.g. -CF3, -CHF2, -CH2F, -CCl3, -CHCl2, -CH2Cl, -CBr3, -CHBr2, -CH2Br, -CI3, -CHI2, -CH2I, -OCF3, -OCC l3, -OCBr3, -OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -N3, -CN, -SH, -SCH3, - SO2H, -SO2CH3, -SO2NH2, -SO2NHCH3, -NHC(O)NH2, -NHC(O)NHCH3, -NO2, -NH2, -NHCH3, -C(O)H, -C(O)CH3, -C(O)O H, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -OH, -OCH3, -NHSO2H, -NHSO2CH3, -NHC(O)H, -NCH3C(O)H, -NHC(O)OH, -NCH3 C(O)OH, -NHOH, -NCH3OH, or -NCH3OCH3), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, or 2-4 membered), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, or 5-6 membered), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted aryl (e.g., C6-C8, C6-C8, or C5-C6). 10 , C6, or phenyl), or substituted (e.g., substituted, size-limited, or lower substituted) or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered). X 5’ is independently -F, -Cl, -Br, or -I.

[0105] In some embodiments, R 5’is hydrogen, -F, -Cl, Br, -I, -CF3, -CHF2, -CH2F, -CCl3, -CHCl2, -CH2Cl, -CBr3, -CHBr2, -CH2Br, -CI3, -CHI2, -CH2I, -OC F3, -OCCl3, -OCBr3, -OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -N3, -CN, -SH, - SCH3, -SO2H, -SO2CH3, -SO2NH2, -SO2NHCH3, -NHC(O)NH2, -NHC(O)NHCH3, -NO2, -NH2, -NHCH3, -C(O)H, -C(O)CH3, - C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -OH, -OCH3, -NHSO2H, -NHSO2CH3, -NHC(O)H, -NCH3C(O)H, -NHC(O)OH, - NCH3C(O)OH, -NHOH, -NCH3OH, or -NCH3OCH3), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, or 2-4 membered), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, or 5-6 membered), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted aryl (e.g., C6-C8, C6-C6, or C7-C6). 10 , C, or phenyl), or substituted (e.g., substituted, size-limited, or lower substituted) or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered). 5’ If is replaced, R 5’ is substituted with a substituent. In some embodiments, R 5’ If is replaced, R 5’is substituted with size-limited substituents. In some embodiments, R 5’ If is replaced, R 5’ is substituted with a lower substituent.

[0106] In some embodiments, R 5’ is hydrogen, -F, -Cl, Br, -I, -CF3, -CHF2, -CH2F, -CCl3, -CHCl2, -CH2Cl, -CBr3, -CHBr2, -CH2Br, -CI3, -CHI2, -CH2I, -OCF3, -OCCl3, -OCBr3, -OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -N3, -CN, -SH, -SCH3, -SO2H, -SO2CH3, -SO2NH2, -SO2NHCH3, -NHC(O)NH 2、 -NHC(O)NHCH 3、 -NO 2、 -NH2, -NHCH 3、 -C(O)H, -C(O)CH3, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -OH, -OCH3, -NHSO2H, -NHSO2CH3, -NHC(O)H, -NCH3C(O)H, -NHC(O)OH, -NCH3C(O)OH, -NHOH, -NCH3OH, or -NCH3OCH3), unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1C4), unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, or 2-4 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, or 5-6 membered), unsubstituted aryl (e.g., C6-C8, C3-C6, or C5-C6), 10 , C6, or phenyl), or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered).

[0107] R 1’ is hydrogen, halogen, -CX 1’ 3. -CHX 1’ 2, -CH2X 1’ , -OCX 1’ 3. -OCHX 1’ 2, -OCH2X 1’, -CN, -S(O)2R 1’A , -SR 1’A , -S(O)R 1’A , -SO2NR 1’A R 1’B , -NHC(O)NR 1’A R 1’B , -N(O)2, -NR 1’A R 1’B , -NHNR 1’A R 1’B , -C(O)R 1’A , -C(O)-OR 1’A , -C(O)NR 1’A R 1’B , -C(O)NHNR 1’A R 1’B , -OR 1’A , -NR 1’A SO2R 1’B , -NR 1’A C(O)R 1’B , -NR 1’A C(O)OR 1’B , -NR 1’A OR 1’B , -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.

[0108] In some embodiments, R 1’ is hydrogen, halogen (e.g., -F, -Cl, Br, -I), -CX 1’ 3. -CHX 1’ 2, -CH2X 1’ , -OCX 1’ 3. -OCHX 1’ 2, -OCH2X 1’ , -CN, -S(O)2R 1’A , -SR 1’A , -S(O)R 1’A , -SO2NR 1’A R 1’B , -NHC(O)NR 1’A R 1’B , -N(O) 2、 -NR 1’A R 1’B , -NHNR 1’A R 1’B, -C(O)R 1’A , -C(O)-OR 1’A , -C(O)NR 1’A R 1’B , -C(O)NHNR 1’A R 1’B , -OR 1’A , -NR 1’A SO2R 1’B , -NR 1’A C(O)R 1’B , -NR 1’A C(O)OR 1’B , -NR 1’A OR 1’B , -N3, (e.g., -CF3, -CHF2, -CH2F, -CCl3, -CHCl2, -CH2Cl, -CBr3, -CHBr2, -CH2Br, -CI3, -CHI2, -CH2I, -OCF3, -OCCl3, -OCBr3, -OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -N3, -CN, -SH, -SCH3, -SO2H, -SO2CH3, -SO2NH2, -SO2NHCH3, -NHC(O)NH 2、-NHC(O)NHCH3, -NO2, -NH2, -NHCH3, -C(O)H, -C(O)CH3, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -OH, -OCH3, -NHSO2H, -NHSO2CH3, -NHC(O)H, -NCH3C(O)H, -NHC(O)OH, -NCH3C(O)OH, -NHOH, -NCH3OH, or -NCH3OCH3), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), substituted (e.g., substituted with a substituent , size-limited substituents, or lower substituents) or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, or 2-4 membered), substituted (e.g., substituted with a substituent, size-limited substituent, or lower substituent) or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), substituted (e.g., substituted with a substituent, size-limited substituent, or lower substituent) or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, or 5-6 membered), substituted (e.g., substituted with a substituent, size-limited substituent, or lower substituent) or unsubstituted aryl (e.g., C6-C8, C6-C8, C6-C8, or C5-C8, 10 , C6, or phenyl), or substituted (e.g., substituted, size-limited, or lower substituted) or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered). X 1’ is independently -F, -Cl, -Br, or -I.

[0109] In some embodiments, R 1’is hydrogen, -F, -Cl, Br, -I, -CF3, -CHF2, -CH2F, -CCl3, -CHCl2, -CH2Cl, -CBr3, -CHBr2, -CH2Br, -CI3, -CHI2, -CH2I, -OC F3, -OCCl3, -OCBr3, -OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -N3, -CN, -SH, - SCH3, -SO2H, -SO2CH3, -SO2NH2, -SO2NHCH3, -NHC(O)NH2, -NHC(O)NHCH3, -NO2, -NH2, -NHCH3, -C(O)H, -C(O)CH3, - C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -OH, -OCH3, -NHSO2H, -NHSO2CH3, -NHC(O)H, -NCH3C(O)H, -NHC(O)OH, - NCH3C(O)OH, -NHOH, -NCH3OH, or -NCH3OCH3), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, or 2-4 membered), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, or 5-6 membered), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted aryl (e.g., C6-C8, C6-C6, or C7-C6). 10 , C, or phenyl), or substituted (e.g., substituted, size-limited, or lower substituted) or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered). 1’ If is replaced, R 1’ is substituted with a substituent. In some embodiments, R 1’ If is replaced, R 1’is substituted with size-limited substituents. In some embodiments, R 1’ If is replaced, R 1’ is substituted with a lower substituent.

[0110] In some embodiments, R 1’ is hydrogen, -F, -Cl, Br, -I, -CF3, -CHF2, -CH2F, -CCl3, -CHCl2, -CH2Cl, -CBr3, -CHBr2, -CH2Br, -CI3, -CHI2, -CH2I, -OCF3, -OCCl3, -OCBr3, -OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -N3, -CN, -SH, -SCH3, -SO2H, -SO2CH3, -SO2NH2, -SO2NHCH3, -NHC(O)NH 2、 -NHC(O)NHCH 3、 -NO 2、 -NH2, -NHCH 3、 -C(O)H, -C(O)CH3, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -OH, -OCH3, -NHSO2H, -NHSO2CH3, -NHC(O)H, -NCH3C(O)H, -NHC(O)OH, -NCH3C(O)OH, -NHOH, -NCH3OH, or -NCH3OCH3), unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1C4), unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, or 2-4 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, or 5-6 membered), unsubstituted aryl (e.g., C6-C8, C3-C6, or C5-C6), 10 , C6, or phenyl), or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered).

[0111] R 2’ is hydrogen, -CX 2’ 3. -CHX 2’ 2, -CH2X 2’ , -OCX 2’ 3. -OCHX 2’ 2, -OCH2X 2’ , -SR2’A , -NR 2’A R 2’B , -NHNR 2’A R 2’B , -OR 2’A , -NR 2’A SO2R 2’B , -NR 2’A C(O)R 2’B , -NR 2’A C(O)OR 2’B , -NR 2’A OR 2’B , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R 2’ and R 3’ may be optionally linked to form a substituted or unsubstituted heterocycloalkyl. In some embodiments, R 2’ and R 3’ are linked to form a substituted heterocycloalkyl, where the heterocycloalkyl is substituted with a substituent. In some embodiments, R 2’ and R 3’ are linked to form a substituted heterocycloalkyl, where the heterocycloalkyl is substituted with a size-limited substituent. In some embodiments, R 2’ and R 3’ are linked to form a substituted heterocycloalkyl, wherein the heterocycloalkyl is substituted with a lower substituent.

[0112] In some embodiments, R 2’ is hydrogen, -CX 2’ 3. -CHX 2’ 2, -CH2X 2’ , -OCX 2’ 3. -OCHX 2’ 2, -OCH2X 2’ , -SR 2’A , -NR 2’A R 2’B , -NHNR 2’A R 2’B , -OR 2’A , -NR 2’A SO2R 2’B , -NR2’A C(O)R 2’B , -NR 2’A C(O)OR 2’B , -NR 2’A OR 2’B , (e.g. -CF3, -CHF2, -CH2F, -CCl3, -CHCl2, -CH2Cl, -CBr3, -CHBr2, -CH2Br, -CI3, -CHI2, -CH2I, -OCF3, -OCCl3, -OCBr3, -OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -SH, -SCH3, -SO2H, -SO2 CH3, -SO2NH2, -SO2NHCH3, -NHC(O)NH2, -NHC(O)NHCH3, -NO2, -NH2, -NHCH3, -C(O)H, -C(O)CH3, -C(O)OH, -C(O)O CH3, -C(O)NH2, -C(O)NHCH3, -OH, -OCH3, -NHSO2H, -NHSO2CH3, -NHC(O)H, -NCH3C(O)H, -NHC(O)OH, -NCH3C(O)OH , -NHOH, -NCH3OH, or -NCH3OCH3), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, or 2-4 membered), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, or 5-6 membered), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted aryl (e.g., C6-C8, C6-C6, or C7-C6). 10 , C6, or phenyl), or substituted (e.g., substituted, size-limited, or lower substituted) or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered). X 2’ is independently -F, -Cl, -Br, or -I.

[0113] In some embodiments, R 2’ is hydrogen, -CF3, -CHF2, -CH2F, -CCl3, -CHCl2, -CH2Cl, -CBr3, -CHBr2, -CH2Br, -CI3, -CHI2, -CH2I, -OCF3, -OCCl3, -OCBr3, -OCI3, -OC HF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -SH, -SCH3, -SO2H, -SO2CH3, -SO2NH2, -SO2NHCH3, -NHC(O)NH 2、 -NHC(O)NHCH 3、 -NO 2、 -NH2, -NHCH 3、 -C(O)H, -C(O)CH3, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -OH, -OCH3, -NHSO2H, -NHSO2CH3, -NHC(O)H, -NCH3C(O)H, -NHC(O)OH, -NCH3C(O)OH, -NHOH, -NCH3OH, or -NCH3OCH3), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4 ... substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, or 2-4 membered), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, or 5-6 membered), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted aryl (e.g., C6-C8, C6-C8, C6-C8, or C5-C6), 10 , C, or phenyl), or substituted (e.g., substituted, size-limited, or lower substituted) or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered). 2’ If is replaced, R 2’is substituted with a substituent. In some embodiments, R 2’ If is replaced, R 2’ is substituted with size-limited substituents. In some embodiments, R 2’ If is replaced, R 2’ is substituted with a lower substituent.

[0114] In some embodiments, R 2’ is hydrogen, -CF3, -CHF2, -CH2F, -CCl3, -CHCl2, -CH2Cl, -CBr3, -CHBr2, -CH2Br, -CI3, -CHI2, -CH2I, -OCF3, -OCCl3, -OCBr3, -OCI3, -OC HF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -SH, -SCH3, -SO2H, -SO2CH3, -SO2NH2, -SO2NHCH3, -NHC(O)NH 2、 -NHC(O)NHCH 3、 -NO 2、 -NH2, -NHCH 3、 -C(O)H, -C(O)CH3, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -OH, -OCH3, -NHSO2H, -NHSO2CH3, -NHC(O)H, -NCH3C(O)H, -NHC(O)OH, -NCH3C(O)OH, -NHOH, -NCH3OH, or -NCH3OCH3), unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1C4), unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, or 2-4 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, or 5-6 membered), unsubstituted aryl (e.g., C6-C8, C3-C6, or C5-C6), 10 , C6, or phenyl), or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered).

[0115] R 3’ is hydrogen, -CX 3’ 3. -CHX 3’ 2, -CH2X 3’ , -OCX 3’ 3. -OCHX3’ 2, -OCH2X 3’ , -SR 3’A , -NR 3’A R 3’B , -NHNR 3’A R 3’B , -OR 3’A , -NR 3’A SO2R 3’B , -NR 3’A C(O)R 3’B , -NR 3’A C(O)OR 3’B , -NR 3’A OR 3’B , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R 2’ and R 3’ can be optionally linked to form a substituted or unsubstituted heterocycloalkyl.

[0116] In some embodiments, R 3’ is hydrogen, -CX 3’ 3. -CHX 3’ 2, -CH2X 3’ , -OCX 3’ 3. -OCHX 3’ 2, -OCH2X 3’ , -SR 3’A , -NR 3’A R 3’B , -NHNR 3’A R 3’B , -OR 3’A , -NR 3’A SO2R 3’B , -NR 3’A C(O)R 3’B , -NR 3’A C(O)OR 3’B , -NR 3’A OR 3’B, (e.g. -CF3, -CHF2, -CH2F, -CCl3, -CHCl2, -CH2Cl, -CBr3, -CHBr2, -CH2Br, -CI3, -CHI2, -CH2I, -OCF3, -OCCl3, -OCBr3, -OCI3, -OCHF2, -OCH Cl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -SH, -SCH3, -SO2H, -SO2CH3, -SO2NH2, -SO2NHCH3, -NHC(O)NH2, -NHC(O)NHCH3, -NO 2、 -NH2, -NHCH 3、 -C(O)H, -C(O)CH3, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -OH, -OCH3, -NHSO2H, -NHSO2CH3, -NHC(O)H, -NCH3C(O)H, -NHC(O)OH, -NCH3C(O)OH, -NHOH, -NCH3OH, or -NCH3OCH3), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4 ... substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, or 2-4 membered), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, or 5-6 membered), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted aryl (e.g., C6-C8, C6-C8, C6-C8, or C5-C6), 10 , C6, or phenyl), or substituted (e.g., substituted, size-limited, or lower substituted) or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered). X 3’ is independently -F, -Cl, -Br, or -I.

[0117] In some embodiments, R 3’is hydrogen, -CHF2, -CH2F, -CCl3, -CHCl2, -CH2Cl, -CBr3, -CHBr2, -CH2Br, -CI3, -CHI2, -CH2I, -OCF3, -OCCl3, -OCBr3, -OCI3, -OCHF 2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -SH, -SCH3, -SO2H, -SO2CH3, -SO2NH2, -SO2NHCH3, -NHC(O)NH 2、 -NHC(O)NHCH 3、 -NO2, -NH2, -NHCH3, -C(O)H, -C(O)CH3, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -OH, -OCH3, -NHSO2H, -NHSO2CH3, -NHC(O)H, -NCH3C(O)H, -NHC(O)OH, -NCH3C(O)OH, -NHOH, -NCH3OH, or -NCH3OCH3), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent), substituted (e.g., substituted with a substituent, size-limited substituent, or lower substituent) or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, or 2-4 membered), substituted (e.g., substituted with a substituent, size-limited substituent, or lower substituent) or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), substituted (e.g., substituted with a substituent, size-limited substituent, or lower substituent) or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, or 5-6 membered), substituted (e.g., substituted with a substituent, size-limited substituent, or lower substituent) or unsubstituted aryl (e.g., C6-C8, C6-C8, C6-C8, or C5-C8), 10 , C, or phenyl), or substituted (e.g., substituted, size-limited, or lower substituted) or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered). 3’ If is replaced, R 3’ is substituted with a substituent. In some embodiments, R 3’ If is replaced, R 3’ is substituted with size-limited substituents. In some embodiments, R3’ If is replaced, R 3’ is substituted with a lower substituent.

[0118] In some embodiments, R 3’ is hydrogen, -CF3, -CHF2, -CH2F, -CCl3, -CHCl2, -CH2Cl, -CBr3, -CHBr2, -CH2Br, -CI3, -CHI2, -CH2I, -OCF3, -OCCl3, -OCBr3, -OCI3, -OC HF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -SH, -SCH3, -SO2H, -SO2CH3, -SO2NH2, -SO2NHCH3, -NHC(O)NH 2、 -NHC(O)NHCH 3、 -NO 2、 -NH2, -NHCH 3、 -C(O)H, -C(O)CH3, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -OH, -OCH3, -NHSO2H, -NHSO2CH3, -NHC(O)H, -NCH3C(O)H, -NHC(O)OH, -NCH3C(O)OH, -NHOH, -NCH3OH, or -NCH3OCH3), unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1C4), unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, or 2-4 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, or 5-6 membered), unsubstituted aryl (e.g., C6-C8, C3-C6, or C5-C6), 10 , C6, or phenyl), or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered).

[0119] In some embodiments, R 2’ and R 3’ are linked to form a substituted or unsubstituted piperidinyl ring. In some embodiments, the piperidinyl is substituted with a substituted or unsubstituted heterocycloalkyl. In some embodiments, the substituted or unsubstituted heterocycloalkyl is a nitrogen-containing 3- to 6-membered heterocycloalkyl.

[0120] R 12’ are independently -OH or NHR 12” In some embodiments, R 12’ is -OH. In some embodiments, R 12’ NHR 12’’ It is.

[0121] R 12’’ is hydrogen, or substituted or unsubstituted alkyl. In some embodiments, R 12’’ is hydrogen. In some embodiments, R 12’’ is substituted or unsubstituted alkyl. In some embodiments, R 12’’ is substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4). In some embodiments, R 12’’ is substituted with a substituent. In some embodiments, R 12’’ is substituted with size-limited substituents. In some embodiments, R 12’’ is substituted with a lower substituent.

[0122] R 1’A , R 1’B , R 2’A , R 2’B , R 3’A , R 3’B , R 4’A , R 4’B , R 5’A , and R 5’Bare independently hydrogen, -F, -Cl, -Br, -I, -CF3, -CHF2, -CH2F, -CCl3, -CHCl2, -CH2Cl, -CBr3, -CHBr2, -CH2Br, -CI3, -CHI2, -CH2I, -OCF3, -OCCl3, -OCBr3, -OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -C(O)OH, -C(O)NH2, -OH, -NH2, -COOH, -CO NH2, -SH, -SO3H, -SO4H, -SON2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)OH, -NHOH, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or R bonded to the same nitrogen atom 2’A and R 2’B The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl, or may be linked together ... 3’A and R 3’B The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

[0123] In some embodiments, R 1’A , R 1’B , R 2’A , R 2’B , R 3’A , R 3’B , R 4’A , R 4’B , R 5’A , and R 5’Bare independently hydrogen, -F, -Cl, -Br, -I, -CF3, -CHF2, -CH2F, -CCl3, -CHCl2, -CH2Cl, -CBr3, -CHBr2, -CH2Br, -CI3, -CHI2, -CH2I, -OCF3, -OCCl3, -OCBr3, -OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -C (O)OH, -C(O)NH2, -OH, -NH2, -COOH, -CONH2, -SH, -SO3H, -SO4H, -SON2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)OH, -NHOH, substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl (e.g., C 1 ~C 8 , C 1 ~C 6 , or C 1 ~C 4 ), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, or 2-4 membered), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, or 5-6 membered), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted aryl (e.g., C6-C 10 , C, or phenyl), or substituted (e.g., substituted, size-limited, or lower substituted) or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered). 1’A , R 1’B , R 2’A , R 2’B , R 3’A , R 3’B , R 4’A , R 4’B , R 5’A , and R 5’Bis substituted and R 1’A , R 1’B , R 2’A , R 2’B , R 3’A , R 3’B , R 4’A , R 4’B , R 5’A and R 5’B is substituted with a substituent. In some embodiments, R 1’A , R 1’B , R 2’A , R 2’B , R 3’A , R 3’B , R 4’A , R 4’B , R 5’A , and R 5’B is substituted and R 1’A , R 1’B , R 2’A , R 2’B , R 3’A , R 3’B , R 4’A , R 4’B , R 5’A and R 5’B is substituted with a size-limited substituent. In some embodiments, R 1’A , R 1’B , R 2’A , R 2’B , R 3’A , R 3’B , R 4’A , R 4’B , R 5’A , and R 5’B is substituted and R 1’A , R 1’B , R 2’A , R 2’B , R 3’A , R 3’B , R 4’A , R 4’B , R 5’A and R 5’B is substituted with a lower substituent. In some embodiments, R 1’A is substituted with a substituent. In some embodiments, R 1’A is substituted with a size-limited substituent. In some embodiments, R 1’A is substituted with a lower substituent. In some embodiments, R1’B is substituted with a substituent. In some embodiments, R 1’B is substituted with a size-limited substituent. In some embodiments, R 1’B is substituted with a lower substituent. In some embodiments, R 2’A is substituted with a substituent. In some embodiments, R 2’A is substituted with a size-limited substituent. In some embodiments, R 2’A is substituted with a lower substituent. In some embodiments, R 2’B is substituted with a substituent. In some embodiments, R 2’B is substituted with a size-limited substituent. In some embodiments, R 2’B is substituted with a lower substituent. In some embodiments, R 3’A is substituted with a substituent. In some embodiments, R 3’A is substituted with a size-limited substituent. In some embodiments, R 3’A is substituted with a lower substituent. In some embodiments, R 3’B is substituted with a substituent. In some embodiments, R 3’B is substituted with a size-limited substituent. In some embodiments, R 3’B is substituted with a lower substituent. In some embodiments, R 4’A is substituted with a substituent. In some embodiments, R 4’A is substituted with a size-limited substituent. In some embodiments, R 4’A is substituted with a lower substituent. In some embodiments, R 4’B is substituted with a substituent. In some embodiments, R 4’B is substituted with a size-limited substituent. In some embodiments, R 4’B is substituted with a lower substituent. In some embodiments, R 5’A is substituted with a substituent. In some embodiments, R 5’A is substituted with a size-limited substituent. In some embodiments, R 5’Ais substituted with a lower substituent. In some embodiments, R 5’B is substituted with a substituent. In some embodiments, R 5’B is substituted with a size-limited substituent. In some embodiments, R 5’B is substituted with a lower substituent.

[0124] In some embodiments, R 1’A , R 1’B , R 2’A , R 2’B , R 3’A , R 3’B , R 4’A , R 4’B , R 5’A , and R 5’B are independently hydrogen, -F, -Cl, -Br, -I, -CF3, -CHF2, -CH2F, -CCl3, -CHCl2, -CH2Cl, -CBr3, -CHBr2, -CH2Br, -CI3, -CHI2, -CH2I, -OCF3, -OCCl3, -OCBr3, -OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2C l, -OCH2Br, -OCH2I, -C(O)OH, -C(O)NH2, -OH, -NH2, -COOH, -CONH2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)OH, -NHOH, unsubstituted alkyl (e.g., C 1 ~C 8 , C 1 ~C 6 , or C 1 ~C 4 ), unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, or 2-4 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, or 5-6 membered), unsubstituted aryl (e.g., C6-C 10 , C6, or phenyl), or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered).

[0125] In some embodiments, reacting the compound of Formula (I) with the compound of Formula (II) is carried out in the absence of a separate catalyst.

[0126] In some embodiments, the compound of formula (I) is

[0127] [ka] and In the formula, R 11’ is -CF3, -CHF2, -CH2F, -CCl3, -CHCl2, -CH2Cl, -CBr3, -CHBr2, -CH2Br, -CI3, -CHI2, -CH2I, -NH2, 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.

[0128] In some embodiments, R 11’ is -CF3, -CHF2, -CH2F, -CCl3, -CHCl2, -CH2Cl, -CBr3, -CHBr2, -CH2Br, -CI3, -CHI2, -CH2I, -NH2, substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl (e.g., C1 to C8, C1 to C6, or C1 to C4), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkyl (e.g., 2-8 membered, 2- 6-membered, or 2-4-membered), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heterocycloalkyl (e.g., 3-8-membered, 3-6-membered, or 5-6-membered), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted aryl (e.g., C6-C 10, C, or phenyl), or substituted (e.g., substituted, size-limited, or lower substituted) or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered). 11’ If is replaced, R 11’ is substituted with a substituent. In some embodiments, R 11’ If is replaced, R 11’ is substituted with size-limited substituents. In some embodiments, R 11’ If is replaced, R 11’ is substituted with a lower substituent.

[0129] In some embodiments, R 11’ is -CF3, -CHF2, -CH2F, -CCl3, -CHCl2, -CH2Cl, -CBr3, -CHBr2, -CH2Br, -CI3, -CHI2, -CH2I, -NH2, unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, or 2-4 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, or 5-6 membered), unsubstituted aryl (e.g., C6-C8, C6-C6, or C5-C6), 10 , C6, or phenyl), or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered).

[0130] In some embodiments, R 11’ is substituted or unsubstituted alkyl. In some embodiments, R 11’ is substituted (eg, substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl (eg, C1-C8, C1-C6, or C1-C4).

[0131] The compound of formula III is

[0132] [ka] and In the formula, R 11’is a substituted or unsubstituted alkyl, and n1' and n2' are each 1 or 2. R 1’ , L 1’ , L 2’ , and R 12’ As described above, including several embodiments.

[0133] The compound of formula III is

[0134] [ka] and In the formula, R 11’ is substituted or unsubstituted alkyl.

[0135] In the synthetic methods provided herein, the carboxylic acid-directed reducing agent is represented by formula (IV):

[0136] [ka] It is a 1,4-dihydropyridine. L 3’ and L 4’ are independently O or NR 20’ and R 20’ is hydrogen or R 21’ and R 21’ is hydrogen, -CX 21’ 3. -CHX 21’ 2, -CH2X 21’ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; R 6’ is hydrogen, -CX 6’ 3. -CHX 6’ 2, -CH2X 6’ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or 1,4-dihydropyridine is a bond attaching the polymeric support; R7’ is hydrogen, -CX 7’ 3. -CHX 7’ 2, -CH2X 7’ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or 1,4-dihydropyridine is a bond attaching the polymeric support; R 8’ are independently hydrogen, halogen, -CX 8’ 3. -CHX 8’ 2, -CH2X 8’ , -OCX 8’ 3. -OCHX 8’ 2, -OCH2X 8’ , -CN, -S(O)2R 8’A , -SR 8’A , -S(O)R 8’A , -SO2NR 8’A R 8’B , -NHC(O)NR 8’A R 8’B , -N(O)2, -NR 8’A R 8’B , -NHNR 8’A R 8’B , -C(O)R 8’A , -C(O)-OR 8’A , -C(O)NR 8’A R 8’B , -C(O)NHNR 8’A R 8’B , -OR 8’A , -NR 8’A SO2R 8’B , -NR 8’A C(O)R 8’B , -NR 8’A C(O)OR 8’B , -NR 8’A OR 8’B , -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 9’ are independently hydrogen, halogen, -CX 9’ 3. -CHX 9’ 2, -CH2X9’ , -OCX 9’ 3. -OCHX 9’ 2, -OCH2X 9’ , -CN, -S(O)2R 9’A , -SR 9’A , -S(O)R 9’A , -SO2NR 9’A R 9’B , -NHC(O)NR 9’A R 9’B , -N(O)2, -R 9’A R 9’B , -NHNR 9’A R 9’B , -C(O)R 9’A , -C(O)-OR 9’A , -C(O)NR 9’A R 9’B , -C(O)NHNR 9’A R 9’B , -OR 9’A , -NR 9’A SO2R 9’B , -NR 9’A C(O)R 9’B , -NR 9’A C(O)OR 9’B , -NR 9’A OR 9’B , -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 10’ are independently hydrogen, halogen, -CX 10’ 3. -CHX 10’ 2, -CH2X 10’ , -OCX 10’ 3. -OCHX 10’ 2, -OCH2X 10’ , -CN, -S(O)2R 10’A , -SR 10’A , -S(O)R 10’A , -SO2NR 10’A R 10’B , -NHC(O)NR 10’A R 10’B , -N(O)2, -NR 10’A R 10’B , -NHNR 10’A R 10’B, -C(O)R 10’A , -C(O)-OR 10’A , -C(O)NR 10’A R 10’B , -C(O)NHNR 10’A R 10’B , -OR 10’A , -NR 10’A SO2R 10’B , -NR 10’A C(O)R 10’B , -NR 10’A C(O)OR 10’B , -NR 10’A OR 10’B , -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 8’A , R 8’B , R 9’A , R 9’B , R 10’A , and R 10’B are independently hydrogen, -F, -Cl, -Br, -I, -CF3, -CHF2, -CH2F, -CCl3, -CHCl2, -CH2Cl, -CBr3, -CHBr2, -CH2Br, -CI3, -CHI2, -CH2I, -OCF3, -OCCl3, -OCBr3, -OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -C(O)OH, -C(O)NH2, -OH, -NH2, -CO OH, -CONH2, -SH, -SO3H, -SO4H, -SON2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)OH, -NHOH, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and X is 6’ , X 7’ , X 8’ , X 9’ , X 10’ are independently halogen.

[0137] In some embodiments, L 3’ is O or NR 20’ In some embodiments, L 3’ is O. In some embodiments, L 3’ is NR 20’ In some embodiments, L 3’ is O or NR 21’ It is.

[0138] In some embodiments, L 4’ is O or NR 20’ In some embodiments, L 4’ is O. In some embodiments, L 4’ is NR 20’ In some embodiments, L 4’ is O or NR 21’ It is.

[0139] In some embodiments, R 20’ is hydrogen or R 21’ In some embodiments, R 20’ is hydrogen. In embodiments, R 20 is R 21’ It is.

[0140] In some embodiments, R 21’ is hydrogen, -CX 21’ 3. -CHX 21’ 2, -CH2X 21’ , 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.

[0141] In some embodiments, R 21’ -CX 21’ 3. -CHX 21’ 2, -CH2X 21’, substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, or 2-4 membered), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, or 5-6 membered), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted aryl (e.g., C6-C7, 10 , C, or phenyl), or substituted (e.g., substituted, size-limited, or lower substituted) or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered). 21’ If is replaced, R 21’ is substituted with a substituent. In some embodiments, R 21’ If is replaced, R 21’ is substituted with size-limited substituents. In some embodiments, R 21’ If is replaced, R 21’ is substituted with a lower substituent.

[0142] In some embodiments, R 21’ Hydrogen-CX 21’ 3. -CHX 21’ 2, -CH2X 21’ , unsubstituted alkyl (e.g., C 1 ~C8, C 1 -C6, or C1-C4), unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, or 2-4 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, or 5-6 membered), unsubstituted aryl (e.g., C6-C 10 , C6, or phenyl), or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered).

[0143] In some embodiments, R 6’ is hydrogen, -CX 6’ 3. -CHX 6’ 2, -CH2X 6’ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a bond attaching the 1,4-dihydropyridine to the polymeric support. X 6’ is independently -F, -Cl, -Br, or -I.

[0144] In some embodiments, R 6’ -CX 6’ 3. -CHX 6’ 2, -CH2X 6’ , substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, or 2-4 membered), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, or 5-6 membered), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted aryl (e.g., C6-C7, 10 , C6, or phenyl), or substituted (e.g., substituted, size-limited, or lower substituted) or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered), or a bond attaching the 1,4-dihydropyridine to the polymeric support. X 6’ is independently -F, -Cl, -Br, or -I.

[0145] In some embodiments, R 6’is hydrogen, -CF3, -CHF2, -CH2F, -CCl3, -CHCl2, -CH2Cl, -CBr3, -CHBr2, -CH2Br, -CI3, -CHI2, -CH2I, substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heterocycloalkyl (e.g., 3-8 members, 3-6 members, or 5-6 members), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted aryl (e.g., C6-C 10 , C, or phenyl), or substituted (e.g., substituted, size-limited, or lower substituted) or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered), or a bond that attaches the 1,4-dihydropyridine to the polymeric support. 6’ If is replaced, R 6’ is substituted with a substituent. In some embodiments, R 6’ If is replaced, R 6’ is substituted with size-limited substituents. In some embodiments, R 6’ If is replaced, R 6’ is substituted with a lower substituent.

[0146] In some embodiments, R 6’is hydrogen, -CF3, -CHF2, -CH2F, -CCl3, -CHCl2, -CH2Cl, -CBr3, -CHBr2, -CH2Br, -CI3, -CHI2, -CH2I, unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, or 2-4 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, or 5-6 membered), unsubstituted aryl (e.g., C6-C8, C6-C6, or C5-C6), 10 , C6, or phenyl), or unsubstituted heteroaryl (eg, 5-10 membered, 5-9 membered, or 5-6 membered), or 1,4-dihydropyridine, to the polymeric support.

[0147] In some embodiments, R 7’ is hydrogen, -CX 7’ 3. -CHX 7’ 2, -CH2X 7’ is a bond attaching a substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or 1,4-dihydropyridine to the polymeric support. X 7’ is independently -F, -Cl, -Br, or -I.

[0148] In some embodiments, R 7’ are independently hydrogen, -CX 7’ 3. -CHX 7’ 2, -CH2X 7’, substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, or 2-4 membered), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, or 5-6 membered), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted aryl (e.g., C6-C7, 10 , C6, or phenyl), or substituted (e.g., substituted, size-limited, or lower substituted) or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered), or a bond attaching the 1,4-dihydropyridine to the polymeric support. X 7’ is independently -F, -Cl, -Br, or -I.

[0149] In some embodiments, R 7’are independently hydrogen, -CF3, -CHF2, -CH2F, -CCl3, -CHCl2, -CH2Cl, -CBr3, -CHBr2, -CH2Br, -CI3, -CHI2, -CH2I, substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkyl (e.g., 2-8 membered, 2 cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heterocycloalkyl (e.g., 3-8, 3-6, or 5-6 members), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted aryl (e.g., C6-C 10 , C, or phenyl), or substituted (e.g., substituted, size-limited, or lower substituted) or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered), or a bond that attaches the 1,4-dihydropyridine to the polymeric support. 7’ If is replaced, R 7’ is substituted with a substituent. In some embodiments, R 7’ If is replaced, R 7’ is substituted with size-limited substituents. In some embodiments, R 7’ If is replaced, R 7’ is substituted with a lower substituent.

[0150] In some embodiments, R 7’are independently hydrogen, -CF3, -CHF2, -CH2F, -CCl3, -CHCl2, -CH2Cl, -CBr3, -CHBr2, -CH2Br, -CI3, -CHI2, -CH2I, unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, or 2-4 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, or 5-6 membered), unsubstituted aryl (e.g., C6-C8, C3-C6, or C5-C6), 10 , C6, or phenyl), or unsubstituted heteroaryl (eg, 5-10 membered, 5-9 membered, or 5-6 membered), or 1,4-dihydropyridine, to the polymeric support.

[0151] R 8’ are independently hydrogen, halogen, -CX 8’ 3. -CHX 8’ 2, -CH2X 8’ , -OCX 8’ 3. -OCHX 8’ 2, -OCH2X 8’ , -CN, -S(O)2R 8’A , -SR 8’A , -S(O)R 8’A , -SO2NR 8’A R 8’B , -NHC(O)NR 8’A R 8’B , -N(O)2, -NR 8’A R 8’B , -NHNR 8’A R 8’B , -C(O)R 8’A , -C(O)-OR 8’A , -C(O)NR 8’A R 8’B , -C(O)NHNR 8’A R 8’B , -OR 8’A , -NR 8’A SO2R 8’B , -NR 8’A C(O)R 8’B , -NR 8’A C(O)OR 8’B , -NR 8’A OR 8’B, -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. X 8’ is independently -F, -Cl, -Br, or -I.

[0152] In some embodiments, R 8’ are independently hydrogen, halogen (e.g., -F, -Cl, Br, -I), -CX 8’ 3. -CHX 8’ 2, -CH2X 8’ , -OCX 8’ 3. -OCHX 8’ 2, -OCH2X 8’ , -CN, -S(O)2R 8’A , -SR 8’A , -S(O)R 8’A , -SO2NR 8’A R 8’B , -NHC(O)NR 8’A R 8’B , -N(O) 2、 -NR 8’A R 8’B , -NHNR 8’A R 8’B , -C(O)R 8’A , -C(O)-OR 8’A , -C(O)NR 8’A R 8’B , -C(O)NHNR 8’A R 8’B , -OR 8’A , -NR 8’A SO2R 8’B , -NR 8’A C(O)R 8’B , -NR 8’A C(O)OR 8’B , -NR 8’A OR 8’B, -N3, (e.g. -CF3, -CHF2, -CH2F, -CCl3, -CHCl2, -CH2Cl, -CBr3, -CHBr2, -CH2Br, -CI3, -CHI2, -CH2I, -OCF3, -OCCl3, -OCBr3, -OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -SH, -SCH3, -SO2H, -SO2CH3, -SO2NH2, -SO2NHCH3, -NHC(O)NH 2、 -NHC(O)NHCH 3、 -NO 2、 -NH2, -NHCH 3、 -C(O)H, -C(O)CH3, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -OH, -OCH3, -NHSO2H, -NHSO2CH3, -NHC(O)H, -NCH3C(O)H, -NHC(O)OH, -NCH3C(O)OH, -NHOH, -NCH3OH, or -NCH3OCH3), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4 ... substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, or 2-4 membered), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, or 5-6 membered), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted aryl (e.g., C6-C8, C6-C8, C6-C8, or C5-C6), 10 , C6, or phenyl), or substituted (e.g., substituted, size-limited, or lower substituted) or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered). X 8’ is independently -F, -Cl, -Br, or -I.

[0153] In some embodiments, R 8’are independently hydrogen, -F, -Cl, Br, -I, CF3, -CHF2, -CH2F, -CCl3, -CHCl2, -CH2Cl, -CBr3, -CHBr2, -CH2Br, -CI3, -CHI2, -CH2I, -OCF3, -OCCl3, -OCBr3, -OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -SH, -SCH3, -SO2H, -SO2CH3, -SO2NH2, -SO2NHCH3, -NHC(O)NH 2、 -NHC(O)NHCH 3、 -NO 2、 -NH2, -NHCH 3、 -C(O)H, -C(O)CH3, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -OH, -OCH3, -NHSO2H, -NHSO2CH3, -NHC(O)H, -NCH3C(O)H, -NHC(O)OH, -NCH3C(O)OH, -NHOH, -NCH3OH, or -NCH3OCH3), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4 ... substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, or 2-4 membered), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, or 5-6 membered), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted aryl (e.g., C6-C8, C6-C8, C6-C8, or C5-C6), 10 , C, or phenyl), or substituted (e.g., substituted, size-limited, or lower substituted) or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered). 8’ If is replaced, R 8’ is substituted with a substituent. In some embodiments, R 8’ If is replaced, R8’ is substituted with size-limited substituents. In some embodiments, R 8’ If is replaced, R 8’ is substituted with a lower substituent.

[0154] In some embodiments, R 8’ are independently hydrogen, -F, -Cl, Br, -I, -CF3, -CHF2, -CH2F, -CCl3, -CHCl2, -CH2Cl, -CBr3, -CHBr2, -CH2Br, -CI3, -CHI2, -CH2I, -OCF3, -OCCl3, -OCBr3, -OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -SH, -SCH3, -SO2H, -SO2CH3, -SO2NH2, -SO2NHCH3, -NHC(O)NH 2、 -NHC(O)NHCH 3、 -NO 2、 -NH2, -NHCH 3、 -C(O)H, -C(O)CH3, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -OH, -OCH3, -NHSO2H, -NHSO2CH3, -NHC(O)H, -NCH3C(O)H, -NHC(O)OH, -NCH3C(O)OH, -NHOH, -NCH3OH, or -NCH3OCH3), unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1C4), unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, or 2-4 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, or 5-6 membered), unsubstituted aryl (e.g., C6-C8, C3-C6, or C5-C6), 10 , C6, or phenyl), or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered).

[0155] R 9’ are independently hydrogen, halogen, -CX 9’ 3. -CHX 9’ 2, -CH2X 9’ , -OCX 9’ 3. -OCHX 9’ 2, -OCH2X9’ , -CN, -S(O)2R 9’A , -SR 9’A , -S(O)R 9’A , -SO2NR 9’A R 9’B , -NHC(O)NR 9’A R 9’B , -N(O)2, -NR 9’A R 9’B , -NHNR 9’A R 9’B , -C(O)R 9’A , -C(O)-OR 9’A , -C(O)NR 9’A R 9’B , -C(O)NHNR 9’A R 9’B , -OR 9’A , -NR 9’A SO2R 9’B , -NR 9’A C(O)R 9’B , -NR 9’A C(O)OR 9’B , -NR 9’A OR 9’B , -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. X 9’ is independently -F, -Cl, -Br, or -I.

[0156] In some embodiments, R 9’ are independently hydrogen, halogen (e.g., -F, -Cl, Br, -I), -CX 9’ 3. -CHX 9’ 2, -CH2X 9’ , -OCX 9’ 3. -OCHX 9’ 2, -OCH2X 9’ , -CN, -S(O)2R 9’A , -SR 9’A , -S(O)R 9’A , -SO2NR 9’A R 9’B , -NHC(O)NR 9’A R 9’B , -N(O) 2、 -NR9’A R 9’B 、-NHNR 9’A R 9’B 、-C(O)R 9’A 、-C(O)-OR 9’A 、-C(O)NR 9’A R 9’B 、-C(O)NHNR 9’A R 9’B 、-OR 9’A 、-NR 9’A SO2R 9’B 、-NR 9’A C(O)R 9’B 、-NR 9’A C(O)OR 9’B 、-NR 9’A OR 9’B 、-N3、(eg、-CF3、-CHF2、-CH2F、-CCl3、-CHCl2、-CH2Cl、-CBr3、-CHBr2、-CH2Br、-CI3、-CHI2、-CH2I、-OCF3、-OCCl3、-OCBr3、-OCI3、 -OCHF2、-OCHCl2、-OCHBr2、-OCHI2、-OCH2F、-OCH2Cl、-OCH2Br、-OCH2I、-SH、-SCH3、-SO2H、-SO2CH3、-SO2NH2、-SO2NHCH3、-NHC(O)NH 2、 -NHC(O)NHCH 3、-NO2, -NH2, -NHCH3, -C(O)H, -C(O)CH3, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -OH, -OCH3, -NHSO2H, -NHSO2CH3, -NHC(O)H, -NCH3C(O)H, -NHC(O)OH, -NCH3C(O)OH, -NHOH, -NCH3OH, or -NCH3OCH3), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent), substituted (e.g., substituted with a substituent, size-limited substituent, or lower substituent) or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, or 2-4 membered), substituted (e.g., substituted with a substituent, size-limited substituent, or lower substituent) or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), substituted (e.g., substituted with a substituent, size-limited substituent, or lower substituent) or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, or 5-6 membered), substituted (e.g., substituted with a substituent, size-limited substituent, or lower substituent) or unsubstituted aryl (e.g., C6-C8, C6-C8, C6-C8, or C5-C8), 10 , C6, or phenyl), or substituted (e.g., substituted, size-limited, or lower substituted) or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered). X 9’ is independently -F, -Cl, -Br, or -I.

[0157] In some embodiments, R 9’ are independently hydrogen, -F, -Cl, Br, -I, CF3, -CHF2, -CH2F, -CCl3, -CHCl2, -CH2Cl, -CBr3, -CHBr2, -CH2Br, -CI3, -CHI2, -CH2I, -OCF3, -OCCl3, -OCBr3, -OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -SH, -SCH3, -SO2H, -SO2CH3, -SO2NH2, -SO2NHCH3, -NHC(O)NH 2、 -NHC(O)NHCH 3、 -NO 2、-NH2, -NHCH 3、 -C(O)H, -C(O)CH3, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -OH, -OCH3, -NHSO2H, -NHSO2CH3, -NHC(O)H, -NCH3C(O)H, -NHC(O)OH, -NCH3C(O)OH, -NHOH, -NCH3OH, or -NCH3OCH3), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4 ... substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, or 2-4 membered), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, or 5-6 membered), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted aryl (e.g., C6-C8, C6-C8, C6-C8, or C5-C6), 10 , C, or phenyl), or substituted (e.g., substituted, size-limited, or lower substituted) or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered). 9’ If is replaced, R 9’ is substituted with a substituent. In some embodiments, R 9’ If is replaced, R 9’ is substituted with size-limited substituents. In some embodiments, R 9’ If is replaced, R 9’ is substituted with a lower substituent.

[0158] In some embodiments, R 9’are independently hydrogen, -F, -Cl, Br, -I, -CF3, -CHF2, -CH2F, -CCl3, -CHCl2, -CH2Cl, -CBr3, -CHBr2, -CH2Br, -CI3, -CHI2, -CH2I, -OCF3, -OCCl3, -OCBr3, -OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -SH, -SCH3, -SO2H, -SO2CH3, -SO2NH2, -SO2NHCH3, -NHC(O)NH 2、 -NHC(O)NHCH 3、 -NO 2、 -NH2, -NHCH 3、 -C(O)H, -C(O)CH3, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -OH, -OCH3, -NHSO2H, -NHSO2CH3, -NHC(O)H, -NCH3C(O)H, -NHC(O)OH, -NCH3C(O)OH, -NHOH, -NCH3OH, or -NCH3OCH3), unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, or 2-4 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, or 5-6 membered), unsubstituted aryl (e.g., C6-C8, C3-C6, or C5-C6), 10 , C6, or phenyl), or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered).

[0159] R 10’ are independently hydrogen, halogen, -CX 10’ 3. -CHX 10’ 2, -CH2X 10’ , -OCX 10’ 3. -OCHX 10’ 2, -OCH2X 10’ , -CN, -S(O)2R 10’A , -SR 10’A , -S(O)R 10’A , -SO2NR 10’A R 10’B , -NHC(O)NR 10’A R 10’B, -N(O)2, -NR 10’A R 10’B , -NHNR 10’A R 10’B , -C(O)R 10’A , -C(O)-OR 10’A , -C(O)NR 10’A R 10’B , -C(O)NHNR 10’A R 10’B , -OR 10’A , -NR 10’A SO2R 10’B , -NR 10’A C(O)R 10’B , -NR 10’A C(O)OR 10’B , -NR 10’A OR 10’B , -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. X 10’ is independently -F, -Cl, -Br, or -I.

[0160] In some embodiments, R 10’ are independently hydrogen, halogen (e.g., -F, -Cl, Br, -I), -CX 10’ 3. -CHX 10’ 2, -CH2X 10’ , -OCX 10’ 3. -OCHX 10’ 2, -OCH2X 10’ , -CN, -S(O)2R 10’A , -SR 10’A , -S(O)R 10’A , -SO2NR 10’A R 10’B , -NHC(O)NR 10’A R 10’B , -N(O) 2、 -N 10’A R 10’B , -NHNR 10’A R 10’B , -C(O)R 10’A , -C(O)-OR 10’A , -C(O)NR 10’A R 10’B , -C(O)NHNR10’A R 10’B , -OR 10’A , -NR 10’A SO2R 10’B , -NR 10’A C(O)R 10’B , -NR 10’A C(O)OR 10’B , -NR 10’A OR 10’B , -N3, (e.g. -CF3, -CHF2, -CH2F, -CCl3, -CHCl2, -CH2Cl, -CBr3, -CHBr2, -CH2Br, -CI3, -CHI2, -CH2I, -OCF3, -OCCl3, -OCBr3, -OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -SH, -SCH3, -SO2H, -SO2CH3, -SO2NH2, -SO2NHCH3, -NHC(O)NH 2、 -NHC(O)NHCH 3、 -NO 2、 -NH2, -NHCH 3、 -C(O)H, -C(O)CH3, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -OH, -OCH3, -NHSO2H, -NHSO2CH3, -NHC(O)H, -NCH3C(O)H, -NHC(O)OH, -NCH3C(O)OH, -NHOH, -NCH3OH, or -NCH3OCH3), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4 ... substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, or 2-4 membered), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, or 5-6 membered), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted aryl (e.g., C6-C8, C6-C8, C6-C8, or C5-C6), 10, C6, or phenyl), or substituted (e.g., substituted, size-limited, or lower substituted) or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered). X 10’ is independently -F, -Cl, -Br, or -I.

[0161] In some embodiments, R 10’ are independently hydrogen, -F, -Cl, Br, -I, CF3, -CHF2, -CH2F, -CCl3, -CHCl2, -CH2Cl, -CBr3, -CHBr2, -CH2Br, -CI3, -CHI2, -CH2I, -OCF3, -OCCl3, -OCBr3, -OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -SH, -SCH3, -SO2H, -SO2CH3, -SO2NH2, -SO2NHCH3, -NHC(O)NH 2、 -NHC(O)NHCH 3、 -NO 2、 -NH2, -NHCH 3、 -C(O)H, -C(O)CH3, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -OH, -OCH3, -NHSO2H, -NHSO2CH3, -NHC(O)H, -NCH3C(O)H, -NHC(O)OH, -NCH3C(O)OH, -NHOH, -NCH3OH, or -NCH3OCH3), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4 ... substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, or 2-4 membered), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, or 5-6 membered), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted aryl (e.g., C6-C8, C6-C8, C6-C8, or C5-C6),10 , C, or phenyl), or substituted (e.g., substituted, size-limited, or lower substituted) or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered). 10’ If is replaced, R 10’ is substituted with a substituent. In some embodiments, R 10’ If is replaced, R 10’ is substituted with size-limited substituents. In some embodiments, R 10’ If is replaced, R 10’ is substituted with a lower substituent.

[0162] In some embodiments, R 10’ are independently hydrogen, -F, -Cl, Br, -I, -CF3, -CHF2, -CH2F, -CCl3, -CHCl2, -CH2Cl, -CBr3, -CHBr2, -CH2Br, -CI3, -CHI2, -CH2I, -OCF3, -OCCl3, -OCBr3, -OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -SH, -SCH3, -SO2H, -SO2CH3, -SO2NH2, -SO2NHCH3, -NHC(O)NH 2、 -NHC(O)NHCH 3、 -NO 2、 -NH2, -NHCH 3、 -C(O)H, -C(O)CH3, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, -OH, -OCH3, -NHSO2H, -NHSO2CH3, -NHC(O)H, -NCH3C(O)H, -NHC(O)OH, -NCH3C(O)OH, -NHOH, -NCH3OH, or -NCH3OCH3), unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1C4), unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, or 2-4 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, or 5-6 membered), unsubstituted aryl (e.g., C6-C8, C3-C6, or C5-C6), 10, C6, or phenyl), or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered).

[0163] R 8’A , R 8’B , R 9’A , R 9’B , R 10’A , and R 10’B are independently hydrogen, -F, -Cl, -Br, -I, -CF3, -CHF2, -CH2F, -CCl3, -CHCl2, -CH2Cl, -CBr3, -CHBr2, -CH2Br, -CI3, -CHI2, -CH2I, -OCF3, -OCCl3, -OCBr3, -OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -C(O)OH, -C(O)NH2, -OH, -NH2, -C OOH, -CONH2, -SH, -SO3H, -SO4H, -SON2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)OH, -NHOH, 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.

[0164] In some embodiments, R 8’A , R 8’B , R 9’A , R 9’B , R 10’A , and R 10’Bare independently hydrogen, -F, -Cl, -Br, -I, -CF3, -CHF2, -CH2F, -CCl3, -CHCl2, -CH2Cl, -CBr3, -CHBr2, -CH2Br, -CI3, -CHI2, -CH2I, -OCF3, -OCCl3, -OCBr3, -OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -C (O)OH, -C(O)NH2, -OH, -NH2, -COOH, -CONH2, -SH, -SO3H, -SO4H, -SON2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)OH, -NHOH, substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl (e.g., C 1 ~C 8 , C 1 ~C 6 , or C 1 ~C 4 ), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, or 2-4 membered), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, or 5-6 membered), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted aryl (e.g., C6-C 10 , C, or phenyl), or substituted (e.g., substituted, size-limited, or lower substituted) or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered). 6’A , R 6’B , R 7’A , R 7’B , R 8’A , R 8’B , R 9’A , R 9’B , R 10’A , and R 10’Bis substituted, and RR 6’A , R 6’B , R 7’A , R 7’B , R 8’A , R 8’B , R 9’A , R 9’B , R 10’A and R 10’B is substituted with a substituent. In some embodiments, R 6’A , R 6’B , R 7’A , R 7’B , R 8’A , R 8’B , R 9’A , R 9’B , R 10’A , and R 10’B is substituted and R 6’A , R 6’B , R 7’A , R 7’B , R 8’A , R 8’B , R 9’A , R 9’B , R 10’A and R 10’B is substituted with a size-limited substituent. In some embodiments, R 6’A , R 6’B , R 7’A , R 7’B , R 8’A , R 8’B , R 9’A , R 9’B , R 10’A , and R 10’B is substituted and R 6’A , R 6’B , R 7’A , R 7’B , R 8’A , R 8’B , R 9’A , R 9’B , R 10’A and R 10’B is substituted with a lower substituent. In some embodiments, R 6’A is substituted with a substituent. In some embodiments, R 6’A is substituted with a size-limited substituent. In some embodiments, R 6’A is substituted with a lower substituent. In some embodiments, R6’B is substituted with a substituent. In some embodiments, R 6’B is substituted with a size-limited substituent. In some embodiments, R 6’B is substituted with a lower substituent. In some embodiments, R 7’A is substituted with a substituent. In some embodiments, R 7’A is substituted with a size-limited substituent. In some embodiments, R 7’A is substituted with a lower substituent. In some embodiments, R 7’B is substituted with a substituent. In some embodiments, R 7’B is substituted with a size-limited substituent. In some embodiments, R 7’B is substituted with a lower substituent. In some embodiments, R 8’A is substituted with a substituent. In some embodiments, R 8’A is substituted with a size-limited substituent. In some embodiments, R 8’A is substituted with a lower substituent. In some embodiments, R 8’B is substituted with a substituent. In some embodiments, R 8’B is substituted with a size-limited substituent. In some embodiments, R 8’B is substituted with a lower substituent. In some embodiments, R 9’A is substituted with a substituent. In some embodiments, R 9’A is substituted with a size-limited substituent. In some embodiments, R 9’A is substituted with a lower substituent. In some embodiments, R 9’B is substituted with a substituent. In some embodiments, R 9’B is substituted with a size-limited substituent. In some embodiments, R 9’B is substituted with a lower substituent. In some embodiments, R 10’A is substituted with a substituent. In some embodiments, R 10’A is substituted with a size-limited substituent. In some embodiments, R 10’Ais substituted with a lower substituent. In some embodiments, R 10’B is substituted with a substituent. In some embodiments, R 10’B is substituted with a size-limited substituent. In some embodiments, R 10’B is substituted with a lower substituent.

[0165] In some embodiments, R 8’A , R 8’B , R 9’A , R 9’B , R 10’A , and R 10’B are independently hydrogen, -F, -Cl, -Br, -I, -CF3, -CHF2, -CH2F, -CCl3, -CHCl2, -CH2Cl, -CBr3, -CHBr2, -CH2Br, -CI3, -CHI2, -CH2I, -OCF3, -OCCl3, -OCBr3, -OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2C l, -OCH2Br, -OCH2I, -C(O)OH, -C(O)NH2, -OH, -NH2, -COOH, -CONH2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)OH, -NHOH, unsubstituted alkyl (e.g., C 1 ~C 8 , C 1 ~C 6 , or C 1 ~C 4 ), unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, or 2-4 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 5-6 membered), unsubstituted aryl (e.g., C6-C 10 , C6, or phenyl), or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered).

[0166] X is -Cl, -Br, -I, -OSOR 15 , or -OCOR 15In some embodiments, X is -Cl. In some embodiments, X is -Br. In some embodiments, X is -I. In some embodiments, X is -OSO2R 15 In some embodiments, X is -OCOR 15 It is.

[0167] R 15 is substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0168] In some embodiments, R 15 is substituted or unsubstituted alkyl. In some embodiments, R 15 is substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4). In some embodiments, R 15 is unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4). In some embodiments, R 15 If is replaced, R 15 is substituted with a substituent. In some embodiments, R 15 If is replaced, R 15 is substituted with size-limited substituents. In some embodiments, R 15 If is replaced, R 15 is substituted with a lower substituent.

[0169] In some embodiments, R 15 is substituted or unsubstituted aryl. In some embodiments, R 15 is a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl (e.g., C6-C 10 , C, or phenyl). In some embodiments, R 15 is an unsubstituted aryl (e.g., C6-C 10 , C, or phenyl). In some embodiments, R 15 If is replaced, R 15is substituted with a substituent. In some embodiments, R 15 If is replaced, R 15 is substituted with size-limited substituents. In some embodiments, R 15 If is replaced, R 15 is substituted with a lower substituent.

[0170] In some embodiments, R 15 is substituted or unsubstituted heteroaryl. In some embodiments, R 15 is substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered). 15 is unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered). In some embodiments, R 15 If is replaced, R 15 is substituted with a substituent. In some embodiments, R 15 If is replaced, R 15 is substituted with size-limited substituents. In some embodiments, R 15 If is replaced, R 15 is substituted with a lower substituent.

[0171] R 16 is hydrogen, -OH, -C(O)R 16A , substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0172] In some embodiments, R 16 is hydrogen. In some embodiments, R 16 is -OH. In some embodiments, R 16 is -C(O)R 16A In some embodiments, R 16A is hydrogen, or substituted or unsubstituted alkyl. In some embodiments, R 16A is hydrogen. In some embodiments, 16Ais substituted or unsubstituted alkyl. In some embodiments, R 16A is substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4). In some embodiments, R 16A is unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4).

[0173] In some embodiments, R 16 is substituted or unsubstituted alkyl. In some embodiments, R 16 is substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4). In some embodiments, R 16 is unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4). In some embodiments, R 16 If is replaced, R 16 is substituted with a substituent. In some embodiments, R 16 If is replaced, R 16 is substituted with size-limited substituents. In some embodiments, R 16 If is replaced, R 16 is substituted with a lower substituent.

[0174] In some embodiments, R 16 is substituted or unsubstituted aryl. In some embodiments, R 16 is a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl (e.g., C6-C 10 , C, or phenyl). In some embodiments, R 16 is an unsubstituted aryl (e.g., C6-C 10 , C, or phenyl). In some embodiments, R 16 If is replaced, R 16 is substituted with a substituent. In some embodiments, R 16 If is replaced, R 16is substituted with size-limited substituents. In some embodiments, R 16 If is replaced, R 16 is substituted with a lower substituent.

[0175] In some embodiments, R 16 is substituted or unsubstituted heteroaryl. In some embodiments, R 16 is substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered). 16 is unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered). In some embodiments, R 16 If is replaced, R 16 is substituted with a substituent. In some embodiments, R 16 If is replaced, R 16 is substituted with size-limited substituents. In some embodiments, R 16 If is replaced, R 16 is substituted with a lower substituent.

[0176] R 17 is hydrogen, -OH, -C(O)R 17A , substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 17A is hydrogen, or substituted or unsubstituted alkyl.

[0177] In some embodiments, R 17 is hydrogen. In some embodiments, R 17 is -OH. In some embodiments, R 17 is -C(O)R 17A In some embodiments, R 17A is hydrogen, or substituted or unsubstituted alkyl. In some embodiments, R 17A is hydrogen. In some embodiments, 17A is substituted or unsubstituted alkyl. In some embodiments, R 17Ais substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4). In some embodiments, R 17A is unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4).

[0178] In some embodiments, R 17 is substituted or unsubstituted alkyl. In some embodiments, R 17 is substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4). In some embodiments, R 17 is unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4). In some embodiments, R 17 If is replaced, R 17 is substituted with a substituent. In some embodiments, R 17 If is replaced, R 17 is substituted with size-limited substituents. In some embodiments, R 17 If is replaced, R 17 is substituted with a lower substituent.

[0179] In some embodiments, R 17 is substituted or unsubstituted aryl. In some embodiments, R 17 is a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl (e.g., C6-C 10 , C, or phenyl). In some embodiments, R 17 is an unsubstituted aryl (e.g., C6-C 10 , C, or phenyl). In some embodiments, R 17 If is replaced, R 17 is substituted with a substituent. In some embodiments, R 17 If is replaced, R 17 is substituted with size-limited substituents. In some embodiments, R 17 If is replaced, R17 is substituted with a lower substituent.

[0180] In some embodiments, R 17 is substituted or unsubstituted heteroaryl. In some embodiments, R 17 is substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered). 17 is unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered). In some embodiments, R 17 If is replaced, R 17 is substituted with a substituent. In some embodiments, R 17 If is replaced, R 17 is substituted with size-limited substituents. In some embodiments, R 17 If is replaced, R 17 is substituted with a lower substituent.

[0181] In some embodiments, n1' and n2' are each an integer between 0 and 5, and the sum of n1' and n2' is at least 1 and not more than 6. In some embodiments, n1' is 0 and n2' is 1. In some embodiments, n1' is 0 and n2' is 2. In some embodiments, n1' is 0 and n2' is 3. In some embodiments, n1' is 0 and n2' is 4. In some embodiments, n1' is 0 and n2' is 5. In some embodiments, n1' is 0 and n2' is 6. In some embodiments, n1' is 1 and n2' is 0. In some embodiments, n1' is 1 and n2' is 1. In some embodiments, n1' is 1 and n2' is 2. In some embodiments, n1' is 1 and n2' is 3. In some embodiments, n1' is 1 and n2' is 4. In some embodiments, n1' is 1 and n2' is 5. In some embodiments, n1' is 2 and n2' is 0. In some embodiments, n1' is 2 and n2' is 1. In some embodiments, n1' is 2 and n2' is 2. In some embodiments, n1' is 2 and n2' is 3. In some embodiments, n1' is 2 and n2' is 4. In some embodiments, n3' is 1 and n2' is 0. In some embodiments, n1' is 3 and n2' is 1. In some embodiments, n1' is 3 and n2' is 2. In some embodiments, n1' is 3 and n2' is 3. In some embodiments, n1' is 4 and n2' is 0. In some embodiments, n1' is 4 and n2' is 1. In some embodiments, n1' is 4 and n2' is 2. In some embodiments, n1' is 5 and n2' is 0. In some embodiments, n1' is 5 and n2' is 1. In some embodiments, n1' is 6 and n2' is 0.

[0182] In some embodiments, n3' is an integer from 0 to 5. In some embodiments, n3' is 0. In some embodiments, n3' is 1. In some embodiments, n3' is 2. In some embodiments, n3' is 3. In some embodiments, n3' is 4. In some embodiments, n3' is 5.

[0183] In some embodiments, L 1 ' is C(R 4’ )2, and R 4’ As described herein, including in some embodiments.

[0184] In some embodiments, L 2 ' is C(R 5’ )2, and R 5’ As described herein, including in some embodiments.

[0185] In some embodiments, L 3’ is O or NR 20’ In some embodiments, L 3 In some embodiments, L′ is O. 3 'NR 20’ and R 20’ As described herein, including in some embodiments.

[0186] In an embodiment, L 4 ' is O or NR 20’ In some embodiments, L 4 In some embodiments, L′ is O. 4 'NR 20’ and R 20’ As described herein, including in some embodiments.

[0187] In some embodiments, X 1 In some embodiments, X′ is —F, —Cl, —Br, or —I. 1 In some embodiments, X′ is —F. 1In some embodiments, X′ is —Cl. 1 In some embodiments, X′ is —Br. 1 ' is -I.

[0188] In some embodiments, X 2 In some embodiments, X′ is —F, —Cl, —Br, or —I. 2 In some embodiments, X′ is —F. 2 In some embodiments, X′ is —Cl. 2 In some embodiments, X′ is —Br. 2 ' is -I.

[0189] In some embodiments, X 3 In some embodiments, X′ is —F, —Cl, —Br, or —I. 3 In some embodiments, X′ is —F. 3 In some embodiments, X′ is —Cl. 3 In some embodiments, X′ is —Br. 3 ' is -I.

[0190] In some embodiments, X 4 In some embodiments, X′ is —F, —Cl, —Br, or —I. 4 In some embodiments, X′ is —F. 4 In some embodiments, X′ is —Cl. 4 In some embodiments, X′ is —Br. 4 ' is -I.

[0191] In some embodiments, X 5 In some embodiments, X′ is —F, —Cl, —Br, or —I. 5 In some embodiments, X′ is —F. 5 In some embodiments, X′ is —Cl. 5 In some embodiments, X′ is —Br. 5 ' is -I.

[0192] In some embodiments, X 6 In some embodiments, X′ is —F, —Cl, —Br, or —I. 6 In some embodiments, X′ is —F. 6 In some embodiments, X′ is —Cl. 6 In some embodiments, X′ is —Br. 6 ' is -I.

[0193] In some embodiments, X 7 In some embodiments, X′ is —F, —Cl, —Br, or —I. 7 In some embodiments, X′ is —F. 7 In some embodiments, X′ is —Cl. 7 In some embodiments, X′ is —Br. 7 ' is -I.

[0194] In some embodiments, X 8 In some embodiments, X′ is —F, —Cl, —Br, or —I. 8 In some embodiments, X′ is —F. 8 In some embodiments, X′ is —Cl. 8 In some embodiments, X′ is —Br. 8 ' is -I.

[0195] In some embodiments, X 9 In some embodiments, X′ is —F, —Cl, —Br, or —I. 9 In some embodiments, X′ is —F. 9 In some embodiments, X′ is —Cl. 9 In some embodiments, X′ is —Br. 9 ' is -I.

[0196] In some embodiments, X 10In some embodiments, X′ is —F, —Cl, —Br, or —I. 10 In some embodiments, X′ is —F. 10 In some embodiments, X′ is —Cl. 10 In some embodiments, X′ is —Br. 10 ' is -I.

[0197] compound The synthetic methods provided herein include those comprising compounds of structural formula (V):

[0198] [ka] or a pharma- ceutically acceptable salt thereof. 1 CR 8 Or N. X 2 CR 9 Or N. X 3 is CR 10 or N. Symbols n1, n2, n3, n4, n5, n6, n7, n8, n9, n10, and n44 are independently an integer of 0 to 4. Symbols m1, m2, m3, m4, m5, m6, m7, m8, m9, m10, v1, v2, v3, v4, v5, v6, v7, v8, v9, v10, and v44 are independently 1 or 2. Symbol z1 is an integer of 0 to 5. Symbol z2 is an integer of 0 to 5. Symbol z3 is an integer of 0 to 11. Symbol z4 is an integer of 0 to 2. L 7 R is a substituted or unsubstituted cycloalkylene. 1 is hydrogen, halogen, -CX 1.1 3. -CHX 1.1 2. -CH2X 1.1 , -CN, -N3, -SO n1 R 1A , -SO v1 NR 1B R 1C , -NHNR 1B R 1C , -ONR 1B R 1C , -NHC(O)NHNR 1B R1C , -NHC(O)NR 1B R 1C , -N(O) m1 , -NR 1B R 1C , -C(O)R 1D , -C(O)OR 1D , -C(O)NR 1B R 1C , -OR 1A , -NR 1B SO2R 1A , -NR 1B C(O)R 1D , -NR 1B C(O)OR 1D , -NR 1B OR 1D , -OCX 1.1 3. -OCHX 1.1 2, -OCH2X 1.1 , 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 2 is hydrogen, halogen, -CX 2.1 3. -CHX 2.1 2, -CH2X 2.1 , -CN, -N3, -SO n2 R 2A , -SO v2 NR 2B R 2C , -NHNR 2B R 2C , -ONR 2B R 2C , -NHC(O)NHNR 2B R 2C , -NHC(O)NR 2B R 2C , -N(O) m2 , -NR 2B R 2C , -C(O)R 2D , -C(O)OR 2D , -C(O)NR 2B R 2C , -OR 2A , -NR 2B SO2R 2A, -NR 2B C(O)R 2D , -NR 2B C(O)OR 2D , -NR 2B OR 2D , -OCX 2.1 3. -OCHX 2.1 2, -OCH2X 2.1 , 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 3 are independently halogen, -CX 3.1 3. -CHX 3.1 2, -CH2X 3.1 , -CN, -N3, -SO n3 R 3A , -SO v3 NR 3B R 3C , -NHNR 3B R 3C , -ONR 3B R 3C , -NHC(O)NHNR 3B R 3C , -NHC(O)NR 3B R 3C , -N(O) m3 , -NR 3B R 3C , -C(O)R 3D , -C(O)OR 3D , -C(O)NR 3B R 3C , -OR 3A , -NR 3B SO2R 3A , -NR 3B C(O)R 3D , -NR 3B C(O)OR 3D , -NR 3B OR 3D , -OCX 3.1 3. -OCHX 3.1 2, -OCH2X 3.1, 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 4 is hydrogen, halogen, -CX 4.1 3. -CHX 4.1 2, -CH2X 4.1 , -CN, -N3, -SO n4 R 4A , -SO v4 NR 4B R 4C , -NHNR 4B R 4C , -ONR 4B R 4C , -NHC(O)NHNR 4B R 4C , -NHC(O)NR 4B R 4C , -N(O) m4 , -NR 4B R 4C , -C(O)R 4D , -C(O)OR 4D , -C(O)NR 4B R 4C , -OR 4A , -NR 4B SO2R 4A , -NR 4B C(O)R 4D , -NR 4B C(O)OR 4D , -NR 4B OR 4D , -OCX 4.1 3. -OCHX 4.1 2, -OCH2X 4.1 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; 2 CR 9 If R 4 and R 9R may be optionally linked to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. 5 are independently halogen, oxo, -CX 5.1 3. -CHX 5.1 2, -CH2X 5.1 , -CN, -N3, -SO n5 R 5A , -SO v5 NR 5B R 5C , -NHNR 5B R 5C , -ONR 5B R 5C , -NHC(O)NHNR 5B R 5C , -NHC(O)NR 5B R 5C , -N(O) m5 , -NR 5B R 5C , -C(O)R 5D , -C(O)OR 5D , -C(O)NR 5B R 5C , -OR 5A , -NR 5B SO2R 5A , -NR 5B C(O)R 5D , -NR 5B C(O)OR 5D , -NR 5B OR 5D , -OCX 5.1 3. -OCHX 5.1 2, -OCH2X 5.1 , 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 6 are independently halogen, oxo, -CX 6.1 3. -CHX 6.1 2, -CH2X 6.1 , -CN, -N3, -SO n6 R 6A , -SO v6 NR 6B R6C , -NHNR 6B R 6C , -ONR 6B R 6C , -NHC(O)NHNR 6B R 6C , -NHC(O)NR 6B R 6C , -N(O) m6 , -NR 6B R 6C , -C(O)R 6D , -C(O)OR 6D , -C(O)NR 6B R 6C , -OR 6A , -NR 6B SO2R 6A , -NR 6B C(O)R 6D , -NR 6B C(O)OR 6D , -NR 6B OR 6D , -OCX 6.1 3. -OCHX 6.1 2, -OCH2X 6.1 , 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 7 is hydrogen, halogen, -CX 7.1 3. -CHX 7.1 2, -CH2X 7.1 , -CN, -N3, -SO n7 R 7A , -SO v7 NR 7B R 7C , -NHNR 7B R 7C , -ONR 7B R 7C , -NHC(O)NHNR 7B R 7C , -NHC(O)NR 7B R 7C , -N(O) m7 , -NR 7B R 7C , -C(O)R 7D , -C(O)OR 7D , -C(O)NR7B R 7C , -OR 7A , -NR 7B SO2R 7A , -NR 7B C(O)R 7D , -NR 7B C(O)OR 7D , -NR 7B OR 7D , -OCX 7.1 3. -OCHX 7.1 2, -OCH2X 7.1 , 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 8 is hydrogen, halogen, -CX 8.1 3. -CHX 8.1 2, -CH2X 8.1 , -CN, -N3, -SO n8 R 8A , -SO v8 NR 8B R 8C , -NHNR 8B R 8C , -ONR 8B R 8C , -NHC(O)NHNR 8B R 8C , -NHC(O)NR 8B R 8C , -N(O) m8 , -NR 8B R 8C , -C(O)R 8D , -C(O)OR 8D , -C(O)NR 8B R 8C , -OR 8A , -NR 8B SO2R 8A , -NR 8B C(O)R 8D , -NR 8B C(O)OR 8D , -NR 8B OR 8D , -OCX 8.1 3. -OCHX 8.1 2, -OCH2X 8.1, 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 9 is hydrogen, halogen, -CX 9.1 3. -CHX 9.1 2, -CH2X 9.1 , -CN, -N3, -SO n9 R 9A , -SO v9 NR 9B R 9C , -NHNR 9B R 9C , -ONR 9B R 9C , -NHC(O)NHNR 9B R 9C , -NHC(O)NR 9B R 9C , -N(O) m9 , -NR 9B R 9C , -C(O)R 9D , -C(O)OR 9D , -C(O)NR 9B R 9C , -OR 9A , -NR 9B SO2R 9A , -NR 9B C(O)R 9D , -NR 9B C(O)OR 9D , -NR 9B OR 9D , -OCX 9.1 3. -OCHX 9.1 2, -OCH2X 9.1 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and X 2 CR 9 Yes If so, R 4 and R 9may be optionally linked to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or X 2 CR 9 and X 3 CR 10 If R 9 and R 10 R may be optionally linked to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. 10 is hydrogen, halogen, -CX 10.1 3. -CHX 10.1 2, -CH2X 10.1 , -CN, -SO n10 R 10A , -SO v10 NR 10B R 10C , -NHNR 10B R 10C , -ONR 10B R 10C , -NHC(O)NHNR 10B R 10C , -NHC(O)NR 10B R 10C , -N(O) m10 , -NR 10B R 10C , -C(O)R 10D , -C(O)OR 10D , -C(O)NR 10B R 10C , -OR 10A , -NR 10B SO2R 10A , -NR 10B C(O)R 10D , -NR 10B C(O)OR 10D , -NR 10B OR 10D , -OCX 10.1 3. -OCHX 10.1 2, -OCH2X 10.1, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or X 2 CR 9 and X 3 CR 10 If R 9 and R 10 R may be optionally linked to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. 44 is hydrogen, -CX 44.1 3. -CHX 44.1 2, -CH2X 44.1 , -SO n44 R 44A , -SO v44 NR 44B R 44C , -C(O)R 44D , -C(O)OR 44D , -C(O)NR 44B R 44C , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. R 1A , R 1B , R 1C , R 1D , R 2A , R 2B , R 2C , R 2D , R 3A , R 3B , R 3C , R 3D , R 4A , R 4B , R 4C , R 4D , R 5A , R 5B , R 5C , R 5D , R 6A , R 6B , R 6C , R 6D , R 7A , R7B , R 7C , R 7D , R 7.2B , R 8A , R 8B , R 8C , R 8D , R 9A、 R 9B , R 9C , R 9D , R 10A , R 10B , R 10C , R 10D , R 44A , R 44B , R 44C and R 44D are independently hydrogen, halogen, -CF3, -CCl3, -CBr3, -CI3, -COOH, -CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and R 1B , R 1C , R 2B , R 2C , R 3B , R 3C , R 4B , R 4C , R 5B , R 5C , R 6B , R 6C , R 7B , R 7C , R 8B , R 8C , R 9B , R 9C , R 10B , R 10C , R 44B , and R 44C The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl. X 1.1 , X 2.1 , X 3.1 , X 4.1 , X 5.1 , X 6.1 , X 7.1 , X 8.1 , X 9.1 , X 10.1, and X 44.1 are independently -Cl, -Br, -I, or -F and X 1 , X 2 and X 3 At least one of is N.

[0199] The methods described herein can be used to synthesize a class of C-C chemokine receptor 4 (CCR4) inhibitors / antagonists, or intermediates and precursors thereof, as described in U.S. Patent No. 10,683,280, issued to Jackson et al. on June 16, 2020, the disclosure of which is incorporated herein by reference. Structural Formula (VI):

[0200] [ka] or a pharma- ceutically acceptable salt thereof, wherein R 1 , R 2 , R 4 , R 44 , X 2 , z4, L 7 , and R 7 R is as described herein, including in some embodiments, or a pharma- ceutically acceptable salt thereof. 3.2 and R 3.3 are independent, R 3 In some embodiments, R 3.2 is hydrogen, halogen, -CX 3.2 3. -CHX 3.2 2, -CH2X 3.2 , -CN, -N3, -SO n3.2 R 3.2A , -SO v3.2 NR 3.2B R 3.2C , -NHNR 3.2B R 3.2C , -ONR 3.2B R 3.2C , -NHC(O)NHNR 3.2B R 3.2C , -NHC(O)NR 3.2B R 3.2C , -N(O) m3.2, -NR 3.2B R 3.2C , -C(O)R 3.2D , -C(O)OR 3.2D , -C(O)NR 3.2B R 3.2C , -OR 3.2A , -NR 3.2B SO2R 3.2A , -NR 3.2B C(O)R 3.2D , -NR 3.2B C(O)OR 3.2D , -NR 3.2B OR 3.2D , -OCX 3.2 3. -OCHX 3.2 2, -OCH2X 3.2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In some embodiments, R 3.3 is hydrogen, halogen, -CX 3.3 3. -CHX 3.3 2, -CH2X 3.3 , -CN, -N3, -SO n3.3 R 3.3A , -SO v3.3 NR 3.3B R 3.3C , -NHNR 3.3B R 3.3C , -ONR 3.3B R 3.3C , -NHC(O)NHNR 3.3B R 3.3C , -NHC(O)NR 3.3B R 3.3C , -N(O) m3.3 , -NR 3.3B R 3.3C , -C(O)R 3.3D , -C(O)OR 3.3D , -C(O)NR 3.3B R 3.3C , -OR 3.3A , -NR 3.3B SO2R 3.3A , -NR 3.3B C(O)R 3.3D , -NR 3.3B C(O)OR 3.3D , -NR3.3B OR 3.3D , -OCX 3.3 3. -OCHX 3.3 2, -OCH2X 3.3 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. The symbols n3.2 and n3.3 are independently integers from 0 to 4. The symbols m3.2, m3.3, v3.2, and v3.3 are independently 1 or 2. In some embodiments, R 4 is hydrogen, -CX 4.1 3. -CN, -C(O)NR 4B R 4C , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In some embodiments, R 3.2A , R 3.2B , R 3.2C , R 3.2D , R 3.3A , R 3.3B , R 3.3C , and R 3.3D are independently hydrogen, halogen, -CF3, -CCl3, -CBr3, -CI3, -COOH, -CONH2, 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. 3.2B , R 3.2C , R 3.3B , and R 3.3C The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl, or a substituted or unsubstituted heteroaryl; X 3.2 and X 3.3 is independently -Cl, -Br, -I or -F.

[0201] Using the methods described herein, a substituted or unsubstituted cycloalkylene, L7 moieties and carboxylic acid or carboxylic acid-like moieties, e.g., -C(O)OR 7D , -CH2C(O)OR 7D OR-NHC(O)OR 7D R 7 The trans isomeric form of the compound of formula (VI) can be synthesized having a moiety R 7D is selected from hydrogen, halogen, -CF3, -CCl3, -CBr3, -CI3, -COOH, -CONH2, 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.

[0202] In some embodiments, the substituted or unsubstituted C3-C8 cycloalkylene, L 7 Compounds of formula (VI) having a moiety can be synthesized using the methods described herein. In certain embodiments, the compounds of formula (VI) having a moiety L that is a substituted or unsubstituted C4-C6 cycloalkylene can be synthesized using the methods described herein. 7 In another embodiment, the compounds of formula (VI) having a moiety, L, which is a substituted or unsubstituted C3-C8 cyclobutylene, can be synthesized using the methods described herein. 7 Compounds of formula (VI) can be synthesized bearing moieties.

[0203] In some embodiments, the methods described herein are used to produce the L 7 Part and R 7 Compounds of formula (VI) can be synthesized having one of the moieties R 7 The moieties are -C(O)OH, -C(O)OCH3, -C(O)OCH2CH3, -CH2C(O)OH, -NHC(O)OH, -NHC(O)OCH3, -NHC(O)OCH2CH3, -CH2C(O)OH, -CH2C(O)OCH3, or -CH2C(O)OCH2CH3.

[0204] In certain embodiments, the methods described herein can be used to 7Part and R 7 Compounds of formula (VI) can be synthesized having one of the moieties R 7 The moiety is -C(O)OH.

[0205] In some embodiments, the methods described herein are used to produce the L 7 Part and R 7 Compounds of formula (VI) can be synthesized having one of the moieties R 7 The moiety is one or more of: z4 is 1; z3 is 0; and / or z2 is 0.

[0206] In some embodiments, the methods described herein can be used to produce a compound of formula (VII):

[0207] [ka] In the formula, z2, z3, z4, R 5 , and R 6 As described herein, including in some embodiments.

[0208] Those skilled in the art will recognize that compounds of the above classes having five or more rings are typically synthesized using multiple steps, with intermediates being used as building blocks to prepare the final CCR4 inhibitors / antagonists. In such synthetic approaches, the step of synthesizing the desired trans isomer with high trans isomer purity using a carboxylic acid-directed reducing agent is typically performed on an intermediate or precursor of the final CCR4 inhibitor / antagonist. Thus, the step of synthesizing the desired trans isomer with high trans isomer purity using a carboxylic acid-directed reducing agent is typically only used to synthesize intermediate or precursor compounds similar to the following moieties, which may have additional blocking and / or leaving moieties attached, and which do not necessarily represent the remaining moieties of the final CCR4 inhibitors / antagonists:

[0209] [ka] Instead, L 7 , R 6 , R 7 , z3, and z4 are as described herein, including in some embodiments.

[0210] In some embodiments, the methods described herein can be used to produce a compound having the following structure:

[0211] [ka]

[0212] [ka] It is possible to synthesize a compound of the formula:

[0213] In some embodiments, the formula:

[0214] [ka] The compound of formula (III) can be reacted with the compound of formula:

[0215] [ka] in the presence of tBuOH, H2O and base.

[0216] In some embodiments, the formula:

[0217] [ka] The compound of formula (III) can be reacted with the compound of formula:

[0218] [ka] in the presence of tBuOH, H2O and base.

[0219] In some embodiments, the formula:

[0220] [ka] The compound of formula:

[0221] [ka] It is formed by removing from a compound of

[0222] In some embodiments, the formula:

[0223] [ka] The compound of formula:

[0224] [ka] Compounds of the formula:

[0225] [ka] in the presence of a base and a solvent, where X is -Cl, -Br, -I, -OSO2R 15 Or -OCOR 15 and R 15 is substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0226] In some embodiments, the formula:

[0227] [ka] The compound of formula:

[0228] [ka] Compounds of the formula:

[0229] [ka] in the presence of a base and a solvent, where n is an integer from 0 to 5, and R 16 is hydrogen, -OH, -C(O)R 16A , substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 16A is hydrogen or substituted or unsubstituted alkyl.

[0230] In some embodiments, the formula:

[0231] [ka] is -C(O)NHR 16 It is formed by partial hydrolysis of

[0232] In some embodiments, the formula:

[0233] [ka] is the expression:

[0234] [ka] wherein R 17 is hydrogen, -OH, -C(O)R 17A , substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 17A is hydrogen, or substituted or unsubstituted alkyl.

[0235] In some embodiments, the formula:

[0236] [ka] The compound of formula:

[0237] [ka] Compounds of the formula:

[0238] [ka] in the presence of a base and a solvent.

[0239] In some embodiments, the formula:

[0240] [ka] The compound of formula:

[0241] [ka] The compound of formula M(OH) n3’ in the presence of an organic solvent, where M is Li, Na, K, Cs, Ba, Ca, Mg, Be, Rb or Sr, and n3' is an integer from 1 to 2.

[0242] In some embodiments, the formula:

[0243] [ka] The compound of formula (I):

[0244] [ka] Compounds of the formula:

[0245] [ka] in the presence of a solvent and a base, where PG1 is a protecting group and n is an integer from 0 to 5.

[0246] In some embodiments, the formula:

[0247] [ka] The compound of formula:

[0248] [ka] It is formed by removing from a compound of

[0249] In some embodiments, the formula:

[0250] [ka] The compound of formula:

[0251] [ka] is formed by reacting a compound of formula (II) with a compound of formula (II) in the presence of 1,4-dihydropyridine and toluene.

[0252] In some embodiments, the formula:

[0253] [ka] The compound of formula:

[0254] [ka] Compound

[0255] It is formed by reacting a compound of formula (II) in the presence of 1,4-dihydropyridine, where PG2 is a protecting group.

[0256] In some embodiments, the formula:

[0257] [ka] The compound of formula:

[0258] [ka] It is formed by removing from a compound of

[0259] In embodiments, the compounds are useful as comparator compounds, which may be used to evaluate the activity of a test compound in an assay (e.g., an assay such as those described herein, e.g., in the Examples section, Figures, or Tables).

[0260] Working Example General synthetic procedure Reductive amination of intermediate compounds used to synthesize the trans isomeric forms of G protein coupled receptor modulators can be carried out using either the following general synthetic procedures A or B.

[0261] General Procedure A A solution of a primary or secondary amine (10 mmol, 1 equiv.), 1-methyl-3-oxocyclobutane-1-carboxylic acid (1.66 g, 13 mmol, 1.3 equiv.), and a reducing agent (13 mmol, 1.3 equiv.) in toluene (0.2 M) is heated to reflux using a Dean-Stark apparatus. After residual water appears in the trap, the reaction is cooled to ambient temperature. Workup can then be performed according to one of the following protocols: (1) First, the toluene is removed in vacuum, and the residue is partitioned between water (30 mL) and methyl t-butyl ether (50 mL). The aqueous layer is washed two more times with methyl t-butyl ether (50 mL each). After removing the water in high vacuum, the ratio of cis / trans isomers is measured by HPLC. (2) Toluene is replaced with ethyl acetate, and heptane is added to obtain a solid material, which is filtered, dried in vacuum, and the ratio of cis / trans diastereomers is measured by HPLC.

[0262] The methods used to measure the cis / trans diastereomeric ratio were: (a) XBridge C18 3.5 mm 4.6 x 150 mm HPLC column, flow rate 1 mL / min, 0-100% water (+0.1% ammonia) / acetonitrile (+0.1% ammonia) over 30 min; or (b) 1 H NMR.

[0263] General Procedure B A solution of a primary or secondary amine (1 eq.), g-ketocarboxylic acid (1.0-1.3 eq.), and Hantzsch ester (1.0-1.3 eq.) in toluene (0.2 M) is heated to reflux using a Dean-Stark apparatus. After residual water appears in the trap, the reaction is cooled to ambient temperature. The toluene is removed in vacuo, and the residue is partitioned between water and methyl t-butyl ether. If necessary, 5 eq. of 3M aqueous NaOH is added. The aqueous layer is then washed two more times with methyl t-butyl ether, and then the pH is brought to neutral by adding 3M HCl solution if NaOH is used. The product is extracted with dichloromethane, and the ratio of cis / trans diastereomers is measured by HPLC or NMR.

[0264] Example 1-5. Reductive amination using general procedure A in the preparation of trans-3-((R)-3-(1-(tert-butoxycarbonyl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid.

[0265] [ka] A solution of tert-butyl 3-[(3R)-3-piperidyl]azetidine-1-carboxylate (23.2 g, 96.5 mmol), 1-methyl-3-oxocyclobutane-1-carboxylic acid (16.1 g, 125.5 mmol, 1.3 equiv.), and reducing agent (see Table 1) in toluene (480 mL, 0.2 M) was heated to reflux with a Dean-Stark trap and fitted with a condenser. After water appeared in the trap, the reaction was cooled to ambient temperature. The toluene was removed in vacuo and the residue was partitioned between water (300 mL) and methyl t-butyl ether (500 mL). The aqueous layer was then washed two more times with methyl t-butyl ether (500 mL each). After removing the water under high vacuum, the ratio of cis / trans diastereomers was 3:97 as determined by HPLC. The trans diastereomer was retained at 9.1 min and the cis diastereomer was retained at 10.1 min.

[0266] 1 H NMR (400 MHz, CDCl3) trans diastereomer: 3.82 (q, J = 8.0 Hz, 2H), 3.60 (dt, J = 28.6, 7.6 Hz, 2H), 3.24-2.97 (m, 3H), 2.51 (s, 2H), 2.15 (d, J = 8.6 Hz, 3H), 2.08-1.86 (m, 2H), 1.84-1.57 (m, 4H), 1.31 (s, 9H), 1.25 (s, 3H), 0.92-0.70 (m, 1H) ppm.

[0267] 13C NMR (400 MHz, CDCl3) trans diastereomer: 181.25, 156.14, 79.32, 55.75, 51.95, 51.93, 49.40, 38.28, 37.16, 36.15, 31.94, 28.31, 26.03, 25.94, 22.18 ppm.

[0268] LCMS[M+H]: 353.1.

[0269] [Table 1]

[0270] Example 6. Reductive amination using general procedure B in the preparation of trans-3-((R)-3-(1-(tert-butoxycarbonyl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclopentane-1-carboxylic acid (mixture of diastereomers).

[0271] [ka] A 25 mL round bottom flask was charged with 1-methyl-3-oxo-cyclopentane carboxylic acid (231 mg, 1.62 mmol), tert-butyl 3-[(3R)-3-piperidyl]azetidine-1-carboxylate (300 mg, 1.25 mmol), and 6 mL of toluene. Diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (411 mg, 1.62 mmol) was added to the solution, the flask was fitted with a Dean-Stark apparatus, and the mixture was then heated to reflux. Reflux was continued for 3 hours, and then the reaction was cooled to ambient temperature. The reaction mixture was concentrated in vacuo to remove toluene, and the residue was partitioned between water and methyl tert-butyl ether. The separated phases were then washed with methyl tert-butyl ether (4×5 mL). The aqueous phase was then concentrated in vacuo to give 362 mg of trans-3-((R)-3-(1-(tert-butoxycarbonyl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclopentane-1-carboxylic acid as a mixture of diastereomers (79% yield). The cis / trans diastereomer ratio was: 1 The ratio was determined by 1 H NMR to be less than 1:20 (i.e., more than 20 times the amount of trans diastereomer than the cis diastereomer).

[0272] Trans isomer 1 H NMR (400MHz, methanol-d4) mixture: δ4.07-3.90(m,2H),3.83-3.65(m,2H),3.65-3.47(m,2H),3.45-3.31(m,1H),2.87-2.65(m,1H),2.55-2.34(m,3 H),2.26-2.12(m,1H),2.12-1.91(m,4H),1.91-1.70(m,3H),1.61(ddd ,J=13.2,7.5,5.5Hz,1H),1.43(s,9H),1.27(s,3H),1.23-1.06(m,1H).

[0273] LCMS [M+H]: 367.2.

[0274] Example 7. Reductive amination using general procedure B in the preparation of trans-3-(dibenzylamino)-1-methylcyclopentane-1-carboxylic acid (mixture of enantiomers).

[0275] [ka] 1-Methyl-3-oxo-cyclopentane carboxylic acid (72 mg, 0.51 mmol, 1 equiv.), dibenzylamine (100 mg, 0.51 mmol, 1 equiv.), and Hantzsch ester (141 mg, 0.56 mmol, 1.1 equiv.) were dissolved in 3 mL of toluene (0.17 M). The reaction mixture was refluxed in a Dean-Stark apparatus for 2 h and then brought to ambient temperature. The toluene was removed in vacuo and the residue was partitioned between water (5 mL) containing 5 equiv. of 3 M NaOH and methyl tert-butyl ether (5 mL). The aqueous layer was washed with two further portions of methyl tert-butyl ether (5 mL each) and then neutralized to pH 7 with 3 M HCl. The aqueous layer was then extracted with dichloromethane and the organic layer was dried over MgSO4, filtered through Celite, and concentrated in vacuo. The yield of crude trans-3-(dibenzylamino)-1-methylcyclopentane-1-carboxylic acid (a mixture of the two trans enantiomers) was 100 mg (61%), with a cis / trans ratio of the enantiomers of 1 The ratio was 1:9 as determined by 1 H NMR.

[0276] Trans isomer 1 H NMR (400MHz, methanol-d4) mixture:d 7.36-7.21(m,10H),3.93(s,0.2H),3.74(s,3.8H),3.62-3.53(m,0.1H),3.52-3.40(m,0.9H),2.52-2 .38(m,1H),2.17-2.06(1H),2.03-1.70(m,2H),1.59-1.44(m,2H),1.30(s,2.7H),1.21(s,0.3H)ppm.

[0277] LCMS[M+H]:324.1.

[0278] Example 8. Reductive amination using general procedure A in the preparation of trans-4-((R)-3-(1-(tert-butoxycarbonyl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclohexane-1-carboxylic acid.

[0279] [ka] 1-Methyl-4-oxocyclohexane-1-carboxylic acid (169 mg, 1.08 mmol, 1.3 equiv.) in 4.5 mL of toluene was mixed with tert-butyl 3-[(3R)-3-piperidyl]azetidine-1-carboxylate (200 mg, 0.83 mmol, 1 equiv.) and Hantzsch ester (274 mg, 1.08 mmol, 1.3 equiv.) and the mixture was refluxed under inert atmosphere using a Dean-Stark apparatus for 3 h. The toluene was then removed in vacuo, 3M NaOH (5 equiv.) was added and the residue was partitioned between water (10 mL) and methyl tert-butyl ether (10 mL). The aqueous layer was washed two more times with methyl tert-butyl ether and then neutralized to pH 7 with 3M HCl. The mixture was extracted with dichloromethane, dried over MgSO4, filtered through Celite and concentrated in vacuo. The yield of trans-4-((R)-3-(1-(tert-butoxycarbonyl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclohexane-1-carboxylic acid was 75% (236 mg), and the cis / trans diastereomeric ratio was 1 The ratio was determined by 1 H NMR to be less than 1:20 (i.e., more than 20 times the amount of trans diastereomer than the cis diastereomer).

[0280] 1H NMR(400MHz, methanol-d4)δ 4.03-3.94(m,2H),3.81-3.65(m,2H),3.44(d,J=12.0Hz,1H),3.29(d,J=9.6Hz,1H),3.07-2.98(m,1H),2.83(td,J=12.2,3 .1Hz,1H),2.55(t,J=11.8Hz,1H),2.45-2.27(m,1H),2.09-1.62(m,12H),1.43(s,9H),1.19(s,3H),1.12-1.03(m,1H)ppm.

[0281] LCMS[M+H]:381.0.

[0282] Example 9. Reductive amination using general procedure A in the preparation of trans-4-(4-(4-methoxyphenyl)piperidin-1-yl)-1-methylcyclohexane-1-carboxylic acid.

[0283] [ka] 1-Methyl-4-oxocyclohexane-1-carboxylic acid (169 mg, 1.08 mmol, 1.3 equiv.) was mixed with tert-butyl 4-(4-methoxyphenyl)piperidine (159 mg, 0.83 mmol, 1 equiv.) and Hantzsch ester (274 mg, 1.08 mmol, 1.3 equiv.) in 4.5 mL of toluene, and the mixture was refluxed under inert atmosphere using a Dean-Stark apparatus for 3 h. The toluene was then removed in vacuo, 3M NaOH (5 equiv.) was added, and the residue was partitioned between water (10 mL) and methyl tert-butyl ether (10 mL). The aqueous layer was washed two more times with methyl tert-butyl ether and then neutralized to pH 7 with 3M HCl. The mixture was extracted with dichloromethane, dried over MgSO4, filtered through Celite, and concentrated in vacuo. The yield of trans-4-(4-(4-methoxyphenyl)piperidin-1-yl)-1-methylcyclohexane-1-carboxylic acid was 63% (173 mg), and the cis / trans isomer ratio was 1The ratio was determined by 1 H NMR to be less than 1:20 (i.e., the amount of trans isomer is more than 20 times that of the cis isomer).

[0284] 1 H NMR (400MHz, methanol-d4) δ7.20-7.13(m,2H),6.90-6.85(m,2H),3.77(s,3H),3.62-3.55(m, 2H),3.16-3.07(m,3H),2.81(tt,J=12.0,4.0Hz,1H),2.11-1.66(m,12H),1.22(s,3H)ppm.

[0285] LCMS [M+H]: 332.0.

[0286] General synthetic procedure for the synthesis of CCR4 antagonists:

[0287] [ka]

[0288] General Procedure C Trans-3-((R)-3-(1-(tert-butoxycarbonyl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid is dissolved in water (the telescoped aqueous solution of general procedure A can also be used for this step), 5 equivalents of concentrated HCl are added to the solution, and the mixture is stirred at room temperature until complete conversion is observed by LC-MS. The solution is neutralized to pH 7 with 6N NaOH and used in the next step.

[0289] Alternatively, 5 equivalents of 1N HCl in ethyl acetate is added to trans-3-((R)-3-(1-(tert-butoxycarbonyl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid at ambient temperature, and the solution is stirred until complete conversion is reached, precipitating the deprotected solid product. The solid trans-3-((R)-3-(azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid hydrochloride is filtered and dried under high vacuum. In addition to HCl, other strong acids (e.g., sulfuric acid, mesic acid, tosic acid, bezic acid, phosphoric acid, HBr, HI, etc.) can be used for deprotection in general procedure C.

[0290] General Procedure D An electrophilic intermediate compound is first selected (i.e., one of the intermediate compounds in Table 1 for the synthesis of CCR4 antagonists in Examples 10-19; 1 equivalent) and mixed with trans-3-((R)-3-(azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid (1.2-1.5 equivalents) by dissolving in equal volumes of water and tert-butanol to prepare a 0.2-0.5 M biphasic solution. Six equivalents of sodium hydroxide (as a 50% by weight aqueous solution) are added to the solution, and the reaction mixture is heated to 80° C. until complete conversion is observed by LC-MS. The reaction mixture is then cooled to ambient temperature and the layers are separated. The aqueous layer is washed with fresh tert-butanol, and the organic fractions are combined. The tert-butanol is removed under reduced pressure to give the desired CCR4 antagonist compound. In addition to tert-butanol, other organic solvents such as methanol, ethanol, isopropanol, butanol, dioxanes, THF, MeTHF, DMSO, etc. can be used in general procedure D. In addition to NaOH, other bases such as KOH, LiOH, Ba(OH)2, Ca(OH)2, amines, phosphates, carbonates, etc. can be used in general procedure D.

[0291] Examples 10 to 19 The syntheses of the following CCR4 antagonists were carried out according to general procedures A, C, and D, with general procedure D being used with the intermediates shown in Table 1 to produce the final CCR4 antagonist compounds shown in Table 1. In these intermediates, X is F, Cl, Br, I, or -OS(O)2R, where R is alkyl, perfluoroalkyl, or aryl.

[0292] [Table 2-1]

[0293] [Table 2-2]

[0294] Example 20 The synthesis of the CCR4 antagonist trans-3-((R)-3-(1-(tert-butoxycarbonyl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid is carried out as follows: A solution of tert-butyl 3-[(3R)-3-piperidyl]azetidine-1-carboxylate (55.6 mol) in toluene (69 L, 0.80 M) was added to a reactor containing 1-methyl-3-oxocyclobutane-1-carboxylic acid (9.27 kg, 72.3 mol, 1.3 equiv.) and Hantzsch ester diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (18.3 kg, 72.3 mmol, 1.3 equiv.). Toluene (170 L) was charged, a Dean-Stark trap was attached, and the reaction mixture was heated to 100-110 °C for not less than 3 h. The reaction volume is reduced in vacuo (to ca. 115 L total), nBuOAc (230 L) is added, and the mixture is concentrated again (to 200-230 L total). This cycle is repeated two more times before heptane (135 L) is added. The resulting solid is collected by filtration, washed with a 1:1 mixture of EtOAc / heptane (ca. 60 L), and dried under vacuum to give trans-3-((R)-3-(1-(tert-butoxycarbonyl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid as a white solid (16.7 kg, 47.4 mol, 85% yield, >99% trans by HPLC).

[0295] Given the foregoing detailed description of preferred embodiments of the present disclosure, those skilled in the art will readily appreciate that the present disclosure is susceptible to broad utility and application. Although various aspects have been described in the context of screenshots, further aspects, features, and methods of the present disclosure will be readily discernible therefrom. Many embodiments and adaptations of the present disclosure other than those described herein, as well as many variations, modifications, and equivalent structures and methodologies, will be apparent from, or reasonably suggested by, the present disclosure and its foregoing description, without departing from the substance or scope of the present disclosure. Furthermore, any sequence and / or chronological order of the steps of the various processes described and claimed herein is deemed to be the best mode contemplated for carrying out the present disclosure. Although the steps of the various processes may be shown and described in a preferred sequence or chronological order, it should also be understood that the steps of any such process are not limited to being performed in any particular sequence or order unless such specific indications are present to achieve a particular intended result. In most cases, the steps of such processes may be performed in a variety of different sequences and orders while still being within the scope of the present invention. Furthermore, multiple steps may be performed simultaneously. Thus, while the present disclosure has been described in detail herein in connection with preferred embodiments, it should be understood that this disclosure is merely illustrative and exemplary of the present disclosure, presented solely for the purpose of providing a complete and enabling disclosure of the present disclosure. The foregoing disclosure is not intended, nor should it be construed, to limit the present disclosure or otherwise exclude any such other embodiments, adaptations, variations, modifications, and equivalent arrangements, and the present disclosure is limited only by the claims appended hereto and the equivalents thereof.

[0296] It is understood that the examples and embodiments described herein are for illustrative purposes only, and that various modifications or changes in light of them will be suggested to those skilled in the art and are to be included within the spirit and scope of this application and the scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.

[0297] Embodiment Embodiment 1. A method of synthesizing a compound of formula (III), the method comprising reacting a compound of formula (I) with a compound of formula (II) in the presence of a carboxylic acid-directed reducing agent to form a compound of formula (III);

[0298] [ka] During the ceremony, n1' and n2' each independently represent an integer of 0 to 5, and the sum of n1' and n2' is at least 1 and not more than 6; L 1’ is C(R 4’ )2, L 2’ is C(R 5’ )2, R 1’ is hydrogen, halogen, -CX 1’ 3. -CHX 1’ 2, -CH2X 1’ , -OCX 1’ 3. -OCHX 1’ 2, -OCH2X 1’ , -CN, -S(O)2R 1’A , -SR 1’A , -S(O)R 1’A , -SO2NR 1’A R 1’B , -NHC(O)NR 1’A R 1’B , -N(O)2, -NR 1’A R 1’B , -NHNR 1’A R 1’B , -C(O)R 1’A , -C(O)-OR 1’A , -C(O)NR 1’A R1’B , -C(O)NHNR 1’A R 1’B , -OR 1’A , -NR 1’A SO2R 1’B , -NR 1’A C(O)R 1’B , -NR 1’A C(O)OR 1’B , -NR 1’A OR 1’B , -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 2’ is hydrogen, -CX 2’ 3. -CHX 2’ 2, -CH2X 2’ , -OCX 2’ 3. -OCHX 2’ 2, -OCH2X 2’ , -SR 2’A , -NR 2’A R 2’B , -NHNR 2’A R 2’B , -OR 2’A , -NR 2’A SO2R 2’B , -NR 2’A C(O)R 2’B , -NR 2’A C(O)OR 2’B , -NR 2’A OR 2’B , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R 2’ and R 3’ can be optionally linked to form a substituted or unsubstituted heterocycloalkyl; R 3’ is halogen, -CX 3’ 3. -CHX 3’ 2, -CH2X 3’ , -OCX 3’ 3. -OCHX 3’ 2, -OCH2X3’ , -SR 3’A , -NR 3’A R 3’B , -NHNR 3’A R 3’B , -OR 3’A , -NR 3’A SO2R 3’B , -NR 3’A C(O)R 3’B , -NR 3’A C(O)OR 3’B , -NR 3’A OR 3’B , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R 2’ and R 3’ can be optionally linked to form a substituted or unsubstituted heterocycloalkyl; R 4’ are independently hydrogen, halogen, -CX 4’ 3. -CHX 4’ 2, -CH2X 4’ , -OCX 4’ 3. -OCHX 4’ 2, -OCH2X 4’ , -CN, -S(O)2R 4’A , -SR 4’A , -S(O)R 4’A , -SO2NR 4’A R 4’B , -NHC(O)NR 4’A R 4’B , -N(O)2, -NR 4’A R 4’B , -NHNR 4’A R 4’B , -C(O)R 4’A , -C(O)-OR 4’A , -C(O)NR 4’A R 4’B , -C(O)NHNR 4’A R 4’B , -OR 4’A , -NR 4’A SO2R 4’B , -NR 4’A C(O)R 4’B , -NR 4’A C(O)OR4’B , -NR 4’A OR 4’B , -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 5’ are independently hydrogen, halogen, -CX 5’ 3. -CHX 5’ 2, -CH2X 5’ , -OCX 5’ 3. -OCHX 5’ 2, -OCH2X 5’ , -CN, -S(O)2R 5’A , -SR 5’A , -S(O)R 5’A , -SO2NR 5’A R 5’B , -NHC(O)NR 5’A R 5’B , -N(O)2, -NR 5’A R 5’B , -NHNR 5’A R 5’B , -C(O)R 5’A , -C(O)-OR 5’A , -C(O)NR 5’A R 5’B , -C(O)NHNR 5’A R 5’B , -OR 5’A , -NR 5’A SO2R 5’B , -NR 5’A C(O)R 5’B , -NR 5’A C(O)OR 5’B , -NR 5’A OR 5’B , -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 12’ are independently -OH or NHR 12” and R 12’’ is hydrogen, or substituted or unsubstituted alkyl; R 1’A , R 1’B , R 2’A , R 2’B , R 3’A , R 3’B , R 4’A , R 4’B , R 5’A , and R 5’B are independently hydrogen, -F, -Cl, -Br, -I, -CF3, -CHF2, -CH2F, -CCl3, -CHCl2, -CH2Cl, -CBr3, -CHBr2, -CH2Br, -CI3, -CHI2, -CH2I, -OCF3, -OCCl3, -OCBr3, -OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -C(O)OH, -C(O)NH2, -OH, -NH2, -COOH, -CO NH2, -SH, -SO3H, -SO4H, -SON2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)OH, -NHOH, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or R bonded to the same nitrogen atom 2’A and R 2’B The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl, or may be linked together ... 3’A and R 3’B The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; X 1’ , X 2’ , X 3’ , X 4’ , and X 5’ is independently a halogen.

[0299] Embodiment 2. The method of embodiment 1, wherein said method is used to prepare an antagonist of C-C chemokine receptor type 4 (CCR4), or a salt or ester thereof.

[0300] Embodiment 3. The method of embodiment 1 or 2, wherein the compound of formula (III) is in at least 80% trans-isomerically pure form.

[0301] Embodiment 4. The method of any one of embodiments 1-3, wherein the carboxylic acid-directed reducing agent is a 1,4-dihydropyridine.

[0302] Embodiment 5. The carboxylic acid directed reducing agent has the formula (IV):

[0303] [ka] is a 1,4-dihydropyridine of the formula L 3’ and L 4’ are independently O or NR 20’ and R 20’ are independently hydrogen or R 21’ and R 21’ are independently hydrogen, -CX 21’ 3. -CHX 21’ 2, -CH2X 21’ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; R 6’ are independently hydrogen, -CX 6’ 3. -CHX 6’ 2, -CH2X 6’ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a bond attaching 1,4-dihydropyridine to a polymeric support; R 7’ are independently hydrogen, -CX 7’ 3. -CHX 7’ 2, -CH2X 7’ is a bond attaching a substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or 1,4-dihydropyridine to a polymeric support; R 8’ are independently hydrogen, halogen, -CX 8’ 3. -CHX 8’ 2, -CH2X 8’ , -OCX 8’ 3. -OCHX 8’ 2, -OCH2X 8’ , -CN, -S(O)2R 8’A , -SR 8’A , -S(O)R 8’A , -SO2NR 8’A R 8’B , -NHC(O)NR 8’A R 8’B , -N(O)2, -NR 8’A R 8’B , -NHNR 8’A R 8’B , -C(O)R 8’A , -C(O)-OR 8’A , -C(O)NR 8’A R 8’B , -C(O)NHNR 8’A R 8’B , -OR 8’A , -NR 8’A SO2R 8’B , -NR 8’A C(O)R 8’B , -NR 8’A C(O)OR 8’B , -NR 8’A OR 8’B , -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 9’are independently hydrogen, halogen, -CX 9’ 3. -CHX 9’ 2, -CH2X 9’ , -OCX 9’ 3. -OCHX 9’ 2, -OCH2X 9’ , -CN, -S(O)2R 9’A , -SR 9’A , -S(O)R 9’A , -SO2NR 9’A R 9’B , -NHC(O)NR 9’A R 9’B , -N(O)2, -NR 9’A R 9’B , -NHNR 9’A R 9’B , -C(O)R 9’A , -C(O)-OR 9’A , -C(O)NR 9’A R 9’B , -C(O)NHNR 9’A R 9’B , -OR 9’A , -NR 9’A SO2R 9’B , -NR 9’A C(O)R 9’B , -NR 9’A C(O)OR 9’B , -NR 9’A OR 9’B , -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 10’ are independently hydrogen, halogen, -CX 10’ 3. -CHX 10’ 2, -CH2X 10’ , -OCX 10’ 3. -OCHX 10’ 2, -OCH2X 10’ , -CN, -S(O)2R 10’A , -SR 10’A , -S(O)R 10’A , -SO2NR 10’A R 10’B , -NHC(O)NR 10’A R 10’B, -N(O)2, -NR 10’A R 10’B , -NHNR 10’A R 10’B , -C(O)R 10’A , -C(O)-OR 10’A , -C(O)NR 10’A R 10’B , -C(O)NHNR 10’A R 10’B , -OR 10’A , -NR 10’A SO2R 10’B , -NR 10’A C(O)R 10’B , -NR 10’A C(O)OR 10’B , -NR 10’A OR 10’B , -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 8’A , R 8’B , R 9’A , R 9’B , R 10’A , and R 10’B are independently hydrogen, -F, -Cl, -Br, -I, -CF3, -CHF2, -CH2F, -CCl3, -CHCl2, -CH2Cl, -CBr3, -CHBr2, -CH2Br, -CI3, -CHI2, -CH2I, -OCF3, -OCCl3, -OCBr3, -OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -C(O)OH, -C(O)NH2, -OH, -NH2, -C OOH, -CONH2, -SH, -SO3H, -SO4H, -SON2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)OH, -NHOH, 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; X 6’, X 7’ , X 8’ , X 9’、 X 10’ , and X 21’ The method of any one of embodiments 1-4, wherein is independently a halogen.

[0304] Embodiment 6.L 3’ and L 4’ The method of any one of embodiments 1 to 5, wherein:

[0305] Embodiment 7.R 6’ and R 7’ is independently substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a bond attaching the 1,4-dihydropyridine to the polymeric support.

[0306] Embodiment 8.R 8’ , R 9’ , and R 10’ is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0307] Embodiment 9. n1' and n2' are independently 1 or 2, and R 1’ The method of any one of the preceding embodiments, wherein is substituted or unsubstituted C1-C4 alkyl.

[0308] Embodiment 10. n1' and n2' are independently 1; L 1’ and L 2’ The method of any one of embodiments 1-9, wherein is independently a substituted or unsubstituted C1-C2 alkyl.

[0309] Embodiment 11.R 2’and R 3’ The method of any one of embodiments 1-10, wherein:

[0310] Embodiment 12. The method of any one of embodiments 1-11, wherein piperidinyl is a substituted or unsubstituted heterocycloalkyl.

[0311] Embodiment 13. The method of any one of embodiments 1 to 12, wherein the substituted or unsubstituted heterocycloalkyl is a nitrogen-containing 3- to 6-membered heterocycloalkyl.

[0312] Embodiment 14. A compound of formula (I) is

[0313] [ka] where: R 11’ are independently -CF3, -CHF2, -CH2F, -CCl3, -CHCl2, -CH2Cl, -CBr3, -CHBr2, -CH2Br, -CI3, -CHI2, -CH2I, -NH2, 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.

[0314] Embodiment 15.R 11’ 15. The method of embodiment 14, wherein is substituted or unsubstituted alkyl.

[0315] Embodiment 16.R 11’ The method of embodiment 14 or 15, wherein is substituted or unsubstituted C1-C4 alkyl.

[0316] Embodiment 17. The compound of formula III is

[0317] [ka] where R 11’ 17. The method of any one of embodiments 14-16, wherein n is substituted or unsubstituted alkyl; and each of n1' and n2' is 1 or 2.

[0318] Embodiment 18. A compound of formula (III)

[0319] [ka] where R 11’ The method of any one of embodiments 14-17, wherein is t-butyl or benzyl.

[0320] Embodiment 19. The CCR4 antagonist is

[0321] [ka]

[0322] [ka] or a pharma- ceutically acceptable salt or ester thereof.

[0323] Embodiment 20. The CCR4 antagonist is

[0324] [ka]

[0325] [ka] or a pharma- ceutically acceptable salt or ester thereof.

Claims

1. A method of synthesizing a compound of formula (III), said method comprising reacting a compound of formula (I) with a compound of formula (II) in the presence of a carboxylic acid directed reducing agent to form a compound of formula (III), said carboxylic acid directed reducing agent being a 1,4-dihydropyridine; 【Chemistry 1】 During the ceremony, n1' and n2' are each independently an integer from 0 to 5, and the sum of n1' and n2' is at least 1 and not more than 6; L １’ is C(R ４’ ) ２ and L ２’ is C(R ５’ ) ２ and R １’ is hydrogen or substituted or unsubstituted C 1 -C 4 alkyl; R ２’ and R ３’ are linked to form a substituted piperidinyl, said piperidinyl being substituted with a substituted or unsubstituted nitrogen-containing 4- to 6-membered heterocycloalkyl or a substituted or unsubstituted aryl; R ４’ is hydrogen or substituted or unsubstituted C 1 -C 4 alkyl; R ５’ is hydrogen or substituted or unsubstituted C 1 -C 4 alkyl, and R １２’ is --OH.

2. 2. The method of claim 1, wherein the compound of formula (III) is in at least 80% trans-isomerically pure form.

3. The carboxylic acid-directed reducing agent is a 1,4-dihydropyridine of formula (IV): 【Chemistry 2】 During the ceremony, L ３’ and L ４’ are independently O; R ６’ is a substituted or unsubstituted C 1 -C 4 alkyl; R ７’ is a substituted or unsubstituted C 1 -C 4 alkyl; R ８’ is a substituted or unsubstituted C 1 -C 4 alkyl; R ９’ is hydrogen, and R １０’ The method of claim 1 , wherein is a substituted or unsubstituted C 1 -C 4 alkyl.

4. n1′ and n2′ are independently 1 or 2; R １’ is a substituted or unsubstituted C １ The method of claim 1, wherein the alkyl group is C1 to C2 alkyl.

5. n1′ and n2′ are independently 1; L １’ and L ２’ is independently a substituted or unsubstituted C １ ~C ２ The method of claim 4, wherein the alkyl group is an alkyl group.

6. The compound of formula (I) 【Chemistry 3】 where: R １１’ The method of claim 1 , wherein is substituted or unsubstituted alkyl, or substituted or unsubstituted aryl.

7. R １１’ is a substituted or unsubstituted C １ ~C ４ The method of claim 6, wherein the alkyl group is an alkyl group.

8. The compound of formula III is 【Chemistry 4】 and In the formula, R １１’ The method of claim 1, wherein n1′ and n2′ are each 1 or 2.

9. The compound of formula (III) 【Chemistry 5】 and In the formula, R １１’ The method of claim 8, wherein is t-butyl or benzyl.

10. The method of claim 1, wherein R 2' and R 3' are linked to form a substituted piperidinyl, said piperidinyl being substituted with a substituted or unsubstituted nitrogen-containing 6-membered heterocycloalkyl.

11. The method of claim 10, wherein the nitrogen-containing 6-membered heterocycloalkyl is selected from substituted or unsubstituted tetrahydropyridyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted morpholinyl, and substituted or unsubstituted piperazinyl.

12. The method of claim 11, wherein the nitrogen-containing 6-membered heterocycloalkyl is a substituted piperidinyl.

13. The method of claim 12, wherein said nitrogen-containing 6-membered heterocycloalkyl is piperidinyl substituted with -COOR 11' , where R 11' is a substituted or unsubstituted C 1 -C 4 alkyl.

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