Methods of making trans isomeric forms of g protein-coupled receptor modulators

Abstract

This article specifically reveals a method for preparing G protein-coupled receptor regulators with high trans-isomer purity.

Description

[Technical Field]

[0001] This application claims priority to U.S. Provisional Application No. 63 / 144,878, filed on February 2, 2021, the entire contents of which are incorporated herein by reference.

[0002] This disclosure relates to a method for preparing G protein-coupled receptor modulators with high trans isomeric purity. [Previous Technology]

[0003] Methods for preparing receptor regulators comprising G protein-coupled chemokine receptor type 4 (CCR4) inhibitors and antagonists have been previously described. For example, see U.S. Patent Publication No. US2019 / 0233397, published August 1, 2019, which discloses chemokine receptor 4 (CCR4) inhibitors / antagonists having a trans isomer configuration, wherein the carboxylic acid moiety and the amine moiety are cyclically bonded to a cycloalkyl group (e.g., cyclobutane) in a trans isomer configuration. In compounds such as these, when the desired regulator has a trans isomeric chemical structure, known synthetic methods tend to produce racemic mixtures of desired and undesired isomers / non-mirror image isomers, such as racemic mixtures of cis and trans isomers, making it uneconomical to produce the desired trans isomer or trans non-mirror image isomer in commercial quantities by such methods. Therefore, there is a desire for a method to synthesize G protein-coupled receptor regulators that are trans- or trans-non-mirror image isomers, and that have relatively low levels of any undesirable cis- or non-mirror image isomers, which would be economically viable for commercial scale-up. These and other needs in the art are addressed herein. [Summary of the Invention]

[0004] This document specifically provides a method for synthesizing a trans isomer of a chemokine receptor 4 (CCR4) regulator or a salt or ester thereof. In this embodiment, the method relates to synthesizing a G protein-coupled receptor regulator or a salt or ester thereof having at least one amine moiety and a partially substituted carboxylic acid or carboxylic acid-derived cycloalkyl ring having a 3 to 8-membered cycloalkyl ring, wherein the amine moiety and the partially substituted carboxylic acid or carboxylic acid-derived cycloalkyl ring are capable of being in cis or trans isomer configurations. In this embodiment, the method includes using 1,4-dihydropyridine as a carboxylic acid-directed reducing agent for an imine or enamine to prepare a regulator or a precursor thereof comprising a 3 to 8-membered cycloalkyl ring having an amine moiety and a partially substituted carboxylic acid or carboxylic acid-derived cycloalkyl ring, primarily in the trans isomer pure form.

[0005] In one embodiment, this document provides a method for synthesizing the trans isomer of a chemokine receptor 4 (CCR4) regulator or its salt or ester. In this embodiment, the method comprises reacting a compound of formula (I) with a compound of formula (II) in the presence of a carboxylic acid-directed reducing agent to prepare a trans isomer of formula (III), wherein the compound of formula (III) is primarily in its pure trans isomer form.

[0006] In one embodiment, this document provides a method for synthesizing the trans isomer of a chemokine receptor 4 (CCR4) regulator or a salt or ester thereof. In this embodiment, the method comprises preparing the trans isomer of formula (III) by reacting a compound of formula (1) with a compound of formula (II) in an environment having a carboxylic acid-directed reducing agent, wherein at least 80% of the compound of formula (III) is in the pure trans isomer form:

[0006] Among them:

[0006] n1' and n2' are each independent integers from 0 to 5, where the sum of n1' and n2' is at least 1 and does not exceed 6;

[0006] L1' is C(R4')2;

[0006] L2' is C(R5')2;

[0006] R1' is hydrogen, halogen, -CX1'3, -CHX1'2, -CH2X1', -OCX1'3, -OCHX1'2, -OCH2X1', -CN, -S(O)2R1'A, -SR1'A, -S(O)R1'A, -SO2NR1'AR1'B, -NHC(O)NR1'AR1'B, -N(O)2, -NR1'AR1'B, -NHNR1'AR1'B, -C(O)R1'A, -C(O)-OR1'A -C(O)NR1'AR1'B, -C(O)NHNR1'AR1'B, -OR1'A, -NR1'ASO2R1'B, -NR1'AC(O)R1'B, -NR1'AC(O)OR1'B, -NR1'AOR1'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;

[0006] R2' is hydrogen, -CX2'3, -CHX2'2, -CH2X2', -OCX2'3, -OCHX2'2, -OCH2X2', -SR2'A, -NR2'AR2'B, -NHNR2'AR2'B, -OR2'A, -NR2'ASO2R2'B, -NR2'AC(O)R2'B, -NR2'AC(O)OR2'B, -NR2'AOR2'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 wherein R2' and R3' may optionally be linked to form a substituted or unsubstituted heterocycloalkyl;

[0006] R3' is hydrogen, -CX3'3, -CHX3'2, -CH2X3', -OCX3'3, -OCHX3'2, -OCH2X3', -SR3'A, -NR3'AR3'B, -NHNR3'AR3'B, -OR3'A, -NR3'ASO2R3'B, -NR3'AC(O)R3'B, -NR3'AC(O)OR3'B, -NR3'AOR3'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 wherein R2' and R3' may optionally be connected to form a substituted or unsubstituted heterocycloalkyl;

[0006] R4' is hydrogen, halogen, -CX4'3, -CHX4'2, -CH2X4', -OCX4'3, -OCHX4'2, -OCH2X4', -CN, -S(O)2R4'A, -SR4'A, -S( O)R4'A, -SO2NR4'AR4'B, -NHC(O)NR4'AR4'B, -N(O)2, -NR4'AR4'B, -NHNR4'AR4'B, -C(O)R4'A, -C(O)-OR4'A -C(O)NR4'AR4'B, -C(O)NHNR4'AR4'B, -OR4'A, -NR4'ASO2R4'B, -NR4'AC(O)R4'B, -NR4'AC(O)OR4'B, -NR4'AOR4'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;

[0006] R5' is hydrogen, halogen, -CX5'3, -CHX5'2, -CH2X5', -OCX5'3,

[0006] -OCHX5'2, -OCH2X5', -CN, -S(O)2R5'A, -SR5'A, -S(O)R5'A, -SO2NR5'AR5'B, -NHC(O)NR 5'AR5'B, -N(O)2, -NR5'AR5'B, -NHNR5'AR5'B, -C(O)R5'A, -C(O)-OR5'A, -C(O)NR5'AR5'B, -C(O )NHNR5'AR5'B, -OR5'A, -NR5'ASO2R5'B, -NR5'AC(O)R5'B, -NR5'AC(O)OR5'B, -NR5'AOR5'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;

[0006] R12' is independently -OH or NHR12”;

[0006] R12” is hydrogen or a substituted or unsubstituted alkyl group;

[0006] R1'A, R1'B, R2'A, R2'B, R3'A, R3'B, R4'A, R4'B, R5'A, and R5'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, -CONH2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)OH, -NHOH, substituted or unsubstituted alkyl groups, substituted or unsubstituted heteroalkyl groups, substituted or unsubstituted cycloalkyl groups, substituted or unsubstituted heterocycloalkyl groups, substituted or unsubstituted aryl groups, or substituted or unsubstituted heteroaryl groups; or R2'A and R2'B substituents bonded to the same nitrogen atom may optionally be linked to form substituted or unsubstituted heterocycloalkyl groups or substituted or unsubstituted heteroaryl groups; or R3'A and R3'B substituents bonded to the same nitrogen atom may optionally be linked to form substituted or unsubstituted heterocycloalkyl groups or substituted or unsubstituted heteroaryl groups; and

[0006] X1', X2', X3', X4', and X5 are halogens independently.

[0007] In this embodiment, at least 80% of the compounds of formula (III) are in the trans isomer pure form. In this embodiment, at least 85% of the compounds of formula (III) are in the trans isomer pure form. In this embodiment, at least 90% of the compounds of formula (III) are in the trans isomer pure form. In this embodiment, at least 95% of the compounds of formula (III) are in the trans isomer pure form. In this embodiment, at least 98% of the compounds of formula (III) are in the trans isomer pure form. In this embodiment, at least 99% of the compounds of formula (III) are in the trans isomer pure form. In this embodiment, 100% of the compounds of formula (III) are in the trans isomer pure form.

[0008] In this embodiment, the reaction between the compound of formula (1) and the compound of formula (II) occurs in the absence of an additional catalyst.

[0009] In this embodiment, R2' and R3' are linked to form a substituted or unsubstituted piperidinyl ring. In this embodiment, the piperidinyl group is substituted with a substituted or unsubstituted heterocyclic alkyl group. In this embodiment, the substituted or unsubstituted heterocyclic alkyl group is a nitrogen-containing 3- to 6-membered heterocyclic alkyl group.

[0010] In this embodiment, the compound system of formula (I) is:

[0010] Among them:

[0010] R11' 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 this embodiment, R11' is a substituted or unsubstituted alkyl.

[0011] In this embodiment, the compound of formula III is:

[0011] wherein R11' is a substituted or unsubstituted alkyl group and each of n1' and n2' is 1 or 2. R1', L1', L2' and R12” are as described above, including embodiments.

[0012] In this embodiment, the carboxylic acid-directed reducing agent is 1,4-dihydropyridine. In this embodiment, the 1,4-dihydropyridine is a compound of formula (IV):

[0012] Among them:

[0012] L3' and L4' are independently O or NR20';

[0012] R20' is hydrogen or R21';

[0012] R21' is hydrogen, -CX21'3, -CHX21'2, -CH2X21', 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;

[0012] R6' is hydrogen, -CX6'3, -CHX6'2, -CH2X6', 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 in which 1,4-dihydropyridine is attached to the polymer support;

[0012] R7' is hydrogen, -CX7'3, -CHX7'2, -CH2X7', 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 in which 1,4-dihydropyridine is attached to the polymer support;

[0012] R8' is independently hydrogen, halogen, -CX8'3, -CHX8'2, -CH2X8', -OCX8'3, -OCHX8'2, -OCH2X8', -CN, -S(O)2R8'A, -SR8'A, -S(O)R8'A, -SO2NR8'AR8'B, -NHC(O)NR8'AR8'B, -N(O)2, -NR8'AR8'B, -NHNR8'AR8'B, -C(O)R8'A, -C(O)-OR8 'A、-C(O)NR8'AR8'B、-C(O)NHNR8'AR8'B、-OR8'A、-NR8'ASO2R8'B、-NR8'AC(O)R8'B、-NR8'AC(O)OR8'B、-NR8'AOR8'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;

[0012] R9' is independently hydrogen, halogen, -CX9'3, -CHX9'2, -CH2X9', -OCX9'3, -OCHX9'2, -OCH2X9', -CN, -S(O)2R9'A, -SR9'A, -S(O)R9'A, -SO2NR9'AR9'B, -NHC(O)NR9'AR9'B, -N(O)2, -NR9'AR9'B, -NHNR9'AR9'B, -C(O)R9'A, -C(O)-OR9 'A、-C(O)NR9'AR9'B、-C(O)NHNR9'AR9'B、-OR9'A、-NR9'ASO2R9'B、-NR9'AC(O)R9'B、-NR9'AC(O)OR9'B、-NR9'AOR9'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;

[0012] R10' is independently hydrogen, halogen, -CX10'3, -CHX10'2, -CH2X10', -OCX10'3, -OCHX10'2, -OCH2X10', -CN, -S(O)2R10'A, -SR10'A, -S(O)R10'A, -SO2NR10'AR10'B, -NHC(O)NR10'AR10'B, -N(O)2, -NR10'AR10'B, -NHNR10'AR10'B, -C(O)R10'A, -C(O)-O R10'A, -C(O)NR10'AR10'B, -C(O)NHNR10'AR10'B, -OR10'A, -NR10'ASO2R10'B, -NR10'AC(O)R10'B, -NR10'AC(O)OR10'B, -NR10'AOR10'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;

[0012] R8'A, R8'B, R9'A, R9'B, R10'A, and R10'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, -CONH2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)OH, -NHOH, substituted or unsubstituted alkyl groups, substituted or unsubstituted heteroalkyl groups, substituted or unsubstituted cycloalkyl groups, substituted or unsubstituted heterocycloalkyl groups, substituted or unsubstituted aryl groups, or substituted or unsubstituted heteroaryl groups; and

[0012] X6', X7', X8', X9' and X10 are halogens independently.

[0013] These and other embodiments of this disclosure will become apparent from the following description of preferred embodiments, although variations and modifications therein may affect them without departing from the spirit and scope of the novel concept of this disclosure.

[0013] Detailed Description

[0014] This document provides a method for synthesizing a G protein-coupled receptor regulator or a salt or ester thereof. The method involves synthesizing a G protein-coupled receptor regulator or a salt or ester thereof having at least one amine moiety and one carboxylic acid or carboxylic acid-derived moiety with a 3 to 8-membered cycloalkyl ring having a partial substitution of a carboxylic acid or carboxylic acid-derived carboxylic acid ring, wherein the amine moiety and the carboxylic acid or carboxylic acid-derived carboxylic acid ring can be in cis or trans isomer configurations.

[0014] Definition

[0015] The abbreviations used herein have their conventional meanings in the fields of chemistry and biology. The chemical structures and formulas described herein are constructed according to the standard rules of chemical valence known in the field of chemistry.

[0016] The substituents are specified by their conventional chemical formula and written from left to right. They also contain chemically identical substituents written from right to left, such as -CH2O- being equivalent to -OCH2-.

[0017] Unless otherwise stated, the term "alkyl" itself, or as part of another substituent, refers to a straight-chain (i.e., unbranched) or branched carbon chain (or carbon) or combination thereof, which may be fully saturated, mono- or polyunsaturated, and may include monovalent, divalent, and polyvalent groups. The alkyl group may include a specified number of carbons (e.g., C1-C10 refers to 1 to 10 carbons). Alkyl groups are uncyclic chains. Examples of saturated hydrocarbon groups include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, di-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, etc. Unsaturated alkyl groups are alkyl groups having one or more double or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotonyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologues and isomers. Alkyl groups are attached to the alkyl group of the remainder of the molecule via an oxygen graft (-O-). The alkyl moiety may be an alkenyl moiety. The alkyl moiety may be an alkynyl moiety. The alkyl moiety may be fully saturated. In addition to one or more double bonds, the alkenyl group may include more than one double bond and / or one or more triple bonds. In addition to one or more triple bonds, the alkynyl group may include more than one triple bond and / or one or more double bonds.

[0018] The term "alkenylene," either itself or as part of another substituent, may refer to a divalent group derived from an alkyl group, such as -CH2CH2CH2CH2-, unless otherwise specified, but is not limited thereto. Typical alkyl (or alkenylene) groups have 1 to 24 carbon atoms, and preferably 10 or fewer. "Low-chain alkyl" or "low-chain alkenylene" refers to a shorter-chain alkyl or alkenylene group, typically having 8 or fewer carbon atoms. The term "alkenylene," either itself or as part of another substituent, refers to a divalent group derived from an alkene, unless otherwise specified.

[0019] Unless otherwise stated, the term "heteroalkyl" itself, or in combination with another term, refers to a stable straight or branched chain or combination thereof, comprising at least one carbon atom and at least one heteroatom (e.g., O, N, P, Si, and S), wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. The heteroatom (e.g., N, S, Si, or P) may be located at any internal position of the heteroalkyl group or at a position where the alkyl group is attached to the remainder of the molecule. The heteroalkyl group is an uncyclic 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-CH2-CH3, and -CN. Up to two or three heteroatoms may be consecutive, examples include -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. The heteroalkyl moiety may include one heteroatom (e.g., O, N, S, Si, or P). The heteroalkyl moiety may include two optional different heteroatoms (e.g., O, N, S, Si, or P). The heteroalkyl moiety may include three optional different heteroatoms (e.g., O, N, S, Si, or P). The heteroalkyl moiety may include four optional different heteroatoms (e.g., O, N, S, Si, or P). The heteroalkyl moiety may include five optional different heteroatoms (e.g., O, N, S, Si, or P). The heteroalkyl moiety may include up to eight optional different heteroatoms (e.g., O, N, S, Si, or P). Unless otherwise stated, the term "heteroalkenyl" itself or in combination with another term refers to a heteroalkyl group comprising at least one double bond. In addition to one or more double bonds, a heteroalkenyl group may optionally include more than one double bond and / or one or more triple bonds. Unless otherwise stated, the term "heteroyneyl" itself or in combination with another term refers to a heteroalkyl group comprising at least one triple bond. In addition to one or more triple bonds, a heteroyneyl group may optionally include more than one triple bond and / or one or more double bonds.

[0020] Similarly, the term "heteroalkyl" itself, or as part of another substituent, can, unless otherwise stated, represent a divalent group derived from a heteroalkyl group, such as -CH2-CH2-S-CH2-CH2- and -CH2-S-CH2-CH2-NH-CH2-, but is not limited thereto. For heteroalkyl groups, the heteroatom can also occupy one or both chain ends (e.g., alkyloxy, alkyldioxy, alkylamino, alkyldiamino, etc.). Furthermore, for alkyl and heteroalkyl linking groups, the direction written in the formula of the linking group does not imply the direction of the linking group. For example, the formula -C(O)2R'- represents both -C(O)2R'- and -R'C(O)2-. As described above, heteroalkyl groups as used herein include those groups attached to the remainder of the molecule by a heteroatom, such as -C(O)R', -C(O)NR', ​​-NR'R", -OR', -SR', and / or -SO2R'. When referring to "heteroalkyl" and subsequently mentioning a specific heteroalkyl group, such as -NR'R", it should be understood that the terms heteroalkyl and -NR'R are not redundant or mutually exclusive. Rather, listing specific heteroalkyl groups is for clarity. Therefore, the term "heteroalkyl" should not be construed herein as excluding specific heteroalkyl groups, such as -NR'R".

[0021] Unless otherwise stated, the terms "cycloalkyl" and "heterocycloalkyl" on their own or in combination with other terms refer to cyclic "alkyl" and "heteroalkyl," respectively. Cycloalkyl and heterocycloalkyl are not aromatic hydrocarbons. Furthermore, for heterocycloalkyl, the heteroatom may occupy the position where the heterocycle is attached to the rest of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, etc. 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, etc. "Cycloalkyl" and "heterocyclic alkyl" alone or as part of another substituent refer to divalent groups derived from cycloalkyl and heterocyclic alkyl, respectively.

[0022] In this embodiment, the term "cycloalkyl" refers to a monocyclic, bicyclic, or polycyclic cycloalkyl ring system. In this embodiment, a monocyclic system is a cyclic hydrocarbon group containing 3 to 8 carbon atoms, wherein these groups may be saturated or unsaturated, but are not aromatic hydrocarbons. In this embodiment, the cycloalkyl group is fully saturated. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. Bicyclic cycloalkyl ring systems are bridged monocyclic or fused bicyclic rings. In this embodiment, the bridged monocyclic ring contains a monocyclic alkyl ring, wherein two non-adjacent carbon atoms of the monocyclic ring are connected by an extended alkyl bridge between one and three additional carbon atoms (i.e., a bridging group in the form of (CH2)w, where w is 1, 2, or 3). Representative examples of bicyclic ring systems include, but are not limited to, bicyclic [3.1.1]heptane, bicyclic [2.2.1]heptane, bicyclic [2.2.2]octane, bicyclic [3.2.2]nonane, bicyclic [3.3.1]nonane, and bicyclic [4.2.1]nonane. In this embodiment, the fused bicyclic alkyl ring system contains a monocyclic alkyl ring fused to a phenyl, monocyclic alkyl, monocyclic alkenyl, monocyclic heterocyclic, or monocyclic heteroaryl group. In this embodiment, the bridging or fused bicyclic cycloalkyl group is connected to the parent molecule moiety via any carbon atom contained within the monocyclic cycloalkyl ring. In this embodiment, the cycloalkyl group is optionally substituted with one or two separate side oxygen or thio groups. In this embodiment, the fused bicyclic cycloalkyl group is a 5- or 6-membered monocyclic cycloalkyl ring fused with a phenyl ring, a 5- or 6-membered monocyclic cycloalkyl group, a 5- or 6-membered monocyclic cycloalkenyl group, a 5- or 6-membered monocyclic heterocyclic group, or a 5- or 6-membered monocyclic heteroaryl group, wherein the fused bicyclic cycloalkyl group is optionally substituted with one or two independent side oxygen or thio groups. In this embodiment, the polycyclic cycloalkyl ring system is formed by fusing a monocyclic cycloalkyl ring (base ring) with (i) any ring system selected from the group consisting of bicyclic aryl, bicyclic heteroaryl, bicyclic cycloalkyl, bicyclic cycloalkenyl, and bicyclic heterocyclic groups; or with (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 heterocyclic groups. In this embodiment, the polycyclic cycloalkyl group is attached to the parent molecule moiety by any carbon atom contained within the base ring. In this embodiment, the polycyclic cycloalkyl ring system is formed by fusing a monocyclic cycloalkyl ring (base ring) with (i) any ring system selected from the group consisting of bicyclic aryl, bicyclic heteroaryl, bicyclic cycloalkyl, bicyclic cycloalkenyl, and bicyclic heterocyclic groups; or by fusing with (ii) two other ring systems independently selected from the group consisting of phenyl, monocyclic heteroaryl, monocyclic cycloalkyl, monocyclic cycloalkenyl, and monocyclic heterocyclic groups.Examples of polycyclic cycloalkyl groups include, but are not limited to, tetradecahydrophenanthrenyl, perhydrophenothiazin-1-yl, and perhydrophenoxazin.

[0023] In this embodiment, the cycloalkyl group is a cycloalkenyl group. The term "cycloalkenyl" is used according to its general meaning. In this embodiment, cycloalkenyl refers to a monocyclic, bicyclic, or polycyclic cycloalkenyl ring system. In this embodiment, a monocyclic cycloalkenyl ring system is a cyclic hydrocarbon group containing 3 to 8 carbon atoms, wherein these groups are unsaturated (i.e., contain at least one cyclic carbon double bond) but are not aromatic. Examples of monocyclic cycloalkenyl ring systems include cyclopentenyl and cyclohexenyl. In this embodiment, the monocyclic cycloalkenyl ring is a bridged monocyclic or fused bicyclic. In this embodiment, the bridged monocyclic contains a monocyclic cycloalkenyl ring, wherein the two non-adjacent carbon atoms of the monocyclic are connected by an alkyl bridge between one and three additional carbon atoms (i.e., a bridging group of the form (CH2)w, where w is 1, 2, or 3). Representative examples of bicyclic cycloalkenyl groups include, but are not limited to, norbornenyl and bicyclo[2.2.2]oct 2enyl. In this embodiment, the fused bicyclic cycloalkenyl system contains a monocyclic cycloalkenyl ring fused to a phenyl, monocyclic alkyl, monocyclic alkenyl, monocyclic heterocyclic, or monocyclic heteroaryl group. In this embodiment, the bridged or fused bicyclic cycloalkenyl group is connected to the parent molecule moiety by any carbon atom contained within the monocyclic cycloalkenyl ring. In this embodiment, the cycloalkenyl group is optionally substituted with one or two independent side oxygen or thio groups. In this embodiment, the polycyclic cycloalkenyl ring comprises a monocyclic cycloalkenyl ring (base ring) fused with any ring system selected from the group consisting of (i) bicyclic aryl, bicyclic heteroaryl, bicyclic cycloalkyl, bicyclic cycloalkenyl, and bicyclic heterocyclic groups; or fused with 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 heterocyclic groups. In this embodiment, the polycyclic cycloalkenyl group is attached to the parent molecule moiety by any carbon atom contained within the base ring. In this embodiment, the polycyclic cycloalkenyl ring comprises a monocyclic cycloalkenyl ring (base ring) formed by fusion with any ring system selected from the group consisting of (i) bicyclic aryl, bicyclic heteroaryl, bicyclic cycloalkyl, bicyclic cycloalkenyl and bicyclic heterocyclic groups; or formed by fusion with (ii) two ring systems independently selected from the group consisting of phenyl, monocyclic heteroaryl, monocyclic cycloalkyl, monocyclic cycloalkenyl and monocyclic heterocyclic groups.

[0024] In this embodiment, the heterocyclic alkyl group is a heterocyclic group. The term "heterocyclic group" as used herein refers to a monocyclic, bicyclic, or polycyclic heterocycle. A heterocyclic monocyclic heterocycle is a 3, 4, 5, 6, or 7-membered ring containing at least one heteroatom independently selected from the group consisting of O, N, and S, wherein the ring is saturated or unsaturated, but not aromatic. A 3- or 4-membered ring contains one heteroatom selected from the group consisting of O, N, and S. A 5-membered ring may 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 contains zero, one, or two double bonds and one, two, or three heteroatoms selected from the group consisting of O, N, and S. The heterocyclic monocyclic heterocycle is attached to the parent molecule moiety by any carbon atom or any nitrogen atom contained within the heterocyclic monocyclic heterocycle.Representative examples of heterocyclic monocyclic heterocycles include, but are not limited to, azetidinyl / azepanyl, aziridinyl / aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, and 1,3-dithiophenyl / 1,3-Dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl, diazolidinyl oxadiazolidinyl), oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxothiomorpholinyl (thiomorpholine) sulfone), thiopyranyl, and trithianyl. Heterocyclic bicyclic heterocycles are monocyclic heterocycles fused with phenyl, monocyclic alkyl, monocyclic alkenyl, monocyclic heterocyclic group, or monocyclic heteroaryl group. Heterocyclic bicyclic heterocycles are attached to the parent molecule by any carbon atom or any nitrogen atom contained in the monocyclic heterocyclic portion of the bicyclic system.Representative examples of bicyclic heterocyclic groups 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 this embodiment, the heterocyclic group is optionally substituted with one or two independent side oxygen or thio groups. In some embodiments, the bicyclic heterocyclic group is a 5- or 6-membered monocyclic heterocyclic ring fused to a phenyl ring, a 5- or 6-membered monocyclic cycloalkyl group, a 5- or 6-membered monocyclic cycloalkenyl group, a 5- or 6-membered monocyclic heterocyclic group, or a 5- or 6-membered monocyclic heteroaryl group, wherein the bicyclic heterocyclic group is optionally substituted by one or two independent side oxygen or thio groups. The polycyclic heterocyclic ring system is formed by fusing a monocyclic heterocyclic ring (base ring) with (i) any ring system selected from the group consisting of bicyclic aryl, bicyclic heteroaryl, bicyclic cycloalkyl, bicyclic cycloalkenyl, and bicyclic heterocyclic groups; or with (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 heterocyclic groups. The polycyclic heterocyclic group is attached to the parent molecule moiety by any carbon or nitrogen atom contained within the base ring. In this embodiment, the polycyclic heterocyclic base ring system is formed by fusing a monocyclic heterocyclic base ring (base ring) with (i) any ring system selected from the group consisting of bicyclic aryl, bicyclic heteroaryl, bicyclic cycloalkyl, bicyclic cycloalkenyl, and bicyclic heterocyclic groups; or by fusing with (ii) two other ring systems independently selected from the group consisting of phenyl, monocyclic heteroaryl, monocyclic cycloalkyl, monocyclic cycloalkenyl, and monocyclic heterocyclic groups.Examples of polycyclic heterocyclic 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, and 10,11-dihydro-5H-dibenzo[b,f]acridin-5-yl. hydro-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.

[0025] Unless otherwise stated, the term "halogen" itself, or as part of another substituent, refers to a fluorine, chlorine, bromine, or iodine atom. Furthermore, terms such as "halogenated alkyl" mean both monohalogenated and polyhalogenated alkyl groups. For example, the term "halogenated (C1-C4) alkyl" includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, etc.

[0026] Unless otherwise stated, the term "acetylated" means -C(O)R, wherein R is a substituted or unsubstituted alkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl.

[0027] Unless otherwise stated, the term "aryl" refers to a polyunsaturated, aromatic, hydrocarbon substituent that may be a monocyclic or polycyclic ring (preferably 1 to 3 rings) fused together (i.e., a fused-ring aryl) or covalently linked. A fused-ring aryl refers to a plurality of fused rings, wherein at least one fused ring is an aryl ring. The term "heteroaryl" refers to an aryl (or ring) containing at least one heteroatom (such as N, O, or S), wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternarily ammonized. Thus, the term "heteroaryl" includes fused-ring heteroaryl groups (i.e., multiple rings fused together, wherein at least one fused ring is a heteroaryl ring). 5,6-fused-ring heteroaryleline refers to two rings fused together, one ring being 5-membered and the other ring being 6-membered, wherein at least one ring is a heteroaryl ring. Similarly, 6,6-fused-ring heteroaryleline refers to two rings fused together, one ring being 6-membered and the other ring being 6-membered, wherein at least one ring is a heteroaryl ring. 6,5-Fused-ring heteroaryl refers to two rings fused together, one ring being 6-membered and the other 5-membered, with at least one ring being a heteroaryl ring. Heteroaryl groups can be attached to the rest of the molecule via carbon or heteroatoms. Unrestricted examples of aryl and heteroaryl groups include phenyl, naphthyl, pyrrolyl, pyrazolyl, pyridazinyl, triazinyl, pyrimidinyl, imidazolyl, pyrazinyl, purinyl, oxazolyl, isoxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidyl, benzothiazolyl, benzoxazolyl, and benzimidazolyl. (The following are listed as unrelated terms: enzimidazolyl, benzofuran, isobenzofuranyl, indolyl, isoindolyl, benzothiophenyl, isoquinolyl, quinoxalinyl, quinolyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl)4-Imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl The substituents for each of the above aryl and heteroaryl ring systems are selected from the acceptable substituent group described below. "Arylidene" and "heteroarylidene," whether alone or as part of another substituent, refer to divalent groups derived from aryl and heteroaryl groups, respectively. Heteroaryl substituents can bond to the nitrogen-O- atom of a cyclic heteroatom.

[0028] A spirocyclic ring system consists of two or more rings, wherein adjacent rings are connected by a single atom. Individual rings within a spirocyclic ring may be identical or different. Individual rings within a spirocyclic ring may be substituted or unsubstituted and may have substituents different from those of other individual rings in a group of spirocyclic rings. When not part of a spirocyclic ring, possible substituents of individual rings within a spirocyclic ring are possible substituents of the same ring (e.g., substituents of cycloalkyl or heterocyclic alkyl rings). A spirocyclic ring may be a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heteroalkyl, or a substituted or unsubstituted heteroalkyl, and individual rings within a spirocyclic ring group may be any of those in the preceding list, including all rings of one type (e.g., all substituted heteroalkyl rings, wherein each ring may be the same or different substituted heteroalkyl). 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 wherein each ring may be a different ring. When referring to spirocyclic systems, a substituted spirocyclic system means that at least one ring is substituted, and each substituent may optionally be different.

[0029] The symbol "" indicates the attachment point between the chemical part and the rest of the molecule or chemical formula.

[0030] As used herein, the term "side oxygen" refers to oxygen that is double-bonded to a carbon atom.

[0031] The term "alkylarylene" refers to an arylene moiety covalently bonded to an alkyl linker (also referred to herein as an alkyl linker). In this embodiment, the alkylarylene has the following formula:

[0031]

[0032] The alkyl aryl moiety may be substituted (e.g., with a substituent) by a halogen, a side oxygen group, -N3, -CF3, -CCl3, -CBr3, -CI3, -CN, -CHO, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO2CH3, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, a substituted or unsubstituted C1 to C5 alkyl group, or a substituted or unsubstituted 2 to 5 heteroalkyl group (e.g., with a substituent) into the alkyl moiety or the aryl linker (e.g., at carbon 2, 3, 4, or 6). In this embodiment, the alkyl aryl group is unsaturated.

[0033] Each of the above terms (e.g., "alkyl", "heteroalkyl", "cycloalkyl", "heterocycloalkyl", "aryl" and "heteroaryl") includes both substituted and unsubstituted forms of the indicated group. Preferred substituents for each type of group are provided below.

[0034] The substituents of alkyl and heteroalkyl groups (including groups commonly referred to as alkylene, alkenyl, heteroalkenyl, heteroalkenyl, ynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) may be selected from -OR', =O, =NR', =N-OR', -NR'R”, -SR', -halogen, -SiR'R”R''', -OC(O)R', -C(O)R', -CO2R', -CONR'R”, -OC(O)NR'R”, -NR”C(O)R', -NR'-C(O)NR”R''', -NR”C(O)2R', -NR-C(NR'R”R''')=NR'''', -NR-C(NR'R”)=NR''', -S(O)R', -S(O)2R', -S(O)2NR'R”, -NRSO2R', One or more of the following groups, but not limited to: -NR'NR”R''', -ONR'R”, -NR'C(O)NR”NR'''R'''', -CN, -NO2, -NR'SO2R”, -NR'C(O)R”, -NR'C(O)-OR”, -NR'OR”, and the number ranges from 0 to (2m'+1), where m' is the total number of carbon atoms in the group. R, R', R”, R''' and R'''' are each preferably independently hydrogen, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl (e.g., an aryl substituted with 1 to 3 halogens), a substituted or unsubstituted heteroaryl, a substituted or unsubstituted alkyl, an alkoxy or thioalkoxy group or an arylalkyl group. When the compounds described herein include multiple R groups, for example, when multiple such groups are present, each R group is independently selected as an R', R”, R''', and R'''' group. When R' and R” are attached to the same nitrogen atom, they can combine with the nitrogen atom to form a 4-, 5-, 6-, or 7-membered ring. For example, -NR'R” includes, but is not limited to, 1-pyrrolidyl and 4-morpholinyl. From the above discussion of substituents, those skilled in the art will understand that the term "alkyl" means a group comprising a carbon atom including a group other than a hydrogen group, such as haloalkyl (e.g., -CF3 and -CH2CF3) and acetyl (e.g., -C(O)CH3, -C(O)CF3, -C(O)CH2OCH3, etc.).

[0035] Similar to the substituents described for alkyl groups, the substituents for aryl and heteroaryl groups are diverse and selected from, for example: -OR', -NR'R”, -SR', -halogen, -SiR'R”R''', -OC(O)R', -C(O)R', -CO2R', -CONR'R”, -OC(O)NR'R”, -NR”C(O)R', -NR'-C(O)NR”R''', -NR”C(O)2R', -NR-C(NR'R”R''')=NR'''', -NR-C(NR'R”)=NR' The quantities of '', -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, fluoro(C1-C4)alkyl, -NR'SO2R”, -NR'C(O)R”, -NR'C(O)-OR”, -NR'OR”, range from zero to the open valence of the aromatic ring system. The total number of valence groups; wherein 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 multiple R groups, for example, when multiple such groups are present, each R group is independently selected as each R', R”, R''', and R'''' group.

[0036] Substituents on the ring (e.g., cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cyclopyranyl, heterocyclopyranyl, arylene, or heteroarylene) can be described as substituents on the ring, rather than on a specific atom of the ring (often referred to as floating substituents). In this case, the substituent can be attached to any ring atom (obeying the rules of valence), and in the case of fused or spirocyclic rings, it is described as a substituent associated with one of the members of the fused or spirocyclic ring (floating substituents on a single ring), and can be substituents on any fused or spirocyclic ring (floating substituents on multiple rings). When a substituent is attached to a ring but not to a specific atom (a floating substituent), and the substituent's subscript is an integer greater than one, multiple substituents can 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 attachment point of the ring to the remainder of the molecule is not limited to a single atom (floating substituent), the attachment point can be any atom of the ring, and in the case of fused or spirocyclic rings, any atom of any fused or spirocyclic ring simultaneously obeys the chemical valence rules. If the ring, fused, or spirocyclic ring contains one or more cyclic heteroatoms, and the ring, fused, or spirocyclic ring shows having more than one floating substituent (including, but not limited to, attachment points to the remainder of the molecule), then the floating substituent can be bonded to the heteroatom. When the cyclic heteroatom is shown to be bonded to one or more hydrogen atoms in a structure or chemical formula having a floating substituent (e.g., a cyclic nitrogen, two bonds connecting the ring atoms, and a third bond connecting the hydrogen), then when the heteroatom is bonded to a floating substituent, the substituent will be understood as replacing the hydrogen, simultaneously obeying the chemical valence rules.

[0037] Two or more substituents may optionally be linked to form aryl, heteroaryl, cycloalkyl, or heterocycloalkyl groups. Such so-called cycloforming substituents are typically (though not always) found attached to a cyclic matrix. In this embodiment, the cycloforming substituent is attached to adjacent members of the base structure. For example, two cycloforming substituents attached to adjacent members of the cyclic matrix structure produce a fused ring structure. In another embodiment, the cycloforming substituent is attached to a single member of the base structure. For example, two cyclic substituents attached to a single member of the cyclic matrix structure produce a spirocyclic structure. In yet another embodiment, the cycloforming substituent is attached to a non-adjacent member of the base structure.

[0038] The two substituents on adjacent atoms of the aryl or heteroaryl ring may optionally form a ring of the formula -TC(O)-(CRR')qU-, wherein T and U are independently -NR-, -O-, -CRR'-, or a single bond, and q is an integer between 0 and 3. Alternatively, the two substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be substituted with a substituent of the formula -A-(CH2)rB-, wherein A and B are independently -CRR'-, -O-, -NR-, -S-, -S(O)-, -S(O)2-, -S(O)2NR'-, or a single bond, and r is an integer between 1 and 4. One of the single bonds in the newly formed ring may optionally be replaced by a double bond. Alternatively, the two substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced by substituents of the formula -(CRR')s-X'-(C”R”R''')d-, where s and d are independent integers between 0 and 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.

[0039] As used herein, the term "heteroatom" or "cyclic heteroatom" refers to oxygen (O), nitrogen (N), sulfur (S), phosphorus (P) and silicon (Si).

[0040] As used herein, “substituent” refers to a group selected from the following:

[0040] (A) Side oxygen group, 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 groups (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl groups (e.g., 2 to 8-membered heteroalkyl, 2 to 6-membered heteroalkyl, or 2 to 4-membered heteroalkyl), unsubstituted cycloalkyl groups (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl groups (e.g., 3 to 8-membered heterocycloalkyl, 3 to 6-membered heterocycloalkyl, or 5 to 6-membered heterocycloalkyl), unsubstituted aryl groups (e.g., C6-C10 aryl, C10 aryl, or phenyl), or unsubstituted heteroaryl groups (e.g., 5 to 10-membered heteroaryl, 5 to 9-membered heteroaryl, or 5 to 6-membered heteroaryl), and

[0040] (B) Alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl substituted with at least one of the following substituents:

[0040] (i) Side oxygen group, 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 groups (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl groups (e.g., 2 to 8-membered heteroalkyl, 2 to 6-membered heteroalkyl, or 2 to 4-membered heteroalkyl), unsubstituted cycloalkyl groups (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl groups (e.g., 3 to 8-membered heterocycloalkyl, 3 to 6-membered heterocycloalkyl, or 5 to 6-membered heterocycloalkyl), unsubstituted aryl groups (e.g., C6-C10 aryl, C10 aryl, or phenyl), or unsubstituted heteroaryl groups (e.g., 5 to 10-membered heteroaryl, 5 to 9-membered heteroaryl, or 5 to 6-membered heteroaryl), and

[0040] (ii) Alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl substituted with at least one of the following substituents:

[0040] (a) Side oxygen group, 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, -OCH F2, unsubstituted alkyl groups (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl groups (e.g., 2 to 8-membered heteroalkyl, 2 to 6-membered heteroalkyl, or 2 to 4-membered heteroalkyl), unsubstituted cycloalkyl groups (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl groups (e.g., 3 to 8-membered heterocycloalkyl, 3 to 6-membered heterocycloalkyl, or 5 to 6-membered heterocycloalkyl), unsubstituted aryl groups (e.g., C6-C10 aryl, C10 aryl, or phenyl), or unsubstituted heteroaryl groups (e.g., 5 to 10-membered heteroaryl, 5 to 9-membered heteroaryl, or 5 to 6-membered heteroaryl), and

[0040] (b) An alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl group substituted with at least one of the following substituents: lateral oxygen, 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, -O CHBr2, -OCHI2, -OCHF2, unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2 to 8-membered heteroalkyl, 2 to 6-membered heteroalkyl, or 2 to 4-membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8-membered heterocycloalkyl, 3 to 6-membered heterocycloalkyl, or 5 to 6-membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10-membered heteroaryl, 5 to 9-membered heteroaryl, or 5 to 6-membered heteroaryl).

[0041] As used herein, “size-restricted substituent” or “size-restricted substituent group” means “substituent” of a group selected from all of the above substituents, wherein each substituted or unsubstituted alkyl group is a substituted or unsubstituted C1-C20 alkyl group, each substituted or unsubstituted heteroalkyl group is a substituted or unsubstituted 2- to 20-membered heteroalkyl group, each substituted or unsubstituted cycloalkyl group is a substituted or unsubstituted C3-C8 cycloalkyl group, each substituted or unsubstituted heterocycloalkyl group is a substituted or unsubstituted 3- to 8-membered heterocycloalkyl group, each substituted or unsubstituted aryl group is a substituted or unsubstituted C6-C10 aryl group, and each substituted or unsubstituted heteroaryl group is a substituted or unsubstituted 5- to 10-membered heteroaryl group.

[0042] As used herein, “lower substituent” or “lower substituent group” refers to a “substituent” selected from all of the above substituents, wherein each substituted or unsubstituted alkyl group is a substituted or unsubstituted C1-C8 alkyl group, each substituted or unsubstituted heteroalkyl group is a substituted or unsubstituted 2- to 8-membered heteroalkyl group, each substituted or unsubstituted cycloalkyl group is a substituted or unsubstituted C3-C7 cycloalkyl group, each substituted or unsubstituted heterocycloalkyl group is a substituted or unsubstituted 3- to 7-membered heterocycloalkyl group, each substituted or unsubstituted aryl group is a substituted or unsubstituted C6- to C10 aryl group, and each substituted or unsubstituted heteroaryl group is a substituted or unsubstituted 5- to 9-membered heteroaryl group.

[0043] In some embodiments, each substituent group in the compounds described herein is substituted with at least one substituent. More specifically, in some embodiments, each substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene in the compounds described 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-restricted substituent. In other embodiments, at least one or all of these groups are substituted with at least one lower substituent.

[0044] In other embodiments of the compounds herein, each substituted or unsubstituted alkyl group may be a substituted or unsubstituted C1-C20 alkyl group, each substituted or unsubstituted heteroalkyl group may be a substituted or unsubstituted 2- to 20-membered heteroalkyl group, each substituted or unsubstituted cycloalkyl group may be a substituted or unsubstituted C3-C8 cycloalkyl group, each substituted or unsubstituted heterocycloalkyl group may be a substituted or unsubstituted 3- to 8-membered heterocycloalkyl group, each substituted or unsubstituted aryl group may be a substituted or unsubstituted C6- to C10 aryl group, and / or each substituted or unsubstituted heteroaryl group may be a substituted or unsubstituted 5- to 10-membered heteroaryl group. In other embodiments of the compounds herein, each substituted or unsubstituted alkyl group is a substituted or unsubstituted C1-C20 alkyl group, each substituted or unsubstituted heteroalkyl group is a substituted or unsubstituted 2- to 20-membered heteroalkyl group, each substituted or unsubstituted cycloalkyl group is a substituted or unsubstituted C3-C8 cycloalkyl group, each substituted or unsubstituted heteroalkyl group is a substituted or unsubstituted 3- to 8-membered heteroalkyl group, each substituted or unsubstituted aryl group is a substituted or unsubstituted C6-C10 aryl group, and / or each substituted or unsubstituted heteroaryl group is a substituted or unsubstituted 5- to 10-membered heteroaryl group.

[0045] In certain embodiments, each substituted or unsubstituted alkyl group is a substituted or unsubstituted C1-C8 alkyl group, each substituted or unsubstituted heteroalkyl group is a substituted or unsubstituted 2- to 8-membered heteroalkyl group, each substituted or unsubstituted cycloalkyl group is a substituted or unsubstituted C3-C7 cycloalkyl group, each substituted or unsubstituted heterocycloalkyl group is a substituted or unsubstituted 3- to 7-membered heterocycloalkyl group, each substituted or unsubstituted aryl group is a substituted or unsubstituted C6- to C10 aryl group, and / or each substituted or unsubstituted heteroaryl group is a substituted or unsubstituted 5- to 9-membered heteroaryl group. In certain embodiments, each substituted or unsubstituted alkyl group is a substituted or unsubstituted C1-C8 alkyl group, each substituted or unsubstituted heteroalkyl group is a substituted or unsubstituted 2- to 8-membered heteroalkyl group, each substituted or unsubstituted cycloalkyl group is a substituted or unsubstituted C3-C7 cycloalkyl group, each substituted or unsubstituted heteroalkyl group is a substituted or unsubstituted 3- to 7-membered heteroalkyl group, each substituted or unsubstituted aryl group is a substituted or unsubstituted C6- to C10 aryl group, and / or each substituted or unsubstituted heteroaryl group is a substituted or unsubstituted 5- to 9-membered heteroaryl group. In certain embodiments, the compound is a chemical substance listed in the following embodiments section, figures, or tables.

[0046] In this embodiment, the substituted or unsubstituted portions (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 heterocycloalkylene, substituted or unsubstituted arylene, and / or substituted or unsubstituted heteroarylene) are unsubstituted (e.g., unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted alkylene, unsubstituted cycloalkylene, unsubstituted heterocycloalkylene, unsubstituted arylene and / or unsubstituted heteroarylene, respectively). In this embodiment, the substituted or unsubstituted portions (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 heterocycloalkylene, substituted or unsubstituted arylene, and / or substituted or unsubstituted heteroarylene) are substituted (e.g., respectively 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).

[0047] In this embodiment, the substituted portion (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, wherein if the substituted portion is substituted with multiple substituents, each substituent may optionally be different. In this embodiment, if the substituted portion is substituted with multiple substituents, each substituent is different.

[0048] In this embodiment, the substituted portion (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-restricted substituent, wherein if the substituted portion is substituted with multiple size-restricted substituents, each size-restricted substituent may optionally be different. In this embodiment, if the substituted portion is substituted with multiple size-restricted substituents, each size-restricted substituent is different.

[0049] In this embodiment, the substituted portion (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 low-position substituent, wherein if the substituted portion is substituted with multiple low-position substituents, each low-position substituent may optionally be different. In this embodiment, if the substituted portion is substituted with multiple low-position substituents, each low-position substituent is different.

[0050] In this embodiment, the substituted portion (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, a size-restricted substituent, or a low-position substituent; wherein, if the substituted portion is substituted by a plurality of groups selected from substituents, size-restricted substituents, and low-position substituents, then each substituent, size-restricted substituent, and / or low-position substituent may optionally be different. In this embodiment, if the substituted portion is substituted by a plurality of groups selected from substituents, size-restricted substituents, and low-position substituents, then each substituent, size-restricted substituent, and / or low-position substituent is different.

[0051] Certain compounds disclosed herein have asymmetric carbon atoms (optical or chiral centers) or double bonds; for amino acids, mirror-image isomers, racemates, non-mirror-image isomers, tautomers, geometric isomers, stereoisomers in the form of (R)- or (S)-, or (D)- or (L)-, are defined by absolute stereochemistry, and any single isomer is included within the scope of this disclosure. The compounds disclosed herein do not include compounds known in the art to be too unstable to synthesize and / or isolate. This disclosure is intended to include compounds in racemic and optically pure forms. Optically active (R)- and (S)-, or (D)- and (L)- isomers can be prepared using chiral synthetic members or chiral reagents, or identified using conventional techniques. When the compounds described herein contain olefinic bonds or other geometrically asymmetric centers, and unless otherwise specified, the compound is intended to include both E and Z geometric isomers.

[0052] As used herein, "isomers" refers to compounds that have the same number and type of atoms and therefore the same molecular weight, but differ in the arrangement or configuration of the atoms.

[0053] The term "tautomer" as used herein refers to one of two or more structural isomers existing in an equilibrium state, and is easily transformed from one isomer form to another.

[0054] It is obvious to those skilled in the art that certain compounds may exist in tautomeric forms, and all such tautomeric forms of these compounds fall within this scope.

[0055] Unless otherwise stated, the structure described herein also means all stereochemical forms of that structure; that is, the R and S configurations of each asymmetric center. Therefore, single stereochemical isomers of this compound as well as mixtures of mirror- and non-mirror-mirror isomers are included within this scope.

[0056] Unless otherwise stated, the structures described herein also mean that compounds differ only in the presence of one or more isotope-rich atoms. For example, compounds having existing structures are within the scope of this disclosure, except that hydrogen is replaced by deuterium or tritium, or carbon is replaced by carbon rich in 13C- or 14C-.

[0057] The compounds disclosed herein may also contain atomic isotopes in non-natural proportions on one or more atoms constituting the compound. For example, the compound may be radiolabeled with radioactive isotopes, such as tritium (3H), iodine-125 (125I), or carbon-14 (14C). Regardless of whether they are radioactive, all isotopic variations of the compounds disclosed herein are included within the scope of this disclosure.

[0058] It should be noted that throughout the application, substitutes are written in the Markusi group, for example, each amino acid position contains more than one possible amino acid. Specifically, it should be conceived that each member of the Markusi group should be considered individually, thereby including another embodiment, and the Markusi group should not be understood as a single member.

[0059] The term "analogue" is used according to its usual meaning in chemistry and biology, referring to a compound that is structurally similar to another compound (i.e., the so-called "reference" compound) but different in composition. For example, replacing an atom with an atom of a different element, or having a specific functional group, replacing one functional group with another, or having absolute stereochemistry of one or more chiral centers of the reference compound. Thus, an analogue is a compound that is functionally and morphologically similar or comparable, but structurally or derived from the reference compound.

[0060] The term “a” or “an” as used herein refers to one or more. Furthermore, the phrase “substituted with a[n]” as used herein means that the specified group may be substituted with one or more of any or all named substituents. For example, when a group such as an alkyl or heteroaryl group is “substituted with an unsubstituted C1-C20 alkyl or an unsubstituted 2 to 20 heteroalkyl group”, the group may contain one or more unsubstituted C1-C20 alkyl groups and / or one or more unsubstituted 2 to 20 heteroalkyl groups.

[0061] Furthermore, when a moiety is substituted with an R substituent, the group may be referred to as "R-substituted". When a moiety is "R-substituted", the moiety is substituted with at least one R substituent, and each R substituent may optionally be different. If a specific R group is present in the description of a chemical genus (e.g., formula (I)), Roman letter symbols may be used to distinguish the various appearances of that specific R group. For example, when multiple R13 substituents are present, each R13 substituent may be distinguished as R13A, R13B, R13C, R13D, etc., where each of R13A, R13B, R13C, R13D, etc. is defined within the scope of R13 and may optionally be different.

[0062] As used herein, "detectable portion" refers to a portion capable of being covalently or non-covalently attached to a compound or biomolecule and detected using techniques known in the art. In this embodiment, the detectable portion is covalently linked. The detectable portion can provide imaging of the attached compound or biomolecule. The detectable portion can show the contact between two compounds. Typical detectable portions are fluorophores, antibodies, reactive dyes, radiolabeled portions, magnetic contrast agents, and quantum dots. Exemplary fluorophores include fluorophores, rose red, 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 thorium, iron oxide, iron platinum, and manganese.

[0063] The description of the compounds disclosed herein is limited by the principles of chemical bonding known to those skilled in the art. Therefore, if a group can be substituted by one or more of a plurality of substituents, such a substitution is chosen to conform to the principles of chemical bonding, resulting in compounds that are inherently unstable and / or known to those skilled in the art to be unstable under environmental conditions such as aqueous, neutral, and several known physiological conditions. For example, heterocyclic alkyl or heteroaryl groups, by means of cyclic heteroatoms attached to the remainder of the molecule, conform to the principles of chemical bonding known to those skilled in the art, thereby avoiding inherently unstable compounds.

[0064] The term "pharmaceutically acceptable salt" means a salt comprising an active compound prepared with a relatively non-toxic acid or base, depending on the specific substituent found on the compound described herein. When the compounds disclosed herein contain relatively acidic functionality, a base addition salt can be obtained by contacting the neutral form of the compound with a sufficient amount of the desired base, whether pure or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine, or magnesium salts, or similar salts. When the compounds disclosed herein contain relatively basic functionality, an acid addition salt can be obtained by contacting the neutral form of the compound with a sufficient amount of the desired acid, whether pure or in a suitable inert solvent. Pharmaceutically acceptable examples of acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrocarbonic acid, phosphoric acid, monohydrophosphoric acid, dihydrophosphoric acid, sulfate, monohydrosulfuric acid, hydroic acid, or phosphorous acid. Salts of acids, etc., and 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 arginine, and salts of organic acids such as glucose or galacturonic acids (see example, Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds disclosed herein possess basic and acidic functionalities that enable the conversion of the compound into a base or acid addition salt.

[0065] Therefore, the compounds disclosed herein can exist as salts with pharmaceutically acceptable acids. This disclosure includes such salts. Non-limiting examples of such salts include hydrochlorides, hydrobromides, phosphates, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, propionates, tartrates (e.g., (+)-tartrate, (-)-tartrate, or mixtures thereof, including racemic mixtures), succinates, benzoates, and salts of 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.

[0066] The neutral form of the compound is preferably regenerated by contacting the salt with a base or acid and separating the parent compound in a conventional manner. The parent form of the compound may differ from various salt forms in certain physical properties, such as solubility in polar solvents. In this embodiment, the disclosed compound contains basic and acidic functionalities that convert the compound into a base or acid addition salt. The neutral form of the compound can be regenerated by contacting the salt with a base or acid and separating the parent compound in a conventional manner. The parent form of the compound differs from various salt forms in certain physical properties, such as solubility in polar solvents, but unless specifically indicated, the salt disclosed herein is equivalent to the parent form of the compound for the purposes of this disclosure.

[0067] In addition to the salt form, this disclosure also provides compounds in the form of prodrugs. The prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds disclosed herein. The prodrugs of the compounds described herein can be converted in vivo after administration. Furthermore, the prodrugs can be converted into the compounds disclosed herein in vitro by chemical or biochemical methods (e.g., upon contact with suitable enzymes or chemical reagents).

[0068] Some of the compounds disclosed herein may exist in unsolvated and solvated forms, including hydrated forms. Generally, the solvated form is equivalent to the unsolvated form and is included within the scope of this disclosure. Some of the compounds disclosed herein may exist in various crystalline or amorphous forms. Generally, all physical forms are equivalent to the uses contemplated in this disclosure and are intended to be within the scope of this disclosure.

[0069] "Pharmaceutically acceptable excipients" and "pharmaceutically acceptable carriers" refer to substances that facilitate administration and absorption of the compound to a subject and can be included in the compositions disclosed herein without causing significant adverse toxicological effects on the patient. Unrestricted examples of pharmaceutically acceptable excipients include water, sodium chloride, physiological saline solutions, lactated Ringer's solution, sucrose, glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavorings, saline solutions (such as Ringer's solution), alcohols, oils, gelatin, carbohydrates (such as lactose), amylose or starch, fatty acid esters, hydroxymethylcellulose, polyvinylpyrrolidone, and pigments. These formulations are sterilizable and, if necessary, can be mixed with excipients such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts used to affect osmotic pressure, buffers, colorants, and / or aromatics, which do not react adversely with the compounds disclosed herein. Those skilled in the art will recognize that other pharmaceutical excipients are useful in this disclosure.

[0070] The term "formulation" is intended to include formulations of active compounds carried by an encapsulating material, which provides that the active component, with or without other carriers, is surrounded and bound to the capsule by the carrier. Similarly, it also includes tablets and lozenges. Tablets, powders, capsules, pills, tablets, and lozenges are solid dosage forms suitable for oral administration.

[0071] "CCR4 inhibitor" refers to a compound (such as the compound described herein) that can reduce CCR4 activity (e.g., by binding to CCR4) compared to a control group (e.g., a compound lacking the compound or a compound known to be inactive).

[0072] The term "CCR4-mediated disease or disorder" refers to a disease or disorder characterized by CCR4 participating in the activities and / or functions of the body through a CCR4-mediated pathway.

[0073] "Contact" is used in its simple, ordinary sense and should be understood as a process that brings at least two different substances (e.g., compounds including biomolecules or cells) close enough to react, interact, or physically contact. However, the resulting reaction product may arise directly from the reaction between the added reagents or from intermediates of one or more added reagents that can be produced in the reaction mixture.

[0074] The term "contact" can include bringing two reacting, interacting, or physically contacting substances, wherein the two substances can be the compound and protein or enzyme described herein. In some embodiments, contact includes interacting the compound described herein with a protein or enzyme involved in a signaling pathway (e.g., the USP7, p53, or Foxp3 pathway).

[0075] As defined herein, the term “activation” in relation to proteins means the conversion of a protein from an initial inactive or inactivated state to a biologically active derivative. This term relates to activation, or activation, sensitization, or upregulation of signal transduction or enzyme activity or the amount of protein (e.g., reduction in disease).

[0076] The terms "activator," "promoter," and "upregulator" refer to substances that can be detected as increasing the expression or activity of a specific gene or protein. Compared to a control group lacking a activator, the activator can increase expression or activity by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or more. In some cases, the expression or activity is 1.5, 2, 3, 4, 5, 10, or more times higher than that lacking the activator. In this embodiment, the activator is a molecule that interacts with the target to cause or promote an increase in target activity. In this embodiment, the activator is a molecule that increases, activates, promotes, enhances, sensitizes, or upregulates, such as genes, proteins, ligands, receptors, or cells.

[0077] As defined herein, the term "inhibition" in relation to protein-inhibitor interactions refers to a negative impact (e.g., reduction) on the activity or function of a protein in the absence of an inhibitor. In this embodiment, inhibition refers to a negative impact (e.g., reduction) on the concentration or level of a protein in the absence of an inhibitor. In this embodiment, inhibition refers to a reduction in disease or symptoms of disease. In this embodiment, inhibition refers to a reduction in the activity of a specific protein target. Thus, at least in part, inhibition includes partially or completely blocking stimulation, reducing, preventing or delaying activation, or deactivating, desensitizing, or downregulating signal transduction or enzyme activity or the amount of protein. In this embodiment, inhibition refers to a reduction in the activity of a target protein caused by a direct interaction (e.g., the binding of an inhibitor to a target protein). In this embodiment, inhibition refers to a reduction in the activity of a target protein caused by an indirect interaction (e.g., the binding of an inhibitor to a protein that activates the target protein, thereby preventing the activation of the target protein).

[0078] The terms "inhibitor," "suppressant," "antagonist," or "downregulator" refer to substances that can be detected as reducing the expression or activity of a specific gene or protein. Compared to a control group lacking an antagonist, an antagonist can reduce expression or activity by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or more. In some cases, expression or activity is 1.5, 2, 3, 4, 5, 10, or more times lower than in the absence of an antagonist. Antagonists can prevent, reduce, inhibit, or neutralize agonist activity, and can also prevent, inhibit, or reduce the constitutive activity of a target (e.g., a target receptor), even in the absence of a definite agonist. In this embodiment, an inhibitor is a molecule that reduces, blocks, prevents, delays activation, deactivates, desensitizes, or downregulates a gene, protein, ligand, receptor, or cell. An inhibitor can also be defined as a molecule that reduces, blocks, or deactivates constitutive activity. An "antagonist" is a molecule that acts oppositely to a agonist.

[0079] The term "chemokine receptor type 4" (CCR4) refers to a high-affinity receptor protein (including its homologs, isoforms, and functional fragments) for CC-type chemokines (e.g., CCL2 (MCP-1), CCL4 (MIP-1), CCL5 (RANTES), CCL17 (TARC), and CCL22 (MDC)). It is referred to by many different names in the scientific literature, including "CC-CKR-4", "CC CKR-4", "K5-5", "CD194", "CMKBR4", "ChemR13", "HGCN", and "14099". The term includes any recombinant or naturally occurring form of CCR4 and / or its variants that maintain CCR4 activity (e.g., activity at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% compared to wild-type CCR4). This term includes any CCR4 variant that maintains CCR4 activity through mutations (e.g., frameshift mutations) (e.g., activity at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% compared to wild-type CCR4). In this embodiment, the CCR4 protein encoded by the CCR4 gene has an amino acid sequence specified or corresponding to that in Entrez 1233, UniProt P51679, or RefSeq (protein) NP_005499.1. In this embodiment, the CCR4 gene has a nucleic acid sequence specified in RefSeq (mRNA) NM_005508. In this embodiment, the amino acid or nucleic acid sequence is a sequence known at the time of filing this application. In this embodiment, the sequence corresponds to GI: 5031627. In this embodiment, the sequence corresponds to NP_005499.1. In this embodiment, the sequence corresponds to NM_005508.4. In this embodiment, the sequence corresponds to GI:48762930. In this embodiment, CCR4 is human CCR4, as in human cancers that cause CCR4. Although CCR4 is frequently found in dendritic cells, macrophages, NK cells, platelets, and basophils, it is primarily associated with T cells. It plays a role in the progression of various inflammation-related diseases and, as described herein, is also associated with many other conditions. The gene sequence of CCR4 is located on chromosome 3 (NC_000003.12), and its gene is conserved in many species, including chimpanzees, rhesus monkeys, dogs, cattle, mice, rats, chickens, 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 that can be found on the surface of leukocytes (see Horuk (1994) Trends Pharm. Sci. 15: 159-165).

[0080] The term "substantially pure" means that a component comprises about 50% of the total content of the component, and generally more than about 60% of the total content. More typically, "substantially pure" means a component in which at least 75%, at least 85%, at least 90% or more of the total content of the desired component is present. In some cases, the polypeptide will comprise about 90% or more of the total content of the component (on a weight percentage basis).

[0081] The term "trans isomer pure form" refers to a compound having a trans isomer form comprising more than 50% and typically more than 60% of the total content of the compound. More typically, "trans isomer 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 in the trans isomer form (on a weight percentage basis).

[0082] When the terms “specific binding” and “selective binding” refer to ligand / receptor, antibody / antigen, or other binding pairs, they indicate a binding reaction that determines the presence of a protein in a heterogeneous population of proteins and other biological agents. Thus, under specified conditions, a specified ligand binds to a specific receptor without binding a large amount of other proteins present in the sample. The antibody or binding composition derived from the antibody-antigen binding site of the contemplated method binds to its antigen or a variant or mutant protein with an affinity at least two, ten, twenty, or one hundred times greater than that with any other antibody or binding composition derived therefrom. In the present embodiment, the antibody will have an affinity greater than about 10⁹ L / mol when analyzed by means of an analysis such as Scatchard (Munsen, et al., (1980) Analyt. Biochem. 15: 159-239).

[0083] The term "protecting group" refers to a derivative of an existing functional group in a molecule that is reversibly formed, which is temporarily attached to reduce reactivity, so that the protected functional group will not react under synthetic conditions, thereby affecting the molecule in one or more subsequent steps.

[0084] The term "carboxylic acid-directed reducing agent" refers to a compound that binds to the carboxylic acid moiety of a matrix compound and reduces the matrix compound by hydride transfer. One embodiment of a carboxylic acid-directed reducing agent is 1,4-dihydropyridines, amides, or mixed ester-amides or their chemical analogs, all of which are referred to herein as "1,4-dihydropyridines". 1,4-Dihydropyridines are a class of reducing agents used in thermocatalytic hydrogenation reactions. Hantzsch esters are products of the Hantzsch dihydropyridine synthesis. They are mild reducing agents and are commonly used for the transfer hydrogenation of activated C=C bonds, C=O bonds in carbonyl compounds, and C=N bonds in imines. Wang et al. described an overview of these agents (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 two chemical formulas, the first of which is commonly referred to as a Hantzsch ester:

[0084]

[0084] II. Synthesis Method

[0085] In one state, this article provides a method for synthesizing a trans isomer of a chemokine receptor 4 (CCR4) regulator or a salt or ester thereof, the method comprising reacting a compound of formula (1) with a compound of formula (II) in an environment having a carboxylic acid directed reducing agent to prepare a trans isomer of formula (III), wherein the compound of formula (III) is at least 80% trans isomer pure;

[0085] n1' and n2' are each independent integers from 0 to 5, where the sum of n1' and n2' is at least 1 and does not exceed 6; L1' is C(R4')2; L2' is C(R5')2; R1' is hydrogen, halogen, -CX1'3, -CHX1'2, -CH2X1', -OCX1'3, -OCHX1'2, -OCH2X1', -CN, -S(O)2R1'A, -SR1'A, -S(O)R1'A, -SO2NR1'AR1'B, -NHC(O)NR1'AR1'B, -N(O)2, -NR1'AR1'B, -NHNR1'AR1'B, -C(O)R1'A, -C( O)-OR1'A, -C(O)NR1'AR1'B, -C(O)NHNR1'AR1'B, -OR1'A, -NR1'ASO2R1'B, -NR1'AC(O)R1'B, -NR1'AC(O)OR1'B, -NR1'AOR1'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; R2' is hydrogen, -CX2'3, -CHX2'2, -CH2X2', -OCX2'3, -OCHX2'2, -OC H2X2', -SR2'A, -NR2'AR2'B, -NHNR2'AR2'B, -OR2'A, -NR2'ASO2R2'B, -NR2'AC(O)R2'B, -NR2'AC(O)OR2'B, -NR2'AOR2'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 wherein R2' and R3' may optionally be linked to form a substituted or unsubstituted heterocycloalkyl; R3' is hydrogen, -CX3'3, -CHX3'2, -CH 2X3', -OCX3'3, -OCHX3'2, -OCH2X3', -SR3'A, -NR3'AR3'B, -NHNR3'AR3'B, -OR3'A, -NR3'ASO2R3'B, -NR3'AC(O)R3'B, -NR3'AC(O)OR3'B, -NR3'AOR3'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 wherein R2' and R3' may optionally be linked to form a substituted or unsubstituted heterocycloalkyl;R4' is hydrogen, halogen, -CX4'3, -CHX4'2, -CH2X4', -OCX4'3, -OCHX4'2, -OCH2X4', -CN, -S(O)2R4'A, -SR4'A, -S(O)R4'A, -S O2NR4'AR4'B, -NHC(O)NR4'AR4'B, -N(O)2, -NR4'AR4'B, -NHNR4'AR4'B, -C(O)R4'A, -C(O)-OR4'A, -C(O)NR4'AR 4'B, -C(O)NHNR4'AR4'B, -OR4'A, -NR4'ASO2R4'B, -NR4'AC(O)R4'B, -NR4'AC(O)OR4'B, -NR4'AOR4'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; R5' is hydrogen, halogen, -CX5'3, -CH X5'2, -CH2X5', -OCX5'3, -OCHX5'2, -OCH2X5', -CN, -S(O)2R5'A, -SR5'A, -S(O)R5'A, -SO2NR5'AR5'B, -NHC(O) NR5'AR5'B, -N(O)2, -NR5'AR5'B, -NHNR5'AR5'B, -C(O)R5'A, -C(O)-OR5'A, -C(O)NR5'AR5'B, -C(O)NHNR5'AR5' B, -OR5'A, -NR5'ASO2R5'B, -NR5'AC(O)R5'B, -NR5'AC(O)OR5'B, -NR5'AOR5'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; R12' is independently -OH or NHR12”; R12” is hydrogen or substituted or unsubstituted alkyl;R1'A, R1'B, R2'A, R2'B, R3'A, R3'B, R4'A, R4'B, R5'A, and R5'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, -CONH2, -SH, -SO3H, -SO4H, -SO2NH2, - 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 R2'A and R2'B substituents bonded to the same nitrogen atom may optionally be linked to form substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; or R3'A and R3'B substituents bonded to the same nitrogen atom may optionally be linked to form substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; and X1', X2', X3', X4', and X5 are independently halogens.

[0086] In this embodiment, at least 85% of the compounds of formula (III) are in the trans isomer pure form. In this embodiment, at least 90% of the compounds of formula (III) are in the trans isomer pure form. In this embodiment, at least 95% of the compounds of formula (III) are in the trans isomer pure form. In this embodiment, at least 98% of the compounds of formula (III) are in the trans isomer pure form. In this embodiment, at least 99% of the compounds of formula (III) are in the trans isomer pure form. In this embodiment, 100% of the compounds of formula (III) are in the trans isomer pure form.

[0087] In this embodiment, n1' and n2' are each independent integers from 0 to 5, wherein the sum of n1' and n2' is at least 1 and does not exceed 6;

[0088] In this embodiment, L1' is C(R4')2.

[0089] R4' is independently hydrogen, halogen, -CX4'3, -CHX4'2, -CH2X4', -OCX4'3, -OCHX4'2, -OCH2X4', -CN, -S(O)2R4'A, -SR4'A, -S(O)R4'A, -SO2NR4'AR4'B, -NHC(O)NR4'AR4'B, -N(O)2, -NR4'AR4'B, -NHNR4'AR4'B, -C(O)R4'A, -C(O)-OR4 'A、-C(O)NR4'AR4'B、-C(O)NHNR4'AR4'B、-OR4'A、-NR4'ASO2R4'B、-NR4'AC(O)R4'B、-NR4'AC(O)OR4'B、-NR4'AOR4'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;

[0090] In this embodiment, R4' is hydrogen, a halogen (e.g., -F, -Cl, Br, -I), -CX4'3, -CX4'2, -CH2X4', -OCX4'3, -OCHX4'2, -OCH2X4', -CN, -S(O)2R4'A, -SR4'A, -S(O)R4'A, -SO2NR4'AR4'B, -NHC(O)NR4'AR4'B, -N(O)2, -NR4'AR4'B, -NHNR4'AR4'B, -C(O)R4'A, -C(O)-OR4'A, -C(O)NR4'AR4'B, -C(O)NHNR4'AR4'B, -OR4'A, -NR 4'ASO2R4'B, -NR4'AC(O)R4'B, -NR4'AC(O)OR4'B, -NR4'AOR4'B, -N3 (such as -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, -SO 2CH3, -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 substituents, size-restricted substituents, or low-position substituents) or unsubstituted Substituted alkyl groups (e.g., C1-C8, C1-C6, or C1-C4), substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-position substituent) or unsubstituted heteroalkyl groups (e.g., 2 to 8 members, 2 to 6 members, or 2 to 4 members), substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-position substituent) or unsubstituted cycloalkyl groups (e.g., C3-C8, C3-C6, or C5-C6), substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-position substituent) or unsubstituted heterocycloalkyl groups (e.g., 3 to 8 members, 3 to 6 members, or 5 to 6 members), substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-position substituent) or unsubstituted aryl groups (e.g.,X4' is a heteroaryl group (e.g., C6-C10, C6, or phenyl) or substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-position substituent) or unsubstituted (e.g., 5 to 10 members, 5 to 9 members, or 5 to 6 members). X4' is independently -F, -Cl, -Br, or -I.

[0091] In this embodiment, R4' 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, -N 3. -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( -NCH3C(O)OH, -NHOH, -NCH3OH, -NCH3OCH3, substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-substituent) or unsubstituted alkyl groups (e.g., C1-C8, C1-C6, or C1-C4), substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-substituent) or unsubstituted heteroalkyl groups (e.g., 2 to 8 members, 2 to 6 members, or 2 to 4 members), substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-substituent) or unsubstituted cycloalkanes. The alkyl group (e.g., C3-C8, C3-C6, or C5-C6), substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-substituent) or unsubstituted heterocyclic alkyl group (e.g., 3 to 8 members, 3 to 6 members, or 5 to 6 members), substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-substituent) or unsubstituted aryl group (e.g., C6-C10, C6, or phenyl), or substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-substituent) or unsubstituted heteroaryl group (e.g., 5 to 10 members, 5 to 9 members, or 5 to 6 members). In this embodiment, R4' is substituted if it is substituted with a substituent. In this embodiment, R4' is substituted if it is substituted with a size-restricted substituent. In this embodiment, R4' is substituted if it is substituted with a low-substituent.

[0092] In this embodiment, R4' 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)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, -NCH3OCH3, unsubstituted alkyl groups (e.g., C1-C8, C1- C6 or C1-C4), unsubstituted heteroalkyl (e.g., 2 to 8 members, 2 to 6 members, or 2 to 4 members), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 members, 3 to 6 members, or 5 to 6 members), unsubstituted aryl (e.g., C6-C10, C6, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 members, 5 to 9 members, or 5 to 6 members).

[0093] In this embodiment, L2' is C(R5')2.

[0094] R5' is independently hydrogen, halogen, -CX5'3, -CHX5'2, -CH2X5', -OCX5'3, -OCHX5'2, -OCH2X5', -CN, -S(O)2R5'A, -SR5'A, -S(O)R5'A, -SO2NR5'AR5'B, -NHC(O)NR5'AR5'B, -N(O)2, -NR5'AR5'B, -NHNR5'AR5'B, -C(O)R5'A, -C(O)-OR5 'A、-C(O)NR5'AR5'B、-C(O)NHNR5'AR5'B、-OR5'A、-NR5'ASO2R5'B、-NR5'AC(O)R5'B、-NR5'AC(O)OR5'B、-NR5'AOR5'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.

[0095] In this embodiment, R5' is hydrogen, halogen (e.g., -F, -Cl, Br, -I), -CX5'3, -CHX5'2, -CH2X5', -OCX5'3, -OCHX5'2, -OCH2X5', -CN, -S(O)2R5'A, -SR5'A, -S(O)R5'A, -SO2NR5'AR5'B, -NHC(O)NR5'AR5'B, -N(O)2, -NR5'AR5'B, -NHNR5'AR5'B, -C(O)R5'A, -C(O)-OR5'A, -C(O)NR5'AR5'B, -C(O)NHNR5'AR5'B, -OR5'A, -N R5'ASO2R5'B, -NR5'AC(O)R5'B, -NR5'AC(O)OR5'B, -NR5'AOR5'B, -N3 (such as -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, -S O2CH3, -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 substituents, size-restricted substituents or low-position substituents) or unsubstituted Substituted alkyl groups (e.g., C1-C8, C1-C6, or C1-C4), substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-position substituent) or unsubstituted heteroalkyl groups (e.g., 2 to 8 members, 2 to 6 members, or 2 to 4 members), substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-position substituent) or unsubstituted cycloalkyl groups (e.g., C3-C8, C3-C6, or C5-C6), substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-position substituent) or unsubstituted heterocycloalkyl groups (e.g., 3 to 8 members, 3 to 6 members, or 5 to 6 members), substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-position substituent) or unsubstituted aryl groups (e.g.,X5' is a heteroaryl group (e.g., C6-C10, C6, or phenyl) or substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-position substituent) or unsubstituted (e.g., 5 to 10 members, 5 to 9 members, or 5 to 6 members). X5' is independently -F, -Cl, -Br, or -I.

[0096] In this embodiment, R5' 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, -N 3. -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( -NCH3C(O)OH, -NHOH, -NCH3OH, -NCH3OCH3, substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-substituent) or unsubstituted alkyl groups (e.g., C1-C8, C1-C6, or C1-C4), substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-substituent) or unsubstituted heteroalkyl groups (e.g., 2 to 8 members, 2 to 6 members, or 2 to 4 members), substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-substituent) or unsubstituted cycloalkanes. The alkyl group (e.g., C3-C8, C3-C6, or C5-C6), substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-substituent) or unsubstituted heterocyclic alkyl group (e.g., 3 to 8 members, 3 to 6 members, or 5 to 6 members), substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-substituent) or unsubstituted aryl group (e.g., C6-C10, C6, or phenyl), or substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-substituent) or unsubstituted heteroaryl group (e.g., 5 to 10 members, 5 to 9 members, or 5 to 6 members). In this embodiment, R5' is substituted if it is substituted with a substituent. In this embodiment, R5' is substituted if it is substituted with a size-restricted substituent. In this embodiment, R5' is substituted if it is substituted with a low-substituent.

[0097] In this embodiment, R5' 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)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, -NCH3OCH3, unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), unsubstituted heteroalkyl (e.g., 2 to 8 members, 2 to 6 members, or 2 to 4 members), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 members, 3 to 6 members, or 5 to 6 members), unsubstituted aryl (e.g., C6-C10, C6, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 members, 5 to 9 members, or 5 to 6 members).

[0098] R1' is independently hydrogen, halogen, -CX1'3, -CHX1'2, -CH2X1', -OCX1'3, -OCHX1'2, -OCH2X1', -CN, -S(O)2R1'A, -SR1'A, -S(O)R1'A, -SO2NR1'AR1'B, -NHC(O)NR1'AR1'B, -N(O)2, -NR1'AR1'B, -NHNR1'AR1'B, -C(O)R1'A, -C(O)-OR1 'A、-C(O)NR1'AR1'B、-C(O)NHNR1'AR1'B、-OR1'A、-NR1'ASO2R1'B、-NR1'AC(O)R1'B、-NR1'AC(O)OR1'B、-NR1'AOR1'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 this embodiment, R1' is hydrogen, halogen (e.g., -F, -Cl, Br, -I), -CX1'3, -CHX1'2, -CH2X1', -OCX1'3, -OCHX1'2, -OCH2X1', -CN, -S(O)2R1'A, -SR1'A, -S(O)R1'A, -SO2NR1'AR1'B, -NHC(O)NR1'AR1'B, -N(O)2, -NR1'AR1'B, -NHNR1'AR1'B, -C(O)R1'A, -C(O)-OR1'A, -C(O)NR1'AR1'B, -C(O)NHNR1'AR1'B, -OR1'A, -N R1'ASO2R1'B, -NR1'AC(O)R1'B, -NR1'AC(O)OR1'B, -NR1'AOR1'B, -N3 (such as -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, -S O2CH3, -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 substituents, size-restricted substituents or low-position substituents) or unsubstituted Substituted alkyl groups (e.g., C1-C8, C1-C6, or C1-C4), substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-position substituent) or unsubstituted heteroalkyl groups (e.g., 2 to 8 members, 2 to 6 members, or 2 to 4 members), substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-position substituent) or unsubstituted cycloalkyl groups (e.g., C3-C8, C3-C6, or C5-C6), substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-position substituent) or unsubstituted heterocycloalkyl groups (e.g., 3 to 8 members, 3 to 6 members, or 5 to 6 members), substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-position substituent) or unsubstituted aryl groups (e.g.,X1' is a heteroaryl group (e.g., C6-C10, C6, or phenyl) or substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-position substituent) or unsubstituted (e.g., 5 to 10 members, 5 to 9 members, or 5 to 6 members). X1' is independently -F, -Cl, -Br, or -I.

[0100] In this embodiment, R1' 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, -N 3. -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( -NCH3C(O)OH, -NHOH, -NCH3OH, -NCH3OCH3, substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-substituent) or unsubstituted alkyl groups (e.g., C1-C8, C1-C6, or C1-C4), substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-substituent) or unsubstituted heteroalkyl groups (e.g., 2 to 8 members, 2 to 6 members, or 2 to 4 members), substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-substituent) or unsubstituted cycloalkanes. The alkyl group (e.g., C3-C8, C3-C6, or C5-C6), substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-substituent) or unsubstituted heterocyclic alkyl group (e.g., 3 to 8 members, 3 to 6 members, or 5 to 6 members), substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-substituent) or unsubstituted aryl group (e.g., C6-C10, C6, or phenyl), or substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-substituent) or unsubstituted heteroaryl group (e.g., 5 to 10 members, 5 to 9 members, or 5 to 6 members). In this embodiment, R1 is substituted if it is substituted with a substituent. In this embodiment, R1' is substituted if it is substituted with a size-restricted substituent. In this embodiment, R1' is substituted if it is substituted with a low-substituent.

[0101] In this embodiment, R1' 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)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, -NCH3OCH3, unsubstituted alkyl groups (e.g., C1-C8, C1- C6 or C1-C4), unsubstituted heteroalkyl (e.g., 2 to 8 members, 2 to 6 members, or 2 to 4 members), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 members, 3 to 6 members, or 5 to 6 members), unsubstituted aryl (e.g., C6-C10, C6, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 members, 5 to 9 members, or 5 to 6 members).

[0102] R2' is hydrogen, -CX2'3, -CHX2'2, -CH2X2', -OCX2'3, -OCHX2'2, -OCH2X2', -SR2'A, -NR2'AR2' B. -NHNR2'AR2'B, -OR2'A, -NR2'ASO2R2'B, -NR2'AC(O)R2'B, -NR2'AC(O)OR2'B, -NR2'AOR2'B The heterocyclic alkyl group may be substituted or unsubstituted, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or wherein R2' and R3' may optionally be linked to form a substituted or unsubstituted heterocyclic alkyl group; in this embodiment, if R2' and R3' are linked to form a substituted heterocyclic alkyl group, the heterocyclic alkyl group is substituted with a substituent. In this embodiment, if R2' and R3' are linked to form a substituted heterocyclic alkyl group, the heterocyclic alkyl group is substituted with a size-restricted substituent. In this embodiment, if R2' and R3' are linked to form a substituted heterocyclic alkyl group, the heterocyclic alkyl group is substituted with a lower substituent.

[0103] In this embodiment, R2' is hydrogen, -CX2'3, -CHX2'2, -CH2X2', -OCX2'3, -OCHX2'2, -OCH2X2', -SR2'A, -NR2'AR2'B, -NHNR2'AR2'B, -OR2'A, -NR2'ASO2R2'B, -NR2'AC(O)R2'B, -NR2'AC(O)OR2'B, -NR2'AOR2'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 , -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-restricted substituent, or a low-substituent) or unsubstituted alkyl groups (e.g., C1-C8, C1-C6, or C1-C4), substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-substituent) or unsubstituted heteroalkyl groups (e.g., 2 to 8 members, 2 to 6 members, or 2 to 4 members), substituted (e.g. X2' is a cycloalkyl group (e.g., C3-C8, C3-C6, or C5-C6) that is substituted (e.g., substituted, size-restricted, or low-substituent) or unsubstituted heterocycloalkyl group (e.g., 3 to 8 members, 3 to 6 members, or 5 to 6 members), an aryl group (e.g., C6-C10, C6, or phenyl) that is substituted (e.g., substituted, size-restricted, or low-substituent) or unsubstituted heteroaryl group (e.g., 5 to 10 members, 5 to 9 members, or 5 to 6 members). X2' is independently -F, -Cl, -Br, or -I.

[0104] In this embodiment, R2' is hydrogen, -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)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, -NCH3OCH3, substituted (e.g., substituted with a substituent, size-restricted substituent, or low-substituent) or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), substituted (e.g., substituted with a substituent, size-restricted substituent, or low-substituent) or unsubstituted heteroalkyl (e.g., 2 to 8 members, 2 to 6 members, or 2 to 4 members), substituted (e.g., substituted with a substituent, size-restricted substituent, or low-substituent) or unsubstituted cycloalkyl (e.g., C... The alkyl group is a heterocyclic alkyl group (e.g., 3 to 8 members, 3 to 6 members, or 5 to 6 members), substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-substituent) or unsubstituted aryl group (e.g., C6 to C10, C6, or phenyl), or substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-substituent) or unsubstituted heteroaryl group (e.g., 5 to 10 members, 5 to 9 members, or 5 to 6 members). In this embodiment, R2' is substituted if it is substituted with a substituent. In this embodiment, R2' is substituted if it is substituted with a size-restricted substituent. In this embodiment, R2' is substituted if it is substituted with a low-substituent.

[0105] In this embodiment, R2' is hydrogen, -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)NH2, -NHC(O)NHCH3, -NO2, -NH2, -NHCH3, -C(O)H, -C(O)CH3, -C(O)OH, -C(O)H, -C(O)CH3, -C(O)OH, -C(O)CH3 ... -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 C1-C4), unsubstituted heteroalkyl (e.g., 2 to 8 members, 2 to 6 members, or 2 to 4 members), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 members, 3 to 6 members, or 5 to 6 members), unsubstituted aryl (e.g., C6-C10, C6, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 members, 5 to 9 members, or 5 to 6 members).

[0106] R3' is a halogen, -CX3'3, -CHX3'2, -CH2X3', -OCX3'3, -OCHX3'2, -OCH2X3', -SR3'A, -NR3'AR3'B, -NHNR3'AR3'B, -OR3'A, -NR3'ASO2R3'B, -NR3'AC(O)R3'B, -NR3'AC(O)OR3'B, -NR3'AOR3'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 wherein R2' and R3' may optionally be connected to form a substituted or unsubstituted heterocycloalkyl.

[0107] In this embodiment, R3' is hydrogen, -CX3'3, -CHX3'2, -CH2X3', -OCX3'3, -OCHX3'2, -OCH2X3', -SR3'A, -NR3'AR3'B, -NHNR3'AR3'B, -OR3'A, -NR3'ASO2R3'B, -NR3'AC(O)R3'B, -NR3'AC(O)OR3'B, -NR3'AOR3'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 , -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-restricted substituent, or a low-substituent) or unsubstituted alkyl groups (e.g., C1-C8, C1-C6, or C1-C4), substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-substituent) or unsubstituted heteroalkyl groups (e.g., 2 to 8 members, 2 to 6 members, or 2 to 4 members), substituted (e.g. X3' is a cycloalkyl group (e.g., C3-C8, C3-C6, or C5-C6) that is substituted (e.g., substituted, size-restricted, or low-substituent) or unsubstituted heterocycloalkyl group (e.g., 3 to 8 members, 3 to 6 members, or 5 to 6 members), an aryl group (e.g., C6-C10, C6, or phenyl) that is substituted (e.g., substituted, size-restricted, or low-substituent) or unsubstituted heteroaryl group (e.g., 5 to 10 members, 5 to 9 members, or 5 to 6 members). X3' is independently -F, -Cl, -Br, or -I.

[0108] In this embodiment, R3' is hydrogen, 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)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, -NCH3OCH3, substituted (e.g., substituted with a substituent, size-restricted substituent, or low-substituent) or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), substituted (e.g., substituted with a substituent, size-restricted substituent, or low-substituent) or unsubstituted heteroalkyl (e.g., 2 to 8 members, 2 to 6 members, or 2 to 4 members), substituted (e.g., substituted with a substituent, size-restricted substituent, or low-substituent) or unsubstituted cycloalkyl (e.g., C3... -C8, C3-C6, or C5-C6), substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-substituent) or unsubstituted heterocyclic alkyl (e.g., 3 to 8 members, 3 to 6 members, or 5 to 6 members), substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-substituent) or unsubstituted aryl (e.g., C6-C10, C6, or phenyl), or substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-substituent) or unsubstituted heteroaryl (e.g., 5 to 10 members, 5 to 9 members, or 5 to 6 members). In this embodiment, R3' is substituted if it is substituted with a substituent. In this embodiment, R3' is substituted if it is substituted with a size-restricted substituent. In this embodiment, R3' is substituted if it is substituted with a low-substituent.

[0109] In this embodiment, R3' is hydrogen, -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)NH2, -NHC(O)NHCH3, -NO2, -NH2, -NHCH3, -C(O)H, -C(O)CH3, -C(O)OH, -C(O)H, -C(O)CH3, -C(O)OH, -C(O)CH3 ... -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 C1-C4), unsubstituted heteroalkyl (e.g., 2 to 8 members, 2 to 6 members, or 2 to 4 members), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 members, 3 to 6 members, or 5 to 6 members), unsubstituted aryl (e.g., C6-C10, C6, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 members, 5 to 9 members, or 5 to 6 members).

[0110] In this embodiment, R2' and R3' are linked to form a substituted or unsubstituted piperidinyl ring. In this embodiment, the piperidinyl group is substituted with a substituted or unsubstituted heterocyclic alkyl group. In this embodiment, the substituted or unsubstituted heterocyclic alkyl group is a nitrogen-containing 3- to 6-membered heterocyclic alkyl group.

[0111] R12' is independently -OH or NHR12. In this embodiment, R12' is -OH. In this embodiment, R12' is NHR12.

[0112] R12” is hydrogen or a substituted or unsubstituted alkyl group. In this embodiment, R12” is hydrogen. In this embodiment, R12” is a substituted or unsubstituted alkyl group. In this embodiment, R12” is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-position substituent) or unsubstituted alkyl group (e.g., C1-C8, C1-C6, or C1-C4). In this embodiment, if R12” is substituted, it is substituted with a substituent. In this embodiment, if R12” is substituted, it is substituted with a size-restricted substituent. In this embodiment, if R12” is substituted, it is substituted with a low-position substituent.

[0113] R1'A, R1'B, R2'A, R2'B, R3'A, R3'B, R4'A, R4'B, R5'A, and R5'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, -CONH2, -SH, -SO3H -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)OH, -NHOH, substituted or unsubstituted alkyl groups, substituted or unsubstituted heteroalkyl groups, substituted or unsubstituted cycloalkyl groups, substituted or unsubstituted heterocycloalkyl groups, substituted or unsubstituted aryl groups, or substituted or unsubstituted heteroaryl groups; or R2'A and R2'B substituents bonded to the same nitrogen atom may optionally be linked to form substituted or unsubstituted heterocycloalkyl groups or substituted or unsubstituted heteroaryl groups; or R3'A and R3'B substituents bonded to the same nitrogen atom may optionally be linked to form substituted or unsubstituted heterocycloalkyl groups or substituted or unsubstituted heteroaryl groups; and

[0114] In this embodiment, R1'A, R1'B, R2'A, R2'B, R3'A, R3'B, R4'A, R4'B, R5'A, and R5'B are independently hydrogen, -F, -Cl, -Br, -I, -CF3, -CHF2, -CH2F, -CCl3, -CHCl2, -CH2Cl, -CBr3, -CHBr2, -CH2Br, -CI3, -CHI2, -CH2I, -OCF3, -OCCl3, -OCBr3, and -OCI3. , -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, -C(O)OH, -C(O)NH2, -OH, -NH2, -COO H, -CONH2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -N HC(O)OH, -NHOH, substituted (e.g., substituted with a substituent, size-restricted substituent, or low-substituent) or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), substituted (e.g., substituted with a substituent, size-restricted substituent, or low-substituent) or unsubstituted heteroalkyl (e.g., 2 to 8 members, 2 to 6 members, or 2 to 4 members), substituted (e.g., substituted with a substituent, size-restricted substituent, or low-substituent) or unsubstituted cycloalkyl (e.g., C3-C8, C3- Heterocyclic alkyl groups (e.g., 3 to 8, 3 to 6, or 5 to 6 members), substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-position substituent) or unsubstituted (e.g., C6-C10, C6, or phenyl), or substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-position substituent) or unsubstituted heteroaryl groups (e.g., 5 to 10, 5 to 9, or 5 to 6 members). In this embodiment, if R1'A, R1'B, R2'A, R2'B, R3'A, R3'B, R4'A, R4'B, R5'A, and R5'B are substituted, they are substituted with a substituent. In this embodiment, if R1'A, R1'B, R2'A, R2'B, R3'A, R3'B, R4'A, R4'B, R5'A, and R5'B are substituted, they are substituted with size-restricted substituents. In this embodiment, if R1'A, R1'B, R2'A, R2'B, R3'A, R3'B, R4'A, R4'B, R5'A, and R5'B are substituted, they are substituted with lower-position substituents. In this embodiment, R1'A is substituted with a substituent. In this embodiment, R1'A is substituted with a size-restricted substituent.In this embodiment, R1'A is substituted with a low-position substituent. In this embodiment, R1'B is substituted with a substituent. In this embodiment, R1'B is substituted with a size-restricted substituent. In this embodiment, R1'B is substituted with a low-position substituent. In this embodiment, R2'A is substituted with a substituent. In this embodiment, R2'A is substituted with a size-restricted substituent. In this embodiment, R2'A is substituted with a low-position substituent. In this embodiment, R2'B is substituted with a substituent. In this embodiment, R2'B is substituted with a size-restricted substituent. In this embodiment, R2'B is substituted with a low-position substituent. In this embodiment, R3'A is substituted with a size-restricted substituent. In this embodiment, R3'A is substituted with a low-position substituent. In this embodiment, R3'B is substituted with a substituent. In this embodiment, R3'B is substituted with a size-restricted substituent. In this embodiment, R3'B is substituted with a lower-position substituent. In this embodiment, R4'A is substituted with a substituent. In this embodiment, R4'A is substituted with a size-restricted substituent. In this embodiment, R4'A is substituted with a lower-position substituent. In this embodiment, R4'B is substituted with a substituent. In this embodiment, R4'B is substituted with a size-restricted substituent. In this embodiment, R4'B is substituted with a lower-position substituent. In this embodiment, R5'A is substituted with a substituent. In this embodiment, R5'A is substituted with a size-restricted substituent. In this embodiment, R5'A is substituted with a lower-position substituent. In this embodiment, R5'B is substituted with a substituent. In this embodiment, R5'B is substituted with a size-restricted substituent. In this embodiment, R5'B is substituted with a low-position substituent.

[0115] In this embodiment, R1'A, R1'B, R2'A, R2'B, R3'A, R3'B, R4'A, R4'B, R5'A, and R5'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, -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., C1-C8, C1-C6, or C1-C4), unsubstituted heteroalkyl (e.g., 2 to 8 members, 2 to 6 members, or 2 to 4 members), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 members, 3 to 6 members, or 5 to 6 members), unsubstituted aryl (e.g., C6-C10, C6, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 members, 5 to 9 members, or 5 to 6 members).

[0116] In this embodiment, the reaction between the compound of formula (1) and the compound of formula (II) occurs in the absence of an additional catalyst.

[0117] In this embodiment, the compound system of formula (I) is:

[0117] , wherein R11' 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.

[0118] In this embodiment, R11' is -CF3, -CHF2, -CH2F, -CCl3, -CHCl2, -CH2Cl, -CBr3, -CHBr2, -CH2Br, -CI3, -CHI2, -CH2I, -NH2, substituted (e.g., substituted with a substituent, size-restricted substituent, or low-position substituent) or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), substituted (e.g., substituted with a substituent, size-restricted substituent, or low-position substituent) or unsubstituted heteroalkyl (e.g., 2 to 8 members, 2 to 6 members, or 2 to 4 members), substituted (e.g., substituted with a substituent, size-restricted substituent, or low-position substituent) or unsubstituted heteroalkyl (e.g., substituted with a substituent, size-restricted substituent, or low-position substituent). The substituted alkyl group (e.g., C3-C8, C3-C6, or C5-C6), substituted (e.g., substituted with a substituent, size-restricted substituent, or low-substituent) or unsubstituted heterocyclic alkyl group (e.g., 3 to 8 members, 3 to 6 members, or 5 to 6 members), substituted (e.g., substituted with a substituent, size-restricted substituent, or low-substituent) or unsubstituted aryl group (e.g., C6-C10, C6, or phenyl), or substituted (e.g., substituted with a substituent, size-restricted substituent, or low-substituent) or unsubstituted heteroaryl group (e.g., 5 to 10 members, 5 to 9 members, or 5 to 6 members). In this embodiment, R11' is substituted if it is substituted. In this embodiment, R11' is substituted if it is substituted with a size-restricted substituent. In this embodiment, R11' is substituted if it is substituted with a low-substituent.

[0119] In this embodiment, R11' 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 to 8 members, 2 to 6 members or 2 to 4 members), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6 or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 members, 3 to 6 members or 5 to 6 members), unsubstituted aryl (e.g., C6-C10, C6 or phenyl) or unsubstituted heteroaryl (e.g., 5 to 10 members, 5 to 9 members or 5 to 6 members).

[0120] In this embodiment, R11' is a substituted or unsubstituted alkyl group. In this embodiment, R11' is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-position substituent) or unsubstituted alkyl group (e.g., C1-C8, C1-C6, or C1-C4).

[0121] In this embodiment, the compound of formula III is:

[0121] Wherein R11' is a substituted or unsubstituted alkyl group and each of n1' and n2' is 1 or 2. R1', L1', L2' and R12' are as described above, including the present embodiment.

[0122] In this embodiment, the compound of formula III is:

[0122] wherein R11' is a substituted or unsubstituted alkyl group.

[0123] In the synthetic method provided herein, the carboxylic acid directional reducing agent is 1,4-dihydropyridine of formula (IV):

[0123] L3' and L4' are independently oxygen or NR20'; R20' is hydrogen or R21'; R21' is hydrogen, -CX21'3, -CHX21'2, -CH2X21', 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; R6' is hydrogen, -CX6'3, -CHX6'2, -CH2X6', 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 connecting 1,4-dihydropyridine to a polymer support; R7' is hydrogen, -CX7'3, -CHX7'2, -CH2X7', substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroalkyl The aryl group may be a bond that links 1,4-dihydropyridine to the polymer support; R8' is independently hydrogen, halogen, -CX8'3, -CHX8'2, -CH2X8', -OCX8'3, -OCHX8'2, -OCH2X8', -CN, -S(O)2R8'A, -SR8'A, -S(O)R8'A, -SO2NR8'AR8'B, -NHC(O)NR8'AR8'B, -N(O)2, -NR8'AR8'B, -NHNR8'AR8'B, -C(O)R8'A, -C(O)-OR8'A, -C(O)NR8'AR8'B, -C(O)NHNR8'AR8'B, -OR8'A, -NR8'ASO2R8'B, -NR8'AC(O)R8'B, -NR8'AC(O)OR8'B, -NR8'AOR8'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;R9' can be independently hydrogen, halogen, -CX9'3, -CHX9'2, -CH2X9', -OCX9'3, -OCHX9'2, -OCH2X9', -CN, -S(O)2R9'A, -SR9'A, -S(O)R9'A, -SO2NR9'AR9'B, -NHC(O)NR9'AR9'B, -N(O)2, -NR9'AR9'B, -NHNR9'AR9'B, -C(O)R9'A, -C(O)-OR9'A, -C(O)NR9 'AR9'B, -C(O)NHNR9'AR9'B, -OR9'A, -NR9'ASO2R9'B, -NR9'AC(O)R9'B, -NR9'AC(O)OR9'B, -NR9'AOR9'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; R10' is independently hydrogen, halogen, -CX 10'3, -CHX10'2, -CH2X10', -OCX10'3, -OCHX10'2, -OCH2X10', -CN, -S(O)2R10'A, -SR10'A, -S(O)R10'A, -SO2N R10'AR10'B, -NHC(O)NR10'AR10'B, -N(O)2, -NR10'AR10'B, -NHNR10'AR10'B, -C(O)R10'A, -C(O)-OR10'A, -C(O )NR10'AR10'B、-C(O)NHNR10'AR10'B、-OR10'A、-NR10'ASO2R10'B、-NR10'AC(O)R10'B、-NR10'AC(O)OR10'B、-NR10'AOR10'B、-N3、substituted or unsubstituted alkyl、substituted or unsubstituted heteroalkyl、substituted or unsubstituted cycloalkyl、substituted or unsubstituted heterocycloalkyl、substituted or unsubstituted aryl、substituted or unsubstituted heteroaryl;R8'A, R8'B, R9'A, R9'B, R10'A, and R10'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)NH 2. -OH, -NH2, -COOH, -CONH2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)OH, -NHOH, substituted or unsubstituted alkyl groups, substituted or unsubstituted heteroalkyl groups, substituted or unsubstituted cycloalkyl groups, substituted or unsubstituted heterocycloalkyl groups, substituted or unsubstituted aryl groups, or substituted or unsubstituted heteroaryl groups; while X6', X7', X8', X9', and X10' are independently halogens.

[0124] In this embodiment, L3' is oxygen or NR20'. In this embodiment, L3' is oxygen. In this embodiment, L3' is NR20'. In this embodiment, L3' is oxygen or NR21'.

[0125] In this embodiment, L4' is oxygen or NR20'. In this embodiment, L4' is oxygen. In this embodiment, L4' is NR20'. In this embodiment, L4' is oxygen or NR21'.

[0126] In this embodiment, R20' is hydrogen or R21'. In this embodiment, R20' is hydrogen. In this embodiment, R20' is R21'.

[0127] In this embodiment, R21' is hydrogen, -CX21'3, -CHX21'2, -CH2X21', 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 this embodiment, R21' is hydrogen, -CX21'3, -CHX21'2, -CH2X21', a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-substituent) or unsubstituted alkyl group (e.g., C1-C8, C1-C6, or C1-C4), a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-substituent) or unsubstituted heteroalkyl group (e.g., 2 to 8 members, 2 to 6 members, or 2 to 4 members), a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-substituent) or unsubstituted. The alkyl group (e.g., C3-C8, C3-C6, or C5-C6), substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-position substituent) or unsubstituted heterocyclic alkyl group (e.g., 3 to 8 members, 3 to 6 members, or 5 to 6 members), substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-position substituent) or unsubstituted aryl group (e.g., C6-C10, C6, or phenyl), or substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-position substituent) or unsubstituted heteroaryl group (e.g., 5 to 10 members, 5 to 9 members, or 5 to 6 members). In this embodiment, R21' is substituted if it is substituted with a substituent. In this embodiment, R21' is substituted if it is substituted with a size-restricted substituent. In this embodiment, R21' is substituted if it is substituted with a low-position substituent.

[0129] In this embodiment, R21' is hydrogen, -CX21'3, -CHX21'2, -CH2X21', unsubstituted alkyl (e.g., C1-C8, C1-C6 or C1-C4), unsubstituted heteroalkyl (e.g., 2 to 8 members, 2 to 6 members or 2 to 4 members), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6 or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 members, 3 to 6 members or 5 to 6 members), unsubstituted aryl (e.g., C6-C10, C6 or phenyl) or unsubstituted heteroaryl (e.g., 5 to 10 members, 5 to 9 members or 5 to 6 members).

[0130] In this embodiment, R6' is hydrogen, -CX6'3, -CHX6'2, -CH2X6', a substituted or unsubstituted alkyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, or a bond in which 1,4-dihydropyridine is attached to the polymer support. X6' is independently -F, -Cl, -Br, or -I.

[0131] In this embodiment, R6' is hydrogen, -CX6'3, -CHX6'2, -CH2X6', a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-position substituent) or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-position substituent) or unsubstituted heteroalkyl (e.g., 2 to 8 members, 2 to 6 members, or 2 to 4 members), a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-position substituent) or unsubstituted cycloalkyl (e.g., C3-C8). The aryl group (e.g., C3-C6 or C5-C6), substituted (e.g., substituted with a substituent, size-restricted substituent, or low-substituent) or unsubstituted heterocyclic alkyl (e.g., 3 to 8 members, 3 to 6 members, or 5 to 6 members), substituted (e.g., substituted with a substituent, size-restricted substituent, or low-substituent) or unsubstituted aryl (e.g., C6-C10, C6, or phenyl), substituted (e.g., substituted with a substituent, size-restricted substituent, or low-substituent) or unsubstituted heteroaryl (e.g., 5 to 10 members, 5 to 9 members, or 5 to 6 members), or a bond to which 1,4-dihydropyridine is attached to the polymer support. X6' is independently -F, -Cl, -Br, or -I.

[0132] In this embodiment, R6' is hydrogen, -CF3, -CHF2, -CH2F, -CCl3, -CHCl2, -CH2Cl, -CBr3, -CHBr2, -CH2Br, -CI3, -CHI2, -CH2I, substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-position substituent) or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-position substituent) or unsubstituted heteroalkyl (e.g., 2 to 8 members, 2 to 6 members, or 2 to 4 members), substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-position substituent) The alkyl group (e.g., C3-C8, C3-C6, or C5-C6) is substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-substituent) or unsubstituted heterocyclic alkyl group (e.g., 3 to 8 members, 3 to 6 members, or 5 to 6 members), substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-substituent) or unsubstituted aryl group (e.g., C6-C10, C6, or phenyl), substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-substituent) or unsubstituted heteroaryl group (e.g., 5 to 10 members, 5 to 9 members, or 5 to 6 members), or a bond connecting 1,4-dihydropyridine to the polymer support. In this embodiment, R6' is substituted if it is substituted with a substituent. In this embodiment, R6' is substituted if it is substituted with a size-restricted substituent. In this embodiment, R6' is substituted if it is substituted with a lower substituent.

[0133] In this embodiment, R6' 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 to 8 members, 2 to 6 members, or 2 to 4 members), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 members, 3 to 6 members, or 5 to 6 members), unsubstituted aryl (e.g., C6-C10, C6, or phenyl), unsubstituted heteroaryl (e.g., 5 to 10 members, 5 to 9 members, or 5 to 6 members), or a bond connecting 1,4-dihydropyridine to the polymer support.

[0134] In this embodiment, R7' is hydrogen, -CX7'3, -CHX7'2, -CH2X7', a substituted or unsubstituted alkyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, or a bond in which 1,4-dihydropyridine is attached to the polymer support. X7' is independently -F, -Cl, -Br, or -I.

[0135] In this embodiment, R7' is independently hydrogen, -CX7'3, -CHX7'2, -CH2X7', substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-substituent) or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-substituent) or unsubstituted heteroalkyl (e.g., 2 to 8 members, 2 to 6 members, or 2 to 4 members), substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-substituent) or unsubstituted cycloalkyl (e.g., C3- C8, C3-C6, or C5-C6), substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-substituent) or unsubstituted heterocyclic alkyl (e.g., 3 to 8 members, 3 to 6 members, or 5 to 6 members), substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-substituent) or unsubstituted aryl (e.g., C6-C10, C6, or phenyl), substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-substituent) or unsubstituted heteroaryl (e.g., 5 to 10 members, 5 to 9 members, or 5 to 6 members), or a bond with 1,4-dihydropyridine attached to the polymer support. X7' is independently -F, -Cl, -Br, or -I.

[0136] In this embodiment, R7' is independently hydrogen, -CF3, -CHF2, -CH2F, -CCl3, -CHCl2, -CH2Cl, -CBr3, -CHBr2, -CH2Br, -CI3, -CHI2, -CH2I, substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-substituent) or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-substituent) or unsubstituted heteroalkyl (e.g., 2 to 8 members, 2 to 6 members, or 2 to 4 members), substituted (e.g., substituted with a substituent, a size-restricted substituent) The substituted alkyl group (e.g., C3-C8, C3-C6, or C5-C6), substituted (e.g., substituted with a substituent, size-restricted substituent, or low-substituent), or unsubstituted heterocyclic alkyl group (e.g., 3 to 8 members, 3 to 6 members, or 5 to 6 members), substituted (e.g., substituted with a substituent, size-restricted substituent, or low-substituent), or unsubstituted aryl group (e.g., C6-C10, C6, or phenyl), substituted (e.g., substituted with a substituent, size-restricted substituent, or low-substituent), or unsubstituted heteroaryl group (e.g., 5 to 10 members, 5 to 9 members, or 5 to 6 members), or a bond connecting 1,4-dihydropyridine to the polymer support, may be substituted. In this embodiment, R7' is substituted if it is substituted with a substituent. In this embodiment, R7' is substituted if it is substituted with a size-restricted substituent. In this embodiment, R7' is substituted if it is substituted with a lower substituent.

[0137] In this embodiment, R7' is 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 to 8 members, 2 to 6 members, or 2 to 4 members), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 members, 3 to 6 members, or 5 to 6 members), unsubstituted aryl (e.g., C6-C10, C6, or phenyl), unsubstituted heteroaryl (e.g., 5 to 10 members, 5 to 9 members, or 5 to 6 members), or a bond connecting 1,4-dihydropyridine to the polymer support.

[0138] R8' is independently hydrogen, halogen, -CX8'3, -CHX8'2, -CH2X8', -OCX8'3, -OCHX8'2, -OCH2X8', -CN, -S(O)2R8'A, -SR8'A, -S(O)R8'A, -SO2NR8'AR8'B, -NHC(O)NR8'AR8'B, -N(O)2, -NR8'AR8'B, -NHNR8'AR8'B, -C(O)R8'A, -C(O)-OR8 'A, -C(O)NR8'AR8'B, -C(O)NHNR8'AR8'B, -OR8'A, -NR8'ASO2R8'B, -NR8'AC(O)R8'B, -NR8'AC(O)OR8'B, -NR8'AOR8'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. X8' is independently -F, -Cl, -Br or -I.

[0139] In this embodiment, R8' is independently hydrogen, halogen (e.g., -F, -Cl, -Br, -I), -CX8'3, -CHX8'2, -CH2X8', -OCX8'3, -OCHX8'2, -OCH2X8', -CN, -S(O)2R8'A, -SR8'A, -S(O)R8'A, -SO2NR8'AR8'B, -NHC(O)NR8'AR8'B, -N(O)2, -NR8'AR8'B, -NHNR8'AR8'B, -C(O)R8'A, -C(O)-OR8'A, -C(O)NR8'AR8'B, -C(O)NHNR8'AR8'B, -OR8' A. -NR8'ASO2R8'B, -NR8'AC(O)R8'B, -NR8'AC(O)OR8'B, -NR8'AOR8'B, -N3 (such as -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)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 substituents, size-restricted substituents or low-position substituents) or unsubstituted Alkyl groups (e.g., C1-C8, C1-C6, or C1-C4), substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-position substituent) or unsubstituted heteroalkyl groups (e.g., 2 to 8 members, 2 to 6 members, or 2 to 4 members), substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-position substituent) or unsubstituted cycloalkyl groups (e.g., C3-C8, C3-C6, or C5-C6), substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-position substituent) or unsubstituted heterocycloalkyl groups (e.g., 3 to 8 members, 3 to 6 members, or 5 to 6 members), substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-position substituent) or unsubstituted aryl groups (e.g.,X8' is a heteroaryl group (e.g., C6-C10, C6, or phenyl) or substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-position substituent) or unsubstituted (e.g., 5 to 10 members, 5 to 9 members, or 5 to 6 members). X8' is independently -F, -Cl, -Br, or -I.

[0140] In this embodiment, R8' is 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, -OCH2 I, -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)O H, -NCH3C(O)OH, -NHOH, -NCH3OH, -NCH3OCH3, substituted (e.g., substituted with a substituent, size-restricted substituent, or low-substituent) or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), substituted (e.g., substituted with a substituent, size-restricted substituent, or low-substituent) or unsubstituted heteroalkyl (e.g., 2 to 8 members, 2 to 6 members, or 2 to 4 members), substituted (e.g., substituted with a substituent, size-restricted substituent, or low-substituent) or unsubstituted cycloalkyl ( For example, a heterocyclic alkyl group (e.g., 3 to 8 members, 3 to 6 members, or 5 to 6 members), a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-substituent) or unsubstituted aryl group (e.g., C6 to C10, C6, or phenyl), or a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-substituent) or unsubstituted heteroaryl group (e.g., 5 to 10 members, 5 to 9 members, or 5 to 6 members). In this embodiment, R8' is substituted if it is substituted with a substituent. In this embodiment, R8' is substituted if it is substituted with a size-restricted substituent. In this embodiment, R8' is substituted if it is substituted with a low-substituent.

[0141] In this embodiment, R8' is 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)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, -NCH3OCH3, unsubstituted alkyl groups (e.g., C1-C8, C1-C6) (or C1-C4), unsubstituted heteroalkyl (e.g., 2 to 8 members, 2 to 6 members, or 2 to 4 members), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 members, 3 to 6 members, or 5 to 6 members), unsubstituted aryl (e.g., C6-C10, C6, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 members, 5 to 9 members, or 5 to 6 members).

[0142] R9' is independently hydrogen, halogen, -CX9'3, -CHX9'2, -CH2X9', -OCX9'3, -OCHX9'2, -OCH2X9', -CN, -S(O)2R9'A, -SR9'A, -S(O)R9'A, -SO2NR9'AR9'B, -NHC(O)NR9'AR9'B, -N(O)2, -NR9'AR9'B, -NHNR9'AR9'B, -C(O)R9'A, -C(O)-OR9 'A, -C(O)NR9'AR9'B, -C(O)NHNR9'AR9'B, -OR9'A, -NR9'ASO2R9'B, -NR9'AC(O)R9'B, -NR9'AC(O)OR9'B, -NR9'AOR9'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. X9' is independently -F, -Cl, -Br or -I.

[0143] In this embodiment, R9' is independently hydrogen, halogen (e.g., -F, -Cl, -Br, -I), -CX9'3, -CHX9'2, -CH2X9', -OCX9'3, -OCHX9'2, -OCH2X9', -CN, -S(O)2R9'A, -SR9'A, -S(O)R9'A, -SO2NR9'AR9'B, -NHC(O)NR9'AR9'B, -N(O)2, -NR9'AR9'B, -NHNR9'AR9'B, -C(O)R9'A, -C(O)-OR9'A, -C(O)NR9'AR9'B, -C(O)NHNR9'AR9'B, -OR9 'A, -NR9'ASO2R9'B, -NR9'AC(O)R9'B, -NR9'AC(O)OR9'B, -NR9'AOR9'B, -N3 (for example, -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, -SO 2CH3, -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 substituents, size-restricted substituents or low-position substituents) or unsubstituted Alkyl groups (e.g., C1-C8, C1-C6, or C1-C4), substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-position substituent) or unsubstituted heteroalkyl groups (e.g., 2 to 8 members, 2 to 6 members, or 2 to 4 members), substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-position substituent) or unsubstituted cycloalkyl groups (e.g., C3-C8, C3-C6, or C5-C6), substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-position substituent) or unsubstituted heterocycloalkyl groups (e.g., 3 to 8 members, 3 to 6 members, or 5 to 6 members), substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-position substituent) or unsubstituted aryl groups (e.g.,X9' is a heteroaryl group (e.g., C6-C10, C6, or phenyl) or substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-position substituent) or unsubstituted (e.g., 5 to 10 members, 5 to 9 members, or 5 to 6 members). X9' is independently -F, -Cl, -Br, or -I.

[0144] In this embodiment, R9' is 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)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, -NCH3OCH3, substituted (e.g., substituted with a substituent, size-restricted substituent, or low-substituent) or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), substituted (e.g., substituted with a substituent, size-restricted substituent, or low-substituent) or unsubstituted heteroalkyl (e.g., 2 to 8 members, 2 to 6 members, or 2 to 4 members), substituted (e.g., substituted with a substituent, size-restricted substituent, or low-substituent) or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C4). In this embodiment, R9' is substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-position substituent) or unsubstituted heterocyclic alkyl (e.g., 3 to 8 members, 3 to 6 members, or 5 to 6 members), substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-position substituent) or unsubstituted aryl (e.g., C6-C10, C6, or phenyl), or substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-position substituent) or unsubstituted heteroaryl (e.g., 5 to 10 members, 5 to 9 members, or 5 to 6 members). If R9' is substituted, it is substituted with a substituent. If R9' is substituted, it is substituted with a size-restricted substituent. If R9' is substituted, it is substituted with a low-position substituent.

[0145] In this embodiment, R9' is 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)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, -NCH3OCH3, unsubstituted alkyl groups (e.g., C1-C8, C1-C6) (or C1-C4), unsubstituted heteroalkyl (e.g., 2 to 8 members, 2 to 6 members, or 2 to 4 members), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 members, 3 to 6 members, or 5 to 6 members), unsubstituted aryl (e.g., C6-C10, C6, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 members, 5 to 9 members, or 5 to 6 members).

[0146] R10' is independently hydrogen, halogen, -CX10'3, -CHX10'2, -CH2X10', -OCX10'3, -OCHX10'2, -OCH2X10', -CN, -S(O)2R10'A, -SR10'A, -S(O)R10'A, -SO2NR10'AR10'B, -NHC(O)NR10'AR10'B, -N(O)2, -NR10'AR10'B, -NHNR10'AR10'B, -C(O)R10'A, -C(O)-O R10'A, -C(O)NR10'AR10'B, -C(O)NHNR10'AR10'B, -OR10'A, -NR10'ASO2R10'B, -NR10'AC(O)R10'B, -NR10'AC(O)OR10'B, -NR10'AOR10'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. X10' is independently -F, -Cl, -Br or -I.

[0147] In this embodiment, R10' is independently hydrogen, halogen (e.g., -F, -Cl, Br, -I), -CX10'3, -CHX10'2, -CH2X10', -OCX10'3, -OCHX10'2, -OCH2X10', -CN, -S(O)2R10'A, -SR10'A, -S(O)R10'A, -SO2NR10'AR10'B, -NHC(O)NR10'AR10'B, -N(O)2, -NR10'AR10'B, -NHNR10'AR10'B, -C(O)R10'A, -C(O)-OR10'A, -C(O)NR10'AR10'B , -C(O)NHNR10'AR10'B, -OR10'A, -NR10'ASO2R10'B, -NR10'AC(O)R10'B, -NR10'AC(O)OR10'B, -NR10'AOR10'B, -N3 (for example, -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)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) Alkyl groups that are substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-position substituent) or unsubstituted (e.g., C1-C8, C1-C6, or C1-C4), heteroalkyl groups that are substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-position substituent) or unsubstituted (e.g., 2 to 8 members, 2 to 6 members, or 2 to 4 members), cycloalkyl groups that are substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-position substituent) or unsubstituted (e.g., C3-C8, C3-C6, or C5-C6), heteroalkyl groups that are substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-position substituent) or unsubstituted (e.g., 3 to 8 members, 3 to 6 members, or 5 to 6 members), and heteroalkyl groups that are substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-position substituent) or un ...The aryl group (e.g., C6-C10, C6, or phenyl) is either substituted (e.g., substituted, size-restricted, or low-substituent) or unsubstituted heteroaryl group (e.g., 5 to 10 members, 5 to 9 members, or 5 to 6 members). X10' is independently -F, -Cl, -Br, or -I.

[0148] In this embodiment, R10' is 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, -OCH 2I, -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, -NCH3OCH3, substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-substituent) or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-substituent) or unsubstituted heteroalkyl (e.g., 2 to 8 members, 2 to 6 members, or 2 to 4 members), substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-substituent) or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-substituent) or unsubstituted heterocyclic alkyl (e.g., 3 to 8 members, 3 to 6 members, or 5 to 6 members), substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-substituent) or unsubstituted aryl (e.g., C6-C10, C6, or phenyl), or substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-substituent) or unsubstituted heteroaryl (e.g., 5 to 10 members, 5 to 9 members, or 5 to 6 members). In this embodiment, R10' is substituted if it is substituted with a substituent. In this embodiment, R10' is substituted if it is substituted with a size-restricted substituent. In this embodiment, R10' is substituted if it is substituted with a low-substituent.

[0149] In this embodiment, R10' is 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)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, -NCH3OCH3, unsubstituted alkyl groups (e.g., C1-C8, C1-C) Unsubstituted heteroalkyl (e.g., 2 to 8, 2 to 6, or 2 to 4 members), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8, 3 to 6, or 5 to 6 members), unsubstituted aryl (e.g., C6-C10, C6, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10, 5 to 9, or 5 to 6 members).

[0150] R8'A, R8'B, R9'A, R9'B, R10'A, and R10'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, -OCH2 I, -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, 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.

[0151] In this embodiment, R8'A, R8'B, R9'A, R9'B, R10'A, and R10'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, -OCHCl 2. -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -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, substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-substituent) or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-substituent) or unsubstituted heteroalkyl (e.g., 2 to 8 members, 2 to 6 members, or 2 to 4 members), substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-substituent) or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C1-C4), Heterocyclic alkyl groups (e.g., 3 to 8, 3 to 6, or 5 to 6 members), substituted (e.g., substituted with a substituent, size-restricted substituent, or low-substituent) or unsubstituted aryl groups (e.g., C6-C10, C6, or phenyl), or substituted (e.g., substituted with a substituent, size-restricted substituent, or low-substituent) or unsubstituted heteroaryl groups (e.g., 5 to 10, 5 to 9, or 5 to 6 members). In this embodiment, if R6'A, R6'B, R7'A, R7'B, R8'A, R8'B, R9'A, R9'B, R10'A, and R10'B are substituted, they are substituted with a substituent. In this embodiment, if R6'A, R6'B, R7'A, R7'B, R8'A, R8'B, R9'A, R9'B, R10'A, and R10'B are substituted, they are substituted with size-restricted substituents. In this embodiment, if R6'A, R6'B, R7'A, R7'B, R8'A, R8'B, R9'A, R9'B, R10'A, and R10'B are substituted, they are substituted with lower-position substituents. In this embodiment, R6'A is substituted with a substituent. In this embodiment, R6'A is substituted with a size-restricted substituent. In this embodiment, R6'A is substituted with a lower-position substituent.In this embodiment, R6'B is substituted with a substituent. In this embodiment, R6'B is substituted with a size-restricted substituent. In this embodiment, R6'B is substituted with a lower-position substituent. In this embodiment, R7'A is substituted with a substituent. In this embodiment, R7'A is substituted with a size-restricted substituent. In this embodiment, R7'A is substituted with a lower-position substituent. In this embodiment, R7'B is substituted with a substituent. In this embodiment, R7'B is substituted with a size-restricted substituent. In this embodiment, R7'B is substituted with a lower-position substituent. In this embodiment, R8'A is substituted with a substituent. In this embodiment, R8'A is substituted with a size-restricted substituent. In this embodiment, R8'A is substituted with a lower-position substituent. In this embodiment, R8'B is substituted with a substituent. In this embodiment, R8'B is substituted with a size-restricted substituent. In this embodiment, R8'B is substituted with a lower-position substituent. In this embodiment, R9'A is substituted with a substituent. In this embodiment, R9'A is substituted with a size-restricted substituent. In this embodiment, R9'A is substituted with a lower-position substituent. In this embodiment, R9'B is substituted with a substituent. In this embodiment, R9'B is substituted with a size-restricted substituent. In this embodiment, R9'B is substituted with a lower-position substituent. In this embodiment, R10'A is substituted with a substituent. In this embodiment, R10'A is substituted with a size-restricted substituent. In this embodiment, R10'A is substituted with a lower-position substituent. In this embodiment, R10'B is substituted with a substituent. In this embodiment, R10'B is substituted with a size-restricted substituent. In this embodiment, R10'B is substituted with a low-position substituent.

[0152] In this embodiment, R8'A, R8'B, R9'A, R9'B, R10'A, and R10'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, -CONH2, -S H, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)OH, -NHOH, unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), unsubstituted heteroalkyl (e.g., 2 to 8 members, 2 to 6 members, or 2 to 4 members), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 members, 3 to 6 members, or 5 to 6 members), unsubstituted aryl (e.g., C6-C10, C6, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 members, 5 to 9 members, or 5 to 6 members).

[0153] X is -Cl, -Br, -I, -OSO2R15, or -OCOR15. In this embodiment, X is -Cl. In this embodiment, X is -Br. In this embodiment, X is -I. In this embodiment, X is -OSO2R15. In this embodiment, X is -OCOR15.

[0154] R15 is a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group.

[0155] In this embodiment, R15 is a substituted or unsubstituted alkyl group. In this embodiment, R15 is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-position substituent) or unsubstituted alkyl group (e.g., C1-C8, C1-C6, or C1-C4). In this embodiment, R15 is an unsubstituted alkyl group (e.g., C1-C8, C1-C6, or C1-C4). In this embodiment, if R15 is substituted, it is substituted with a substituent. In this embodiment, if R15 is substituted, it is substituted with a size-restricted substituent. In this embodiment, if R15 is substituted, it is substituted with a low-position substituent.

[0156] In this embodiment, R15 is a substituted or unsubstituted aryl group. In this embodiment, R15 is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-position substituent) or unsubstituted aryl group (e.g., C6-C10, C6, or phenyl). In this embodiment, R15 is an unsubstituted aryl group (e.g., C6-C10, C6, or phenyl). In this embodiment, if R15 is substituted, it is substituted with a substituent. In this embodiment, if R15 is substituted, it is substituted with a size-restricted substituent. In this embodiment, if R15 is substituted, it is substituted with a low-position substituent.

[0157] In this embodiment, R15 is a substituted or unsubstituted heteroaryl group. In this embodiment, R15 is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-position substituent) or unsubstituted heteroaryl group (e.g., 5 to 10 members, 5 to 9 members, or 5 to 6 members). In this embodiment, R15 is an unsubstituted heteroaryl group (e.g., 5 to 10 members, 5 to 9 members, or 5 to 6 members). In this embodiment, if R15 is substituted, it is substituted with a substituent. In this embodiment, if R15 is substituted, it is substituted with a size-restricted substituent. In this embodiment, if R15 is substituted, it is substituted with a low-position substituent.

[0158] R16 is hydrogen, -OH, -C(O)R16A, substituted or unsubstituted alkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

[0159] In this embodiment, R16 is hydrogen. In this embodiment, R16 is -OH. In this embodiment, R16 is -C(O)R16A. In this embodiment, R16A is hydrogen or a substituted or unsubstituted alkyl group. In this embodiment, R16A is hydrogen. In this embodiment, R16A is a substituted or unsubstituted alkyl group. In this embodiment, R16A is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-position substituent) or unsubstituted alkyl group (e.g., C1-C8, C1-C6, or C1-C4). In this embodiment, R16A is an unsubstituted alkyl group (e.g., C1-C8, C1-C6, or C1-C4).

[0160] In this embodiment, R16 is a substituted or unsubstituted alkyl group. In this embodiment, R16 is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-position substituent) or unsubstituted alkyl group (e.g., C1-C8, C1-C6, or C1-C4). In this embodiment, R16 is an unsubstituted alkyl group (e.g., C1-C8, C1-C6, or C1-C4). In this embodiment, if R16 is substituted, it is substituted with a substituent. In this embodiment, if R16 is substituted, it is substituted with a size-restricted substituent. In this embodiment, if R16 is substituted, it is substituted with a low-position substituent.

[0161] In this embodiment, R16 is a substituted or unsubstituted aryl group. In this embodiment, R16 is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted aryl group (e.g., C6-C10, C6, or phenyl). In this embodiment, R16 is an unsubstituted aryl group (e.g., C6-C10, C6, or phenyl). In this embodiment, if R16 is substituted, it is substituted with a substituent. In this embodiment, if R16 is substituted, it is substituted with a size-restricted substituent. In this embodiment, if R16 is substituted, it is substituted with a lower substituent.

[0162] In this embodiment, R16 is a substituted or unsubstituted heteroaryl group. In this embodiment, R16 is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-position substituent) or unsubstituted heteroaryl group (e.g., 5 to 10 members, 5 to 9 members, or 5 to 6 members). In this embodiment, R16 is an unsubstituted heteroaryl group (e.g., 5 to 10 members, 5 to 9 members, or 5 to 6 members). In this embodiment, if R16 is substituted, it is substituted with a substituent. In this embodiment, if R16 is substituted, it is substituted with a size-restricted substituent. In this embodiment, if R16 is substituted, it is substituted with a low-position substituent.

[0163] is formed from a compound wherein R17 is hydrogen, -OH, -C(O)R17A, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group, and R17A is hydrogen or a substituted or unsubstituted alkyl group.

[0164] In this embodiment, R17 is hydrogen. In this embodiment, R17 is -OH. In this embodiment, R17 is -C(O)R17A. In this embodiment, R17A is hydrogen or a substituted or unsubstituted alkyl group. In this embodiment, R17A is hydrogen. In this embodiment, R17A is a substituted or unsubstituted alkyl group. In this embodiment, R17A is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-position substituent) or unsubstituted alkyl group (e.g., C1-C8, C1-C6, or C1-C4). In this embodiment, R17A is an unsubstituted alkyl group (e.g., C1-C8, C1-C6, or C1-C4).

[0165] In this embodiment, R17 is a substituted or unsubstituted alkyl group. In this embodiment, R17 is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-position substituent) or unsubstituted alkyl group (e.g., C1-C8, C1-C6, or C1-C4). In this embodiment, R17 is an unsubstituted alkyl group (e.g., C1-C8, C1-C6, or C1-C4). In this embodiment, if R17 is substituted, it is substituted with a substituent. In this embodiment, if R17 is substituted, it is substituted with a size-restricted substituent. In this embodiment, if R17 is substituted, it is substituted with a low-position substituent.

[0166] In this embodiment, R17 is a substituted or unsubstituted aryl group. In this embodiment, R17 is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-position substituent) or unsubstituted aryl group (e.g., C6-C10, C6, or phenyl). In this embodiment, R17 is an unsubstituted aryl group (e.g., C6-C10, C6, or phenyl). In this embodiment, if R17 is substituted, it is substituted with a substituent. In this embodiment, if R17 is substituted, it is substituted with a size-restricted substituent. In this embodiment, if R17 is substituted, it is substituted with a low-position substituent.

[0167] In this embodiment, R17 is a substituted or unsubstituted heteroaryl group. In this embodiment, R17 is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a low-position substituent) or unsubstituted heteroaryl group (e.g., 5 to 10 members, 5 to 9 members, or 5 to 6 members). In this embodiment, R17 is an unsubstituted heteroaryl group (e.g., 5 to 10 members, 5 to 9 members, or 5 to 6 members). In this embodiment, if R17 is substituted, it is substituted with a substituent. In this embodiment, if R17 is substituted, it is substituted with a size-restricted substituent. In this embodiment, if R17 is substituted, it is substituted with a low-position substituent.

[0168] In this embodiment, n1' and n2' are each independently an integer from 0 to 5, wherein the sum of n1' and n2' is at least 1 and does not exceed 6. In this embodiment, n1' is 0 and n2' is 1. In this embodiment, n1' is 0 and n2' is 2. In this embodiment, n1' is 0 and n2' is 3. In this embodiment, n1' is 0 and n2' is 4. In this embodiment, n1' is 0 and n2' is 5. In this embodiment, n1' is 0 and n2' is 6. In this embodiment, n1' is 1 and n2' is 0. In this embodiment, n1' is 1 and n2' is 1. In this embodiment, n1' is 1 and n2' is 2. In this embodiment, n1' is 1 and n2' is 3. In this embodiment, n1' is 1 and n2' is 4. In this embodiment, n1' is 1 and n2' is 5. In this embodiment, n1' is 2 and n2' is 0. In this embodiment, n1' is 2 and n2' is 1. In this embodiment, n1' is 2 and n2' is 2. In this embodiment, n1' is 2 and n2' is 3. In this embodiment, n1' is 2 and n2' is 4. In this embodiment, n3' is 1 and n2' is 0. In this embodiment, n1' is 3 and n2' is 1. In this embodiment, n1' is 3 and n2' is 2. In this embodiment, n1' is 3 and n2' is 3. In this embodiment, n1' is 4 and n2' is 0. In this embodiment, n1' is 4 and n2' is 1. In this embodiment, n1' is 4 and n2' is 2. In this embodiment, n1' is 5 and n2' is 0. In this embodiment, n1' is 5 and n2' is 1. In this embodiment, n1' is 6 and n2' is 0.

[0169] In this embodiment, n3' is an integer between 0 and 5. In this embodiment, n3' is 0. In this embodiment, n3' is 1. In this embodiment, n3' is 2. In this embodiment, n3' is 3. In this embodiment, n3' is 4. In this embodiment, n3' is 5.

[0170] In this embodiment, L1 is C(R4')2, where R4' is as described above, including the embodiments.

[0171] In this embodiment, L2 is C(R5')2, where R5' is as described above, including the embodiments.

[0172] In this embodiment, L3' is oxygen or NR20'. In this embodiment, L3' is oxygen. In this embodiment, L3' is NR20', wherein R20' is as described above, including the examples.

[0173] In this embodiment, L4' is oxygen or NR20'. In this embodiment, L4' is oxygen. In this embodiment, L4' is NR20', wherein R20' is as described above, including the examples.

[0174] In this embodiment, X1 is -F, -Cl, -Br, or -I. In this embodiment, X1 is -F. In this embodiment, X1 is -Cl. In this embodiment, X1 is -Br. In this embodiment, X1 is -I.

[0175] In this embodiment, X2 is -F, -Cl, -Br, or -I. In this embodiment, X2 is -F. In this embodiment, X2 is -Cl. In this embodiment, X2 is -Br. In this embodiment, X2 is -I.

[0176] In this embodiment, X3 is -F, -Cl, -Br, or -I. In this embodiment, X3 is -F. In this embodiment, X3 is -Cl. In this embodiment, X3 is -Br. In this embodiment, X3 is -I.

[0177] In this embodiment, X4 is -F, -Cl, -Br, or -I. In this embodiment, X4 is -F. In this embodiment, X4 is -Cl. In this embodiment, X4 is -Br. In this embodiment, X4 is -I.

[0178] In this embodiment, X5 is -F, -Cl, -Br, or -I. In this embodiment, X5 is -F. In this embodiment, X5 is -Cl. In this embodiment, X5 is -Br. In this embodiment, X5 is -I.

[0179] In this embodiment, X6 is -F, -Cl, -Br, or -I. In this embodiment, X6 is -F. In this embodiment, X6 is -Cl. In this embodiment, X6 is -Br. In this embodiment, X6 is -I.

[0180] In this embodiment, X7 is -F, -Cl, -Br, or -I. In this embodiment, X7 is -F. In this embodiment, X7 is -Cl. In this embodiment, X7 is -Br. In this embodiment, X7 is -I.

[0181] In this embodiment, X8 is -F, -Cl, -Br, or -I. In this embodiment, X8 is -F. In this embodiment, X8 is -Cl. In this embodiment, X8 is -Br. In this embodiment, X8 is -I.

[0182] In this embodiment, X9 is -F, -Cl, -Br, or -I. In this embodiment, X9 is -F. In this embodiment, X9 is -Cl. In this embodiment, X9 is -Br. In this embodiment, X9 is -I.

[0183] In this embodiment, X10 is -F, -Cl, -Br, or -I. In this embodiment, X10 is -F. In this embodiment, X10 is -Cl. In this embodiment, X10 is -Br. In this embodiment, X10 is -I.

[0183] Compound

[0184] The synthetic method provided herein can be used to synthesize compounds of formula (V):

[0184] , or a pharmaceutically acceptable salt thereof. X1 is CR8 or N. X2 is CR9 or N. X3 is CR10 or N. Symbols n1, n2, n3, n4, n5, n6, n7, n8, n9, n10, and n44 are independently integers from 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. z1 is an integer from 0 to 5. z2 is an integer from 0 to 5. z3 is an integer from 0 to 11. z4 is an integer from 0 to 2. R7 is a substituted or unsubstituted cycloalkyl group. R1 represents hydrogen, halogen, -CX1.13, -CHX1.12, -CH2X1.1, -CN, -N3, -SOn1R1A, -SOv1NR1BR1C, -NHNR1BR1C, -ONR1BR1C, -NHC(O)NHNR1BR1C, -NHC(O)NR1BR1C, -N(O)m1, -NR1BR1C, -C(O)R1D, -C(O)OR1D, -C(O)NR1BR 1C, -OR1A, -NR1BSO2R1A, -NR1BC(O)R1D, -NR1BC(O)OR1D, -NR1BOR1D, -OCX1.13, -OCHX1.12, -OCH2X1.1, 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. R2 can be hydrogen, halogen, -CX2.13, -CHX2.12, -CH2X2.1, -CN, -N3, -SOn2R2A, -SOv2NR2BR2C, -NHNR2BR2C, -ONR2BR2C, -NHC(O)NHNR2BR2C, -NHC(O)NR2BR2C, -N(O)m2, -NR2BR2C, -C(O)R2D, -C(O)OR2D, -C(O)NR2BR 2C, -OR2A, -NR2BSO2R2A, -NR2BC(O)R2D, -NR2BC(O)OR2D, -NR2BOR2D, -OCX2.13, -OCHX2.12, -OCH2X2.1, 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.R3 is independently a halogen, -CX3.13, -CHX3.12, -CH2X3.1, -CN, -N3, -SOn3R3A, -SOv3NR3BR3C, -NHNR3BR3C, -ONR3BR3C, -NHC(O)NHNR3BR3C, -NHC(O)NR3BR3C, -N(O)m3, -NR3BR3C, -C(O)R3D, -C(O)OR3D, -C(O)NR3BR 3C, -OR3A, -NR3BSO2R3A, -NR3BC(O)R3D, -NR3BC(O)OR3D, -NR3BOR3D, -OCX3.13, -OCHX3.12, -OCH2X3.1, 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. R4 represents hydrogen, halogens, -CX4.13, -CHX4.12, -CH2X4.1, -CN, -N3, -SOn4R4A, -SOv4NR4BR4C, -NHNR4BR4C, -ONR4BR4C, -NHC(O)NHNR4BR4C, -NHC(O)NR4BR4C, -N(O)m4, -NR4BR4C, -C(O)R4D, -C(O)OR4D, -C(O)NR4BR 4C, -OR4A, -NR4BSO2R4A, -NR4BC(O)R4D, -NR4BC(O)OR4D, -NR4BOR4D, -OCX4.13, -OCHX4.12, -OCH2X4.1, 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. R5 is independently a halogen, a side oxygen group, -CX5.13, -CHX5.12, -CH2X5.1, -CN, -N3, -SOn5R5A, -SOv5NR5BR5C, -NHNR5BR5C, -ONR5BR5C, -NHC(O)NHNR5BR5C, -NHC(O)NR5BR5C, -N(O)m5, -NR5BR5C, -C(O)R5D, -C(O)OR5D, -C(O)NR5 BR5C, -OR5A, -NR5BSO2R5A, -NR5BC(O)R5D, -NR5BC(O)OR5D, -NR5BOR5D, -OCX5.13, -OCHX5.12, -OCH2X5.1, 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.R6 is independently a halogen, a side oxygen group, -CX6.13, -CHX6.12, -CH2X6.1, -CN, -N3, -SOn6R6A, -SOv6NR6BR6C, -NHNR6BR6C, -ONR6BR6C, -NHC(O)NHNR6BR6C, -NHC(O)NR6BR6C, -N(O)m6, -NR6BR6C, -C(O)R6D, -C(O)OR6D, -C(O)NR6 BR6C, -OR6A, -NR6BSO2R6A, -NR6BC(O)R6D, -NR6BC(O)OR6D, -NR6BOR6D, -OCX6.13, -OCHX6.12, -OCH2X6.1, 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. R7 represents hydrogen, halogens, -CX7.13, -CHX7.12, -CH2X7.1, -CN, -N3, -SOn7R7A, -SOv7NR7BR7C, -NHNR7BR7C, -ONR7BR7C, -NHC(O)NHNR7BR7C, -NHC(O)NR7BR7C, -N(O)m7, -NR7BR7C, -C(O)R7D, -C(O)OR7D, -C(O)NR7BR 7C, -OR7A, -NR7BSO2R7A, -NR7BC(O)R7D, -NR7BC(O)OR7D, -NR7BOR7D, -OCX7.13, -OCHX7.12, -OCH2X7.1, 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. R8 represents hydrogen, halogens, -CX8.13, -CHX8.12, -CH2X8.1, -CN, -N3, -SOn8R8A, -SOv8NR8BR8C, -NHNR8BR8C, -ONR8BR8C, -NHC(O)NHNR8BR8C, -NHC(O)NR8BR8C, -N(O)m8, -NR8BR8C, -C(O)R8D, -C(O)OR8D, -C(O)NR8BR 8C, -OR8A, -NR8BSO2R8A, -NR8BC(O)R8D, -NR8BC(O)OR8D, -NR8BOR8D, -OCX8.13, -OCHX8.12, -OCH2X8.1, 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.R9 represents hydrogen, halogens, -CX9.13, -CHX9.12, -CH2X9.1, -CN, -N3, -SOn9R9A, -SOv9NR9BR9C, -NHNR9BR9C, -ONR9BR9C, -NHC(O)NHNR9BR9C, -NHC(O)NR9BR9C, -N(O)m9, -NR9BR9C, -C(O)R9D, -C(O)OR9D, -C(O)NR9BR9C, -OR9A, -NR9BSO2R9A, -NR9BC(O)R9D, -NR9BC(O)OR9D, -NR9BOR9D, -OCX9.13, -OCHX9.12, -OCH 2X9.1, 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; when X2 is CR9, R4 and R9 may optionally be linked to form a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, or an unsubstituted aryl or a substituted or unsubstituted heteroaryl; or when X2 is CR9 and X3 is CR10, CR9 and CR10 may optionally be linked to form a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, or an unsubstituted aryl or a substituted or unsubstituted heteroaryl. R10 represents hydrogen, halogens, -CX10.13, -CHX10.12, -CH2X10.1, -CN, -SOn10R10A, -SOv10NR10BR10C, -NHNR10BR10C, -ONR10BR10C, -NHC(O)NHNR10BR10C, -NHC(O)NR10BR10C, -N(O)m10, -NR10BR10C, -C(O)R10D, -C(O)OR10D, -C(O)NR10BR10C, -OR10A, -NR10BSO2R10A, -NR10BC(O)R10D -NR10BC(O)OR10D, -NR10BOR10D, -OCX10.13, -OCHX10.12, -OCH2X10.1, 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 when X2 is CR9 and X3 is CR10, R9 and R10 may optionally be linked to form substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, or unsubstituted aryl, or substituted or unsubstituted heteroaryl.R44 can be hydrogen, -CX44.13, -CHX44.12, -CH2X44.1, -SOn44R44A, -SOv44NR44BR44C, -C(O)R44D, -C(O)OR44D, -C(O)NR44BR44C, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl. R1A, R1B, R1C, R1D, R2A, R2B, R2C, R2D, R3A, R3B, R3C, R3D, R4A, R4B, R4C, R4D, R5A, R5B, R5C, R5D, R6A, R6B, R6C, R6D, R7A, R7B, R7C, R7D, R7.2B, R8A, R8B, R8C, R8D, R9A, R9B, R9C, R9D, R10A, R10B, R10C, R10D, R44A, R44B, R44C, and R44D are independently hydrogen, halogen, -CF3, -CCl3, -CBr3, -CI3, and -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; R1B, R1C, R2B, R2C, R3B, R3C, R4B, R4C, R5B, R5C, R6B, R6C, R7B, R7C, R8B, R8C, R9B, R9C, R10B, R10C, R44B and R44C substituents bonded to the same nitrogen atom may optionally be linked to form substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl. X1.1, X2.1, X3.1, X4.1, X5.1, X6.1, X7.1, X8.1, X9.1, X10.1 and X44.1 are independently -Cl, -Br, -I or -F, wherein at least one of X1, X2 and X3 is N.

[0185] The methods described herein can be used to synthesize a class of chemokine receptor type 4 (CCR4) inhibitors / antagonists, or intermediates and precursors thereof, as described in U.S. Patent 10,683,280 to Jackson et al., dated June 16, 2020, the disclosure of which is incorporated herein by reference. These compounds have formula (VI):

[0185] , or a pharmaceutically acceptable salt thereof, wherein R1, R2, R4, R44, X2, Z4, L7, and R7 are as described herein, including the embodiments. R3.2 and R3.3 are independent substituents included in the definition of R3. In this embodiment, R3.2 is hydrogen, halogen, -CX3.23, -CHX3.22, -CH2X3.2, -CN, -N3, -SOn3.2R3.2A, -SOv3.2NR3.2BR3.2C, -NHNR3.2BR3.2C, -ONR3.2BR3.2C, -NHC(O)NHNR3.2BR3.2C, -NHC(O)NR3.2BR3.2C, -N(O)m3.2, -NR3.2BR3.2C, -C(O)R3.2D, -C(O)OR3.2 D, -C(O)NR3.2BR3.2C, -OR3.2A, -NR3.2BSO2R3.2A, -NR3.2BC(O)R3.2D, -NR3.2BC(O)OR3.2D, -NR3.2BOR3.2D, -OCX3.23, -OCHX3.22, -OCH2X3.2, 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 this embodiment, R3.3 is hydrogen, halogen, -CX3.33, -CHX3.32, -CH2X3.3, -CN, -N3, -SOn3.3R3.3A, -SOv3.3NR3.3BR3.3C, -NHNR3.3BR3.3C, -ONR3.3BR3.3C, -NHC(O)NHNR3.3BR3.3C, -NHC(O)NR3.3BR3.3C, -N(O)m3.3, -NR3.3BR3.3C, -C(O)R3.3D, -C(O)OR3.3. D, -C(O)NR3.3BR3.3C, -OR3.3A, -NR3.3BSO2R3.3A, -NR3.3BC(O)R3.3D, -NR3.3BC(O)OR3.3D, -NR3.3BOR3.3D, -OCX3.33, -OCHX3.32, -OCH2X3.3, 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. Symbols n3.2 and n3.3 are independently integers between 0 and 4. Symbols m3.2, m3.3, v3.2 and v3.3 are independently 1 or 2.In this embodiment, R4 is hydrogen, -CX4.13, -CN, -C(O)NR4BR4C, a substituted or unsubstituted alkyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group. In this embodiment, R3.2A, R3.2B, R3.2C, R3.2D, R3.3A, R3.3B, R3.3C, and R3.3D are independently hydrogen, halogen, -CF3, -CCl3, -CBr3, -CI3, -COOH, -CONH2, a substituted or unsubstituted alkyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group. The substituents R3.2B, R3.2C, R3.3B and R3.3C bonded to the same nitrogen atom may optionally be linked to form substituted or unsubstituted heterocyclic alkyl or substituted or unsubstituted heteroaryl groups; while X3.2 and X3.3 are independently -Cl, -Br, -I or -F.

[0186] The method described herein can be used to synthesize the trans isomer of compound (VI), wherein the L7 moiety is a substituted or unsubstituted cycloalkyl group and the R7 moiety is a carboxylic acid or carboxylic acid-like moiety, such as -C(O)OR7D, -CH2C(O)OR7D or -NHC(O)OR7D, wherein R7D is selected from hydrogen, halogen, -CF3, -CCl3, -CBr3, -CI3, -COOH, -CONH2, substituted or unsubstituted alkyl group, substituted or unsubstituted heteroalkyl group, substituted or unsubstituted cycloalkyl group, substituted or unsubstituted heterocycloalkyl group, substituted or unsubstituted aryl group or substituted or unsubstituted heteroaryl group.

[0187] In this embodiment, the method described herein can be used to synthesize compounds of formula (VI) having an L7 moiety of a substituted or unsubstituted C3-C8 cycloalkyl group. In some embodiments, the method described herein can be used to synthesize compounds of formula (VI) having an L7 moiety of a substituted or unsubstituted C4-C6 cycloalkyl group. In other embodiments, the method described herein can be used to synthesize compounds of formula (VI) having an L7 moiety of a substituted or unsubstituted cyclobutene.

[0188] In this embodiment, the method described herein can be used to synthesize compounds of formula (VI) having one of the above-described L7 and R7 moieties of -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.

[0189] In some embodiments, the method described herein can be used to synthesize compounds of formula (VI) having one of the L7 and R7 moieties described above with -C(O)OH.

[0190] In this embodiment, the method described herein can be used to synthesize a compound of formula (VI) having one of the above-mentioned L7 and R7 moieties, and the compound has one or more of the following: z4 is 1, z3 is 0 and / or z2 is 0.

[0191] In this embodiment, the method described herein can be used to synthesize compounds of formula (VII):

[0191] , wherein z2, z3, z4, R5 and R6 are as described herein, including embodiments.

[0192] Those skilled in the art will understand that the above-mentioned class of compounds having 5 or more rings are typically synthesized in multiple steps, with intermediates serving as building blocks to produce the final CCR4 inhibitor / antagonist. In this synthetic method, at high trans-isomer purity, the step of synthesizing the desired trans-isomer using a carboxylic acid-directed reducing agent is typically performed on the intermediate or precursor of the final CCR4 inhibitor / antagonist. Therefore, at high trans-isomer purity, the step of synthesizing the desired trans-isomer using a carboxylic acid-directed reducing agent is typically used only to synthesize intermediate or precursor compounds similar to the following, which may have additional attached blocking and / or residual portions, and are not necessarily the remainder of the final CCR4 inhibitor / antagonist:

[0192] , wherein L7, R6, R7, z3 and z4 are as described herein, including embodiments.

[0193] In this embodiment, the method described herein can be used to synthesize compounds with the following structures:

[0193]

[0193]

[0194] In this embodiment, the formula is...

[0194] The compound is derived from compound (III) and formula:

[0194] The compound is formed by reacting in an environment containing tBuOH, water and an alkaline environment.

[0195] In this embodiment, the formula is...

[0195] The compound is formed by reacting the compound of formula (III) and the compound of formula: in an environment containing tBuOH, water and alkali.

[0196] In this embodiment, the formula is...

[0196] The compound is derived from the formula

[0196] is formed by removing the protecting group PG3 from the compound.

[0197] In this embodiment, the formula is...

[0197] The compound is derived from the formula

[0197] The compound is formed by reacting the compound of formula in an environment with a base and a solvent, wherein X is -Cl, -Br, -I, -OSO2R15 or -OCOR15, and wherein R15 is a substituted or unsubstituted alkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl.

[0198] In this embodiment, the formula is...

[0198] The compound is derived from the formula

[0198] The compound is formed by reacting the compound of formula in an environment with a base and a solvent, wherein n is an integer between 0 and 5, and R16 is hydrogen, -OH, -C(O)R16A, substituted or unsubstituted alkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, wherein R16A is hydrogen or substituted or unsubstituted alkyl.

[0199] In this embodiment, the formula is...

[0199] is formed by hydrolyzing the -C(O)NHR16 portion.

[0200] In this embodiment, the formula is...

[0200] The compound is formed by hydrolysis of the compound, wherein R17 is hydrogen, -OH, -C(O)R17A, substituted or unsubstituted alkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, and R17A is hydrogen or substituted or unsubstituted alkyl.

[0201] In this embodiment, the formula is...

[0201] The compound is derived from the formula

[0201] The compound is formed by reacting the compound of formula with a base and a solvent in an environment.

[0202] In this embodiment, the formula is...

[0202] The compound is derived from the formula

[0202] The compound is formed by reacting a base of formula M(OH)n3 with an organic solvent in an environment, wherein M is Li, Na, K, Cs, Ba, Ca, Mg, Be, Rb or Sr, and n3' is an integer between 1 and 2.

[0203] In this embodiment, the formula is...

[0203] The compound is derived from formula (I)

[0203] The compound is formed by reacting the compound of formula with a base and a solvent in an environment, wherein PG1 is a protecting group and n is an integer between 0 and 5.

[0204] In this embodiment, the formula is...

[0204] The compound is derived from the formula

[0204] is formed by removing the protecting group PG1 from the compound.

[0205] In this embodiment, the formula is...

[0205] The compound is derived from the formula

[0205] The compound is formed by reacting the compound of formula (II) in an environment containing 1,4-dihydropyridine and toluene.

[0206] In this embodiment, the formula is...

[0206] The compound is formed by reacting the compound of formula (II) with the compound of formula (II) in an environment containing 1,4-dihydropyridine, wherein PG2 is a protecting group.

[0207] In this embodiment, the formula is...

[0207] The compound is derived from the formula

[0207] is formed by removing the protecting group PG2 from the compound.

[0208] In this embodiment, the compound may be used as a comparator compound. In this embodiment, the comparator compound may be used to evaluate the activity of the test compound in an assay (e.g., as described herein, and illustrated in the Examples section, figures, or tables).

Implementation Method

[0208] General Synthesis Steps

[0209] The reductive amination of the intermediate compound used to synthesize the receptor regulator of G protein coupling can be carried out using one of the following general synthetic steps A or B.

[0209] General Step A

[0210] A 0.2 M toluene solution containing a primary or secondary amine (10 mmol, 1 equivalent), 1-methyl-3-oxocyclobutane-1-carboxylic acid (1.66 g, 13 mmol, 1.3 equivalent), and a reducing agent (13 mmol, 1.3 equivalent) was heated to reflux using a Dean-Stark apparatus. After residual water appeared in the valve, the reaction was cooled to ambient temperature. The reaction was then carried out according to one of the following schemes: (1) the first toluene was removed under vacuum, and the residue was partitioned between water (30 mL) and methyl tributyl ether (50 mL). The aqueous layer was washed twice with methyl tributyl ether (50 mL each time). After removing water under high vacuum, the ratio of cis / trans isomers was determined by HPLC. (2) Toluene was replaced with acetate, and heptane was added to obtain a solid substance. The solid substance was then filtered, dried under vacuum, and the ratio of cis / trans diastereomers was determined by HPLC.

[0211] The method for determining the ratio of cis / trans diastereomers may be: (a) XBridge C18 3.5mM 4.6x150mm HPLC column, flow rate 1mL / min, 0 to 100% water (+0.1% ammonia) / acetonitrile (+0.1% ammonia) for more than 30 minutes; or (b) 1H NMR.

[0211] General Step B

[0212] A 0.2 M toluene solution containing a primary or secondary amine (1 equivalent), g-ketocarboxylic acid (1.0-1.3 equivalents), and Hantzsch ester (1.0-1.3 equivalents) was heated to reflux using a Dean-Stark apparatus. After residual water appeared in the valve, the reaction was cooled to ambient temperature. (1) Toluene was removed under vacuum, and the residue was partitioned between water and methyl tributyl ether. If necessary, 5 equivalents of 3 M NaOH water were added. The aqueous layer was then washed twice with methyl tributyl ether, or, if NaOH was used, the pH was neutralized by adding 3 M HCl solution. The product was extracted with dichloromethane, and the ratio of cis / trans non-mirror image isomers was determined by HPLC or NMR.

[0212] Examples 1-5: Reductive amination in the preparation of trans-3-((R)-3-(1-(tert-butoxycarbonyl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid using general step A.

[0212]

[0213] A toluene solution (480 mL, 0.2 M) containing 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 equivalents), and a reducing agent (see Table 1) was heated to reflux using a Dean-Stark apparatus equipped with a valve and a condenser. After water appeared in the valve, the reaction was cooled to ambient temperature. Toluene was removed under vacuum, and the residue was partitioned between water (300 mL) and methyl tert-butyl ether (500 mL). The aqueous layer was then washed twice with methyl tert-butyl ether (500 mL each time). After removing water under high vacuum, the ratio of cis / trans non-mirror image isomers was determined by HPLC to be 3:97. The trans non-mirror image isomer retained for 9.1 min, and the cis non-mirror image isomer retained for 10.1 min.

[0214] 1H NMR (400MHz, CDCl3) trans-non-mirror image isomers: 3.82 (q, J=8.0Hz, 2H), 3.60 (dt, J=28.6, 7.6Hz, 2H), 3.24-2.97 (m, 3H), 2.51 (s, 2H), 2.15 (d, J=8.6Hz, 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.

[0215] 13C NMR (400MHz, CDCl3) trans-non-mirror image isomers: 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.

[0216] LCMS[M+H]: 353.1.

[0216]

[0216] Example 6: Reductive amination (non-mirror image isomer mixture) in the preparation of trans-3-((R)-3-(1-(tert-butoxycarbonyl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclopentane-1-carboxylic acid using general step B.

[0216]

[0217] Add 1-methyl-3-oxo-cyclopentanecarboxylic 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 to a 25 mL round-bottom flask. Add diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (411 mg, 1.62 mmol) to the solution to the flask, which is equipped with a Dean-Stark apparatus. Then heat the mixture under reflux for 3 hours, and then cool the reaction to ambient temperature. The reaction mixture was concentrated under vacuum to remove toluene, and the residue was partitioned between water and methyl tributyl ether. The separated phase was then washed with methyl tributyl ether (4 × 5 mL). The aqueous phase was then concentrated under vacuum to give 362 mg (79% yield) of trans-3-((R)-3-(1-(tert-butoxycarbonyl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclopentane-1-carboxylic acid as a mixture of non-mirror image isomers. ¹H NMR analysis showed that the cis / trans mirror image isomer ratio was less than 1:20 (i.e., the amount of trans non-mirror image isomer was 20 times greater than that of cis non-mirror image isomer).

[0218] ¹H NMR (400MHz, methanol-d4) trans isomer mixture: δ 4.07-3.90(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,3H), 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).

[0219] LCMS[M+H]: 367.2.

[0219] Example 7: Reductive amination (mirror image isomer mixture) in the preparation of trans-3-(dibenzylamino)-1-methylcyclopentane-1-carboxylic acid using general step B.

[0219]

[0220] 1-Methyl-3-oxo-cyclopentanecarboxylic acid (72 mg, 0.51 mmol, 1 equivalent), dibenzylamine (100 mg, 0.51 mmol, 1 equivalent), and Hantzsch ester (141 mg, 0.56 mmol, 1.1 equivalent) were dissolved in 3 mL of toluene (0.17 M). The reaction mixture was refluxed in a Dean-Stark apparatus for 2 hours and then allowed to reach ambient temperature. Toluene was removed under vacuum, and the residue was partitioned between 5 equivalents of 3 M NaOH water (5 mL) and methyl tributyl ether (5 mL). The aqueous layer was washed with two additional 5 mL portions of methyl tributyl ether and neutralized to pH 7 with 3 M HCl. The aqueous layer was then extracted with dichloromethane, the organic layer was dried over MgSO4, filtered through celite, and concentrated under vacuum. The crude product of trans-3-(dibenzylamino)-1-methylcyclopentane-1-carboxylic acid (a mixture of two trans mirror isomers) had a yield of 100 mg (61%), and the cis / trans ratio of its mirror isomers was determined to be 1:9 by 1H NMR.

[0221] 1H NMR (400MHz, methanol-d4) trans isomer 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.

[0222] LCMS[M+H]: 324.1.

[0222] Example 8: Reductive amination in the preparation of trans-4-((R)-3-(1-(tert-butoxycarbonyl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclohexane-1-carboxylic acid using general step A.

[0222]

[0223] 1-Methyl-4-oxocyclohexane-1-carboxylic acid (169 mg, 1.08 mmol, 1.3 equivalents) was mixed with tert-butyl 3-[(3R)-3-piperidyl]azetidine-1-carboxylate (200 mg, 0.83 mmol, 1 equivalent) and Hantzsch ester (274 mg, 1.08 mmol, 1.3 equivalents) in 4.5 mL of toluene, and the mixture was refluxed under inert conditions for 3 hours using a Dean-Stark apparatus. The toluene was then removed under vacuum, and the residue was partitioned between water (10 mL) and methyl tert-butyl ether (10 mL) with 3 M NaOH (5 equivalents) added. The aqueous layer was washed twice with methyl tributyl ether and then neutralized to pH 7 with 3M HCl. The mixture was extracted with dichloromethane, the organic layer was dried with MgSO4, filtered through celite, and concentrated under vacuum. The yield of trans-4-((R)-3-(1-(tributyloxycarbonyl)tetrahydroacrylonitrile-3-yl)piperidin-1-yl)-1-methylcyclohexane-1-carboxylic acid was 75% (236 mg), and the ratio of cis to trans non-mirror image isomers was less than 1:20 (i.e., the amount of trans non-mirror image isomer was 20 times greater than that of cis non-mirror image isomer) determined by 1H NMR.

[0224] 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.

[0225] LCMS[M+H]: 381.0.

[0225] Example 9: Reductive amination in the preparation of trans-4-(4-methoxyphenyl)piperidin-1-yl)-1-methylcyclohexane-1-carboxylic acid using general step A.

[0225]

[0226] 1-Methyl-4-oxocyclohexane-1-carboxylic acid (169 mg, 1.08 mmol, 1.3 equivalents) was mixed with tert-butyl 4-(4-methoxyphenyl)piperidine (159 mg, 0.83 mmol, 1 equivalent) and Hantzsch ester (274 mg, 1.08 mmol, 1.3 equivalents) in 4.5 mL of toluene, and the mixture was refluxed under inert conditions for 3 hours using a Dean-Stark apparatus. Toluene was then removed under vacuum, and the residue was partitioned between water (10 mL) and methyl tert-butyl ether (10 mL) with 3 M NaOH (pentavalent). The aqueous layer was washed twice with methyl tert-butyl ether and then neutralized to pH 7 with 3 M HCl. The mixture was extracted with dichloromethane, the organic layer was dried with MgSO4, filtered through celite, and concentrated under vacuum. The yield of trans-4-(4-methoxyphenyl)piperidin-1-yl)-1-methylcyclohexane-1-carboxylic acid was 63% (173 mg), and the cis / trans isomer ratio was less than 1:20 (i.e., the trans isomer was 20 times greater than the cis isomer) as determined by 1H NMR.

[0227] 1H NMR (400MHz, methanol-d4) δ 7.20-7.13(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.

[0228] LCMS[M+H]: 332.0.

[0228] General synthetic steps for synthesizing CCR4 antagonists:

[0228]

[0228] General Steps C

[0229] Dissolve trans-3-((r)-3-(1-(tert-butoxycarbonyl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid in water (the aqueous solution from step A can also be used in this step), and add 5 equivalents of concentrated HCl to the solution. Stir the mixture at room temperature until complete conversion is observed by LC-MS. Neutralize the solution to pH 7 with 6N NaOH and use it in the next step.

[0230] Alternatively, 5 equivalents of 1N HCl in ethyl acetate are added to trans-(R)-3-(1-(tert-butoxycarbonyl)tetrahydroacrylonitr-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid at ambient temperature, and the solution is stirred until complete conversion and precipitation of the solid deprotected product. The solid trans-3-(R)-3-(tetrahydroacrylonitr-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid hydrochloride is filtered and dried under high vacuum. Other strong acids besides HCl can also be used in general step C, such as sulfuric acid, mesic acid, tosic acid, bezic acid, phosphoric acid, HBr, HI, etc. Other organic solvents besides ethyl acetate can also be used in general step C for deprotection.

[0230] General Steps D

[0231] First, an electrophilic intermediate compound (i.e., one of the intermediate compounds used in Table 1 for the synthesis of the CCR4 antagonists of Examples 10-19; 1 equivalent) was selected and mixed with trans-3-(R)-3-(tetrahydroacryl-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid (1.2-1.5 equivalents) in an equal volume of water and terbutanol to form a 0.2 to 0.5 M biphase solution. 6 equivalents of sodium hydroxide (as a 50% wt aqueous solution) were added to this solution, and the reaction mixture was heated to 80°C until complete conversion was observed by LC-MS. The reaction mixture was then cooled to ambient temperature and the layers were separated. The aqueous layer was washed with fresh terbutanol, binding the organic portion. The terbutanol was removed under reduced pressure to obtain the desired CCR4 antagonist compound. Besides tertiary butanol, other organic solvents can also be used in general step D, such as methanol, ethanol, isopropanol, butanol, dioxane, THF, meTHF, DMSO, etc. Besides NaOH, other bases can be used in general step D, such as KOH, LiOH, Ba(OH)2, Ca(OH)2, amines, phosphates, carbonates, etc.

[0231] Examples 10-19

[0232] The synthesis of the following CCR4 antagonists was carried out according to general steps A, C, and D, wherein general step D was used in conjunction 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; and R is alkyl, perfluoroalkyl, or aryl.

[0233] Table 1.

[0233]

[0233] Example 20

[0234] The synthesis of the CCR4 antagonist trans-3-((R)-3-(1-(tert-butoxycarbonyl)tetrahydroacryl-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid was carried out as follows. A solution of tert-butyl 3-[(3R)-3-piperidinyl]tetrahydroacryl-1-carboxylic acid in toluene (69 L, 0.80 M) (55.6 mol) was added to a reactor containing 1-methyl-3-oxocyclobutane-1-carboxylic acid (9.27 kg, 72.3 mol, 1.3 equivalents) and Hantzsch ester 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester (18.3 kg, 72.3 mmol, 1.3 equivalents). Toluene (170 L) was introduced, the Dean-Stark valve was connected, and the reaction mixture was heated to 100-110 °C for 3 hours. The reaction volume was reduced under vacuum (to a total of approximately 115 L), BuOAc (230 L) was added, and the mixture was concentrated again (to a total of 200-230 L). This cycle was repeated twice before the addition of heptane (135 L). The resulting solid was collected by filtration, washed with a 1:1 mixture of EtOAc / heptane (~60 L), and dried under vacuum to obtain a white solid of trans-3-(R)-3-(1-(tert-butoxycarbonyl)tetrahydroacere-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid (16.7 kg, 47.4 mol, 85% yield, >99% trans as determined by HPLC).

[0235] Given the detailed description of the preferred embodiments of this disclosure above, those skilled in the art will readily understand that this disclosure has broad utility and applicability. Although various embodiments have been described in the context of the screenshots, other embodiments, features, and methods of this disclosure can be readily identified from them. Many embodiments and adaptations of this disclosure, as well as many variations, modifications, and equivalent arrangements and methods, besides those described herein, will be apparent or reasonably suggested from this disclosure and its foregoing description, without departing from the essence or scope of this disclosure. Furthermore, any sequence of steps and / or chronological order of the various processes described and claimed herein is considered the best mode contemplated for performing this disclosure. It should also be understood that although the steps of various processes may be shown and described in a preferred sequence or chronological order, the steps of any such process are not limited to being performed in any particular sequence or order, nor is there any specific indication that a particular expected result will be achieved. In most cases, the steps of these processes can be performed in various different sequences and orders while still falling within the scope of protection of this invention. Furthermore, some steps may be performed simultaneously. Therefore, although this disclosure has been described in detail with respect to preferred embodiments, it should be understood that this disclosure is merely illustrative and exemplary, and is made solely for the purpose of providing a complete understanding of the disclosure and enabling the implementation of its contents. The foregoing disclosure is not, and should not be construed as, limiting this disclosure or otherwise excluding any such other embodiments, adaptations, alterations, modifications, and equivalent arrangements; this disclosure is limited only by the appended claims and their equivalents.

[0236] It should be understood that the embodiments and examples described herein are for illustrative purposes only and will suggest various modifications or alterations to those skilled in the art, and are 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 incorporated herein by reference in their entirety for all purposes.

[0236] Implementation Status

[0237] Embodiment 1: A method for synthesizing a compound of formula (III), the method comprising reacting a compound of formula (I) with a compound of formula (II) in an environment having a carboxylic acid-directed reducing agent to form a compound of formula (III):

[0237] of which

[0237] n1' and n2' are each independent integers from 0 to 5, where the sum of n1' and n2' is at least 1 and does not exceed 6;

[0237] L1' is C(R4')2;

[0237] L2' is C(R5')2;

[0237] R1' is hydrogen, halogen, -CX1'3, -CHX1'2, -CH2X1', -OCX1'3, -OCHX1'2, -OCH2X1', CN, -S(O)2R1'A, -SR1'A, -S(O)R1'A, -SO2NR1'AR1'B, -NHC(O)NR1'AR1'B, -N(O)2, -NR1'AR1'B, -NHNR1'AR1'B, -C(O)R1'A, -C(O)-OR1'A -C(O)NR1'AR1'B, -C(O)NHNR1'AR1'B, -OR1'A, -NR1'ASO2R1'B, -NR1'AC(O)R1'B, -NR1'AC(O)OR1'B, -NR1'AOR1'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;

[0237] R2' is hydrogen, -CX2'3, -CHX2'2, -CH2X2', -OCX2'3, -OCHX2'2, -OCH2X2', -SR2'A, -NR2'AR2'B, -NHNR2'AR2'B, -OR2'A, -NR2'ASO2R2'B, -NR2'AC(O)R2'B, -NR2'AC(O)OR2'B, -NR2'AOR2'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 wherein R2' and R3' may optionally be linked to form a substituted or unsubstituted heterocycloalkyl;

[0237] R3' is a halogen, -CX3'3, -CHX3'2, -CH2X3', -OCX3'3, -OCHX3'2, -OCH2X3', -SR3'A, -NR3'AR3'B, -NHNR3'AR3'B, -OR3'A, -NR3'ASO2R3'B, -NR3'AC(O)R3'B, -NR3'AC(O)OR3'B, -NR3'AOR3'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 wherein R2' and R3' may optionally be linked to form a substituted or unsubstituted heterocycloalkyl;

[0237] R4' is independently hydrogen, halogen, -CX4'3, -CHX4'2, -CH2X4', -OCX4'3, -OCHX4'2, -OCH2X4', -CN, -S(O)2R4'A, -SR4'A, -S(O)R4'A, -SO2NR4'AR4'B, -NHC(O)NR4'AR4'B, -N(O)2, -NR4'AR4'B, -NHNR4'AR4'B, -C(O)R4'A, -C(O)-OR4 'A、-C(O)NR4'AR4'B、-C(O)NHNR4'AR4'B、-OR4'A、-NR4'ASO2R4'B、-NR4'AC(O)R4'B、-NR4'AC(O)OR4'B、-NR4'AOR4'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;

[0237] R5' is independently hydrogen, halogen, -CX5'3, -CHX5'2, -CH2X5', -OCX5'3, -OCHX5'2, -OCH2X5', -CN, -S(O)2R5'A, -SR5'A, -S(O)R5'A, -SO2NR5'AR5'B, -NHC(O)NR5'AR5'B, -N(O)2, -NR5'AR5'B, -NHNR5'AR5'B, -C(O)R5'A, -C(O)-OR5 'A、-C(O)NR5'AR5'B、-C(O)NHNR5'AR5'B、-OR5'A、-NR5'ASO2R5'B、-NR5'AC(O)R5'B、-NR5'AC(O)OR5'B、-NR5'AOR5'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;

[0237] R12' is independently -OH or NHR12”;

[0237] R12” is hydrogen or a substituted or unsubstituted alkyl group;

[0237] R1'A, R1'B, R2'A, R2'B, R3'A, R3'B, R4'A, R4'B, R5'A, and R5'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, -CONH2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)OH, -NHOH, substituted or unsubstituted alkyl groups, substituted or unsubstituted heteroalkyl groups, substituted or unsubstituted cycloalkyl groups, substituted or unsubstituted heterocycloalkyl groups, substituted or unsubstituted aryl groups, or substituted or unsubstituted heteroaryl groups; or R2'A and R2'B substituents bonded to the same nitrogen atom may optionally be linked to form substituted or unsubstituted heterocycloalkyl groups or substituted or unsubstituted heteroaryl groups; or R3'A and R3'B substituents bonded to the same nitrogen atom may optionally be linked to form substituted or unsubstituted heterocycloalkyl groups or substituted or unsubstituted heteroaryl groups; and

[0237] X1', X2', X3', X4', and X5 are halogens independently.

[0238] Embodiment 2 is the same as the method of Embodiment 1, wherein the method is used to prepare chemokine receptor 4 (CCR4), or an antagonist of its salt or ester.

[0239] Example 3 is the same as the method of Example 1 or 2, wherein at least 80% of the compound of formula (III) is in the pure trans isomer form.

[0240] Example 4 is performed by any of Examples 1 to 3, wherein the carboxylic acid directional reducing agent is 1,4-dihydropyridine.

[0241] Example 5 is performed by any of Examples 1 to 4, wherein the carboxylic acid directional reducing agent is 1,4-dihydropyridine of formula (IV):

[0241]

[0241] Among them:

[0241] L3' and L4' are independently O or NR20';

[0241] R20' is independently hydrogen or R21';

[0241] R21' is independently hydrogen, -CX21'3, -CHX21'2, -CH2X21', substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;

[0241] R6' is independently hydrogen, -CX6'3, -CHX6'2, -CH2X6', 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 connecting the 1,4-dihydropyridine to the polymer support;

[0241] R7' is independently hydrogen, -CX7'3, -CHX7'2, -CH2X7', 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 connecting the 1,4-dihydropyridine to the polymer support;

[0241] R8' is independently hydrogen, halogen, -CX8'3, -CHX8'2, -CH2X8', -OCX8'3, -OCHX8'2, -OCH2X8', -CN, -S(O)2R8'A, -SR8'A, -S(O)R8'A, -SO2NR8'AR8'B, -NHC(O)NR8'AR8'B, -N(O)2, -NR8'AR8'B, -NHNR8'AR8'B, -C(O)R8'A, -C(O)-OR8 'A、-C(O)NR8'AR8'B、-C(O)NHNR8'AR8'B、-OR8'A、-NR8'ASO2R8'B、-NR8'AC(O)R8'B、-NR8'AC(O)OR8'B、-NR8'AOR8'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;

[0241] R9' is independently hydrogen, halogen, -CX9'3, -CHX9'2, -CH2X9', -OCX9'3, -OCHX9'2, -OCH2X9', -CN, -S(O)2R9'A, -SR9'A, -S(O)R9'A, -SO2NR9'AR9'B, -NHC(O)NR9'AR9'B, -N(O)2, -NR9'AR9'B, -NHNR9'AR9'B, -C(O)R9'A, -C(O)-OR9 'A、-C(O)NR9'AR9'B、-C(O)NHNR9'AR9'B、-OR9'A、-NR9'ASO2R9'B、-NR9'AC(O)R9'B、-NR9'AC(O)OR9'B、-NR9'AOR9'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;

[0241] R10' is independently hydrogen, halogen, -CX10'3, -CHX10'2, -CH2X10', -OCX10'3, -OCHX10'2, -OCH2X10', -CN, -S(O)2R10'A, -SR10'A, -S(O)R10'A, -SO2NR10'AR10'B, -NHC(O)NR10'AR10'B, -N(O)2, -NR10'AR10'B, -NHNR10'AR10'B, -C(O)R10'A, -C(O)-O R10'A, -C(O)NR10'AR10'B, -C(O)NHNR10'AR10'B, -OR10'A, -NR10'ASO2R10'B, -NR10'AC(O)R10'B, -NR10'AC(O)OR10'B, -NR10'AOR10'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;

[0241] R8'A, R8'B, R9'A, R9'B, R10'A, and R10'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, -CONH2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)OH, -NHOH, substituted or unsubstituted alkyl groups, substituted or unsubstituted heteroalkyl groups, substituted or unsubstituted cycloalkyl groups, substituted or unsubstituted heterocycloalkyl groups, substituted or unsubstituted aryl groups, or substituted or unsubstituted heteroaryl groups; and

[0241] X6', X7', X8', X9', X10' and X21' are halogens independently.

[0241] Implementation 6 is as in any of Implementation 1 to 5, wherein L3' and L4' are both O.

[0242] Embodiment 7 is as described in any of Embodiments 1 to 5, wherein R6' and R7' are 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 the 1,4-dihydropyridine is attached to a polymer support by a bond.

[0243] Example 8 is as described in any of Examples 1 to 5, wherein R8', R9' and R10' are 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.

[0244] Example 9 is as described in any of Examples 1 to 8, wherein n1' and n2' are independently 1 or 2, and R1' is a substituted or unsubstituted C1-C4 alkyl group.

[0245] Example 10 is performed by any of Examples 1 to 9, wherein n1' and n2' are independently 1, and L1' and L2' are independently substituted or unsubstituted C1-C2 alkyl groups.

[0246] Embodiment 11 is as described in any of Embodiments 1 to 10, wherein R2' and R3' are connected to form a substituted or unsubstituted piperidinyl group.

[0247] Embodiment 12 is performed by any of Embodiments 1 to 11, wherein the piperidinyl group is substituted with or without a heterocyclic alkyl group.

[0248] Embodiment 13 is as described in any of Embodiments 1 to 12, wherein the substituted or unsubstituted heterocyclic alkyl group is a nitrogen-containing 3- to 6-membered heterocyclic alkyl group.

[0249] Embodiment 14 is the method of claim 1, wherein the compound of formula (III) is:

[0249] , where:

[0249] R11' is 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.

[0250] Sample 15 is the method of Sample 14, wherein R11' is a substituted or unsubstituted alkyl group.

[0251] Sample 16 is the method of Sample 14 or 15, wherein R11' is a substituted or unsubstituted C1-C4 alkyl group.

[0252] Embodiment 17 is performed by any of Embodiments 14 to 16, wherein the compound of Formula III is:

[0252] , wherein R11' is a substituted or unsubstituted alkyl group, and each of n1' and n2' is 1 or 2.

[0253] Example 18 is as described in any of Examples 14 to 17, wherein the compound of formula (III) is: , wherein R11' is tertiary butyl or benzyl.

[0254] Embodiment 19 is the method of Embodiment 1 or 2, wherein the CCR4 antagonist is selected from:

[0254]

[0254]

[0254] and, or a pharmaceutically acceptable salt or ester thereof.

[0255] Embodiment 20 is the method of Embodiment 1 or 2, wherein the CCR4 antagonist is selected from:

[0255]

[0255] and, or a pharmaceutically acceptable salt or ester thereof.

Claims

1. A method for 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, wherein the carboxylic acid-directed reducing agent is 1,4-dihydropyridine, to form a compound of formula (III):

1. Among them: n1' and n2' are each independently an integer from 0 to 5, wherein the sum of n1' and n2' is at least 1 and not more than 6; L1' is C(R4')2; L2' is C(R5')2; R1' is hydrogen or a substituted or unsubstituted C1-C4 alkyl group; R2' and R3' are linked to form a substituted piperidinyl group, wherein the piperidinyl group is substituted or unsubstituted with a nitrogen-containing 4- to 6-membered heterocyclic alkyl group or a substituted or unsubstituted aryl group; R4' is hydrogen or a substituted or unsubstituted C1-C4 alkyl group; R5' is hydrogen or a substituted or unsubstituted C1-C4 alkyl group; and R12' is -OH.

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

3. The method as described in claim 1, wherein the carboxylic acid-directed reducing agent is 1,4-dihydropyridine of formula (IV): where: L3' and L4' are independently -O-; R6' is a substituted or unsubstituted C1-C4 alkyl; R7' is a substituted or unsubstituted C1-C4 alkyl; R8' is a substituted or unsubstituted C1-C4 alkyl; R9' is hydrogen; and R10' is a substituted or unsubstituted C1-C4 alkyl.

4. The method as described in claim 1, wherein n1' and n2' are independently 1 or 2, and R1' is a substituted or unsubstituted C1-C2 alkyl group.

5. The method as described in claim 4, wherein n1' and n2' are independently 1, and L1' and L2' are independently substituted or unsubstituted C1-C2 alkyl groups.

6. The method as described in claim 1, wherein the compound of formula (I) is: , wherein: R11' is a substituted or unsubstituted alkyl group or a substituted or unsubstituted aryl group.

7. The method as described in claim 6, wherein R11' is a substituted or unsubstituted C1-C4 alkyl group.

8. The method as described in claim 1, wherein the compound of formula III is:

8. Wherein R11' is a substituted or unsubstituted alkyl group and each of n1' and n2' is 1 or 2.

9. The method as described in claim 8, wherein the compound of formula (III) is: wherein R11' is tert-butyl or benzyl.

10. The method as claimed in claim 1, wherein the method is used to prepare an antagonist of chemokine receptor 4 (CCR4) or a salt or ester thereof.

11. The method as described in claim 10, wherein the CCR4 antagonist is: or a pharmaceutically acceptable salt thereof, wherein: z4 is 1; X2 is CR9; R1 and R2 are independently hydrogen or substituted or unsubstituted alkyl groups; R3.2 and R3.3 are independently halogen or substituted or unsubstituted alkyl groups; R4 is halogen or substituted or unsubstituted alkyl groups; R9 is hydrogen, -CX9.13, -CHX9.12, -CH2X9.1 or substituted or unsubstituted alkyl groups; X9.1 is independently -Cl, -Br, -I or -F; R44 is hydrogen; and L7-R7 are...