Chemokine receptor modulators and uses thereof

Abstract

Disclosed herein are, inter alia, compounds of Formula (I) and methods of use thereof for modulating the activity of certain chemokine receptors. # imgabs0 #

Description

[0001] Cross-reference to related applications

[0002] This application claims the preferred benefit of U.S. Provisional Application 63 / 328,214, filed April 6, 2022, which is incorporated herein by reference in its entirety and for all purposes. Background Technology

[0003] The successful operation of the host defense system is the result of several processes working together to eliminate foreign pathogens. Coordinated innate and adaptive immune responses are required, and many secreted and cell-associated factors have been identified as important mediators coordinating and regulating these two host defenses. Chemokines are a family of cytokines that function as chemical inducers guiding leukocyte migration. They are secreted by a variety of cells and functionally can be divided into two groups: hemostatic chemokines and inflammatory chemokines. Hemostatic chemokines are constitutively produced in certain tissues and control the cells of the immune system during immune surveillance, such as guiding lymphocytes to lymph nodes to allow them to screen for pathogen invasion. Inflammatory chemokines are released from cells in response to pathological events, such as pro-inflammatory stimuli, such as IL-1 or viruses. As part of the inflammatory response, they primarily function as chemical inducers and are used to guide cells of both the innate and adaptive immune systems to sites of inflammation. CC chemokine receptor type 4 (CCR4) plays a role in the progression of many inflammation-related conditions and other diseases. Identifying compounds that regulate CCR4 function is an ongoing challenge. Solutions to these and other problems in the art are specifically disclosed herein. Summary of the Invention

[0004] On the one hand, this paper provides a compound having structural formula (I):

[0005] Or a pharmaceutically acceptable salt thereof, wherein: X 1 For CR 8 Or N; X 2 For CR 9 Or N; X 3 For CR 10 Or N and X 1 X 2 and X 3At least one of them is N; n1, n2, n3, n4, n5, n6, n7, n8, n9, n10 and n44 are independently integers from 0 to 4; 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 4; z3 is an integer from 0 to 11; z4 is an integer from 0 to 2; z5 is an integer from 1 to 2; L 7 For key, –O–, –S–, –NR 7.2B –、–C(O)–、-C(O)O–、–S(O)–、–S(O)2–、substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R 1 Hydrogen, halogen, -CX 1.1 3. -CHX 1.1 2. -CH2X 1.1 –CN, –N3, –SO n1 R 1A –SO v1 NR 1B R 1C -NHNR 1B R 1C -ONR 1B R 1C -NHC(O)NHNR 1B R 1C -NHC(O)NR 1B R 1C –N(O) m1 –NR 1B R 1C –C(O)R 1D –C(O)OR 1D –C(O)NR 1B R 1C –OR 1A -NR 1B SO2R 1A -NR 1B C(O)R 1D -NR 1B C(O)OR 1D –NR 1B OR 1D –OCX 1.1 3. –OCHX 1.1 2. –OCH2X 1.1, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R 2 Hydrogen, halogen, -CX 2.1 3. -CHX 2.1 2. -CH2X 2.1 –CN, –N3, –SO n2 R 2A –SO v2 NR 2B R 2C -NHNR 2B R 2C -ONR 2B R 2C -NHC(O)NHNR 2B R 2C -NHC(O)NR 2B R 2C –N(O) m2 –NR 2B R 2C –C(O)R 2D –C(O)OR 2D –C(O)NR 2B R 2C –OR 2A -NR 2B SO2R 2A -NR 2B C(O)R 2D -NR 2B C(O)OR 2D –NR 2B OR 2D –OCX 2.1 3. –OCHX 2.1 2. –OCH2X 2.1 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R 3 Independently halogen, –CX 3.1 3. -CHX 3.1 2. -CH2X 3.1 –CN, –N3, –SO n3 R 3A –SO v3 NR 3B R 3C -NHNR 3B R 3C -ONR 3B R 3C-NHC(O)NHNR 3B R 3C -NHC(O)NR 3B R 3C –N(O) m3 –NR 3B R 3C –C(O)R 3D –C(O)OR 3D –C(O)NR 3B R 3C –OR 3A -NR 3B SO2R 3A -NR 3B C(O)R 3D -NR 3B C(O)OR 3D –NR 3B OR 3D –OCX 3.1 3. –OCHX 3.1 2. –OCH2X 3.1 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R 4 Hydrogen, halogen, -CX 4.1 3. -CHX 4.1 2. -CH2X 4.1 –CN, –N3, –SO n4 R 4A –SO v4 NR 4B R 4C -NHNR 4B R 4C -ONR 4B R 4C -NHC(O)NHNR 4B R 4C -NHC(O)NR 4B R 4C –N(O) m4 –NR 4B R 4C –C(O)R 4D –C(O)OR 4D –C(O)NR 4B R 4C –OR 4A -NR 4B SO2R 4A -NR 4B C(O)R 4D -NR4B C(O)OR 4D –NR 4B OR 4D –OCX 4.1 3. –OCHX 4.1 2. –OCH2X 4.1 substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, or when X 2 For CR 9 When, then R 4 and R 9 It can be optionally linked to form substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 5 Independently halogen, oxo group, -CX 5.1 3. -CHX 5.1 2. -CH2X 5.1 –CN, –N3, –SO n5 R 5A –SO v5 NR 5B R 5C -NHNR 5B R 5C -ONR 5B R 5C -NHC(O)NHNR 5B R 5C -NHC(O)NR 5B R 5C –N(O) m5 –NR 5B R 5C –C(O)R 5D –C(O)OR 5D –C(O)NR 5B R 5C –OR 5A -NR 5B SO2R 5A -NR 5B C(O)R 5D -NR 5B C(O)OR 5D –NR 5B OR 5D –OCX 5.1 3. –OCHX 5.1 2. –OCH2X 5.1, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R 6 Independently halogen, oxo group, -CX 6.1 3. -CHX 6.1 2. -CH2X 6.1 –CN, –N3, –SO n6 R 6A –SO v6 NR 6B R 6C -NHNR 6B R 6C -ONR 6B R 6C -NHC(O)NHNR 6B R 6C -NHC(O)NR 6B R 6C –N(O) m6 –NR 6B R 6C –C(O)R 6D –C(O)OR 6D –C(O)NR 6B R 6C –OR 6A -NR 6B SO2R 6A -NR 6B C(O)R 6D -NR 6B C(O)OR 6D –NR 6B OR 6D –OCX 6.1 3. –OCHX 6.1 2. –OCH2X 6.1 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R 7 Hydrogen, halogen, -CX 7.1 3. -CHX 7.1 2. -CH2X 7.1 –CN, –N3, –SO n7 R 7A –SO v7 NR 7B R 7C -NHNR 7B R 7C -ONR 7B R 7C-NHC(O)NHNR 7B R 7C -NHC(O)NR 7B R 7C –N(O) m7 –NR 7B R 7C –C(O)R 7D –C(O)OR 7D –C(O)NR 7B R 7C –OR 7A -NR 7B SO2R 7A -NR 7B C(O)R 7D -NR 7B C(O)OR 7D –NR 7B OR 7D –OCX 7.1 3. –OCHX 7.1 2. –OCH2X 7.1 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R 8 Hydrogen, halogen, -CX 8.1 3. -CHX 8.1 2. -CH2X 8.1 –CN, –N3, –SO n8 R 8A –SO v8 NR 8B R 8C -NHNR 8B R 8C -ONR 8B R 8C -NHC(O)NHNR 8B R 8C -NHC(O)NR 8B R 8C –N(O) m8 –NR 8B R 8C –C(O)R 8D –C(O)OR 8D –C(O)NR 8B R 8C –OR 8A -NR 8B SO2R 8A -NR 8B C(O)R 8D -NR8B C(O)OR 8D –NR 8B OR 8D –OCX 8.1 3. –OCHX 8.1 2. –OCH2X 8.1 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R 9 Hydrogen, halogen, -CX 9.1 3. -CHX 9.1 2. -CH2X 9.1 –CN, –N3, –SO n9 R 9A –SO v9 NR 9B R 9C -NHNR 9B R 9C -ONR 9B R 9C -NHC(O)NHNR 9B R 9C -NHC(O)NR 9B R 9C –N(O) m9 –NR 9B R 9C –C(O)R 9D –C(O)OR 9D –C(O)NR 9B R 9C –OR 9A -NR 9B SO2R 9A -NR 9B C(O)R 9D -NR 9B C(O)OR 9D –NR 9B OR 9D –OCX 9.1 3. –OCHX 9.1 2. –OCH2X 9.1 substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, or when X 2 For CR 9 When, then R 4 and R 9It can be optionally linked to form a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl; or when X 2 For CR 9 And X 3 For CR 10 When, then R 9 and R 10 It can be optionally linked to form a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, or an unsubstituted aryl or a substituted or unsubstituted heteroaryl; R 10 Hydrogen, halogen, -CX 10.1 3. -CHX 10.1 2. -CH2X 10.1 –CN, –N3, –SO n10 R 10A –SO v10 NR 10B R 10C -NHNR 10B R 10C -ONR 10B R 10C -NHC(O)NHNR 10B R 10C -NHC(O)NR 10B R 10C –N(O) m10 –NR 10B R 10C –C(O)R 10D –C(O)OR 10D –C(O)NR 10B R 10C –OR 10A -NR 10B SO2R 10A -NR 10B C(O)R 10D -NR 10B C(O)OR 10D –NR 10B OR 10D –OCX 10.1 3. –OCHX 10.1 2. –OCH2X 10.1 substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; or when X 2 For CR 9 And X 3 For CR 10 When, then R 9 and R10 It can be optionally linked to form a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, or an unsubstituted aryl or a substituted or unsubstituted heteroaryl; R 44 For hydrogen, –CX 44.1 3. -CHX 44.1 2. -CH2X 44.1 –SO n44 R 44A –SO v44 NR 44B R 44C –C(O)R 44D –C(O)OR 44D –C(O)NR 44B R 44C , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R 1A R 1B R 1C R 1D R 2A R 2B R 2C R 2D R 3A R 3B R 3C R 3D R 4A R 4B R 4C R 4D R 5A R 5B R 5C R 5D R 6A R 6B R 6C R 6D R 7A R 7B R 7C R 7D R 7.2B R 8A R 8B R 8C R 8D R 9A、 R 9B R 9C R 9D R 10A R 10B R 10C R 10D R 44A R 44B R44C and R 44D Independently hydrogen, halogen, –CF3, –CCl3, –CBr3, –CI3, –COOH, –CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R bonded to the same nitrogen atom 1B R 1C R 2B R 2C R 3B R 3C R 4B R 4C R 5B R 5C R 6B R 6C R 7B R 7C R 8B R 8C R 9B R 9C R 10B R 10C R 44B and R 44C Substituents can optionally be linked to form substituted or unsubstituted heterocyclic alkyl groups or substituted or unsubstituted heteroaryl groups; and X 1.1 X 2.1 X 3.1 X 4.1 X 5.1 X 6.1 X 7.1 X 8.1 X 9.1 X 10.1 and X 44.1 It can be independently –Cl, –Br, –I, or –F.

[0006] In one aspect, a compound of structural formula (II) or a pharmaceutically acceptable salt thereof is provided:

[0007] Where R 1 R 2 X 2 X 3 z4, z5, L 7 R 7 and R 44 Each as described elsewhere in this document (including implementation schemes). R 4 Hydrogen, halogen, -CX 4.1 3. –CN, –C(O)NR 4B R 4C, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R 3.2 Hydrogen, halogen, -CX 3.2 3. -CHX 3.2 2. -CH2X 3.2 –CN, –N3, –SO n3.2 R 3.2A –SO v3.2 NR 3.2B R 3.2C -NHNR 3.2B R 3.2C -ONR 3.2B R 3.2C -NHC(O)NHNR 3.2B R 3.2C -NHC(O)NR 3.2B R 3.2C –N(O) m3.2 –NR 3.2B R 3.2C –C(O)R 3.2D –C(O)OR 3.2D –C(O)NR 3.2B R 3.2C –OR 3.2A -NR 3.2B SO2R 3.2A -NR 3.2B C(O)R 3.2D -NR 3.2B C(O)OR 3.2D –NR 3.2B OR 3.2D –OCX 3.2 3. –OCHX 3.2 2. –OCH2X 3.2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R 3.3 Hydrogen, halogen, -CX 3.3 3. -CHX 3.3 2. -CH2X 3.3 –CN, –N3, –SO n3.3 R 3.3A –SO v3.3 NR 3.3B R 3.3C -NHNR 3.3B R 3.3C -ONR 3.3B R 3.3C-NHC(O)NHNR 3.3B R 3.3C -NHC(O)NR 3.3B R 3.3C –N(O) m3.3 –NR 3.3B R 3.3C –C(O)R 3.3D –C(O)OR 3.3D –C(O)NR 3.3B R 3.3C –OR 3.3A -NR 3.3B SO2R 3.3A -NR 3.3B C(O)R 3.3D -NR 3.3B C(O)OR 3.3D –NR 3.3B OR 3.3D –OCX 3.3 3. –OCHX 3.3 2. –OCH2X 3.3 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R 3.2A R 3.2B R 3.2C R 3.2D R 3.3A R 3.3B R 3.3C and R 3.3D Independently hydrogen, halogen, –CF3, –CCl3, –CBr3, –CI3, –COOH, –CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R bonded to the same nitrogen atom 3.2B R 3.2C R 3.3B and R 3.3C Substituents may optionally be linked to form substituted or unsubstituted heterocyclic alkyl groups or substituted or unsubstituted heteroaryl groups; n3.2 and n3.3 are independently integers from 0 to 4; m3.2, m3.3, v3.2 and v3.3 are independently 1 or 2; and X 3.2 and X 3.3 It can be independently –Cl, –Br, –I, or –F.

[0008] In one aspect, a pharmaceutical composition is provided comprising a compound as described herein (including embodiments) and a pharmaceutically acceptable excipient.

[0009] In one aspect, a method for inhibiting CC chemokine receptor type 4 (CCR4) is provided, the method comprising contacting CCR4 with a compound as described herein (including embodiments) or a pharmaceutically acceptable salt thereof.

[0010] In one aspect, a method for treating or preventing a disease or condition mediated by CCR4 is provided, the method comprising administering to a subject in need a therapeutically effective amount of a compound as described herein (including embodiments) or a pharmaceutically acceptable salt thereof.

[0011] On the other hand, this document provides a kit comprising the compounds described herein (e.g., CCR4 inhibitors) or pharmaceutical compositions thereof. As described below, the kit may be in the form of a physical structure accommodating various components and may be used, for example, to carry out the methods described herein. Detailed Implementation

[0012] For example, this document provides compounds and compositions for inhibiting CCR4 chemokine receptor type 4, and pharmaceutical compositions comprising them. This document also provides methods for treating or preventing diseases, conditions, or symptoms thereof, such as those mediated by regulation (e.g., inhibition) of CCR4.

[0013] I. Definition

[0014] The abbreviations used in this article have their conventional meanings in the fields of chemistry and biology. The chemical structures and formulas described in this article are constructed according to the standard rules of chemical valence known in the field of chemistry.

[0015] When substituents are described by their conventional chemical formulas written from left to right, these substituents equally cover chemically identical substituents produced by structures written from right to left; for example, -CH2O- is equivalent to -OCH2-.

[0016] Unless otherwise stated, the term "alkyl" itself, or as part of another substituent, means that it can be fully saturated, monounsaturated, or polyunsaturated and can comprise straight-chain (i.e., unbranched) or branched carbon chains (or carbons) or combinations thereof, including monovalent, divalent, and polyvalent free radicals. Alkyl groups may contain a specified number of carbons (e.g., C1-C1). 10(This refers to one to ten carbons). In embodiments, the alkyl group is fully saturated. In embodiments, the alkyl group is monounsaturated. In embodiments, the alkyl group is polyunsaturated. The alkyl group is an uncyclic chain. Examples of saturated hydrocarbon groups include, but are not limited to, groups such as: methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, methyl, and homologs and isomers of, for example, 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 homologs and isomers. The alkoxy group is an alkyl group connected to the rest of the molecule via an oxygen linker (-O-). The alkyl moiety can be an alkenyl moiety. The alkyl moiety can be an alkynyl moiety. The alkyl moiety may be fully saturated. The alkenyl group may include more than one double bond and / or one or more triple bonds in addition to one or more double bonds. The alkynyl group may contain more than one triple bond and / or one or more double bonds in addition to one or more triple bonds.

[0017] Unless otherwise stated, the term "alkylene" alone or as part of another substituent means a divalent group derived from an alkyl group, such as, but not limited to, -CH2CH2CH2CH2-. Typically, an alkyl (or alkylene) will have 1 to 24 carbon atoms, with those having 10 or fewer carbon atoms being preferred herein. "Lower alkyl" or "lower alkylene" is a short-chain alkyl or alkylene group typically having eight or fewer carbon atoms. Unless otherwise stated, the term "alkenyl" alone or as part of another substituent means a divalent group derived from an alkene. Unless otherwise stated, the term "alkynyl" alone or as part of another substituent means a divalent group derived from an alkyne. In embodiments, the alkylene is fully saturated. In embodiments, the alkylene is monounsaturated. In embodiments, the alkylene is polyunsaturated. An alkenyl group includes one or more double bonds. An alkynyl group includes one or more triple bonds. The term "unsubstituted methylene" refers to a partial -CH2-. The term "substituted methylene" refers to a portion in which one or both hydrogen atoms are replaced by a substituent.

[0018] Unless otherwise stated, the term "heteroalkyl" alone or in combination with another term means 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. One or more heteroatoms (e.g., N, S, Si, or P) may be placed at any internal position of the heteroalkyl group or at the position where the alkyl group is attached to the rest of the molecule. Heteroalkyl groups are uncyclic chains. 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 can be consecutive, such as, for example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. The heteroalkyl moiety may contain one heteroatom (e.g., O, N, S, Si, or P). The heteroalkyl moiety may contain two optionally different heteroatoms (e.g., O, N, S, Si, or P). The heteroalkyl moiety may contain three optionally different heteroatoms (e.g., O, N, S, Si, or P). The heteroalkyl moiety may contain four optionally different heteroatoms (e.g., O, N, S, Si, or P). The heteroalkyl moiety may contain five optionally different heteroatoms (e.g., O, N, S, Si, or P). The heteroalkyl moiety may contain up to eight optionally different heteroatoms (e.g., O, N, S, Si, or P). Unless otherwise stated, the term "heteroalkenyl" itself, or in combination with another term, means a heteroalkyl group containing at least one double bond. A heteroalkenyl group may optionally include more than one double bond and / or one or more triple bonds in addition to one or more double bonds. Unless otherwise stated, the term "heteroyneyl" itself, or in combination with another term, means a heteroalkyl group containing at least one triple bond. A heteroyneyl group may optionally include more than one triple bond and / or one or more double bonds in addition to one or more triple bonds. In embodiments, the heteroalkyl group is fully saturated. In embodiments, the heteroalkyl group is monounsaturated. In embodiments, the heteroalkyl group is polyunsaturated.

[0019] Similarly, unless otherwise stated, the term "heteroalkylene" itself, or as part of another substituent, refers to a divalent group derived from a heteroalkylene group, such as, but not limited to, -CH2-CH2-S-CH2-CH2- and -CH2-S-CH2-CH2-NH-CH2-. For heteroalkylene groups, the heteroatom may also occupy any one or both of the chain ends (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, etc.). Furthermore, for alkylene and heteroalkyl linking groups, the direction in which the formula of the linking group is written does not imply the orientation 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 connected to the remainder of the molecule via heteroatoms, such as -C(O)R', -C(O)NR', ​​-NR'R", -OR', -SR', and / or -SO2R'. It should be understood that the terms heteroalkyl and -NR'R" are not redundant or mutually exclusive when a specific heteroalkyl group is described after -NR'R". Rather, the specific heteroalkyl group is described for clarity. Therefore, the term "heteroalkyl" should not be construed herein as excluding specific heteroalkyl groups such as -NR'R". Unless otherwise stated, the term "heteroalkenyl" itself, or as part of another substituent, refers to a divalent group derived from a heteroalkene. Unless otherwise stated, the term "heteroyneyl" itself, or as part of another substituent, refers to a divalent group derived from a heteroalkynylene. In embodiments, the heteroalkylene group is fully saturated. In embodiments, the heteroalkylene group is monounsaturated. In embodiments, the heteroalkylene group is polyunsaturated. The heteroalkylene group comprises one or more double bonds. Heteroylynyl groups include one or more triple bonds. Unless otherwise stated, the terms "cycloalkyl" and "heterocycloalkyl," alone or in combination with other terms, refer to the cyclic form of "alkyl" and "heteroalkyl," respectively. Cycloalkyl and heterocycloalkyl groups are not aromatic. Additionally, for heterocycloalkyl groups, the heteroatom may occupy the position where the heterocycle is attached to the rest of the molecule. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, etc. Examples of heterocycloalkyl groups 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, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, 1-piperazinyl, 2-piperazinyl, etc. "Cycloalkylene" and "heterocycloalkylene" refer, alone or as part of another substituent, to divalent groups derived from cycloalkyl and heterocycloalkyl groups, respectively. "Cycloalkyl" also refers to bicyclic and polycyclic hydrocarbon rings, such as bicyclic [2.2.1]heptane, bicyclic [2.2.2]octane, etc. In embodiments, the cycloalkyl group is fully saturated. In embodiments, the cycloalkyl group is monounsaturated.In the embodiments, the cycloalkyl group is polyunsaturated. In the embodiments, the heterocycloalkyl group is fully saturated. In the embodiments, the heterocycloalkyl group is monounsaturated. In the embodiments, the heterocycloalkyl group is polyunsaturated. In the embodiments, the term "cycloalkyl" refers to a monocyclic, bicyclic, or polycyclic cycloalkyl ring system. In the embodiments, a monocyclic system is a cycloalkyl group containing 3 to 8 carbon atoms, wherein such a group may be saturated or unsaturated, but is not aromatic. In the embodiments, the cycloalkyl group is fully saturated. A bicyclic or polycyclic cycloalkyl ring system refers to a plurality of rings fused together, wherein at least one fused ring is a cycloalkyl ring, and wherein the plurality of rings are connected to a parent molecule moiety by any carbon atom contained within the cycloalkyl ring of the plurality of rings. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. A bicyclic cycloalkyl ring system is a bridged monocyclic or fused bicyclic ring. In the implementation scheme, the bridged monocyclic ring contains a monocyclic cycloalkyl ring, wherein two non-adjacent carbon atoms of the monocyclic ring are connected by an alkylene bridge between one carbon atom and three other carbon atoms (i.e., in the form of (ch2)). wThe bridging group, 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 embodiments, the fused bicyclic cycloalkyl ring system contains a monocyclic cycloalkyl ring fused with any of phenyl, monocyclic cycloalkyl, monocyclic cycloalkenyl, monocyclic heterocyclic, or monocyclic heteroaryl groups. In embodiments, the bridged or fused bicyclic cycloalkyl group is partially connected to the parent molecule via any carbon atom contained within the monocyclic cycloalkyl ring. A representative example of a polycyclic cycloalkyl ring system is adamantane. In embodiments, the cycloalkyl group is optionally substituted with one or both groups that are independently oxo or thia. In embodiments, the fused bicyclic cycloalkyl group is a 5- or 6-membered monocyclic cycloalkyl 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 fused to a benzene ring, wherein the fused bicyclic cycloalkyl group is optionally substituted by one or both groups that are independently oxo or thio groups. In embodiments, the polycyclic cycloalkyl ring system is a monocyclic cycloalkyl ring (base ring) fused to: (i) a ring system selected from the group consisting of bicyclic aryl, bicyclic heteroaryl, bicyclic cycloalkyl, bicyclic cycloalkenyl, and bicyclic heterocyclic groups; or (ii) two other ring systems independently selected from the group consisting of phenyl, bicyclic aryl, monocyclic or bicyclic heteroaryl, monocyclic or bicyclic cycloalkyl, monocyclic or bicyclic cycloalkenyl, and monocyclic or bicyclic heterocyclic groups. In embodiments, the polycyclic cycloalkyl group is partially connected to the parent molecule via any carbon atom contained within the base ring. In embodiments, a polycyclic cycloalkyl ring system is a monocyclic cycloalkyl ring (base ring) fused with: (i) a ring system selected from the group consisting of bicyclic aryl, bicyclic heteroaryl, bicyclic cycloalkyl, bicyclic cycloalkenyl, and bicyclic heterocyclic groups; or (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, perhydrophenanthiazin-1-yl, and perhydrophenoxazin-1-yl. In embodiments, the cycloalkyl group is a cycloalkenyl group. The term "cycloalkenyl" is used according to its common, general meaning. In embodiments, the cycloalkenyl group is a monocyclic, bicyclic, or polycyclic cycloalkenyl ring system. A bicyclic or polycyclic cycloalkenyl ring system refers to a plurality of rings fused together, wherein at least one fused ring is a cycloalkenyl ring, and wherein the plurality of rings are connected to a parent molecule moiety by any carbon atom contained within the cycloalkenyl ring of the plurality of rings. In the embodiments, the monocyclic cycloalkenyl ring system is a cyclic hydrocarbon group containing 3 to 8 carbon atoms, wherein such groups are unsaturated (i.e., contain at least one cyclic carbon-carbon double bond) but are not aromatic. Examples of monocyclic cycloalkenyl ring systems include cyclopentenyl and cyclohexenyl.In the embodiments, the bicyclic cycloalkenyl ring is a bridged monocyclic ring or a fused bicyclic ring. In the embodiments, the bridged monocyclic ring contains a monocyclic cycloalkenyl ring, wherein two non-adjacent carbon atoms of the monocyclic ring are connected by an alkylene bridge between one carbon atom and three other carbon atoms (i.e., in the form of (CH2)). wThe bridging group, wherein w is 1, 2, or 3). Representative examples of bicyclic cycloalkenyl groups include, but are not limited to, norbornenyl and bicyclic [2.2.2]octyl-2-enyl. In embodiments, the fused bicyclic cycloalkenyl ring system contains a monocyclic cycloalkenyl ring fused to any of phenyl, monocyclic cycloalkyl, monocyclic cycloalkenyl, monocyclic heterocyclic, or monocyclic heteroaryl groups. In embodiments, the bridged or fused bicyclic cycloalkenyl group is partially connected to the parent molecule via any carbon atom contained within the monocyclic cycloalkenyl ring. In embodiments, the cycloalkenyl group is optionally substituted with one or both groups that are independently oxo or thio groups. In an embodiment, the polycyclic cycloalkenyl ring comprises a monocyclic cycloalkenyl ring (base ring) fused with: (i) a ring system selected from the group consisting of bicyclic aryl, bicyclic heteroaryl, bicyclic cycloalkyl, bicyclic cycloalkenyl, and bicyclic heterocyclic groups; or (ii) two ring systems independently selected from the group consisting of phenyl, bicyclic aryl, monocyclic or bicyclic heteroaryl, monocyclic or bicyclic cycloalkyl, monocyclic or bicyclic cycloalkenyl, and monocyclic or bicyclic heterocyclic groups. In an embodiment, the polycyclic cycloalkenyl group is partially connected to the parent molecule via any carbon atom contained within the base ring. In an embodiment, the polycyclic cycloalkenyl ring comprises a monocyclic cycloalkenyl ring (base ring) fused with: (i) a ring system selected from the group consisting of bicyclic aryl, bicyclic heteroaryl, bicyclic cycloalkyl, bicyclic cycloalkenyl, and bicyclic heterocyclic groups; or (ii) two ring systems independently selected from the group consisting of phenyl, monocyclic heteroaryl, monocyclic cycloalkyl, monocyclic cycloalkenyl, and monocyclic heterocyclic groups. In embodiments, the term "heterocyclic alkyl" refers to a monocyclic, bicyclic, or polycyclic heterocyclic alkyl ring system. In embodiments, the heterocyclic alkyl group is fully saturated. A bicyclic or polycyclic heterocyclic alkyl ring system refers to a plurality of rings fused together, wherein at least one fused ring is a heterocyclic alkyl ring, and wherein the plurality of rings are connected to a parent molecule moiety through any carbon atom contained within the heterocyclic alkyl ring of the plurality of rings. In embodiments, the heterocyclic alkyl is a heterocyclic group. As used herein, the term "heterocyclic group" 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 and unsaturated, but not aromatic. A 3- or 4-membered ring contains one heteroatom of a group 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 of a group 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 of a group selected from O, N, and S. Heterocyclic monocyclic heterocycles are attached to the parent molecule via any carbon atom or nitrogen atom contained within the heterocyclic monocyclic heterocycle.Representative examples of heterocyclic monocyclic heterocycles include, but are not limited to, azahexacyclobutyl, azahexacycloheptyl, aziridinyl, diazacycloheptyl, 1,3-dioxacyclohexyl, 1,3-dioxapentyl, 1,3-dithiopentyl, 1,3-dithiaalkyl, imidazolinyl, imidazolinyl, isothiazolinyl, isothiazolinyl, isoxazolyl, isoxazolyl, morpholinyl, oxadiazolinyl, oxadiazolyl, oxazolinyl, oxazolyl, piperazine, piperidinyl, pyranyl, pyrazolinyl, thiazolinyl, pyrrololinyl, pyrrolyl, tetrahydrofuranyl, tetrahydrothiophenyl, thiadiazolinyl, thiadiazolinyl, thiazolinyl, thiazolinyl, thiazolinyl, thiomorpholinyl, 1,1-thiomorpholinyl dioxide (thiomorpholinone), thiopyranyl, and trithiaalkyl. A heterocyclic bicyclic heterocycle is a monocyclic heterocycle fused with any of the following: phenyl, monocyclic cycloalkyl, monocyclic cycloalkenyl, monocyclic heterocycle, or monocyclic heteroaryl. The heterocyclic bicyclic heterocycle is connected to the parent molecule via any carbon atom or any nitrogen atom contained within the monocyclic heterocycle portion of the bicyclic ring system. Representative examples of bicyclic heterocycles include, but are not limited to, 2,3-dihydrobenzofuran-2-yl, 2,3-dihydrobenzofuran-3-yl, indol-1-yl, indol-2-yl, indol-3-yl, 2,3-dihydrobenzothiophene-2-yl, decahydroquinolinyl, decahydroisoquinolinyl, octahydro-1H-indolyl, and octahydrobenzofuranyl. In embodiments, the heterocyclic group is optionally substituted with one or both groups that are independently oxo or thio groups. In some embodiments, the bicyclic heterocyclic group is a 5- or 6-membered monocyclic heterocycle, a 5- or 6-membered monocyclic cycloalkyl, a 5- or 6-membered monocyclic cycloalkenyl, a 5- or 6-membered monocyclic heterocyclic group, or a 5- or 6-membered monocyclic heteroaryl group fused to a benzene ring, wherein the bicyclic heterocyclic group is optionally substituted by one or both groups that are independently oxo or thio groups. The polycyclic heterocyclic ring system is a monocyclic heterocyclic ring (base ring) fused to: (i) a ring system selected from the group consisting of bicyclic aryl, bicyclic heteroaryl, bicyclic cycloalkyl, bicyclic cycloalkenyl, and bicyclic heterocyclic groups; or (ii) two other ring systems independently selected from the group consisting of phenyl, bicyclic aryl, monocyclic or bicyclic heteroaryl, monocyclic or bicyclic cycloalkyl, monocyclic or bicyclic cycloalkenyl, and monocyclic or bicyclic heterocyclic groups. The polycyclic heterocyclic group is partially connected to the parent molecule via any carbon or nitrogen atom contained within the base ring. In the embodiments, the polycyclic heterocyclic ring system is a monocyclic heterocyclic ring (base ring) fused with: (i) a ring system selected from the group consisting of bicyclic aryl, bicyclic heteroaryl, bicyclic cycloalkyl, bicyclic cycloalkenyl and bicyclic heterocyclic groups; or (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-phenthiazin-10-yl, 9,10-dihydroacryl-9-yl, 9,10-dihydroacryl-10-yl, 10H-phenoxazin-10-yl, 10,11-dihydro-5H-dibenzo[b,f]azapheno-5-yl, 1,2,3,4-tetrahydropyrido[4,3-g]isoquinoline-2-yl, 12H-benzo[b]phenoxazin-12-yl, and dodecahydro-1H-carbazole-9-yl.

[0020] Unless otherwise stated, the terms "halogen" or "halogen" mean, either alone or as part of another substituent, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as "haloalkyl" refer to both monohaloalkyl and polyhaloalkyl groups. For example, the term "halo(C1-C4)alkyl" includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, etc.

[0021] Unless otherwise stated, the term "acyl" means -C(O)R, where 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.

[0022] Unless otherwise stated, the term "aryl" refers to a polyunsaturated aromatic hydrocarbon substituent, which may be fused together (i.e., fused-ring aryl) or covalently linked monocyclic or polycyclic (preferably 1 to 3 rings). Fused-ring aryl refers to a plurality of rings fused together, wherein at least one of the fused rings is an aryl ring. In embodiments, fused-ring aryl refers to a plurality of rings fused together, wherein at least one fused ring is an aryl ring, and wherein the plurality of rings are attached to a parent molecule moiety via any carbon atom contained within the aryl ring of the plurality of rings. 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 quaternized. Thus, the term "heteroaryl" includes fused-ring heteroaryl (i.e., a plurality of rings fused together, wherein at least one of the fused rings is a heteroaryl ring). In the embodiments, the term "heteroaryl" includes fused-ring heteroaryl (i.e., a plurality of rings fused together, wherein at least one of the fused rings is a heteroaryl ring, and wherein the plurality of rings are attached to a portion of the parent molecule via any atoms contained within the heteroaryl rings of the plurality of rings). 5,6-fused-ring heteroaryl refers to two fused rings, one ring having 5 members and the other having 6 members, and wherein at least one ring is a heteroaryl ring. Similarly, 6,6-fused-ring heteroaryl refers to two fused rings, one ring having 6 members and the other having 6 members, and wherein at least one ring is a heteroaryl ring. And 6,5-fused-ring heteroaryl refers to two fused rings, one ring having 6 members and the other having 5 members, and wherein at least one ring is a heteroaryl ring. Heteroaryl groups can be attached to the remainder of the molecule via carbon or heteroatoms. Non-limiting examples of aryl and heteroaryl groups include phenyl, naphthyl, pyrrolyl, pyrazolyl, pyridazinyl, triazinyl, pyrimidinyl, imidazolyl, pyrazinyl, purinyl, oxazolyl, isoxazolyl, thiazolyl, furanyl, thiopheneyl, pyridinyl, pyrimidinyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzofuran, isobenzofuranyl, indoleyl, isoindoleyl, benzothiapheneyl, isoquinolinyl, quinoxalinyl, quinolinyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl The substituents in the aryl and heteroaryl ring systems mentioned above are selected from the acceptable substituent group described below. (The list includes substituents such as pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isooxazolyl, 4-isooxazolyl, 5-isooxazolyl, 2-thiazolyl, 4-thiazolyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-benzothiazolyl, purinel, 2-benzimidazolyl, 5-indolyl, 1-isoquinolinyl, 5-isoquinolinyl, 2-quinoxalolinyl, 5-quinoxalolinyl, 3-quinolinyl, and 6-quinolinyl.)"Arylene" and "heteroarylene," alone or as part of another substituent, refer to divalent groups derived from aryl and heteroaryl groups, respectively. The heteroaryl substituent can be -O- bonded to a nitrogen atom in a cyclic heteroatom. A fused-ring heterocyclic alkyl-aryl is an aryl group fused to a heterocyclic alkyl group. A fused-ring heterocyclic alkyl-heteroaryl is a heteroaryl group fused to a heterocyclic alkyl group. A fused-ring heterocyclic alkyl-heterocyclic alkyl is a heterocyclic alkyl group fused to a cycloalkyl group. A fused-ring heterocyclic alkyl-heterocyclic alkyl is a heterocyclic alkyl group fused to another heterocyclic alkyl group. Fused-ring heterocyclic alkyl-aryl, fused-ring heterocyclic alkyl-heteroaryl, fused-ring heterocyclic alkyl-cycloalkyl, or fused-ring heterocyclic alkyl-heterocyclic alkyl can each be independently unsubstituted or substituted by one or more of the substituents described herein.

[0023] A spirocycle is a group of two or more rings in which adjacent rings are connected by a single atom. Individual rings within a spirocycle can be the same or different. Individual rings within a spirocycle can be substituted or unsubstituted and can have substituents different from other individual rings in the spirocycle group. Possible substituents of individual rings within a spirocycle are possible substituents of the same ring when not part of the spirocycle (e.g., substituents of cycloalkyl or heteroalkyl rings). A spirocycle can be a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted cycloalkylene, a substituted or unsubstituted heteroalkyl, or a substituted or unsubstituted heteroalkylene, and the individual ring within the spirocycle group can be any ring in the immediately preceding list, encompassing all rings of one type (e.g., all rings of substituted heteroalkylene, where each ring can be the same or different substituted heteroalkylene). When referring to a spirocycle system, a heterocyclic spirocycle means a spirocycle in which at least one ring is a heterocycle and each ring can be a different ring. When referring to spirocyclic systems, a substituted spirocycle means that at least one ring is substituted and each substituent may optionally be different.

[0024] symbol It indicates the connection point between the chemical part and the rest of the molecule or chemical formula.

[0025] As used in this article, the term "oxo-group" refers to oxygen that is bonded to a carbon atom in a double bond.

[0026] The term "alkylarylene" refers to an arylene moiety covalently bonded to an alkylene moiety (also referred to herein as an alkylene linker). In embodiments, the alkylarylene has the following formula:

[0027]

[0028] The alkylarylene moiety may be substituted at the alkylene moiety or the arylene junction (e.g., at carbons 2, 3, 4, or 6) with a halogen, oxo group, -N3, -CF3, -CCl3, -CBr3, -CI3, -CN, -CHO, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO2CH3-SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, substituted or unsubstituted C1-C5 alkyl groups, or substituted or unsubstituted 2- to 5-membered heteroalkyl groups (e.g., substituted by a substituent group). In embodiments, the alkylarylene group is unsubstituted.

[0029] 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.

[0030] Substituents in alkyl and heteroalkyl groups (including those commonly referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, ynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) may be selected from, but are not limited to, one or more of the following groups: -OR', =O, =NR', =N-OR', -NR'R”, -SR', -halogen, -SiR'R”R”', -OC(O)R', -C(O)R', -CO2R', -CONR'R”, - OC(O)NR'R", -NR"C(O)R', -NR'-C(O)NR"R"', -NR"C(O)2R', -NR-C(NR'R"R"')=NR"", -NR-C(NR'R" )=NR”', -S(O)R', -S(O)2R', -S(O)2NR'R”, -NRSO2R', -NR'NR"R"', -ONR'R", -NR'C(O)NR"NR"'R"", -CN, -NO2, -NR'SO2R", -NR'C(O)R", -NR'C(O)-OR", -NR'OR", the number of which is in the range of zero to (2m'+1), where m' is the total number of carbon atoms in such groups. R, R', R”, R”' and R”” each preferably independently refer to hydrogen, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl (e.g., using 1 to 3). Halogen-substituted aryl groups, substituted or unsubstituted heteroaryl groups, substituted or unsubstituted alkyl groups, alkoxy or thioalkoxy or aralkyl groups. When the compounds described herein contain more than one R group, each of the R groups is selected independently, for example, as if each R' group, R” group, R”' group and R”” group were selected independently when more than one of these groups were present. When R' and R” are attached to the same nitrogen atom, they can combine with that nitrogen atom to form a 4-membered, 5-membered, 6-membered or 7-membered ring. For example, -NR'R” includes, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl. Based on the above discussion of substituents, those skilled in the art will understand that the term "alkyl" is intended to include groups containing a carbon atom bonded to a group other than a hydrogen group, such as haloalkyl (e.g., -CF3 and -CH2CF3) and acyl (e.g., -C(O)CH3, -C(O)CF3, -C(O)CH2OCH3, etc.).

[0031] Similar to the substituents described for alkyl groups, the substituents for aryl and heteroaryl groups are different 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”', -S(O)R', -S(O)2R', -S(O)2NR'R”, -NRSO2R', -NR'NR”R”', -ONR'R”, -NR'C(O)NR”NR”'R””, -CN, -NO2 The number of R groups is in the range of zero to the total number of open valences on the aromatic ring system; and 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 compound described herein contains more than one R group, each of the R groups is selected independently, for example, as if each R' group, R” group, R”' group and R”” group were selected independently when more than one of these groups were present.

[0032] Substituents on a ring (e.g., cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylene, heterocycloalkylene, 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 (following the valence rules), and in the case of fused or spirocyclic rings, the substituent described as associated with one member of the fused or spirocyclic ring (floating substituents on a single ring) can be a substituent on any of the fused or spirocyclic rings (floating substituents on multiple rings). When the substituent is attached to the ring rather than a specific atom (floating substituent) and the substituent's subscript is an integer greater than one, multiple substituents can be located on the same atom, the same ring, different atoms, different fused rings, or different spirocyclic rings, and each substituent can optionally be different. Where the connection point between the ring and the rest of the molecule is not limited to a single atom (floating substituent), the connection point can be any atom of the ring, and in the case of fused or spirocyclic rings, it can be any atom of any of the fused or spirocyclic rings (following the valence rules). In the case where a ring, fused ring, or spirocyclic ring contains one or more cyclic heteroatoms and the ring, fused ring, or spirocyclic ring is shown having another floating substituent (including, but not limited to, a connection point with the rest of the molecule), the floating substituent may be bonded to the heteroatom. In the case where the cyclic heteroatom is shown bonded to one or more hydrogen atoms in a structure or formula having a floating substituent (e.g., a cyclic nitrogen with two bonds connected to a ring atom and a third bond connected to a hydrogen atom), when the heteroatom is bonded to the floating substituent, the substituent will be understood as replacing the hydrogen while following the rules of chemical valence.

[0033] Two or more substituents can optionally be linked to form aryl, heteroaryl, cycloalkyl, or heterocycloalkyl groups. Such so-called cycloforming substituents are typically (though not mandatory) linked to a cyclic base structure. In one embodiment, the cycloforming substituent is linked to an adjacent member of the base structure. For example, two cycloforming substituents linked to an adjacent member of the cyclic base structure produce a fused-ring structure. In another embodiment, the cycloforming substituent is linked to a single member of the base structure. For example, two cycloforming substituents linked to a single member of the cyclic base structure produce a spirocyclic structure. In yet another embodiment, the cycloforming substituent is linked to a non-adjacent member of the base structure.

[0034] Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally form the formula -TC(O)-(CRR'). q A -U- ring, where T and U are independently -NR-, -O-, -CRR'-, or single bonds, and q is an integer from 0 to 3. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be of the formula -A-(CH2). rThe substituents of -B- are used, where A and B are independently -CRR'-, -O-, -NR-, -S-, -S(O)-, -S(O)2-, -S(O)2NR'-, or single bonds, and r is an integer from 1 to 4. One of the single bonds in the newly formed ring may optionally be replaced by a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be of the formula -(CRR'). s -X'-(C”R”R”') d The substituents are substituted, wherein s and d are independently integers from 0 to 3, and X' is -O-, -NR'-, -S-, -S(O)-, -S(O)2-, or -S(O)2NR'-. The substituents R, R', R” and R”' are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl.

[0035] As used herein, the term “heteroatom” or “cyclic heteroatom” is intended to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).

[0036] As used herein, “substituent group” means a group selected from the following:

[0037] (A) Oxide groups, halogens, -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, -OCHC l2, -OCHBr2, -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-C... 10 Aryl, C 10 Aryl or phenyl) or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl), and

[0038] (B) Alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl substituted with at least one of the following substituents:

[0039] (i) Oxide groups, halogens, -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, -OCHC l2, -OCHBr2, -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-C... 10 Aryl, C 10 Aryl or phenyl) or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl), and

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

[0041] (a) Oxide groups, halogens, -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

[0042] (For example, C6-C) 10 Aryl, C 10 Aryl or phenyl) or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl), and

[0043] (b) An alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl group substituted with at least one of the following substituents: oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2

[0044] , -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2,

[0045] -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -O

[0046] CF3, -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.,

[0047] 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.,

[0048] 3- to 8-membered heterocyclic alkyl, 3- to 6-membered heterocyclic alkyl, or 5- to 6-membered heterocyclic alkyl), unsubstituted aryl

[0049] (For example, C6-C) 10 Aryl, C 10 Aryl or phenyl) or unsubstituted heteroaryl (e.g., 5 to 10-membered heteroaryl, 5 to 9-membered heteroaryl or 5 to 6-membered heteroaryl).

[0050] As used herein, “size-restricted substituent” or “size-restricted substituent” means a group selected from all the substituents described above for “substituent”, wherein each substituted or unsubstituted alkyl group is a substituted or unsubstituted C1-C2 group. 20 Alkyl groups, 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, and each substituted or unsubstituted aryl group is a substituted or unsubstituted C6-C8 cycloalkyl group.10 Aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 10-membered heteroaryl.

[0051] As used herein, “lower substituent” refers to a group selected from all the substituents described above for “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, and each substituted or unsubstituted aryl group is a substituted or unsubstituted C6-C8 cycloalkyl group. 10 Aryl, and each substituted or unsubstituted heteroaryl group is a substituted or unsubstituted 5 to 9-membered heteroaryl group.

[0052] In some embodiments, each substituted group described in the compounds 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 described in the compounds herein is substituted with at least one substituent. In other embodiments, at least one or all of these groups are substituted with at least one size-restricted substituent. In other embodiments, at least one or all of these groups are substituted with at least one lower substituent.

[0053] In other embodiments of the compounds herein, each substituted or unsubstituted alkyl group may be a substituted or unsubstituted C1-C2. 20 Alkyl groups, 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, and each substituted or unsubstituted aryl group is a substituted or unsubstituted C6-C8 cycloalkyl group. 10 The aryl group, and / or each substituted or unsubstituted heteroaryl group is a substituted or unsubstituted 5- to 10-membered heteroaryl group. In some embodiments of the compounds herein, each substituted or unsubstituted alkylene group is a substituted or unsubstituted C1-C... 20Alkylene, each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2- to 20-membered heteroalkylene, each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C3-C8 cycloalkylene, each substituted or unsubstituted heterocyclic alkylene is a substituted or unsubstituted 3- to 8-membered heterocyclic alkylene, and each substituted or unsubstituted arylene is a substituted or unsubstituted C6-C 10 A arylene, and / or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5 to 10-membered heteroarylene.

[0054] In some embodiments, each substituted or unsubstituted alkyl 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, and each substituted or unsubstituted aryl group is a substituted or unsubstituted C6-C8 cycloalkyl group. 10 The aryl group and / or each substituted or unsubstituted heteroaryl group is a substituted or unsubstituted 5- to 9-membered heteroaryl group. In some embodiments, each substituted or unsubstituted alkylene group is a substituted or unsubstituted C1-C8 alkylene group, each substituted or unsubstituted heteroalkylene group is a substituted or unsubstituted 2- to 8-membered heteroalkylene group, each substituted or unsubstituted cycloalkylene group is a substituted or unsubstituted C3-C7 cycloalkylene group, each substituted or unsubstituted heterocycloalkylene group is a substituted or unsubstituted 3- to 7-membered heterocycloalkylene group, and each substituted or unsubstituted aryl group is a substituted or unsubstituted C6-C8 cycloalkylene group. 10 The compound is an arylene, and / or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5 to 9-membered heteroarylene. In some embodiments, the compound is the chemical substance set forth in the Examples section, figures, or tables below.

[0055] Certain compounds of this invention have asymmetric carbon atoms (optical or chiral centers) or double bonds; they can be defined in absolute stereochemistry as enantiomers, racemates, diastereomers, tautomers, geometric isomers, or stereoisomers of amino acids (R)- or (S)- or (D)- or (L)-, and each isomer is included within the scope of this invention. The compounds of this invention do not include those compounds known in the art as too unstable to be synthesized and / or isolated. This invention 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 synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefinic bonds or other geometrically asymmetric centers, and unless otherwise specified, it is intended that these compounds comprise both the E geometric isomer and the Z geometric isomer.

[0056] As used herein, the term "isomer" refers to a compound having the same number and type of atoms and therefore the same molecular weight but different structural arrangements or atomic configurations.

[0057] As used in this article, the term "tautomer" refers to one of two or more structural isomers that exist in equilibrium and are readily transformed from one isomer to another.

[0058] It will be apparent to those skilled in the art that some of the compounds of the present invention may exist in tautomeric forms, and all such tautomeric forms of the compounds are within the scope of the present invention.

[0059] Unless otherwise stated, the structures described herein are also intended to include all stereochemical forms of the structure; that is, the R and S configurations of each asymmetric center. Therefore, single stereochemical isomers of the compounds of the present invention, as well as mixtures of enantiomers and diastereomers, are all within the scope of this invention.

[0060] Unless otherwise stated, the structures described herein are also intended to include compounds that differ only in the presence or absence of one or more isotopically enriched atoms. For example, in addition to hydrogen being replaced by deuterium or tritium, or carbon being... 13 C or 14 Compounds having the structure of this invention, other than carbon substitution enriched by C, are within the scope of this invention.

[0061] The compounds of the present invention may also contain atomic isotopes in non-natural proportions on one or more atoms constituting such compounds. For example, the compounds may use, for example, tritium ( 3 H), Iodine-125 ( 125 I) or carbon-14 ( 14 C) Radiolabeling with radioactive isotopes. All isotopic variations of the compounds of this invention, whether radioactive or non-radioactive, are covered within the scope of this invention.

[0062] It should be noted that throughout the application, alternatives are written in the Markush group, for example, at each amino acid position containing more than one possible amino acid. It is specifically envisioned that each member of the Markush group should be considered individually, thereby including another embodiment, and the Markush group should not be understood as a single unit.

[0063] "Analog / analogue" is used according to its common, general meaning in chemistry and biology, and refers to a compound that is structurally similar but compositionally different from another compound (i.e., the so-called "reference" compound) for example, in the substitution of one atom with an atom of a different element, or in the presence of a particular functional group, or in the substitution of one functional group with another functional group, or in the absolute stereochemistry of one or more chiral centers of a reference compound. Therefore, an analog is a compound that is similar or equivalent to a reference compound in function and appearance, but dissimilar or not equivalent in structure or origin.

[0064] As used herein, the term "a / an" means one or more. Additionally, as used herein, the phrase "replaced by" means that the specified group can be replaced by one or more of any or all of the substituents in the named substituent. For example, in the case of groups such as alkyl or heteroaryl groups, "replaced by unsubstituted C1-C" means... 20 In the case of "alkyl or unsubstituted 2- to 20-membered heteroalkyl substitution", the group may contain one or more unsubstituted C1-C groups. 20 Alkyl groups, and / or one or more substituted 2- to 20-membered heteroalkyl groups.

[0065] Furthermore, when a portion is substituted by an R substituent, the group can be referred to as "R-substituted". When a portion is R-substituted, the portion is substituted by at least one R substituent, and each R substituent is optionally different. When a particular R group is present in the description of a chemical species (such as formula (I)), Roman numeral symbols can be used to distinguish each appearance of that particular R group. For example, in the presence of multiple R groups... 13 In the case of substituents, each R 13 Substituents can be classified as R 13A R 13B R 13C R 13D etc., where R 13A R 13B R 13C R 13D Each of them is in R 13 Defined within the scope of the definition and optionally different.

[0066] As used herein, a “detectable portion” refers to a portion that can be covalently or non-covalently linked to a compound or biomolecule that can be detected, for example, using techniques known in the art. In embodiments, the detectable portion is covalently linked. The detectable portion can provide imaging of the linked compound or biomolecule. The detectable portion can indicate contact between two compounds. Exemplary detectable portions are fluorophores, antibodies, reactive dyes, radiolabeled portions, magnetic contrast agents, and quantum dots. Exemplary fluorophores include fluorescein, rhodamine, GFP, coumarin, FITC, Alexa fluor, Cy3, Cy5, BODIPY, and cyanine dyes. Exemplary radionuclides include fluorescein-18, gallium-68, and copper-64. Exemplary magnetic contrast agents include gadolinium, iron oxide, iron platinum, and manganese.

[0067] The description of the compounds of this invention is limited by the principles of chemical bonding known to those skilled in the art. Therefore, where a group can be substituted with one or more of a plurality of substituents, such substitutions are chosen to conform to the principles of chemical bonding and to obtain compounds that are not inherently unstable and / or, as known to those skilled in the art, may be unstable under environmental conditions (such as aqueous, neutral, and several known physiological conditions). For example, heterocyclic alkyl or heteroaryl groups, according to the principles of chemical bonding known to those skilled in the art, are linked to the rest of the molecule via cyclic heteroatoms, thereby avoiding inherently unstable compounds.

[0068] The term "pharmaceutically acceptable salt" means a salt comprising an active compound prepared with a relatively non-toxic acid or base based on a specific substituent found on the compounds described herein. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting such compounds in neutral form with a sufficient amount of the desired base, either purely 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 of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting such compounds in neutral form with a sufficient amount of the desired acid, either purely or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrocarbonic acid, phosphoric acid, phosphoric acid monohydrogen phosphate, phosphoric acid dihydrogen phosphate, sulfuric acid, hydrosulfuric acid, hydroiodic acid, or phosphorous acid; 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, octanoic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, oxalic acid, and methanesulfonic acid. Also included are salts of amino acids, such as arginine salts; and salts of organic acids, such as glucuronic acid or galacturonic acid (see, for example, Berge et al., “Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain compounds of the present invention contain both basic and acidic functional groups that allow these compounds to be converted into base or acid addition salts.

[0069] Therefore, the compounds of the present invention can exist, for example, in salt form with pharmaceutically acceptable acids. The present invention includes such salts. Non-limiting examples of such salts include hydrochlorides, hydrobromic acids, phosphates, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, propionates, tartrates (e.g., (+)-tartrates, (-)-tartrates, or mixtures thereof including racemic mixtures), succinates, benzoates, and salts with amino acids (such as glutamic acid) and quaternary ammonium salts (e.g., iodomethane, iodoethane, etc.). These salts can be prepared by methods known to those skilled in the art.

[0070] 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 the various salt forms in certain physical properties, such as solubility in polar solvents. In embodiments, the compounds of the present invention contain both basic and acidic functional groups that cause these compounds to be converted into base addition salts or acid addition salts. 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 the various salt forms in certain physical properties, such as solubility in polar solvents, but unless specifically indicated, the salts disclosed herein are equivalent to the parent form of the compound for the purposes of the present invention.

[0071] In addition to salt forms, the present invention provides compounds in prodrug form. The prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention. The prodrugs of the compounds described herein can be converted in vivo after administration. Alternatively, the prodrugs can be converted into the compounds of the present invention in an in vitro environment by chemical or biochemical methods, such as upon contact with suitable enzymes or chemical reagents.

[0072] Some compounds of the present invention can exist in both non-solventized and solvated forms (including hydrated forms). Generally, solvated forms are equivalent to non-solventized forms and are covered within the scope of the present invention. Some compounds of the present invention can exist in various crystalline or amorphous forms. Generally, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.

[0073] "Pharmaceutically acceptable excipients" and "pharmaceutically acceptable carriers" refer to substances that facilitate administration of the compound to a subject and facilitate absorption by the subject, and that can be included in the compositions of the present invention without causing significant adverse toxic effects on the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, physiological saline solutions, lactated Ringer's solutions, plain sucrose, plain glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavorings, salt solutions (e.g., Ringer's solutions), alcohols, oils, gelatin, carbohydrates (e.g., lactose, amylose, or starch), fatty acid esters, carboxymethyl cellulose, polyvinylpyrrolidone, and pigments, etc. Such formulations can be sterilized and, if desired, can be mixed with adjuvants that do not adversely react with the compounds of the present invention, such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring substances, and / or aromatic substances, etc. Those skilled in the art will recognize that other pharmaceutical excipients can be used in the present invention.

[0074] The term "formulation" is intended to include formulations comprising an active compound having an encapsulating material as a carrier, the encapsulating material being provided as a capsule, wherein the active ingredient, with or without another carrier, is surrounded by the carrier to which it is thus associated. Similarly, it includes capsules and tablets. Tablets, powders, capsules, pills, capsules, and tablets can be used as solid dosage forms suitable for oral administration.

[0075] "CCR4 inhibitor" refers to a compound (such as the compound described herein) that can reduce the activity of CCR4 (e.g., by binding to CCR4) when compared to a control, such as a compound that is not present or is known to be inactive.

[0076] The terms “polypeptide,” “peptide,” and “protein” are used interchangeably herein to refer to polymers containing amino acid residues, wherein the polymer may optionally be conjugated with portions not composed of amino acids. The terms apply to amino acid polymers in which one or more amino acid residues are artificial chemical mimics of naturally occurring amino acids, as well as to both naturally occurring and non-naturally occurring amino acid polymers. In embodiments, the terms “polypeptide,” “peptide,” and “protein,” used interchangeably herein, refer to polymeric forms of amino acids of any length, which may include genetically encoded and non-genetically encoded amino acids, chemically or biochemically modified or derived amino acids, and polypeptides having a modified polypeptide backbone. The term includes fusion proteins, including but not limited to fusion proteins having heterologous amino acid sequences; fusion proteins having heterologous and homologous leader sequences, with or without an N-terminal methionine residue; immunolabeled proteins; etc.

[0077] A polypeptide or cell is "recombinant" when it is artificial or engineered, or derived from or contains artificial or engineered proteins or nucleic acids (e.g., non-natural or non-wild-type). For example, a recombinant polynucleotide is a polynucleotide that is inserted into a vector or any other heterologous location (e.g., in the genome of a recombinant organism) such that it does not associate with a nucleotide sequence that is normally side-linked to polynucleotides found in nature. Proteins expressed by recombinant polynucleotides in vitro or in vivo are examples of recombinant polypeptides. Similarly, polynucleotide sequences not found in nature (e.g., variants of naturally occurring genes) are recombinant.

[0078] "Contact" is used in its simple, ordinary sense, and refers to a process that allows at least two different substances (e.g., compounds including biomolecules or cells) to come close enough to react, interact, or physically contact. However, it should be understood that the resulting reaction products can be generated directly from the reaction between the added reagents or from one or more intermediates from the added reagents that can be produced in the reaction mixture.

[0079] The term "contact" can encompass allowing two species to react, interact, or physically touch, wherein the two species can be a compound and a protein or enzyme as described herein. In some embodiments, contact includes causing the compound described herein to interact with a protein or enzyme involved in a signaling pathway (e.g., the MAP kinase pathway).

[0080] As defined herein, the terms “activation,” “activate,” and “activating” in relation to target-inhibitor interactions refer to the positive influence (e.g., increase) on the activity or function of a target (e.g., a protein) relative to the absence of an inhibitor. These terms refer to activation, or activation, sensitization, or upregulation of the amount of protein that is reduced in signal transduction or enzyme activity or disease.

[0081] The terms "agonist," "activator," "upregulator," etc., refer to substances that can detectably increase the expression or activity of a given gene or protein relative to a control (e.g., in the absence of an agonist). An agonist can increase expression or activity by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or more compared to a control in the absence of an agonist. In some cases, expression or activity is 1.5, 2, 3, 4, 5, 10, or higher than that in the absence of an agonist. In embodiments, an agonist is a molecule that interacts with a target to cause or promote an increase in target activation. In embodiments, an activator is a molecule that increases, activates, promotes, enhances activation, sensitizes, or upregulates, for example, a gene, protein, ligand, receptor, or cell.

[0082] As defined herein, the term “inhibition / inhibit / inhibiting” in relation to target-inhibitor interactions means adversely affecting (e.g., reducing) the activity or function of a target (e.g., protein) relative to the absence of an inhibitor. In embodiments, inhibition means negatively affecting (e.g., reducing) the concentration or level of a target (e.g., protein) relative to the absence of an inhibitor. In embodiments, inhibition refers to the reduction of a disease or disease symptoms. In embodiments, inhibition refers to a reduction in the activity of a specific protein target. Therefore, inhibition includes at least partially or completely blocking stimulation, reducing, preventing or delaying activation, inactivating, desensitizing, or downregulating signal transduction or enzyme activity or the amount of a target (e.g., protein). In embodiments, inhibition refers to a reduction in the activity of a target (e.g., protein) due to a direct interaction (e.g., the binding of an inhibitor to a target (e.g., protein)). In the implementation, inhibition refers to a reduction in the activity of a target (e.g., a protein) due to indirect interactions (e.g., an inhibitor binds to a protein that activates the target (e.g., a protein), thereby preventing the target (e.g., a protein) from activation).

[0083] Interchangeably, the terms "inhibitor," "repressor," "antagonist," or "downregulator" refer to a substance that can detectably reduce the expression or activity of a given gene or protein relative to a control (e.g., in the absence of an inhibitor). An antagonist can reduce expression or activity by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or more compared to a control in the absence of an antagonist. In some cases, the expression or activity is 1.5, 2, 3, 4, 5, 10, or higher than the expression or activity in the absence of an antagonist. Antagonists prevent, reduce, inhibit, or neutralize the activity of agonists, and antagonists can also prevent, inhibit, or reduce the constitutive activity of a target (e.g., a target receptor), even in the absence of a defined agonist. In embodiments, an inhibitor is a molecule that reduces, blocks, prevents, delays activation, inactivates, desensitizes, or downregulates, for example, a gene, protein, ligand, receptor, or cell. An inhibitor can also be defined as a molecule that reduces, blocks, or inactivates constitutive activity. "Antagonists" are molecules that counteract the effects of agonists.

[0084] The terms “CC chemokine receptor type 4” and “CCR4” refer to proteins (including their homologs, isotypes, and functional fragments) that are high-affinity receptors for CC-type chemokines (e.g., CCL2 (MCP-1), CCL4 (MIP-1), CCL5 (RANTES), CCL17 (TARC), and CCL22 (MDC)). In the scientific literature, it has many different names, 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 or its variants that maintain CCR4 activity (e.g., at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% of the activity compared to wild-type CCR4). The term encompasses any CCR4 variant with a mutation (e.g., a frameshift mutation) that maintains CCR4 activity (e.g., at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% activity compared to wild-type CCR4). In an embodiment, the CCR4 protein encoded by the CCR4 gene has an amino acid sequence described in or corresponding to Entrez1233, UniProt P51679, or RefSeq (protein) NP_005499.1. In an embodiment, the CCR4 gene has a nucleic acid sequence described in RefSeq (mRNA) NM_005508. In an embodiment, the amino acid or nucleic acid sequence is a sequence known at the time of filing of this application. In an embodiment, the sequence corresponds to GI:5031627. In an embodiment, the sequence corresponds to NP_005499.1. In an embodiment, the sequence corresponds to NM_005508.4. In an embodiment, the sequence corresponds to GI:48762930. In the implementation, CCR4 is human CCR4, such as the CCR4 that causes cancer in humans. Although frequently found in dendritic cells, macrophages, NK cells, platelets, and basophils, CCR4 is primarily associated with T cells. It plays a role in the progression of a variety of inflammation-related conditions and, as described herein, is involved in many other conditions. The genomic sequence of CCR4 is located on chromosome 3 (NC_000003.12), and the CCR4 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, for example, Horuk (1994) Trends Pharm. Sci. 15:159-165).

[0085] The term "expression" encompasses any step involved in the production of a polypeptide, including but not limited to transcription, post-transcriptional modification, translation, post-translational modification, and secretion. Expression can be detected using conventional techniques for protein detection, such as ELISA, Western blotting, flow cytometry, immunofluorescence, immunohistochemistry, etc.

[0086] The terms "disease" or "symptom" refer to the state or health condition of a patient or subject who can be treated with the compounds or methods provided herein. A disease may be cancer. A disease may be an autoimmune disease. A disease may be an inflammatory disease. A disease may be an infectious disease. In some other contexts, "cancer" refers to cancer and carcinoma, sarcoma, adenocarcinoma, lymphoma, leukemia, etc., including solid tumors and lymphoma, kidney cancer, breast cancer, lung cancer, bladder cancer, colon cancer, ovarian cancer, prostate cancer, pancreatic cancer, stomach cancer, brain cancer, head and neck cancer, skin cancer, uterine cancer, testicular cancer, glioma, esophageal cancer and liver cancer (including hepatocellular carcinoma), lymphoma (including acute B-cell lymphoblastic lymphoma), non-Hodgkin's lymphomas (e.g., Burkitt's lymphoma, small cell lymphoma, and large cell lymphoma), Hodgkin's lymphoma, leukemia (including MDS, AML, ALL, ATLL, and CML), or multiple myeloma.

[0087] As used herein, the term “inflammatory disease” refers to a disease or condition characterized by abnormal inflammation (e.g., increased levels of inflammation compared to a control, such as compared to a healthy individual without the disease). Examples of inflammatory diseases include autoimmune diseases, arthritis, rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, multiple sclerosis, systemic lupus erythematosus (SLE), myasthenia gravis, juvenile-onset diabetes, type 1 diabetes, Guillain-Barré syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, ankylosing spondylitis, psoriasis, Sjogren's syndrome, vasculitis, glomerulonephritis, autoimmune thyroiditis, Behcet's disease, Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, ichthyosis, Graves' eye disease, inflammatory bowel disease, and Addison's disease. Inflammatory diseases, vitiligo, asthma, allergic asthma, acne vulgaris, celiac disease, chronic prostatitis, pelvic inflammatory disease, reperfusion injury, ischemia-reperfusion injury, stroke, sarcoidosis, transplant rejection, interstitial cystitis, atherosclerosis, scleroderma, and atopic dermatitis. These conditions are often inextricably linked with other diseases, symptoms, and ailments. A non-limiting list of inflammatory-related diseases, symptoms, and ailments that may be caused by inflammatory cytokines includes, for example, arthritis, kidney failure, lupus, asthma, psoriasis, colitis, pancreatitis, allergies, fibrosis, surgical complications (e.g., inflammatory cytokines inhibit healing), anemia, and fibromyalgia. Other diseases and conditions that may be associated with chronic inflammation include Alzheimer's disease, congestive heart failure, stroke, aortic stenosis, arteriosclerosis, osteoporosis, Parkinson's disease, infections, inflammatory bowel disease (IBD), allergic contact dermatitis and other eczemas, systemic sclerosis, transplantation, and multiple sclerosis. Some of the aforementioned diseases, conditions, and symptoms for which the compounds described herein (e.g., CCR4 inhibitors) may be particularly effective (e.g., due to limitations of current therapies) are described in more detail below.Examples of inflammatory diseases include traumatic brain injury, arthritis, rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, multiple sclerosis, systemic lupus erythematosus (SLE), myasthenia gravis, juvenile-onset diabetes, type 1 diabetes, Graves-Barré syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, ankylosing spondylitis, psoriasis, Schuglian syndrome, vasculitis, glomerulonephritis, autoimmune thyroiditis, Behcet's disease, Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, ichthyosis, Graves' eye disease, inflammatory bowel disease, Addison's disease, vitiligo, asthma, allergic asthma, acne vulgaris, celiac disease, chronic prostatitis, inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, sarcoidosis, transplant rejection, interstitial cystitis, atherosclerosis, and atopic dermatitis.

[0088] As used herein, the term "cancer" refers to all types of cancer, tumors, or malignant tumors found in mammals (e.g., humans), including leukemia, lymphoma, carcinoma, and sarcoma. Exemplary cancers treatable with the compounds or methods provided herein include brain cancer, glioma, glioblastoma, neuroblastoma, prostate cancer, colorectal cancer, pancreatic cancer, cervical cancer, gastric cancer, ovarian cancer, lung cancer, and head cancer. Exemplary cancers treatable with the compounds or methods provided herein include: thyroid cancer, endocrine system cancer, brain cancer, breast cancer, cervical cancer, colon cancer, head and neck cancer, liver cancer, kidney cancer, lung cancer, non-small cell lung cancer, melanoma, mesothelioma, ovarian cancer, sarcoma, gastric cancer, uterine cancer, neuroblastoma, colorectal cancer, and pancreatic cancer. Other examples include thyroid cancer, bile duct cancer, pancreatic cancer, malignant melanoma of the skin, colonic adenocarcinoma, rectal adenocarcinoma, gastric adenocarcinoma, esophageal cancer, squamous cell carcinoma of the head and neck, invasive breast cancer, lung adenocarcinoma, squamous cell carcinoma of the lung, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, essential thrombocytosis, essential macroglobulinemia, primary brain tumors, cancer, malignant pancreatic islet tumors, malignant carcinoid tumors, bladder cancer, precancerous skin lesions, testicular cancer, lymphoma, thyroid cancer, neuroblastoma, esophageal cancer, urogenital tract cancer, malignant hypercalcemia, endometrial cancer, adrenocortical cancer, endocrine or exocrine pancreatic tumors, medullary thyroid cancer, and medullary thyroid carcinoma. (carcinoma), melanoma, colorectal cancer, papillary thyroid carcinoma, hepatocellular carcinoma, or prostate cancer.

[0089] The term “leukemia” refers to a progressive, malignant disease of the blood-forming organs, and is generally characterized by the disordered proliferation and development of leukocytes and their precursors in the blood and bone marrow. Clinical classification of leukemia is usually based on (1) the duration and characteristics of the disease – acute or chronic; (2) the cell type involved; myeloid (myeloid), lymphoid (lymphoblastic), or monocytic; and (3) the increase or absence of abnormal cell numbers in leukemia or non-leukemia (subleukemia). Exemplary leukemias that can be treated with the compounds or methods provided herein include, for example, acute non-lymphocytic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, acute promyelocytic leukemia, adult T-cell leukemia, leukopenic leukemia, leukemic leukemia, basophilic leukemia, blastic leukemia, bovine leukemia, chronic myeloid leukemia, cutaneous leukemia, embryonal leukemia, eosinophilic leukemia, Gross' leukemia, hairy cell leukemia, and hemoblastic leukemia. Leukemia, hematopoietic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphocytic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, small myeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myelocytic leukemia, myelogranulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasma cell leukemia, promyelocytic leukemia, Rieder cell leukemia, Schilling's leukemia Leukemia, stem cell leukemia, subleukemic leukemia, or undifferentiated cell leukemia.

[0090] As used in this article, the term "lymphoma" refers to a group of cancers that affect hematopoietic and lymphatic tissues. It begins with lymphocytes, blood cells primarily found in lymph nodes, spleen, thymus, and bone marrow. The two main types of lymphoma are non-Hodgkin's lymphoma and Hodgkin's disease. Hodgkin's disease accounts for approximately 15% of all diagnosed lymphomas. This is a cancer associated with Reed-Sternberg malignant B lymphocytes. Non-Hodgkin's lymphoma (NHL) can be classified based on the cancer's growth rate and the cell types involved. Aggressive (high-grade) and indolent (low-grade) types of NHL exist. Based on the cell types involved, there are B-cell and T-cell NHL. Exemplary B-cell lymphomas that can be treated with the compounds or methods provided herein include, but are not limited to, small lymphocytic lymphoma, mantle cell lymphoma, follicular lymphoma, marginal zone lymphoma, extranodal (MALT) lymphoma, nodular (monocyte-like B-cell) lymphoma, splenic lymphoma, diffuse large cell B-cell lymphoma, Burkitt's lymphoma, lymphoblastic lymphoma, immunoblastic large cell lymphoma, or precursor B-cell lymphoblastic lymphoma. Exemplary T-cell lymphomas that can be treated with the compounds or methods provided herein include, but are not limited to, cunateous T-cell lymphoma, peripheral T-cell lymphoma, anaplastic large cell lymphoma, mycosis fungoides, and precursor T-cell lymphoblastic lymphoma.

[0091] The term "sarcoma" generally refers to a tumor composed of material similar to embryonic connective tissue, and typically consists of tightly packed cells embedded in fibrous or homogeneous material. Sarcomas that can be treated with the compounds or methods provided in this article include chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abemethy's sarcoma, liposarcoma, liposarcoma, alveolar soft partial sarcoma, ameloblastic sarcoma, botryoid sarcoma, green carcinosarcoma, choriocarcinoma, embryonal sarcoma, Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma, B-cell immunoblastic sarcoma, lymphoma, T-cell immunoblastic sarcoma, Jensen's sarcoma, Kaposi's sarcoma, and Kupffer cell sarcoma. Sarcoma, angiosarcoma, leukosarcoma, malignant mesothelioma sarcoma, extraperiosteal sarcoma, reticulum cell sarcoma, Rous sarcoma, serocystic sarcoma, synovial sarcoma, or telangiectaltic sarcoma.

[0092] The term "melanoma" refers to tumors originating from the melanocyte system of the skin and other organs. Melanomas that can be treated with the compounds or methods provided herein include, for example, acral lentigines melanoma, amelanoma, benign juvenile melanoma, Cloudman's melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, malignant lentigines melanoma, malignant melanoma, nodular melanoma, subungual melanoma, or superficial diffuse melanoma.

[0093] The term "cancer" refers to a malignant new growth composed of epithelial cells that tends to infiltrate surrounding tissues and cause metastasis. Exemplary cancers that can be treated with the compounds or methods provided herein include, for example, thyroid cancer, bile duct cancer, pancreatic adenocarcinoma, skin melanoma, colonic adenocarcinoma, rectal adenocarcinoma, gastric adenocarcinoma, esophageal cancer, head and neck squamous cell carcinoma, invasive breast cancer, lung adenocarcinoma, lung squamous cell carcinoma, medullary thyroid carcinoma, familial medullary thyroid carcinoma, acinar carcinoma, acinar carcinoma, adenoid cystic carcinoma, adenocarcinoma, adrenocortical carcinoma, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, basoid cell tumor, basal cell carcinoma, basal squamous cell carcinoma, bronchioloalveolar carcinoma, bronchiolar carcinoma, bronchial carcinoma, brain carcinoma, bile duct cell carcinoma, choriocarcinoma, colloid carcinoma, comedo carcinoma, uterine corpus cancer, cribriform carcinoma, armored carcinoma, and carcinoma. Cutaneum, columnar carcinoma, columnar cell carcinoma, tubular carcinoma, scleroderma, embryonal carcinoma, medullary carcinoma, epidermoid carcinoma, adenoid epithelial cell carcinoma, explant carcinoma, ulcerative carcinoma, fibrous carcinoma, gelatiniforni carcinoma, gelatinous carcinoma, giant cell carcinoma, giant cell carcinoma, glandular carcinoma, granular cell carcinoma, hair-matrix carcinoma, hematoid carcinoma, hepatocellular carcinoma, Hurthlecell carcinoma, hyaline carcinoma, adrenal carcinoma, naive embryonal carcinoma, carcinoma in situ, intraepithelial carcinoma, intraepithelial carcinoma, Krompecher's carcinoma, Kulchitzky-cell carcinoma, large cell carcinoma, lenticular carcinoma, lenticular carcinoma lenticular carcinoma, lipomatous carcinoma, lymphoepithelial carcinoma, medullary carcinoma, melanoma, soft carcinoma, mucinous carcinoma, mucinous cell carcinoma, mucocellular carcinoma, mucoepidermoid carcinoma, mucinoma mucosum, mucinous carcinoma, myxomatoid carcinoma, nasopharyngeal carcinoma, oat cell carcinoma, ossificans carcinoma, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, acanthosis nigra, pultaceous carcinomaRenal cell carcinoma, renal cell carcinoma, reserve cell carcinoma, sarcomatoid carcinoma, Schneiderian carcinoma, scleroderma, scrotal carcinoma, signet ring cell carcinoma, simple carcinoma, small cell carcinoma, potato-shaped carcinoma, spherical cell carcinoma, spindle cell carcinoma, medullary carcinoma, squamous cell carcinoma, ligamentous carcinoma, telangiectatic carcinoma, carcinomatelangiectodes, transitional cell carcinoma, tuberosum carcinoma, tuberous carcinoma, verrucous carcinoma, or villous carcinoma.

[0094] As used herein, the term "autoimmune disease" refers to a disease or condition in which the immune system of a subject produces an abnormal immune response to a substance that would not normally elicit an immune response in a healthy subject. Examples of autoimmune diseases that can be treated with the compounds, pharmaceutical compositions, or methods described herein include acute disseminated encephalomyelitis (ADEM), acute necrotizing hemorrhagic leukoencephalitis, Addison's disease, agammaglobulinemia, alopecia areata, amyloidosis, ankylosing spondylitis, anti-GBM / anti-TBM nephritis, antiphospholipid syndrome (APS), autoimmune angioedema, autoimmune aplastic anemia, autoimmune autonomic dysregulation, autoimmune hepatitis, autoimmune hyperlipidemia, autoimmune immunodeficiency, autoimmune inner ear disease (AIED), autoimmune myocarditis, autoimmune oophoritis, autoimmune pancreatitis, and other autoimmune diseases. Retinopathy, autoimmune thrombocytopenic purpura (ATP), autoimmune thyroid disease, autoimmune urticaria, axonal or neuropathy, Barlow's disease, Behcet's disease, bullous pemphigoid, cardiomyopathy, Casterman's disease, celiac disease, Chagas disease, chronic fatigue syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic relapsing multifocal osteomyelitis (CRMO), allergic granulomatous vasculitis, cicatricial pemphigoid / benign mucosal pemphigoid, Crohn's disease, Cogan's syndrome, cold agglutinin disease, congenital heart block, Coxsackie myocarditis, Crest disease, primary mixed cryoglobulinemia, demyelinating neuropathy. Herpetic dermatitis, dermatomyositis, Dweck's disease (neuromyelitis optica), discoid lupus, De Lessler syndrome, endometriosis, eosinophilic esophagitis, eosinophilic fasciitis, erythema nodosum, experimental allergic encephalomyelitis, Evans syndrome, fibromyalgia, fibrosing alveolitis, giant cell arteritis (temporal arteritis), giant cell myocarditis, glomerulonephritis, pulmonary hemorrhage nephritis syndrome, granulomatous polyangiitis (GPA) (formerly known as Wegener's granulomatosis), Griev's disease, Guillain-Barré syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, hemolytic anemia, allergic purpura, herpetic pregnancy, hypogammaglobulinemia, idiopathic thrombocytopenic purpura (I-T). TP), IgA nephropathy, IgG4-related sclerotic diseases, immunomodulatory lipoprotein, inclusion body myositis, interstitial cystitis, juvenile arthritis, juvenile diabetes (type 1 diabetes), juvenile myositis, Kawasaki syndrome, myasthenic syndrome, leukocytic destructive vasculitis, lichen planus, lichen sclerosus, woody conjunctivitis, linear IgA disease (LAD), lupus (SLE), Lyme disease, chronic Meniere's disease, microscopic polyangiitis, mixed connective tissue disease (MCTD), Mollen's ulcer, Muller-Haas disease, multiple sclerosis, myasthenia gravis, myositis, somnolence, neuromyelitis optica (Devic's disease), neutropenia.Ocular cicatricial pemphigoid, optic neuritis, relapsing rheumatism, panda (a streptococcal-associated childhood autoimmune neuropsychiatric disorder), paraneoplastic cerebellar degeneration, paroxysmal nocturnal hemoglobinuria (PNH), Parry-Lomber syndrome, Parsenague-Turner syndrome, pars plana (peripheral uveitis), pemphigus, peripheral neuropathy, perivenous encephalomyelitis, pernicious anemia, POEMS syndrome, polyarteritis nodosa, type I, II, and III autoimmune polygonatum syndrome, polymyalgia rheumatica, polymyositis, post-myocardial infarction syndrome, post-pericardiotomy syndrome, progesterone dermatitis, primary biliary cirrhosis, primary sclerosing cholangitis, psoriasis, psoriatic arthritis, idiopathic pulmonary fibrosis, pyoderma gangrenosa, pure red blood cells Aplastic disorders, Raynaud's phenomenon, reactive arthritis, reflex sympathetic dystrophy, Rett syndrome, relapsing polychondritis, restless legs syndrome, retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, Schmidt syndrome, scleritis, scleroderma, Sjögren's syndrome, sperm and testicular autoimmunity, stiff-person syndrome, subacute bacterial endocarditis (SBE), Sussac syndrome, sympathetic ophthalmia, aortitis, temporal arteritis / giant cell arteritis, thrombocytopenic purpura (TTP), Tolosa-Hunter syndrome, rhabdomyomyitis, type 1 diabetes mellitus, ulcerative colitis, undifferentiated connective tissue disease (UCTD), uveitis, vasculitis, vesicular bullous dermatitis, vitiligo, or Wegener's granulomatosis (i.e., granulomatous polyangiitis (GPA)).

[0095] The term "treatment" refers to any successful indication in the treatment or improvement of an injury, disease, pathology, or symptom, including any objective or subjective parameters such as relief; alleviation; reduction of symptoms or increased patient tolerance to the injury, pathology, or symptom; slowing the rate of degeneration or decline; making the final stage of degeneration less debilitating; or improving the patient's physical or mental health. Treatment or improvement of symptoms can be based on objective or subjective parameters, including the results of physical examination, neuropsychiatric examination, and / or psychiatric evaluation. The term "treatment" and its variations can include prevention of injury, pathology, symptom, or disease. In this implementation, treatment is prevention. In this implementation, treatment does not include prevention. In this implementation, treatment (treating or treatment) is not preventative treatment.

[0096] As used herein (and fully understood in the art), “treating” also broadly includes any method used to obtain a beneficial or desired outcome (including clinical outcomes) in a subject’s condition. Beneficial or desired clinical outcomes may include, but are not limited to: reducing or improving one or more symptoms or conditions, reducing the severity of the disease, stabilizing (i.e., not worsening) the disease state, preventing the spread or diffusion of the disease, delaying or slowing the progression of the disease, improving or alleviating the disease state, reducing disease recurrence, and remission, whether local or total, and whether detectable or undetectable. In other words, “treatment” as used herein includes any cure, improvement, or prevention of a disease. Treatment may prevent the onset of a disease; inhibit the spread of a disease; alleviate the symptoms of a disease (e.g., eye pain, seeing halos, red eyes, extremely high intraocular pressure), completely or partially remove the root cause of the disease, shorten the duration of the disease, or a combination of these.

[0097] As used herein, “treating / treatment” includes preventative treatment. A treatment method involves administering a therapeutically effective amount of the compound described herein to a subject. The administration process may consist of a single administration or may include a series of administrations. The length of the treatment period depends on a variety of factors, such as the severity of the symptoms, the patient's age, the concentration of the compound, the activity of the composition used in the treatment, or a combination thereof. It should also be understood that the effective dose of the agent used for treatment or prevention may be increased or decreased during a particular treatment or prevention regimen. Changes in dose can be produced and become apparent using standard diagnostic assays known in the art. In some cases, prolonged administration may be required. For example, administering the composition to a subject in an amount sufficient to treat the patient for a sufficient duration.

[0098] The term "prevention" refers to reducing the occurrence of a patient's disease symptoms. As indicated above, prevention can be complete (without detectable symptoms) or partial, resulting in fewer observed symptoms than would be possible without treatment. In implementation, prevention means slowing the progression of a disease, symptom, or illness, or inhibiting its progression to a harmful or undesirable state.

[0099] "Patient" or "subject in need of treatment" means a living organism that suffers from or is susceptible to a disease or symptom that can be treated by administration of the pharmaceutical compositions provided herein. Non-limiting examples include humans, other mammals, cattle, rats, mice, dogs, monkeys, goats, sheep, dairy cows, deer, and other non-mammals. In some embodiments, the patient is a human.

[0100] "Effective amount" is the amount of a compound sufficient to achieve its stated purpose (e.g., to achieve its effect of administration, to treat a disease, to reduce enzyme activity, to increase enzyme activity, to reduce signal transduction pathways, or to alleviate one or more symptoms of a disease or condition) relative to the absence of the compound. An example of an "effective amount" is an amount sufficient to help treat, prevent, or alleviate one or more symptoms of a disease, which may also be referred to as a "therapeutic effective amount." "Reduction" of one or more symptoms (and its grammatical equivalent) means a reduction in the severity or frequency of one or more symptoms, or the elimination of one or more symptoms. A "preventive effective amount" of a drug is the amount of drug that, when administered to a subject, will have the expected preventive effect, such as preventing or delaying the onset (or recurrence) of an injury, disease, pathology, or condition, or reducing the likelihood of the onset (or recurrence) of an injury, disease, pathology, or condition or its symptoms. A complete preventive effect does not necessarily occur with a single dose and can occur after only a series of doses. Therefore, a preventive effective amount can be administered in the form of a single or multiple doses. As used herein, "activity reduction amount" refers to the amount of antagonist required to reduce the activity of an enzyme relative to the absence of an antagonist. As used herein, “functionally disruptive dose” refers to the amount of antagonist required to disrupt the function of an enzyme or protein relative to the absence of an antagonist. The exact dose will depend on the therapeutic purpose and will be determined by someone skilled in the art using known techniques (see, for example, Lieberman, Pharmaceutical Dosage Forms (Vols. 1–3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins). Therapeuticly effective doses can be determined by measuring the relevant physiological effects and can be adjusted in conjunction with the dosing regimen and diagnostic analysis of the subject's condition. For example, measuring serum levels of a CCR4 inhibitor (or, for example, its metabolites) at a specific time after administration can indicate whether a therapeutically effective dose has been administered.

[0101] For any of the compounds described herein, the therapeutically effective amount can be initially determined using cell culture assays. The target concentration, as measured using methods described herein or known in the art, will be those concentrations of one or more active compounds capable of achieving the methods described herein.

[0102] As is well known in the art, therapeutically effective doses for humans can also be determined using animal models. For example, human doses can be formulated to achieve concentrations found to be effective in animals. As described above, the human dose can be adjusted by monitoring the effectiveness of the compound and by increasing or decreasing the dose. Adjusting the dose in humans to achieve maximum efficacy based on the methods described above and others is entirely within the capabilities of a person skilled in the art. Adjusting the dose in humans to achieve maximum therapeutic window efficacy or toxicity based on the methods described above and others is entirely within the capabilities of a person skilled in the art.

[0103] As used herein, the term "therapeutic effective dose" refers to the amount of a therapeutic agent sufficient to improve the condition as described above. For example, for a given parameter, the therapeutic effective dose will show an increase or decrease of at least 5%, 10%, 15%, 20%, 25%, 40%, 50%, 60%, 75%, 80%, 90%, or at least 100%. Therapeutic efficacy can also be expressed as an increase or decrease in "multiples." For example, the therapeutic effective dose can have an effect of at least 1.2 times, 1.5 times, 2 times, 5 times, or more relative to the control.

[0104] Dosage can vary depending on the patient's needs and the compound used. In the context of this invention, the dose administered to the patient should be sufficient to produce a beneficial therapeutic response in the patient over time. The size of the dose will also be determined by the presence, nature, and extent of any adverse side effects. Determining the appropriate dose for the specific situation is within the skill of the practitioner. Typically, treatment begins with a smaller dose than the optimal dose of the compound. Thereafter, the dose is increased in small increments until optimal effects are achieved in multiple cases. Dosage and intervals can be individually adjusted to provide the level of compound administered that is effective for the specific clinical indication being treated. This will provide a treatment regimen commensurate with the severity of the subject's disease state.

[0105] As used herein, the term "administration" means oral administration to a subject, administration in suppository form, local contact, intravenous, parenteral, intraperitoneal, intramuscular, intralesional, intrathecal, intracranial, intranasal, or subcutaneous administration, or administration via implantation of a slow-release device (e.g., a micro-osmotic pump). Administration can be performed via any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or percutaneous). Parenteral administration includes, for example, intravenous, intramuscular, intraarterial, intradermal, subcutaneous, intraperitoneal, intravenous, and intracranial administration. Other delivery modalities include, but are not limited to, the use of liposome formulations, intravenous infusion, transdermal patches, etc. "Co-administration" means that the composition described herein is administered simultaneously, exactly before, or exactly after the administration of one or more other therapies (e.g., anticancer agents, chemotherapeutic agents, or neurodegenerative disease treatments). In embodiments, administration does not include the administration of any active agent other than the listed active agents. The compounds of the present invention can be administered alone or co-administered to a patient. Co-administration is intended to involve the simultaneous or sequential administration of the compounds, either alone or in combination (more than one compound or agent). Therefore, the formulations can also be used in combination with other active substances when needed (e.g., to reduce metabolic degradation). The compositions of the present invention can be delivered via transdermal or topical routes and can be formulated as applicators, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols. Oral formulations include tablets, pills, powders, sugar-coated pills, capsules, liquids, lozenges, capsules, gels, syrups, slurries, suspensions, etc., suitable for patient ingestion. Solid forms include powders, tablets, pills, capsules, capsules, suppositories, and dispersible particles. Liquid forms include solutions, suspensions, and emulsions, such as water or water / propylene glycol solutions. The compositions of the present invention may additionally contain components that provide sustained release and / or comfort. Such components include high molecular weight, anionic viscous polymers, gelling polysaccharides, and finely fragmented drug carrier substrates. These components are discussed in more detail in U.S. Patents 4,911,920; 5,403,841; 5,212,162; and 4,861,760. The entire contents of these patents are incorporated herein by reference for all purposes. The compositions of the present invention can also be delivered in the form of microspheres for slow release in vivo. For example, microspheres can be administered by intradermal injection of drug-containing microspheres that release slowly subcutaneously (see Rao, J. Biomater Sci. Polym. Ed. 7:623-645, 1995); in the form of biodegradable and injectable gel formulations (see, for example, Gao Pharm. Res. 12:857-863, 1995); or in the form of microspheres for oral administration (see, for example, Eyles, J. Pharm. Pharmacol. 49:669-674, 1997).In another embodiment, formulations of the compositions of the present invention can be delivered using liposomes fused to or endocytosed by cell membranes, i.e., by using receptor ligands attached to the liposomes, which bind to cell surface membrane protein receptors thereby causing endocytosis. By using liposomes, particularly when the liposomes carry receptor ligands specific to target cells or otherwise preferentially targeting specific organs, the compositions of the present invention can be delivered in vivo to target cells in a concentrated manner. (See, for example, Al-Muhammed, J. Microencapsul. 13:293-306, 1996; Chonn, Curr. Opin. Biotechnol. 6:698-708, 1995; Ostro, Am. J. Hosp. Pharm. 46:1576-1587, 1989). The compositions of the present invention can also be delivered as nanoparticles. In embodiments, administration does not include the administration of any active agents other than those listed.

[0106] "Co-administration" means administering the composition described herein simultaneously, immediately before, or immediately after the administration of one or more other therapies. The compounds of the present invention can be administered alone or co-administered to a patient. Co-administration means the simultaneous or sequential administration of compounds (more than one compound) alone or in combination. The compositions of the present invention can be delivered via transdermal or topical routes and can be formulated as applicators, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, ointments, powders, and aerosols.

[0107] For any of the compounds described herein, the therapeutically effective amount can be initially determined using cell culture assays. The target concentration, as measured using methods described herein or known in the art, will be those concentrations of one or more active compounds capable of achieving the methods described herein.

[0108] As is well known in the art, therapeutically effective doses for humans can also be determined using animal models. For example, human doses can be formulated to achieve concentrations found to be effective in animals. As described above, the human dose can be adjusted by monitoring the effectiveness of the compound and by increasing or decreasing the dose. Adjusting the dose based on the methods described above and others to achieve maximum efficacy in humans is entirely within the capabilities of a person skilled in the art.

[0109] Dosage can vary depending on the patient's needs and the compound used. In the context of this invention, the dosage given to the patient should be sufficient to produce a beneficial therapeutic response over time. The dosage will also be determined by the presence, nature, and extent of any adverse side effects. Determining the appropriate dosage for the specific situation is within the skill of the practitioner. Generally, treatment begins with a smaller dose than the optimal dose of the compound. Thereafter, the dosage is increased in small increments until optimal effects are achieved in multiple cases.

[0110] Dosage and intervals can be individually adjusted to provide the administered compound level effective for the specific clinical indication being treated. This will provide a treatment regimen commensurate with the severity of the subject's disease state.

[0111] Using the teachings provided in this article, effective preventative or therapeutic treatment regimens can be planned that do not cause substantial toxicity but effectively treat the clinical symptoms exhibited by a particular patient. This planning should involve the careful selection of active compounds by considering factors such as compound potency, relative bioavailability, patient weight, the presence and severity of adverse side effects, the preferred mode of administration, and the toxicity spectrum of the chosen agent.

[0112] The compounds described herein can be used in combination with other active agents known to be used to treat cancer (e.g., colon cancer), cardiovascular disease, metabolic disease, immune or inflammatory disease or condition.

[0113] In some embodiments, co-administration includes administering one active agent within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, 24 hours, 2 days, 4 days, 1 week, or 1 month of the second active agent. Co-administration includes administering the two active agents simultaneously, nearly simultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each other), or sequentially in any order. In some embodiments, co-administration can be accomplished by co-co-blending, i.e., preparing a single pharmaceutical composition comprising the two active agents. In other embodiments, the active agents may be formulated separately. In yet another embodiment, the active agent and / or adjuvant may be linked or conjugated to each other. In some embodiments, the compounds described herein may be combined with treatments for cancer (e.g., colon cancer), cardiovascular disease, metabolic disease, immune or inflammatory disease or condition.

[0114] "Cardiovascular agent" is used in its ordinary sense and refers to a composition (e.g., compound, drug, antagonist, inhibitor, modulator) used in any way to treat a condition of the heart or circulatory or vascular system relative to a control. In some embodiments, a cardiovascular agent is a drug agent identified herein as having efficacy in a method of treating a cardiovascular disease or condition. In some embodiments, a cardiovascular agent is a drug agent approved by the FDA or a similar regulatory agency in a country other than the United States for the treatment of a cardiovascular disease or condition.

[0115] "Anti-inflammatory agent" is used in its ordinary, common sense and refers to any composition (e.g., compound, drug, antagonist, inhibitor, modulator) used in any way to reduce inflammation or swelling relative to a control (e.g., in the absence of the agent). In some embodiments, an anti-inflammatory agent is a pharmaceutical agent identified herein as having efficacy in a method of treating an inflammatory disease or condition. In some embodiments, an anti-inflammatory agent is a pharmaceutical agent approved by the FDA or a similar regulatory agency in a country other than the United States for the purpose of reducing swelling and inflammation.

[0116] The compounds described herein can be administered to treat immune or inflammatory diseases or conditions, cardiovascular or metabolic diseases or conditions, and / or cancer. In this regard, the compounds disclosed herein can be administered alone to treat such diseases or conditions, or can be administered in combination with another therapeutic agent to treat such diseases or conditions.

[0117] The compounds disclosed herein can be co-administered with cytokines or cytokine agonists or antagonists (including agents acting on cytokine signaling pathways, such as regulators of the SOCS system), including α-interferon, β-interferon, and γ-interferon; insulin-like growth factor type I (IGF-1); interleukins (ILs), including IL1 to 17, and interleukin antagonists or inhibitors, such as analcinra; tumor necrosis factor α (TNF-α) inhibitors, such as anti-TNF monoclonal antibodies (e.g., infliximab; adalimumab and CDP-870) and TNF receptor antagonists, including immunoglobulin molecules (such as etanercept) and low molecular weight agents, such as pentoxifylline.

[0118] The compounds disclosed herein can be co-administered with anti-inflammatory agents such as thalidomide or its derivatives, retinoids, anthraquinone or calcipotriol, nonsteroidal anti-inflammatory agents (hereinafter referred to as NSAIDs), including nonselective cyclooxygenase COX-1 / COX-2 inhibitors, whether administered topically or systemically (such as piroxicam, diclofenac, propionic acid such as naproxen, flurbiprofen, fenprofen, ketoprofen and ibuprofen, fenamic acid such as mefenamic acid, indomethacin, sulindac, azaacetone, pyrazolinones such as phenylbutazone, and salicylates such as aspirin); Selective COX-2 inhibitors (such as meloxicam, celecoxib, rofecoxib, vardicoxib, lumarocoxib, parecoxib, and etorcoxib); cyclooxygenase inhibitors of nitric oxide donors (CINOD); glucocorticoids (whether administered topically, orally, intramuscularly, intravenously, or intra-articularly); methotrexate; leflunomide; hydroxychloroquine; d-penicillamine; auronoxine or other parenteral or oral gold preparations; analgesics; diacerein; intra-articular therapies such as hyaluronic acid derivatives; and nutritional supplements such as glucosamine.

[0119] The compounds disclosed herein can be used in combination with the following: calcium channel blockers, beta-adrenergic receptor blockers, angiotensin-converting enzyme (ACE) inhibitors, angiotensin-2 receptor antagonists; lipid-lowering agents, such as statins or fibrates; blood cell morphology modulators, such as pentoxifylline; thrombolytic agents or anticoagulants, such as platelet aggregation inhibitors.

[0120] "Anticancer agent" is used in its usual or common sense and refers to a composition (e.g., compound, drug, antagonist, inhibitor, modulator) that has antitumor properties or the ability to inhibit cell growth or proliferation. In some embodiments, the anticancer agent is a chemotherapeutic agent. In some embodiments, the anticancer agent is a pharmaceutical agent identified herein as having efficacy in methods of treating cancer. In some embodiments, the anticancer agent is a pharmaceutical agent approved by the FDA or a similar regulatory agency in a country other than the United States for the treatment of cancer. Examples of anticancer agents include, but are not limited to, MEK (e.g., MEK1, MEK2, or MEK1 and MEK2) inhibitors (e.g., XL518, CI-1040, PD035901, selumetinib / AZD6244, GSK1120212 / trametinib, GDC-0973, ARRY-162, ARRY-300, AZD8330, PD0325901, U0126, PD98059, TAK-733, PD318088, AS703026, BAY).869766), alkylating agents (e.g., cyclophosphamide, ifosfamide, chlorambucil, busulfan, melphalan, nitrogen mustard, uramustine, thiotepa, nitrosoureas, nitrogen mustard gas (e.g., nitrogen mustard, cyclophosphamide, chlorambucil, melphalan), ethyleneimine and methylmelamine (e.g., hexamethylmelamine, thiotepa), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomustine, semustine, streptozotocin), triazines ( Dacarbazine), antimetabolites (e.g., 5-thiazolinone, folate, capecitabine, fludarabine, gemcitabine, pemetrexed, raltitrexed, folic acid analogs (e.g., methotrexate) or pyrimidine analogs (e.g., fluorouracil, fluorouracil, cytarabine), purine analogs (e.g., mercaptopurine, thioguanine, pentostatin, etc.), phytoalkaloids (e.g., vincristine, vinblastine, vinorelbine, vindesine, podophyllotoxin, paclitaxel, docetaxel, etc.), and toxins. Isomerase inhibitors (e.g., irinotecan, topotecan, acridine, etoposide (VP16), etoposide phosphate, teniposide, etc.), antitumor antibiotics (e.g., doxorubicin, doxorubicin, daunorubicin, epirubicin, actinomycin, bleomycin, mitomycin, mitoxantrone, procainoxic acid, etc.), platinum-based compounds (e.g., cisplatin, oxaliplatin, carboplatin, etc.), anthraquinones (e.g., mitoxantrone), substituted ureas (e.g., hydroxyurea), methylhydrazine derivatives (e.g., propionyl ether). Carbazine), adrenocortical inhibitors (e.g., mitotane, aminoglutethimide), epipodophyllotoxin (e.g., etoposide), antibiotics (e.g., daunorubicin, doxorubicin, bleomycin), enzymes (e.g., L-asparaginase), mitogen-activated protein kinase signaling inhibitors (e.g., U0126, PD98059, PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY). 43-9006, Wohman penicillin or LY294002, Syk inhibitors, mTOR inhibitors, antibodies (e.g., Rituximab), gossypol, genasense, polyphenol E, Chlorofusin, all-trans retinoic acid (ATRA), lichen styramine, tumor necrosis factor-associated apoptosis-inducing ligand (TRAIL), 5-aza-2'-deoxycytidine, all-trans retinoic acid, doxorubicin, vincristine, etoposide, gemcitabine, imatinib (Gleevec.RTM.), geldromycin, 17-N-allylamino-17-demethoxygeldromycin (17-AAG), fulapin, LY294002, bortezomib, trastuzumab, BAY11-7082, PKC412, PD184352, 20-epi-1,25-dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adenypenol; adozelesin; aldesleukin; ALL-TK antagonists; hexamethylmelamine; ambamustine; dichlorophenoxyacetic acid ( Amidox; Amifostine; Amyloprolol; Amrubicin; Acridine; Anagrelide; Anastrozole; Andrographolide; Angiogenesis inhibitor; Antagonist D; Antagonist G; Antarelix; Anti-morphogenetic protein-1; Anti-androgen, prostate cancer; Anti-estrogen; Anti-tumor ketone; Antisense oligonucleotide; Aphidicolin glycinate; apoptosis gene regulator; apoptosis regulator; depurinated nucleic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane; atrimustine; acetin 1; acetin 2; acetin 3; azasetron; azatoxin; azatyrosine; baccatin III derivatives; balanol; batimastat; BCR / ABL antagonist; benzochlorins; benzoylstaurosporine; β-lactam derivatives; beta-alethine; beta-clanycin B; betulinic acid acid); bFGF inhibitors; bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistratene AA); Bizelesin; Breflate; Bropirimine; Budotiane; Butylthionine sulfoxide; Calcipotriol; Calphostin C; Camptothecin derivatives; Canarypox IL-2; Capecitabine; Carboxyamidotriazole; Carboxyamidotriazole; CaRest M3; CARN 700; Chondrogenic inhibitors; Carzelesin; Casein kinase inhibitors (ICOS); Castanospermine; Cecropin B; Cetrorelix; Chlorins; Chloroquinoxaline sulfonamide; cicaprost; cisporphyrin; cladribine; clomifene analogues; clotrimazole; colismycin A; colismycin B; compretastatin A4; compretastatin analogues; conagenin; crambexetine 816; cristatol; cryptophycin 8; cryptophycin A derivative; curacin A; cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic kinases; cytostatin; dacliximab; decitabine; dehydrodidemnin BB); deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; diziquone; didennin B; didox; diethylnorspermine; dihydro-5-azacytidine; 9-dioxamycin; diphenylspiromustine; docosanol; dolasetron; doxifluridine; droloxifene; dronabinol; duocarmycin SA SA); ebselen; ecomustine; edelfosine; edrecolomab; eflornithine; elemene; emitefur; epirubicin; epristeride; estramustine analogues (analogue); estrogen agonists; estrogen antagonists; etanidazole; etoposide phosphate; exemestane; fadrozole; fazarabine; fenretinide; filgrastim; finasteride; frapine; flezlastine; fluasterone; fludarabine; fluorodaunorunicin hydrochloride hydrochloride; forfenimex; formestane; fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix; gelatinase inhibitor; gemcitabine; glutathione inhibitor; hepsulfam; heregulin; hexamethylene diacetamide; hypericin; ibandronic acidacid); idarubicin; idoxifene; idramantone; ilmofosine; ilomastat; imidazoacridones; imiquimod; immunostimulatory peptides; insulin-like growth factor-1 receptor inhibitors; interferon agonists; interferon; interleukin; iobenguane; iododoxorubicin; ipomeanol; iroplact; isogladine; isobengazole; isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F F); lamellarin-N triacetate; lanreotide; leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia inhibitory factor; leukocyte alpha interferon; leuprolide + estrogen + progesterone; leuprorelin; levamisole; liarozole; linear polyamine analogs; lipophilic disaccharide peptides; lipophilic platinum compounds; lissoclinamide 7 7); Lobaplatin; Lombricine; Lometrexol; Lonidamine; Losoxantrone; Lovastatin; Loxoribine; Lurtotecan; Lutetium texaphyrin; Lysofylline; Cleavage peptide; Maitansine; Mannostatin AA); marimastat; masoprocol; maspin; matrix dissolution factor inhibitor; matrix metalloproteinase inhibitor; menogaril; merbarone; meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone; miltefosine; mirimostim; mismatch Double-stranded RNA; mitoguazone; mitolactal; mitomycin analogues; mitonafide; mitotoxin fibroblast growth factor-saponin; mitoantrone; mofarotene; molgramostim; monoclonal antibody; human chorionic gonadotropin; monophosphoryl lipid A+ mycobacterial cell wall SK; mopidamol; multidrug resistance gene inhibitors; therapies based on multiple tumor inhibitors 1; nitrogen mustard anticancer agents; Indian Ocean sponge B (mycaperoxide) B); Mycobacterium cell wall extract; myriaporone; N-acetyldinaline; N-substituted benzamide; nafarelin; nagrestip; naloxone + pentazocine; napavin; napterpin; nartograstim; nedaplatin; nemorubicin; neridronic acidacid); neutral peptide chain endopeptidase; nilutamide; nisamycin; nitric oxide regulator; nitric oxide antioxidant; nitrullyn; O6-benzylguanine; octreotide; okicenone; oligonucleotide; onapristone; ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin; oxaunomycin; palauamine; palmitoylrhizoxin; pamidronic acid acid); Panaxytriol; Panomifene; Parabactin; Pazelliptine; Pegaspargase; Peldesine; Sodium pentosan polysulfate; Pentostatin; Pentozole; Perflubron; Perfosfamide; Perillyl alcohol; Phenazinomycin; Phenylacetate; Phosphatase inhibitor; Picibanil; Pilocarpine hydrochloride; Pirarubicin; Pirritrexim; Placetin A A); Placetin B; Plasminogen activator inhibitor; Platinum complex; Platinum compound; Platinum-triamine complex; Porfimersodium; Porfiromycin; Prednisone; Propylbisacridone; Prostaglandin J2; Proteasome inhibitor; Protein A-based immunomodulator; Protein kinase C inhibitor; Protein kinase C inhibitor, microalgae; Protein tyrosine phosphatase inhibitor; Purine nucleoside phosphorylase inhibitor; Purpurins; Pyrazoloacridine; Pyridoxoylated hemoglobin polyoxyethylene conjugate; RAF antagonist; Raltitrexed; Ramosetron; RAS farnesyltransferase inhibitor; RAS inhibitor; RAS-GAP inhibitor; Demethylated retriptine; Rhenium etidronate Re186 (rhenium Re 186etidronate); rhizoxin; ribosylase; RII retinamide; rogletimide; rohitukine; romurtide; roquinimex; rubiginone B1; ruboxyl; safingol; saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1. Analog; Semustine; Senescence-derived inhibitor 1; Significant oligonucleotide; Signal transduction inhibitor; Signal transduction regulator; Single-chain antigen-binding protein; Sizofuran; Sobuzoxane; Sodium borocaptate; Sodium phenylacetate; Solvent; Somatostatin-binding protein; Sonermin; Sparfosic acid; Spicamycin D D); Spiromustine; Splenopentin; Spongistatin 1; Squalamine; Stem cell inhibitor; Stem cell division inhibitor; Stipiamide; Lysosome inhibitor; Sulfosine; Super-active vasoactive intestinal peptide antagonist; Suradista; Suramin; Swainsonine; Synthetic glycosaminoglycans; Talimustine; Tamoxifen methyliodide; Tauromustine; Tazarotene; Tecogalan sodium sodium); tegafur; tellurapyrylium; telomerase inhibitor; temoporfin; temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimics; thymalfasin; thymopoietin receptor agonists; thymotrinan; thyroid-stimulating hormone; tin ethylporphyrinEthyletiopurpurin; Tirapazamine; Titanium dichlorophenoxide; Topsentin; Toremifene; Totipotent stem cell factor; Translation inhibitor; Tretinoin; Triacetyluridine; Triciribine; Trimetrexate; Triptorelin; Tropisetron; Turosteride; Tyrosine kinase inhibitor; Tyrphostins; UBC inhibitor; Ubenimex; Urogenital sinus-derived growth inhibitor; Urokinase receptor antagonist; Vapreotide; Varianlin B B); Vector systems, red blood cell gene therapy; Velaresol; Veramine; Verdins; Verteporfin; Vinorelbine; Vinxaltine; Vitaxin; Vorozole; Zanoterone; Zeniplatin; Zilascorb; Zinostatin Stimalamer, doxorubicin, actinomycin D, bleomycin, vinblastine, cisplatin, acivicin; aclarubicin; acodazole hydrochloride; acronin; adozelesin; aldesleukin; hexamethylmelamine; ambomycin; ametatronene acetate acetate; aminoglutethimide; acridine; anastrozole; anhramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfatesulfate); brequinar sodium; bropirimine; busulfan; cactinomycin C; calusterone; caracemide; carbetimer; carplatin; carmustine; carrubicin hydrochloride; carzelesin; cedefingol; chlorambucil; cirolemycin; cladribine; cristatol mesylate; cyclophosphamide; cytarabine; dacarbazine; daunorubicin hydrochloride hydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate; diaziquone; doxorubicin hydrochloride; droloxifene; droloxifenecitrate; dromostanolone propionate; duazomycin; edatrexate; eflornithine hydrochloride Hydrochloride; Eelsamitrucin; Enloplatin; Enpromate; Epipropidine; Epirubicin Hydrochloride; Erbulozole; Esorubicin Hydrochloride; Estrustine; Estrustine Phosphate Sodium; Etanidazole; Etoposide; Etoposide Phosphate; Etoprine; Fadrozole Hydrochloride; Fazarabine; Fenretinide; Floxuridine; Fludarabine PhosphatePhosphate); fluorouracil; fluorocitabine; fosquidone; fostriecin sodium; gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide; iimofosine; interleukin I1 (including recombinant interleukin II or rlL.sub.2), interferon α-2a; interferon α-2b; interferon α-n1; interferon α-n3; interferon β-1a; interferon γ-1b; iproplatin; irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; liarozole Lometrexol sodium; Lomustine; Losoxantrone hydrochloride; Masoprocol; Maytansine; Mechlorethamine hydrochloride; Megestrol acetate; Melengestrol acetate acetate); mefarin; menogaril; mercaptopurine; methotrexate; methotrexate sodium; metoprine; meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin; mitosper; mitotan; mitoxantrone hydrochloride; mycophenolic acid(acid); Nocodazoazole; Nogalamycin; Ormaplatin; Oxisuran; Pegaspargase; Peliomycin; Pentamustine; Peplomycin sulfate; Perfosfamide; Pipobroman; Piposulfan; Piroxantrone hydrochloride; Plomestane; Porfimer sodium; Porfiromycin; Prednimustine; Procarbazine hydrochloride; Puromycin; Puromycin hydrochloride hydrochloride; pyrazofurin; riboprine; rogletimide; safingol; safingol hydrochloride; smustine; simtrazene; sparfosate sodium; sparsomycin; spirogermanium hydrochloride; spiromostatin; spiroplatin; streptonigrin; streptozocin; sulofenur; talisomycin; tecogalan sodium; tegafur; teloxantrone hydrochloride hydrochloride; temoporfin; teniposide; teroxirone; testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin; tirapazamine; toremifene citrate; trestolone acetateacetate); triciribine phosphate; trimetrexate; trimetrexate glucuronate; triptorelin; tobaccochloride hydrochloride; uracil mustard; uredepa; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine sulfate; vinpidine sulfate; vinglycinate sulfate; vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate; vinzolidine sulfate sulfate); vorozole; zeniplatin; zinostatin; zorobacterium hydrochloride; agents that arrest cells in the G2-M phase and / or regulate microtubule formation or stability (e.g., Taxol™ (i.e., paclitaxel), Taxotere™, compounds containing a taxane skeleton, irbuproazole (i.e., R-55104), salicylic acid 10 (i.e., DLS-10 and NSC-376128), mivobulinisethionate (i.e., as CI-980), vincristine, NSC-639829, spongiol octopus (i.e., as NVP-X). X-A-296), ABT-751 (Abbott, i.e., E-7010), Altorhyrtins (e.g., Altorhyrtins A and Altorhyrtins C), Spongistatin (e.g., Spongistatin 1, Spongistatin 2, Spongistatin 3, Spongistatin 4, Spongistatin 5, Spongistatin 6, Spongistatin 7, Spongistatin 8 and Spongistatin 9), Cimadolicine Hydrochloride (i.e., LU-103793 and NSC-D-669356), Epothilone (e.g., Epothilone A, Epothilone B, Epothilone C (i.e., Deoxyepothilone A or dEpoA), Epothilone D (i.e., KOS-862, dEpoB and Deoxyepothilone B), Epothilone E, Epothilone F, Epothilone B N-oxide, Epothilone AN-oxides, 16-aza-epotassium B, 21-aminoepotassium B (i.e., BMS-310705), 21-hydroxyepotassium D (i.e., deoxyepotassium F and dEpoF), 26-fluoroepotassium), auripitin PE (i.e., NSC-654663), soblidotin (i.e., TZT-1027), LS-4559-P (Pharmacia, i.e., LS-4577), LS-4578 (Phar Pharmacia (LS-477-P), LS-4477 (Pharmacia), LS-4559 (Pharmacia), RPR-112378 (Aventis), vincristine sulfate, DZ-3358 (Daiichi), FR-182877 (Fujisawa, WS-9885B), GS-164 (Takeda), GS-198 (Takeda), KAR-2 (Hungarian) Academy of Sciences), BSF-223651 (BASF, i.e., ILX-651 and LU-223651), SAH-49960 (Lilly / Novartis), SDZ-268970 (Lilly / Novartis), AM-97 (Armad / Kyowa Hakko), AM-132 (Armad), AM-138 (Armad / Kyowa Hakko), IDN-5005 (Indena), Nostocin 52 (i.e., LY-355703), AC-7739 (Ajinomoto, i.e., AVE-8063A and CS-39.HCl), AC-7700 (Ajinomoto, i.e., AVE-8062, AVE-8062A, CS-39-L-Ser.HCl and RPR-258062A), Vitiligoamide, Tubulysin A A) Canadensol, Cyanobacterium benzoate (i.e., NSC-106969), T-138067 (Tularik, i.e., T-67, TL-138067, and TI-138067), COBRA-1 (Parker Hughes Institute, i.e., DDE-261 and WHI-261), H10 (Kansas State University), H16 (Kansas State University), Oncocidin A1 (i.e., BTO-956 and DIME), DDE-313 (Parker Hughes Institute), Fijianolide BB) Laulimalide, SPA-2 (Parker Hughes Institute), SPA-1 (Parker Hughes Institute, also known as SPIKET-P), 3-IAABU (Cytoskeleton / Mt. Sinai School of Medicine, also known as MF-569), Narcosine (also known as NSC-5366), Nascapine, D-24851 (Asta Medica), A-105972 (Abbott), Hemiasterlin, 3-BAABU (Cytoskeleton / Mt. Sinai School of Medicine, also known as MF-191), TMPN (Arizona State University). University), Vanadox acetylacetonate, T-138026 (Tularik), Monsatrol, lnanocine (i.e., NSC-698666), 3-IAABE (Cytoskeleton / Mt. Sinai School of Medicine), A-204197 (Abbott), T-607 (Tuiarik, i.e., T-900607), RPR-115781 (Aventis), Eleutherobins (such as desmethyleleutherobin, desaetyleleutherobin, isoelectoeleutherobin A, and Z-Eleutherobin), Caribaeolin, Halichondrin B B), D-64131 (AstaMedica), D-68144 (Asta Medica), Diazonamide A, A-293620 (Abbott), NPI-2350 (Nereus), Taccalonolide A, TUB-245 (Aventis), A-259754 (Abbott), Diozostatin, (-)-Phenylahistin (i.e., NSCL-96F037), D-68838 (Asta Medica), D-68836 (AstaMedica), Myoseverin B, D-43411 (Zentaris, i.e., D-81862), A-289099 (Abbott), A-318315 (Abbott), HTI-286 (i.e., SPA-110, trifluoroacetate) (Wyeth), D-82317 (Zentaris), D-82318 (Zentaris), SC-12983 (NCI), Resverastatin phosphate sodium, BPR-OY-007 (National Health Research... Institutes and SSR-250411 (Sanofi)), steroids (e.g., dexamethasone), finasteride, aromatase inhibitors, gonadotropin-releasing hormone agonists (GnRH) such as goserelin or leuprorelin, corticosteroids (e.g., prednisone), progesterone (e.g., hydroxyprogesterone caproate, megestrol acetate, medroxyprogesterone acetate), estrogens (e.g., diethlystilbestrol, ethinylestradiol), anti-estrogens (e.g., tamoxifen), androgens (e.g., testosterone propionate, fluoxymesterone), anti-androgens (e.g., flutamide), immunostimulants (e.g., BCG). Calmette-Guérin (BCG), levamisole, interleukin-2, alpha-interferon, etc.), monoclonal antibodies (e.g., anti-CD20, anti-HER2, anti-CD52, anti-HLA-DR, and anti-VEGF monoclonal antibodies), immunotoxins (e.g., anti-CD33 monoclonal antibody-calcitrinin conjugate, anti-CD22 monoclonal antibody-pseudomonas exotoxin conjugate, etc.), radioimmunotherapy (e.g., with... 111 In、 90 Y or 131I-conjugated anti-CD20 monoclonal antibodies, triptolide, homoharringtonine, dactinomycin D, doxorubicin, epirubicin, topotecan, itraconazole, vindesin, cerivastatin, vincristine, deoxyadenosine, sertraline, pitavastatin, irinotecan, clofazimine, 5-nonoxytryptamine, vemurafenib, dabrafenib, erlotinib, gefitinib, EGFR inhibitors, epidermal growth factor receptor (EGFR)-targeted therapies or therapeutic agents (e.g., gefitinib). TM ), Erlotinib (Tarceva) TM ), cetuximab (Erbitux) TM Lapatinib (Tykerb) TM Panitumumab (Vectibix) TM ), vandetanib (Caprelsa) TM Afatinib (BIBW2992), CI-1033 (canertinib), neratinib (HKI-272), CP-724714, TAK-285, AST-1306, ARRY334543, ARRY-380, AG-1478, dacomitinib (PF299804), OSI-420 (desmeth) (ylerlotinib), AZD8931, AEE788, pelitinib / EKB-569, CUDC-101, WZ8040, WZ4002, WZ3146, AG-490, XL647, PD153035, BMS-599626), sorafenib, imatinib, sunitinib, dasatinib, etc.

[0121] "Chemotherapy" or "chemotherapeutic agents" is used in its simple, common sense and refers to a chemical composition or compound that has antitumor properties or the ability to inhibit cell growth or proliferation.

[0122] Furthermore, the compounds described herein can be co-administered with conventional immunotherapeutic agents, including but not limited to immunostimulants (e.g., BCG, levamisole, interleukin-2, alpha-interferon, etc.), monoclonal antibodies (e.g., anti-CD20, anti-HER2, anti-CD52, anti-HLA-DR, and anti-VEGF monoclonal antibodies), immunotoxins (e.g., anti-CD33 monoclonal antibody-gallicin conjugate, anti-CD22 monoclonal antibody-Pseudomonas exotoxin conjugate, etc.), and radioimmunotherapy (e.g., with...). 111 In、 90 Y or 131 I-conjugated anti-CD20 monoclonal antibodies, etc.

[0123] The compounds disclosed herein can be co-administered with antiproliferative / antitumor drugs used in medical oncology, or combinations thereof, such as alkylating agents (e.g., cisplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulfan, or nitrosourea); antimetabolites (e.g., antifolate agents, such as fluoropyrimidines, such as 5-fluorouracil or tegafur, raltitrexed, methotrexate, cytarabine, hydroxyurea, gemcitabine, or paclitaxel); and antitumor antibiotics (e.g., anthracyclines, such as doxorubicin, bleomycin, doxorubicin, and doxorubicin). (ii) Antimitotic agents (e.g., vincristine, idarubicin, mitomycin-C, actinomycin, or styracin); antimitotic agents (e.g., vinblastine alkaloids, such as vincristine, vinblastine, vinorelbine, or vinorelbine, or taxanes, such as paclitaxel or tesole); or topoisomerase inhibitors (e.g., epipodophyllotoxin, such as etoposide, teniposide, acridine, topotecan, or camptothecin); (ii) cell growth inhibitors, such as anti-estrogens (e.g., tamoxifen, toremifene, raloxifene, droloxifene, or iodoxyfene), estrogen LHRH receptor downregulators (e.g., fulvestrant), antiandrogens (e.g., bicalutamide, flutamide, nilumid, or cyproterone acetate), LHRH antagonists or LHRH agonists (e.g., goserelin, leuprorelin, or buserelin), progestins (e.g., megestrol acetate), aromatase inhibitors (e.g., anastrozole, letrozole, vorazole, or exemestane), or 5α-reductase inhibitors, such as finasteride; (iii) agents that inhibit cancer cell invasion (e.g., metalloproteinase inhibitors, such as marimastat or urokinase fibrinolytic agents). (iv) Inhibitors of zymogen activator receptor function; growth factor function inhibitors, such as: growth factor antibodies (e.g., anti-erbb2 antibody trastuzumab, or anti-erbb1 antibody cetuximab [C225]), farnesyltransferase inhibitors, tyrosine kinase inhibitors or serine / threonine kinase inhibitors, epidermal growth factor family inhibitors (e.g., EGFR family tyrosine kinase inhibitors, such as N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (gefitinib, AZD) 1839), N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazoline-4-amine (erlotinib, OSI-774) or 6-acryloylamino-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)quinazoline-4-amine (CI1033)), platelet-derived growth factor family inhibitors or hepatocyte growth factor family inhibitors;(v) Anti-angiogenic agents, such as anti-angiogenic agents that inhibit the action of vascular endothelial growth factor (e.g., the anti-vascular endothelial growth factor antibody bevacizumab, compounds disclosed in WO 97 / 22596, WO 97 / 30035, WO 97 / 32856 or WO 98 / 13354), or compounds that act through another mechanism (e.g., linolamine, an inhibitor of integrin α.v.β.3 function or angiostatin); (vi) Vascular damaging agents, such as cobustatin A4, or WO 99 / 02166, WO00 / 40529, WO 00 / 41669, WO 01 / 92224, WO 02 / 04434 or WO The compounds disclosed in 02 / 08213; (vii) agents used in antisense therapy, such as agents targeting one of the aforementioned targets, such as ISIS2503, antiras antisenses; (viii) agents used in gene therapy, such as methods of replacing abnormal genes, such as abnormal p53 or abnormal BRCA1 or BRCA2, GDEPT (gene-guided enzymatic prodrug therapy) methods, such as those using cytosine deaminase, thymidine kinase or bacterial nitroreductase, and methods of increasing patient tolerance to chemotherapy or radiotherapy, such as multidrug resistance gene therapy; or (ix) agents used in immunotherapy, such as in vitro and in vivo methods of increasing the immunogenicity of patient tumor cells, such as transfection with cytokines (such as interleukin-2, interleukin-4 or granulocyte-macrophage colony-stimulating factor), methods of reducing T cell unresponsiveness, methods of using transfected immune cells (such as dendritic cells transfected with cytokines), methods of using tumor cell lines transfected with cytokines, and methods of using anti-idiotypic antibodies.

[0124] In the implementation scheme, the compounds disclosed herein can be co-administered with antibodies such as monoclonal antibodies targeting B lymphocytes (such as CD20 (rituximab), MRA-aIL16R and T lymphocytes, CTLA4-Ig, HuMax I1-15) or antibodies that modulate Ig function, such as anti-IgE (e.g. omalizumab)).

[0125] In some embodiments, cancer treatment comprises administering an effective amount of at least two of the following: a CCR4 inhibitor (e.g., a compound described herein), an inhibitor of the PD-L1 / PD-1 pathway, an inhibitor of CTLA-4, or an agonist antibody against CD137 (4-1BB). In some embodiments, the method may include the use of two or more combinations.

[0126] In the implementation scheme, cancer treatment comprises an effective amount of at least two or more of the following: any combination of a CCR4 inhibitor (e.g., a compound described herein) and an agent that may be an immunomodulator, such as, but not limited to, those listed in Table 1 or described herein (e.g., anticancer agents). These immunomodulators may be depleting antibodies, neutralizing antibodies, blocking antibodies, agonizing antibodies, small molecule modulators (inhibitors or stimulators), or small molecule analogs.

[0127] Table 1

[0128]

[0129]

[0130]

[0131] In another embodiment, the compound described herein can be administered in combination with conventional radiotherapy agents, including but not limited to radionuclides, such as... 47 Sc、 64 Cu、 67 Cu、 89 Sr、 86 Y、 87 Y、 90 Y、 105 Rh、 111 Ag、 111 In、 117m Sn、 149 Pm, 153 Sm、 166 Ho、 177 Lu、 186 Re、 188 Re、 211 At and 212 Bi, optionally conjugated with an antibody against a tumor antigen.

[0132] Furthermore, CCR4 inhibitors (e.g., the compounds described herein) can be combined with the therapeutic administration of immune cells, sometimes referred to as adoptive cell transfer. These cells can be derived from patient, genetically related, or unrelated donors, and can be genetically modified (e.g., CAR-T cells, NK cells, etc.), cell lines, genetically modified cell lines, and live or dead forms of the aforementioned cells. CCR4 inhibitors can also be combined with any type of vaccine (e.g., protein / peptide, viral, bacterial, cellular vaccines) to stimulate an immune response against cancer.

[0133] In the implementation scheme, treatment involves administering an effective amount of a CCR4 inhibitor (e.g., the compound described herein) in combination with an inhibitor of the PD-L1 / PD-1 pathway, an inhibitor of CTLA-4, an agonist antibody against CD137 (4-1BB), or another immunomodulator listed in Table 1.

[0134] In the implementation scheme, treatment involves the therapeutic administration of an effective amount of a CCR4 inhibitor (e.g., the compounds described herein) in combination with an inhibitor of the PD-L1 / PD-1 pathway, an inhibitor of CTLA-4, an agonist antibody against CD137 (4-1BB), or another immunomodulator listed in Table 1. In the implementation scheme, when the tumor reaches approximately 40 mm... 3 -70mm 3 Treatment begins when the size is reached.

[0135] The CCR4 inhibitors disclosed herein (e.g., the compounds described herein) may be administered via any acceptable route, such as oral, intra-adipose, intra-articular, intra-articular, intracranial, intradermal, intralesional, intramuscular, intranasal, intraocular, intraperitoneal, intrapleural, intraprostatic, intrarectal, intrathecal, intratracheal, intratumoral, intraumbilical, intravaginal, intravenous, intracystic, intravitreal, liposome, topical, mucosal, parenteral, rectal, subconjunctival, subcutaneous, sublingual, topical, buccal, percutaneous, vaginal, in cream form, in lipid composition form, via catheter, via irrigation, via continuous infusion, via infusion, via inhalation, via injection, via local delivery, via local perfusion, direct immersion in target cells, or any combination thereof.

[0136] The immunomodulators disclosed herein can be administered via any acceptable route, such as oral, intra-adipose, intra-articular, intra-articular, intracranial, intradermal, intralesional, intramuscular, intranasal, intraocular, intraperitoneal, intrapleural, intraprostatic, intrarectal, intrathecal, intratracheal, intratumoral, intraumbilical, intravaginal, intravenous, intracystic, intravitreal, liposome, topical, mucosal, extra-gastric, rectal, subconjunctival, subcutaneous, sublingual, topical, buccal, percutaneous, vaginal, in the form of cream, in the form of lipid compositions, via catheter, via irrigation, via continuous infusion, via infusion, via inhalation, via injection, via local delivery, via local perfusion, by direct immersion in target cells, or any combination thereof.

[0137] The CCR4 inhibitors disclosed herein (e.g., the compounds described herein) may be administered once daily until the study endpoint is reached. The immunomodulators disclosed herein may be administered at least three times, but in some studies may be administered four or more times, depending on the length of the study and / or the study design.

[0138] The methods disclosed herein can be used in combination with other cancer therapies. In some embodiments, different cancer therapies include surgery, radiation therapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy, or gene therapy. In some embodiments, the cancer is chemotherapy-resistant or radiation-resistant.

[0139] As used herein, "cell" means a cell that performs metabolic or other functions sufficient to maintain or replicate its genomic DNA. Cells can be identified by methods well known in the art, including, for example, the presence of an intact membrane, staining with a specific dye, the ability to reproduce, or, if gametes are present, the ability to combine with a second gamete to produce viable progeny. Cells can include prokaryotic and eukaryotic cells. Prokaryotic cells include, but are not limited to, bacteria. Eukaryotic cells include, but are not limited to, yeast cells and cells derived from plants and animals, such as mammalian, insect (e.g., noctuid moth) and human cells. Cells may be useful when they are naturally non-adhesive or when they are treated to be non-adhesive to surfaces, for example, by trypsin digestion.

[0140] "Control" or "controlled experiment," used in its ordinary sense, refers to an experiment in which subjects or reagents are treated, as in a parallel experiment, except that the experimental procedures, reagents, or variables are omitted. In some cases, a control is used as a standard of comparison when evaluating the effects of an experiment. In some embodiments, a control is a measure of protein activity in the absence of compounds as described herein (including embodiments and examples).

[0141] The term "modifier" refers to a composition that increases or decreases the level or function of a target molecule or the physical state of a target molecule. In some embodiments, a CCR4-related disease modifier is a compound that reduces the severity of one or more symptoms of a CCR4-related disease (e.g., cancer, inflammatory disease, autoimmune disease, or infectious disease). A CCR4 modifier is a compound that increases or decreases the activity or function or level of CCR4. Modifiers can act alone, or they can also use cofactors such as proteins, metal ions, or small molecules. Examples of modifiers include small molecule compounds and other bioorganic molecules. Many small molecule compound libraries (e.g., combinatorial libraries) are commercially available and can serve as a starting point for identifying modifiers. Those skilled in the art are able to develop one or more assays (e.g., biochemical assays or cell-based assays) in which such compound libraries can be screened to identify one or more compounds with desired properties; then, a skilled medicinal chemist can optimize such one or more compounds by, for example, synthesizing and evaluating their analogues and derivatives. Synthetic and / or molecular modeling studies can also be used to identify activators.

[0142] The term "modulate" is used in its general sense and refers to the act of changing or altering one or more properties. "Modulation" refers to the process of changing or altering one or more properties. For example, when applied to the effect of a modulator on a target protein, modulation means altering by increasing or decreasing the property or function of the target molecule or the amount of the target molecule. In embodiments, the terms "modulate," "modulation," etc., refer to the ability of a molecule (e.g., an activator or inhibitor) to directly or indirectly increase or decrease the function or activity of CCR4 relative to the absence of a molecule.

[0143] In the context of a substance, substance activity, or function associated with a disease (e.g., protein-related diseases, cancers associated with CCR4 activity, CCR4-related cancers, CCR4-related diseases (e.g., cancer, inflammatory diseases, autoimmune diseases, or infectious diseases)) or a disease mediated by a substance, substance activity, or substance function, the terms "associated with," "related to," or "mediated by" mean that the disease (e.g., cancer, inflammatory diseases, autoimmune diseases, or infectious diseases) is ( wholly or partially) caused by said substance or substance activity or function, or that the symptoms of the disease are (wholly or partially) caused by said substance or substance activity or function. For example, a cancer associated with CCR4 activity or function can be a cancer (wholly or partially) caused by abnormal CCR4 function (e.g., enzyme activity, protein-protein interactions, signal transduction pathways) or a cancer in which specific symptoms of the disease are (wholly or partially) caused by abnormal CCR4 activity or function. As used herein, if a pathogen can be a target for treating a disease, it is described as being associated with the disease. For example, in cases where increased CCR4 activity or function (e.g., signal transduction pathway activity) causes disease (e.g., cancer, inflammatory disease, autoimmune disease, or infectious disease), cancer or CCR4-related diseases associated with CCR4 activity or function (e.g., cancer, inflammatory disease, autoimmune disease, or infectious disease) can be treated with the compounds described herein (e.g., CCR4 modulators or CCR4 inhibitors). Similarly, in cases where increased CCR4 activity or function (e.g., signal transduction pathway activity) leads to disease, inflammatory diseases associated with CCR4 activity or function or CCR4-related inflammatory diseases can be treated with both CCR4 modulators and CCR4 inhibitors.

[0144] As used herein, the term “abnormal” means different from normal. When used to describe enzyme activity or protein function, abnormality refers to activity or function that is higher or lower than the mean of normal or disease-free control samples. Abnormal activity can refer to the amount of activity that causes disease, wherein restoring abnormal activity to normal or non-disease-related levels (e.g., by administering a compound or using methods as described herein) results in a reduction of disease or one or more disease symptoms.

[0145] As used herein, the term "signaling pathway" refers to a series of interactions between cells and optionally extracellular components (e.g., proteins, nucleic acids, small molecules, ions, lipids) that transmit changes in one component to one or more other components, which in turn transmit changes to other components, optionally propagating to other signaling pathway components. For example, binding of CCR4 to compounds described herein can reduce the level of the product of a CCR4-catalyzed reaction or the level of its downstream derivatives, or binding can reduce the interaction between CCR4 or the reaction product and downstream effectors or signaling pathway components (e.g., the MAP kinase pathway), resulting in changes in cell growth, proliferation, or survival.

[0146] As used herein, the terms “CCR4 inhibitor,” “CCR4 antagonist,” “CC chemokine receptor type 4 inhibitor,” “CC chemokine receptor type 4 antagonist,” and all other related, art-recognized terms (many of which are listed below) refer to compounds that can detectably reduce the expression or activity of the CCR4 receptor directly or indirectly in in vitro assays, in vivo models, and / or other means of indicating therapeutic efficacy. The term may also refer to compounds that exhibit at least some therapeutic benefit in human subjects (e.g., determined by objective parameters such as serum concentration or subjective parameters such as the subject’s perceived well-being).

[0147] The phrase "in a quantity sufficient to achieve change" means a detectable difference between the levels of an indicator measured before (e.g., at baseline or in the presence of a control) and after the administration of a particular therapy. Indicators include any objective parameter (e.g., serum concentration) or subjective parameter (e.g., the subject's perceived health).

[0148] The "activity" of a molecule can describe or refer to the binding of a molecule to a ligand or receptor; catalytic activity; the ability to stimulate gene expression or cell signaling, differentiation, or maturation; antigenic activity; and the ability to regulate the activity of other molecules; etc. The term "proliferative activity" includes activities that promote, for example, normal cell division as well as cancer, tumors, developmental abnormalities, cell transformation, metastasis, and angiogenesis, said activities being necessary for or specifically related to said normal cell division as well as cancer, tumors, developmental abnormalities, cell transformation, metastasis, and angiogenesis.

[0149] "Substantially pure" means that the component constitutes more than about 50% of the total content of the composition, and typically more than about 60%. More typically, "substantially pure" means a composition in which at least 75%, at least 85%, at least 90% or more of the total composition is the component of interest. In some cases, the component will constitute more than about 90%, or more than about 95% (by weight) of the total content of the composition.

[0150] When referring to binder / target, ligand / receptor, antibody / antigen, or other binding pairs, the terms "specific binding" and "selective binding" describe a binding reaction that is decisive in the presence of a target (e.g., a protein) within a heterogeneous population of components (e.g., proteins and other biological products). Thus, under specified conditions, a particular ligand binds to a specific receptor and does not bind other proteins present in the sample in significant quantities. The antibody of the considered method, or a binding composition derived from an antibody's antigen-binding site, binds to its antigen or a variant thereof with an affinity at least 2, at least 10, at least 20, or at least 100 times that of any other target or binding composition derived therefrom. In embodiments, the antibody will have an affinity greater than about 10 9 Affinity in liters per mole, as determined by, for example, Scatchard analysis (Munsen et al., (1980) Analyt. Biochem. 107: 220-239).

[0151] The terms “nucleic acid,” “nucleic acid molecule,” “polynucleotide,” etc., are used interchangeably herein to refer to a polymer of nucleotides (e.g., deoxyribonucleotides or ribonucleotides) or similar molecules of any length. Non-limiting examples of polynucleotides include linear and circular nucleic acids, messenger RNA (mRNA), complementary DNA (cDNA), recombinant polynucleotides, vectors, probes, primers, etc.

[0152] As used herein, the terms “variant” and “homology” are used interchangeably to refer to an amino acid or nucleic acid sequence that is similar to a reference amino acid or nucleic acid sequence, respectively. The term includes both naturally occurring variants and non-naturally occurring variants. Naturally occurring variants include homologues (peptides and nucleic acids that differ in amino acid or nucleotide sequences from one species to another) and allelic variants (peptides and nucleic acids that differ in amino acid or nucleotide sequences from one individual to another within a species). Thus, variants and homologues include naturally occurring amino acids and the nucleic acid sequences they encode, their isotypes, and splicing variants of proteins or genes. The term also includes nucleic acid sequences that differ from naturally occurring nucleic acid sequences at one or more bases but, due to the degeneracy of the genetic code, still translate into amino acid sequences corresponding to naturally occurring proteins. Non-naturally occurring variants and homologues include peptides and nucleic acids that contain variations in amino acid or nucleotide sequences, respectively, where the sequence variations are artificially introduced; for example, the variations are produced in a laboratory through artificial intervention (“artificial”). Therefore, non-natural variants and homologues can also refer to those variants and homologues that differ from naturally occurring sequences through one or more conservative substitutions and / or labels and / or conjugates.

[0153] II.Compounds

[0154] On the one hand, this paper provides a compound having structural formula (I):

[0155] Or its pharmaceutically acceptable salt. X 1 For CR 8 Or N. X 2 For CR 9 Or N. X 3 For CR 10 Or N. The symbols n1, n2, n3, n4, n5, n6, n7, n8, n9, n10, and n44 are independently integers from 0 to 4. The 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. The symbol z1 is an integer from 0 to 5. The symbol z2 is an integer from 0 to 5. The symbol z3 is an integer from 0 to 11. The symbol z4 is an integer from 0 to 2. The symbol z5 is 1 or 2. L 7 For key, –O–, –S–, –NR 7.2B –、–C(O)–、-C(O)O–、–S(O)–、–S(O)2–、substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl. R 1Hydrogen, halogen, -CX 1.1 3. -CHX 1.1 2. -CH2X 1.1 –CN, –N3, –SO n1 R 1A –SO v1 NR 1B R 1C -NHNR 1B R 1C -ONR 1B R 1C -NHC(O)NHNR 1B R 1C -NHC(O)NR 1B R 1C –N(O) m1 –NR 1B R 1C –C(O)R 1D –C(O)OR 1D –C(O)NR 1B R 1C –OR 1A -NR 1B SO2R 1A -NR 1B C(O)R 1D -NR 1B C(O)OR 1D –NR 1B OR 1D –OCX 1.1 3. –OCHX 1.1 2. –OCH2X 1.1 Substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. R 2 Hydrogen, halogen, -CX 2.1 3. -CHX 2.1 2. -CH2X 2.1 –CN, –N3, –SO n2 R 2A –SO v2 NR 2B R 2C -NHNR 2B R 2C -ONR 2B R 2C -NHC(O)NHNR 2B R 2C -NHC(O)NR 2B R 2C –N(O)m2 –NR 2B R 2C –C(O)R 2D –C(O)OR 2D –C(O)NR 2B R 2C –OR 2A -NR 2B SO2R 2A -NR 2B C(O)R 2D -NR 2B C(O)OR 2D –NR 2B OR 2D –OCX 2.1 3. –OCHX 2.1 2. –OCH2X 2.1 substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. R 3 Independently hydrogen, halogen, –CX 3.1 3. -CHX 3.1 2. -CH2X 3.1 –CN, –N3, –SO n3 R 3A –SO v3 NR 3B R 3C -NHNR 3B R 3C -ONR 3B R 3C -NHC(O)NHNR 3B R 3C -NHC(O)NR 3B R 3C –N(O) m3 –NR 3B R 3C –C(O)R 3D –C(O)OR 3D –C(O)NR 3B R 3C –OR 3A -NR 3B SO2R 3A -NR 3B C(O)R 3D -NR 3B C(O)OR 3D –NR 3B OR 3D –OCX 3.13. –OCHX 3.1 2. –OCH2X 3.1 substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. R 4 Hydrogen, halogen, -CX 4.1 3. -CHX 4.1 2. -CH2X 4.1 –CN, –N3, –SO n4 R 4A –SO v4 NR 4B R 4C -NHNR 4B R 4C -ONR 4B R 4C -NHC(O)NHNR 4B R 4C -NHC(O)NR 4B R 4C –N(O) m4 –NR 4B R 4C –C(O)R 4D –C(O)OR 4D –C(O)NR 4B R 4C –OR 4A -NR 4B SO2R 4A -NR 4B C(O)R 4D -NR 4B C(O)OR 4D –NR 4B OR 4D –OCX 4.1 3. –OCHX 4.1 2. –OCH2X 4.1 substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; when X 2 For CR 9 At that time, R 4 and R 9 It can be optionally linked to form a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, or an unsubstituted aryl, or a substituted or unsubstituted heteroaryl. R 5 Independently halogen, oxo group, -CX 5.1 3. -CHX 5.1 2. -CH2X5.1 –CN, –N3, –SO n5 R 5A –SO v5 NR 5B R 5C -NHNR 5B R 5C -ONR 5B R 5C -NHC(O)NHNR 5B R 5C -NHC(O)NR 5B R 5C –N(O) m5 –NR 5B R 5C –C(O)R 5D –C(O)OR 5D –C(O)NR 5B R 5C –OR 5A -NR 5B SO2R 5A -NR 5B C(O)R 5D -NR 5B C(O)OR 5D –NR 5B OR 5D –OCX 5.1 3. –OCHX 5.1 2. –OCH2X 5.1 substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. R 6 Independently halogen, oxo group, -CX 6.1 3. -CHX 6.1 2. -CH2X 6.1 –CN, –N3, –SO n6 R 6A –SO v6 NR 6B R 6C -NHNR 6B R 6C -ONR 6B R 6C -NHC(O)NHNR 6B R 6C -NHC(O)NR 6B R 6C –N(O) m6 –NR 6B R 6C–C(O)R 6D –C(O)OR 6D –C(O)NR 6B R 6C –OR 6A -NR 6B SO2R 6A -NR 6B C(O)R 6D -NR 6B C(O)OR 6D –NR 6B OR 6D –OCX 6.1 3. –OCHX 6.1 2. –OCH2X 6.1 Substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. R 7 Hydrogen, halogen, -CX 7.1 3. -CHX 7.1 2. -CH2X 7.1 –CN, –N3, –SO n7 R 7A –SO v7 NR 7B R 7C -NHNR 7B R 7C -ONR 7B R 7C -NHC(O)NHNR 7B R 7C -NHC(O)NR 7B R 7C –N(O) m7 –NR 7B R 7C –C(O)R 7D –C(O)OR 7D –C(O)NR 7B R 7C –OR 7A -NR 7B SO2R 7A -NR 7B C(O)R 7D -NR 7B C(O)OR 7D –NR 7B OR 7D –OCX 7.1 3. –OCHX 7.1 2. –OCH2X 7.1substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. R 8 Hydrogen, halogen, -CX 8.1 3. -CHX 8.1 2. -CH2X 8.1 –CN, –N3, –SO n8 R 8A –SO v8 NR 8B R 8C -NHNR 8B R 8C -ONR 8B R 8C -NHC(O)NHNR 8B R 8C -NHC(O)NR 8B R 8C –N(O) m8 –NR 8B R 8C –C(O)R 8D –C(O)OR 8D –C(O)NR 8B R 8C –OR 8A -NR 8B SO2R 8A -NR 8B C(O)R 8D -NR 8B C(O)OR 8D –NR 8B OR 8D –OCX 8.1 3. –OCHX 8.1 2. –OCH2X 8.1 substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. R 9 Hydrogen, halogen, -CX 9.1 3. -CHX 9.1 2. -CH2X 9.1 –CN, –N3, –SO n9 R 9A –SO v9 NR 9B R 9C -NHNR 9B R 9C -ONR 9B R 9C-NHC(O)NHNR 9B R 9C -NHC(O)NR 9B R 9C –N(O) m9 –NR 9B R 9C –C(O)R 9D –C(O)OR 9D –C(O)NR 9B R 9C –OR 9A -NR 9B SO2R 9A -NR 9B C(O)R 9D -NR 9B C(O)OR 9D –NR 9B OR 9D –OCX 9.1 3. –OCHX 9.1 2. –OCH2X 9.1 substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; when X 2 For CR 9 At that time, R 4 and R 9 Optionally 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 X 2 For CR 9 And X 3 For CR 10 At that time, R 9 and R 10 It can be optionally linked to form a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, or an unsubstituted aryl, or a substituted or unsubstituted heteroaryl. R 10 Hydrogen, halogen, -CX 10.1 3. -CHX 10.1 2. -CH2X 10.1 -CN, -SO n10 R 10A –SO v10 NR 10B R 10C -NHNR 10B R 10C -ONR 10B R 10C -NHC(O)NHNR 10B R10C -NHC(O)NR 10B R 10C –N(O) m10 –NR 10B R 10C –C(O)R 10D –C(O)OR 10D –C(O)NR 10B R 10C –OR 10A -NR 10B SO2R 10A -NR 10B C(O)R 10D -NR 10B C(O)OR 10D –NR 10B OR 10D –OCX 10.1 3. –OCHX 10.1 2. –OCH2X 10.1 substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or when X 2 For CR 9 And X 3 For CR 10 At that time, R 9 and R 10 It can be optionally linked to form a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, or an unsubstituted aryl, or a substituted or unsubstituted heteroaryl. R 44 For hydrogen, –CX 44.1 3. -CHX 44.1 2. -CH2X 44.1 –SO n44 R 44A –SO v44 NR 44B R 44C –C(O)R 44D –C(O)OR 44D –C(O)NR 44B R 44C substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. R 1A R 1B R 1C R 1D R 2A R 2B R 2C R2D R 3A R 3B R 3C R 3D R 4A R 4B R 4C R 4D R 5A R 5B R 5C R 5D R 6A R 6B R 6C R 6D R 7A R 7B R 7C R 7D R 7.2B R 8A R 8B R 8C R 8D R 9A R 9B R 9C R 9D R 10A R 10B R 10C R 10D R 44A R 44B R 44C and R 44D Independently hydrogen, halogen, –CF3, –CCl3, –CBr3, –CI3, –COOH, –CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R bonded to the same nitrogen atom 1B R 1C R 2B R 2C R 3B R 3C R 4B R 4C R 5B R 5C R 6B R 6C R 7B R 7C R 8B R 8C R 9B R 9C R 10B R 10C R 44B and R44C Substituents may optionally be linked to form substituted or unsubstituted heterocyclic alkyl groups or substituted or unsubstituted heteroaryl groups. X 1.1 X 2.1 X 3.1 X 4.1 X 5.1 X 6.1 X 7.1 X 8.1 X 9.1 X 10.1 and X 44.1 Independently, it is –Cl, –Br, –I, or –F, where X 1 X 2 and X 3 At least one of them is N.

[0156] X 1 X 2 and X 3 At least one of them is N. In the implementation scheme, X 1 Let N be the number of elements. In the implementation plan, X is... 2 Let N be the number of elements. In the implementation plan, X is... 3 Let N be the number of elements. In the implementation plan, X is... 1 and X 2 Each is N and X 3 For CR 10 In the implementation plan, X 1 and X 3 Each is N and X 2 For CR 9 In the implementation plan, X 1 X 2 and X 3 Each is N.

[0157] In the implementation plan, R 1 Halogen, –CX 1.1 3. -CHX 1.1 2. -CH2X 1.1 –CN, –N3, –SO n1 R 1A –SO v1 NR 1B R 1C -NHNR 1B R 1C -ONR 1B R 1C -NHC(O)NHNR 1B R 1C -NHC(O)NR 1B R 1C ,–N(O) m1 –NR1B R 1C –C(O)R 1D –C(O)OR 1D –C(O)NR 1B R 1C –OR 1A -NR 1B SO2R 1A -NR 1B C(O)R 1D -NR 1B C(O)OR 1D –NR 1B OR 1D –OCX 1.1 3. –OCHX 1.1 2. –OCH2X 1.1 Substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In the embodiments, R 1 It is hydrogen.

[0158] In the implementation plan, R 1 Hydrogen, halogen, -CX 1.1 3. -CHX 1.1 2. -CH2X 1.1 –CN, –N3, –SO n1 R 1A –SO v1 NR 1B R 1C -NHNR 1B R 1C -ONR 1B R 1C -NHC(O)NHNR 1B R 1C -NHC(O)NR 1B R 1C –N(O) m1 –NR 1B R 1C –C(O)R 1D –C(O)OR 1D –C(O)NR 1B R 1C –OR 1A -NR 1B SO2R 1A -NR 1B C(O)R 1D -NR 1B C(O)OR 1D –NR 1BOR 1D –OCX 1.1 3. –OCHX 1.1 2. –OCH2X 1.1 R 11 Substituted or unsubstituted alkyl groups (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 11 Substituted or unsubstituted heteroalkyl groups (e.g., 2- to 8-membered heteroalkyl groups, 2- to 6-membered heteroalkyl groups, or 2- to 4-membered heteroalkyl groups), R 11 Substituted or unsubstituted cycloalkyl groups (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R 11 Substituted or unsubstituted heterocyclic alkyl groups (e.g., 3- to 8-membered heterocyclic alkyl groups, 3- to 6-membered heterocyclic alkyl groups, or 5- to 6-membered heterocyclic alkyl groups), R 11 Substituted or unsubstituted aryl groups (e.g., C6-C) 10 Aryl, C 10 (aryl or phenyl) or R 11 Substituted or unsubstituted heteroaryl groups (e.g., 5 to 10-membered heteroaryl, 5 to 9-membered heteroaryl, or 5 to 6-membered heteroaryl).

[0159] In the implementation plan, R 1 For R 11 Substituted or unsubstituted alkyl groups (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In the embodiments, R 1 For R 11 Substituted alkyl groups (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In the embodiments, R 1 It is an unsubstituted alkyl group (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).

[0160] In the implementation plan, R 1 For R 11 Substituted or unsubstituted heteroalkyl groups (e.g., 2- to 8-membered heteroalkyl groups, 2- to 6-membered heteroalkyl groups, or 2- to 4-membered heteroalkyl groups). In the embodiments, R 1 For R 11 Substituted heteroalkyl groups (e.g., 2- to 8-membered heteroalkyl groups, 2- to 6-membered heteroalkyl groups, or 2- to 4-membered heteroalkyl groups). In the embodiments, R 1 It is an unsubstituted heteroalkyl group (e.g., 2 to 8-membered heteroalkyl, 2 to 6-membered heteroalkyl, or 2 to 4-membered heteroalkyl).

[0161] In the implementation plan, R 1 For R 11 Substituted or unsubstituted cycloalkyl groups (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In the embodiments, R 1 For R11 Substituted cycloalkyl groups (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In the embodiments, R 1 It is an unsubstituted cycloalkyl group (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).

[0162] In the implementation plan, R 1 For R 11 Substituted or unsubstituted heterocyclic alkyl groups (e.g., 3- to 8-membered heterocyclic alkyl groups, 3- to 6-membered heterocyclic alkyl groups, or 5- to 6-membered heterocyclic alkyl groups). In the embodiments, R 1 For R 11 Substituted heterocyclic alkyl groups (e.g., 3- to 8-membered heterocyclic alkyl groups, 3- to 6-membered heterocyclic alkyl groups, or 5- to 6-membered heterocyclic alkyl groups). In the embodiments, R 1 It is an unsubstituted heterocyclic alkyl group (e.g., 3- to 8-membered heterocyclic alkyl, 3- to 6-membered heterocyclic alkyl, or 5- to 6-membered heterocyclic alkyl).

[0163] In the implementation plan, R 1 For R 11 Substituted or unsubstituted aryl groups (e.g., C6-C) 10 Aryl, C 10 (aryl or phenyl). In the implementation scheme, R 1 For R 11 Substituted aryl groups (e.g., C6-C) 10 Aryl, C 10 (aryl or phenyl). In the implementation scheme, R 1 For unsubstituted aryl groups (e.g., C6-C) 10 Aryl, C 10 (aryl or phenyl).

[0164] In the implementation plan, R 1 For R 11 Substituted or unsubstituted heteroaryl groups (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In the embodiments, R 1 For R 11 Substituted heteroaryl groups (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In the embodiments, R 1 It is an unsubstituted heteroaryl group (e.g., 5 to 10-membered heteroaryl, 5 to 9-membered heteroaryl, or 5 to 6-membered heteroaryl).

[0165] In the implementation plan, R 1 For R 11 Substituted or unsubstituted alkyl groups (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In the embodiments, R 1 For R 11Substituted alkyl groups (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In the embodiments, R 1 It is an unsubstituted alkyl group (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In the embodiments, R 1 It is hydrogen.

[0166] In the implementation plan, R 1 For R 11 Substituted or unsubstituted methyl groups. In the embodiments, R 1 For R 11 Substituted or unsubstituted C2 alkyl group. In the embodiments, R 1 For R 11 Substituted or unsubstituted C3 alkyl group. In the embodiments, R 1 For R 11 Substituted or unsubstituted C4 alkyl. In the embodiments, R 1 For R 11 Substituted or unsubstituted C5 alkyl group. In the embodiments, R 1 For R 11 Substituted or unsubstituted C6 alkyl. In the embodiments, R 1 For R 11 Substituted or unsubstituted C7 alkyl group. In the embodiments, R 1 For R 11 Substituted or unsubstituted C8 alkyl. In the embodiments, R 1 For R 11 Substituted methyl group. In the implementation scheme, R 1 For R 11 Substituted C2 alkyl group. In the embodiment, R 1 For R 11 Substituted C3 alkyl group. In the embodiment, R 1 For R 11 Substituted C4 alkyl. In the embodiments, R 1 For R 11 Substituted C5 alkyl group. In the embodiment, R 1 For R 11 Substituted C6 alkyl group. In the embodiments, R 1 For R 11 Substituted C7 alkyl group. In the embodiments, R 1 For R 11 Substituted C8 alkyl. In the embodiments, R 1 The methyl group is unsubstituted. In the embodiments, R... 1 It is an unsubstituted C2 alkyl group. In the embodiments, R 1 It is an unsubstituted C3 alkyl group. In the embodiments, R 1It is an unsubstituted C4 alkyl group. In the embodiments, R 1 It is an unsubstituted C5 alkyl group. In the embodiments, R 1 It is an unsubstituted C6 alkyl group. In the embodiments, R 1 It is an unsubstituted C7 alkyl group. In the embodiments, R 1 It is an unsubstituted C8 alkyl group.

[0167] In the implementation plan, R 2 Halogen, –CX 2.1 3. -CHX 2.1 2. -CH2X 2.1 –CN, –N3, –SO n2 R 2A –SO v2 NR 2B R 2C -NHNR 2B R 2C -ONR 2B R 2C -NHC(O)NHNR 2B R 2C -NHC(O)NR 2B R 2C –N(O) m2 –NR 2B R 2C –C(O)R 2D –C(O)OR 2D –C(O)NR 2B R 2C –OR 2A -NR 2B SO2R 2A -NR 2B C(O)R 2D -NR 2B C(O)OR 2D –NR 2B OR 2D –OCX 2.1 3. –OCHX 2.1 2. –OCH2X 2.1 Substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In the embodiments, R 2 It is hydrogen.

[0168] In the implementation plan, R 2 Hydrogen, halogen, -CX 2.1 3. -CHX 2.1 2. -CH2X 2.1–CN, –N3, –SO n2 R 2A –SO v2 NR 2B R 2C -NHNR 2B R 2C -ONR 2B R 2C -NHC(O)NHNR 2B R 2C -NHC(O)NR 2B R 2C –N(O) m2 –NR 2B R 2C –C(O)R 2D –C(O)OR 2D –C(O)NR 2B R 2C –OR 2A -NR 2B SO2R 2A -NR 2B C(O)R 2D -NR 2B C(O)OR 2D –NR 2B OR 2D –OCX 2.1 3. –OCHX 2.1 2. –OCH2X 2.1 R 14 Substituted or unsubstituted alkyl groups (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 14 Substituted or unsubstituted heteroalkyl groups (e.g., 2- to 8-membered heteroalkyl groups, 2- to 6-membered heteroalkyl groups, or 2- to 4-membered heteroalkyl groups), R 14 Substituted or unsubstituted cycloalkyl groups (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R 14 Substituted or unsubstituted heterocyclic alkyl groups (e.g., 3- to 8-membered heterocyclic alkyl groups, 3- to 6-membered heterocyclic alkyl groups, or 5- to 6-membered heterocyclic alkyl groups), R 14 Substituted or unsubstituted aryl groups (e.g., C6-C) 10 Aryl, C 10 (aryl or phenyl) or R 14 Substituted or unsubstituted heteroaryl groups (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0169] In the implementation plan, R 2 For R 14Substituted or unsubstituted alkyl groups (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In the embodiments, R 2 For R 14 Substituted alkyl groups (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In the embodiments, R 2 It is an unsubstituted alkyl group (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In the embodiments, R 2 It is an unsubstituted ethyl group. In the embodiments, R... 2 It is an unsubstituted C3 alkyl group. In the embodiments, R 2 It is an unsubstituted C4 alkyl group.

[0170] In the implementation plan, R 2 For R 14 Substituted or unsubstituted heteroalkyl groups (e.g., 2- to 8-membered heteroalkyl groups, 2- to 6-membered heteroalkyl groups, or 2- to 4-membered heteroalkyl groups). In the embodiments, R 2 For R 14 Substituted heteroalkyl groups (e.g., 2- to 8-membered heteroalkyl groups, 2- to 6-membered heteroalkyl groups, or 2- to 4-membered heteroalkyl groups). In the embodiments, R 2 It is an unsubstituted heteroalkyl group (e.g., 2 to 8-membered heteroalkyl, 2 to 6-membered heteroalkyl, or 2 to 4-membered heteroalkyl).

[0171] In the implementation plan, R 2 For R 14 Substituted or unsubstituted cycloalkyl groups (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In the embodiments, R 2 For R 14 Substituted cycloalkyl groups (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In the embodiments, R 2 It is an unsubstituted cycloalkyl group (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).

[0172] In the implementation plan, R 2 For R 14 Substituted or unsubstituted heterocyclic alkyl groups (e.g., 3- to 8-membered heterocyclic alkyl groups, 3- to 6-membered heterocyclic alkyl groups, or 5- to 6-membered heterocyclic alkyl groups). In the embodiments, R 2 For R 14 Substituted heterocyclic alkyl groups (e.g., 3- to 8-membered heterocyclic alkyl groups, 3- to 6-membered heterocyclic alkyl groups, or 5- to 6-membered heterocyclic alkyl groups). In the embodiments, R 2 It is an unsubstituted heterocyclic alkyl group (e.g., 3- to 8-membered heterocyclic alkyl, 3- to 6-membered heterocyclic alkyl, or 5- to 6-membered heterocyclic alkyl).

[0173] In the implementation plan, R2 For R 14 Substituted or unsubstituted aryl groups (e.g., C6-C) 10 Aryl, C 10 (aryl or phenyl). In the implementation scheme, R 2 For R 14 Substituted aryl groups (e.g., C6-C) 10 Aryl, C 10 (aryl or phenyl). In the implementation scheme, R 2 For unsubstituted aryl groups (e.g., C6-C) 10 Aryl, C 10 (aryl or phenyl).

[0174] In the implementation plan, R 2 For R 14 Substituted or unsubstituted heteroaryl groups (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In the embodiments, R 2 For R 14 Substituted heteroaryl groups (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In the embodiments, R 2 It is an unsubstituted heteroaryl group (e.g., 5 to 10-membered heteroaryl, 5 to 9-membered heteroaryl, or 5 to 6-membered heteroaryl).

[0175] In the implementation plan, R 2 For R 14 Substituted or unsubstituted alkyl groups (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In the embodiments, R 2 For R 14 Substituted alkyl groups (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In the embodiments, R 2 It is an unsubstituted alkyl group (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In the embodiments, R 2 It is hydrogen.

[0176] In the implementation plan, R 2 For R 14 Substituted or unsubstituted methyl groups. In the embodiments, R 2 For R 14 Substituted or unsubstituted C2 alkyl group. In the embodiments, R 2 For R 14 Substituted or unsubstituted C3 alkyl group. In the embodiments, R 2 For R 14 Substituted or unsubstituted C4 alkyl. In the embodiments, R 2 For R 14 Substituted or unsubstituted C5 alkyl group. In the embodiments, R2 For R 14 Substituted or unsubstituted C6 alkyl. In the embodiments, R 2 For R 14 Substituted or unsubstituted C7 alkyl group. In the embodiments, R 2 For R 14 Substituted or unsubstituted C8 alkyl. In the embodiments, R 2 For R 14 Substituted methyl group. In the implementation scheme, R 2 For R 14 Substituted C2 alkyl group. In the embodiment, R 2 For R 14 Substituted C3 alkyl group. In the embodiment, R 2 For R 14 Substituted C4 alkyl. In the embodiments, R 2 For R 14 Substituted C5 alkyl group. In the embodiment, R 2 For R 14 Substituted C6 alkyl group. In the embodiments, R 2 For R 14 Substituted C7 alkyl group. In the embodiments, R 2 For R 14 Substituted C8 alkyl. In the embodiments, R 2 The methyl group is unsubstituted. In the embodiments, R... 2 It is an unsubstituted C2 alkyl group. In the embodiments, R 2 It is an unsubstituted C3 alkyl group. In the embodiments, R 2 It is an unsubstituted C4 alkyl group. In the embodiments, R 2 It is an unsubstituted C5 alkyl group. In the embodiments, R 2 It is an unsubstituted C6 alkyl group. In the embodiments, R 2 It is an unsubstituted C7 alkyl group. In the embodiments, R 2 It is an unsubstituted C8 alkyl group.

[0177] In the implementation plan, R 1 and R 2 Independently, it is hydrogen, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted heteroalkyl group. In the embodiments, R 1 The alkyl group may be substituted or unsubstituted. R 2 It is a substituted or unsubstituted alkyl group. In the embodiments, R 1 For –CH3. In the implementation scheme, R 2 For –CH3. In the implementation scheme, R 1 It is hydrogen. In the implementation scheme, R 2 It is hydrogen.

[0178] In the implementation plan, R 3 Independently halogen, –CX 3.1 3. -CHX 3.1 2. -CH2X 3.1 –CN, –N3, –SO n3 R 3A –SO v3 NR 3B R 3C -NHNR 3B R 3C -ONR 3B R 3C -NHC(O)NHNR 3B R 3C -NHC(O)NR 3B R 3C –N(O) m3 –NR 3B R 3C –C(O)R 3D –C(O)OR 3D –C(O)NR 3B R 3C –OR 3A -NR 3B SO2R 3A -NR 3B C(O)R 3D -NR 3B C(O)OR 3D –NR 3B OR 3D –OCX 3.1 3. –OCHX 3.1 2. –OCH2X 3.1 Substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

[0179] In the implementation plan, R 3 Independently halogen, –CX 3.1 3. -CHX 3.1 2. -CH2X 3.1 –CN, –N3, –SO n3 R 3A –SO v3 NR 3B R 3C -NHNR 3B R 3C -ONR 3B R 3C -NHC(O)NHNR3B R 3C -NHC(O)NR 3B R 3C –N(O) m3 –NR 3B R 3C –C(O)R 3D –C(O)OR 3D –C(O)NR 3B R 3C –OR 3A -NR 3B SO2R 3A -NR 3B C(O)R 3D -NR 3B C(O)OR 3D –NR 3B OR 3D –OCX 3.1 3. –OCHX 3.1 2. –OCH2X 3.1 R 17 Substituted or unsubstituted alkyl groups (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 17 Substituted or unsubstituted heteroalkyl groups (e.g., 2- to 8-membered heteroalkyl groups, 2- to 6-membered heteroalkyl groups, or 2- to 4-membered heteroalkyl groups), R 17 Substituted or unsubstituted cycloalkyl groups (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R 17 Substituted or unsubstituted heterocyclic alkyl groups (e.g., 3- to 8-membered heterocyclic alkyl groups, 3- to 6-membered heterocyclic alkyl groups, or 5- to 6-membered heterocyclic alkyl groups), R 17 Substituted or unsubstituted aryl groups (e.g., C6-C) 10 Aryl, C 10 (aryl or phenyl) or R 17 Substituted or unsubstituted heteroaryl groups (e.g., 5 to 10-membered heteroaryl, 5 to 9-membered heteroaryl, or 5 to 6-membered heteroaryl).

[0180] In the implementation plan, R 3 Independently for R 17 Substituted or unsubstituted alkyl groups (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In the embodiments, R 3 Independently for R 17 Substituted alkyl groups (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In the embodiments, R 3 It is independently an unsubstituted alkyl group (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).

[0181] In the implementation plan, R 3 Independently for R 17 Substituted or unsubstituted heteroalkyl groups (e.g., 2- to 8-membered heteroalkyl groups, 2- to 6-membered heteroalkyl groups, or 2- to 4-membered heteroalkyl groups). In the embodiments, R 3 Independently for R 17 Substituted heteroalkyl groups (e.g., 2- to 8-membered heteroalkyl groups, 2- to 6-membered heteroalkyl groups, or 2- to 4-membered heteroalkyl groups). In the embodiments, R 3 Independently, it is an unsubstituted heteroalkyl group (e.g., 2 to 8-membered heteroalkyl, 2 to 6-membered heteroalkyl, or 2 to 4-membered heteroalkyl).

[0182] In the implementation plan, R 3 Independently for R 17 Substituted or unsubstituted cycloalkyl groups (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In the embodiments, R 3 Independently for R 17 Substituted cycloalkyl groups (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In the embodiments, R 3 Independently, it is an unsubstituted cycloalkyl group (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).

[0183] In the implementation plan, R 3 Independently for R 17 Substituted or unsubstituted heterocyclic alkyl groups (e.g., 3- to 8-membered heterocyclic alkyl groups, 3- to 6-membered heterocyclic alkyl groups, or 5- to 6-membered heterocyclic alkyl groups). In the embodiments, R 3 Independently for R 17 Substituted heterocyclic alkyl groups (e.g., 3- to 8-membered heterocyclic alkyl groups, 3- to 6-membered heterocyclic alkyl groups, or 5- to 6-membered heterocyclic alkyl groups). In the embodiments, R 3 Independently, it is an unsubstituted heterocyclic alkyl group (e.g., 3- to 8-membered heterocyclic alkyl, 3- to 6-membered heterocyclic alkyl, or 5- to 6-membered heterocyclic alkyl).

[0184] In the implementation plan, R 3 Independently for R 17 Substituted or unsubstituted aryl groups (e.g., C6-C) 10 Aryl, C 10 (aryl or phenyl). In the implementation scheme, R 3 Independently for R 17 Substituted aryl groups (e.g., C6-C) 10 Aryl, C 10 (aryl or phenyl). In the implementation scheme, R 3 Independently unsubstituted aryl group (e.g., C6-C) 10 Aryl, C 10 (aryl or phenyl).

[0185] In the implementation plan, R 3 Independently for R 17 Substituted or unsubstituted heteroaryl groups (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In the embodiments, R 3 Independently for R 17 Substituted heteroaryl groups (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In the embodiments, R 3 Independently, it is an unsubstituted heteroaryl group (e.g., 5 to 10-membered heteroaryl, 5 to 9-membered heteroaryl, or 5 to 6-membered heteroaryl).

[0186] In the implementation plan, R 3 Independently halogen, –CF3, -CHF2, -CH2F, –CN, –N3, –SO2R 3A 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. It should be understood that when z3 is 0, R... 3 It is hydrogen. In the implementation scheme, R 3 Independently –Cl. In the implementation scheme, R 3 Independently for –F. In the implementation scheme, R 3 Independently –Br. In the implementation scheme, R 3 Independently for –I. In the implementation plan, R 3 Independently, it is –SO2CH3. In the implementation scheme, R 3 Independently, it is –SO2CH2CH3. In the implementation scheme, R 3 Independently, it is –SO2Cl.

[0187] In the implementation plan, R 3 The definition is assumed to be (independently assigned) to R. 3.1 R 3.2 R 3.3 R 3.4 R 3.5 Substituent R 3.1 R 3.2 R 3.3 R 3.4 and R 3.5 Each is R at a fixed position on the connected ring. 3 In the implementation plan, R 3.2 For R 3 Substituents or hydrogen. In the embodiment, R 3.3 For R 3 Substituents or hydrogen.

[0188] In the implementation plan, R 3.2 Halogen, –CX 3.2 3. -CHX 3.2 2. -CH2X 3.2 –CN, –N3, –SO n3.2 R 3.2A –SO v3.2 NR 3.2B R 3.2C -NHNR 3.2B R 3.2C -ONR 3.2B R 3.2C -NHC(O)NHNR 3.2B R 3.2C -NHC(O)NR 3.2B R 3.2C –N(O) m3.2 –NR 3.2B R 3.2C –C(O)R 3.2D –C(O)OR 3.2D –C(O)NR 3.2B R 3.2C –OR 3.2A -NR 3.2B SO2R 3.2A -NR 3.2B C(O)R 3.2D -NR 3.2B C(O)OR 3.2D –NR 3.2B OR 3.2D –OCX 3.2 3. –OCHX 3.2 2. –OCH2X 3.2 Substituted or unsubstituted alkyl 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. X 3.2 It is a halogen. In the implementation scheme, R 3.2 It is hydrogen. In the implementation scheme, R 3.2 It is a halogen. In the implementation scheme, R 3.2 It is chlorine. In the implementation plan, R 3.2 and R 3.3 Independently halogenated. In the implementation scheme, R 3.2 and R 3.3 Independently chlorine. In the implementation scheme, R 3.2 and R 3.3 Independently fluorine. In the implementation scheme, R 3.2 and R 3.3 It is bromine on its own.

[0189] In the implementation plan, R 3.2 Hydrogen, halogen, -CX 3.2 3. -CHX 3.2 2. -CH2X 3.2 –CN, –N3, –SO n3.2 R 3.2A –SO v3.2 NR 3.2B R 3.2C -NHNR 3.2B R 3.2C -ONR 3.2B R 3.2C -NHC(O)NHNR 3.2B R 3.2C -NHC(O)NR 3.2B R 3.2C –N(O) m3.2 –NR 3.2B R 3.2C –C(O)R 3.2D –C(O)OR 3.2D –C(O)NR 3.2B R 3.2C –OR 3.2A -NR 3.2B SO2R 3.2A -NR 3.2B C(O)R 3.2D -NR 3.2B C(O)OR 3.2D –NR 3.2B OR 3.2D –OCX 3.2 3. –OCHX 3.2 2. –OCH2X 3.2 R 17.2 Substituted or unsubstituted alkyl groups (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 17.2 Substituted or unsubstituted heteroalkyl groups (e.g., 2- to 8-membered heteroalkyl groups, 2- to 6-membered heteroalkyl groups, or 2- to 4-membered heteroalkyl groups), R 17.2 Substituted or unsubstituted cycloalkyl groups (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R 17.2 Substituted or unsubstituted heterocyclic alkyl groups (e.g., 3- to 8-membered heterocyclic alkyl groups, 3- to 6-membered heterocyclic alkyl groups, or 5- to 6-membered heterocyclic alkyl groups), R 17.2 Substituted or unsubstituted aryl groups (e.g., C6-C) 10 Aryl, C 10 (aryl or phenyl) or R 17.2 Substituted or unsubstituted heteroaryl groups (e.g., 5 to 10-membered heteroaryl, 5 to 9-membered heteroaryl, or 5 to 6-membered heteroaryl).

[0190] In the implementation plan, R 3.2 For R 17.2 Substituted or unsubstituted alkyl groups (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In the embodiments, R 3.2 For R 17.2 Substituted alkyl groups (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In the embodiments, R 3.2 It is an unsubstituted alkyl group (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).

[0191] In the implementation plan, R 3.2 For R 17.2 Substituted or unsubstituted heteroalkyl groups (e.g., 2- to 8-membered heteroalkyl groups, 2- to 6-membered heteroalkyl groups, or 2- to 4-membered heteroalkyl groups). In the embodiments, R 3.2 For R 17.2 Substituted heteroalkyl groups (e.g., 2- to 8-membered heteroalkyl groups, 2- to 6-membered heteroalkyl groups, or 2- to 4-membered heteroalkyl groups). In the embodiments, R 3.2 It is an unsubstituted heteroalkyl group (e.g., 2 to 8-membered heteroalkyl, 2 to 6-membered heteroalkyl, or 2 to 4-membered heteroalkyl).

[0192] In the implementation plan, R 3.2 For R 17.2 Substituted or unsubstituted cycloalkyl groups (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In the embodiments, R 3.2 For R 17.2 Substituted cycloalkyl groups (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In the embodiments, R 3.2 It is an unsubstituted cycloalkyl group (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).

[0193] In the implementation plan, R 3.2 For R 17.2 Substituted or unsubstituted heterocyclic alkyl groups (e.g., 3- to 8-membered heterocyclic alkyl groups, 3- to 6-membered heterocyclic alkyl groups, or 5- to 6-membered heterocyclic alkyl groups). In the embodiments, R 3.2 For R 17.2 Substituted heterocyclic alkyl groups (e.g., 3- to 8-membered heterocyclic alkyl groups, 3- to 6-membered heterocyclic alkyl groups, or 5- to 6-membered heterocyclic alkyl groups). In the embodiments, R 3.2 It is an unsubstituted heterocyclic alkyl group (e.g., 3- to 8-membered heterocyclic alkyl, 3- to 6-membered heterocyclic alkyl, or 5- to 6-membered heterocyclic alkyl).

[0194] In the implementation plan, R 3.2 For R 17.2Substituted or unsubstituted aryl groups (e.g., C6-C) 10 Aryl, C 10 (aryl or phenyl). In the implementation scheme, R 3.2 For R 17.2 Substituted aryl groups (e.g., C6-C) 10 Aryl, C 10 (aryl or phenyl). In the implementation scheme, R 3.2 For unsubstituted aryl groups (e.g., C6-C) 10 Aryl, C 10 (aryl or phenyl).

[0195] In the implementation plan, R 3.2 For R 17.2 Substituted or unsubstituted heteroaryl groups (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In the embodiments, R 3.2 For R 17.2 Substituted heteroaryl groups (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In the embodiments, R 3.2 It is an unsubstituted heteroaryl group (e.g., 5 to 10-membered heteroaryl, 5 to 9-membered heteroaryl, or 5 to 6-membered heteroaryl).

[0196] In the implementation plan, R 3.2 Independently halogen, –CF3, -CHF2, -CH2F, –CN, –N3, –SO2R 3.2A 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. It should be understood that when z3 is 0, R... 3.2 It is hydrogen. In the implementation scheme, R 3.2 Independently –Cl. In the implementation scheme, R 3.2 Independently for –F. In the implementation scheme, R 3.2 Independently –Br. In the implementation scheme, R 3.2 Independently for –I. In the implementation plan, R 3.2 Independently, it is –SO2CH3. In the implementation scheme, R 3.2 Independently, it is –SO2CH2CH3. In the implementation scheme, R 3.2 Independently, it is –SO2Cl.

[0197] In the implementation plan, R 3.3 Halogen, –CX 3.3 3. -CHX 3.3 2. -CH2X 3.3 –CN, –N3, –SO n3.3 R 3.3A–SO v3.3 NR 3.3B R 3.3C -NHNR 3.3B R 3.3C -ONR 3.3B R 3.3C -NHC(O)NHNR 3.3B R 3.3C -NHC(O)NR 3.3B R 3.3C –N(O) m3.3 –NR 3.3B R 3.3C –C(O)R 3.3D –C(O)OR 3.3D –C(O)NR 3.3B R 3.3C –OR 3.3A -NR 3.3B SO2R 3.3A -NR 3.3B C(O)R 3.3D -NR 3.3B C(O)OR 3.3D –NR 3.3B OR 3.3D –OCX 3.3 3. –OCHX 3.3 2. –OCH2X 3.3 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. X 3.3 It is a halogen. In the implementation scheme, R 3.3 It is hydrogen. In the implementation scheme, R 3.3 It is a halogen. In the implementation scheme, R 3.3 It is chlorine.

[0198] In the implementation plan, R 3.3 Hydrogen, halogen, -CX 3.3 3. -CHX 3.3 2. -CH2X 3.3 –CN, –N3, –SO n3.3 R 3.3A –SO v3.3 NR 3.3B R 3.3C -NHNR 3.3B R 3.3C -ONR 3.3B R 3.3C -NHC(O)NHNR 3.3B R 3.3C -NHC(O)NR 3.3BR 3.3C –N(O) m3.3 –NR 3.3B R 3.3C –C(O)R 3.3D –C(O)OR 3.3D –C(O)NR 3.3B R 3.3C –OR 3.3A -NR 3.3B SO2R 3.3A -NR 3.3B C(O)R 3.3D -NR 3.3B C(O)OR 3.3D –NR 3.3B OR 3.3D –OCX 3.3 3. –OCHX 3.3 2. –OCH2X 3.3 R 17.3 Substituted or unsubstituted alkyl groups (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 17.3 Substituted or unsubstituted heteroalkyl groups (e.g., 2- to 8-membered heteroalkyl groups, 2- to 6-membered heteroalkyl groups, or 2- to 4-membered heteroalkyl groups), R 17.3 Substituted or unsubstituted cycloalkyl groups (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R 17.3 Substituted or unsubstituted heterocyclic alkyl groups (e.g., 3- to 8-membered heterocyclic alkyl groups, 3- to 6-membered heterocyclic alkyl groups, or 5- to 6-membered heterocyclic alkyl groups), R 17.3 Substituted or unsubstituted aryl groups (e.g., C6-C) 10 Aryl, C 10 (aryl or phenyl) or R 17.3 Substituted or unsubstituted heteroaryl groups (e.g., 5 to 10-membered heteroaryl, 5 to 9-membered heteroaryl, or 5 to 6-membered heteroaryl).

[0199] In the implementation plan, R 3.3 For R 17.3 Substituted or unsubstituted alkyl groups (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In the embodiments, R 3.3 For R 17.3 Substituted alkyl groups (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In the embodiments, R 3.3 It is an unsubstituted alkyl group (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).

[0200] In the implementation plan, R 3.3 For R 17.3Substituted or unsubstituted heteroalkyl groups (e.g., 2- to 8-membered heteroalkyl groups, 2- to 6-membered heteroalkyl groups, or 2- to 4-membered heteroalkyl groups). In the embodiments, R 3.3 For R 17.3 Substituted heteroalkyl groups (e.g., 2- to 8-membered heteroalkyl groups, 2- to 6-membered heteroalkyl groups, or 2- to 4-membered heteroalkyl groups). In the embodiments, R 3.3 It is an unsubstituted heteroalkyl group (e.g., 2 to 8-membered heteroalkyl, 2 to 6-membered heteroalkyl, or 2 to 4-membered heteroalkyl).

[0201] In the implementation plan, R 3.3 For R 17.3 Substituted or unsubstituted cycloalkyl groups (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In the embodiments, R 3.3 For R 17.3 Substituted cycloalkyl groups (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In the embodiments, R 3.3 It is an unsubstituted cycloalkyl group (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).

[0202] In the implementation plan, R 3.3 For R 17.3 Substituted or unsubstituted heterocyclic alkyl groups (e.g., 3- to 8-membered heterocyclic alkyl groups, 3- to 6-membered heterocyclic alkyl groups, or 5- to 6-membered heterocyclic alkyl groups). In the embodiments, R 3.3 For R 17.3 Substituted heterocyclic alkyl groups (e.g., 3- to 8-membered heterocyclic alkyl groups, 3- to 6-membered heterocyclic alkyl groups, or 5- to 6-membered heterocyclic alkyl groups). In the embodiments, R 3.3 It is an unsubstituted heterocyclic alkyl group (e.g., 3- to 8-membered heterocyclic alkyl, 3- to 6-membered heterocyclic alkyl, or 5- to 6-membered heterocyclic alkyl).

[0203] In the implementation plan, R 3.3 For R 17.3 Substituted or unsubstituted aryl groups (e.g., C6-C) 10 Aryl, C 10 (aryl or phenyl). In the implementation scheme, R 3.3 For R 17.3 Substituted aryl groups (e.g., C6-C) 10 Aryl, C 10 (aryl or phenyl). In the implementation scheme, R 3.3 For unsubstituted aryl groups (e.g., C6-C) 10 Aryl, C 10 (aryl or phenyl).

[0204] In the implementation plan, R 3.3 For R 17.3Substituted or unsubstituted heteroaryl groups (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In the embodiments, R 3.3 For R 17.3 Substituted heteroaryl groups (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In the embodiments, R 3.3 It is an unsubstituted heteroaryl group (e.g., 5 to 10-membered heteroaryl, 5 to 9-membered heteroaryl, or 5 to 6-membered heteroaryl).

[0205] In the implementation plan, R 3.3 Independently halogen, –CF3, -CHF2, -CH2F, –CN, –N3, –SO2R 3.3A 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. It should be understood that when z3 is 0, R... 3.3 It is hydrogen. In the implementation scheme, R 3.3 Independently –Cl. In the implementation scheme, R 3.3 Independently for –F. In the implementation scheme, R 3.3 Independently –Br. In the implementation scheme, R 3.3 Independently for –I. In the implementation plan, R 3.3 Independently, it is –SO2CH3. In the implementation scheme, R 3.3 Independently, it is –SO2CH2CH3. In the implementation scheme, R 3.3 Independently, it is –SO2Cl.

[0206] In the implementation plan, R 4 Halogen, –CX 4.1 3. -CHX 4.1 2. -CH2X 4.1 –CN, –N3, –SO n4 R 4A –SO v4 NR 4B R 4C -NHNR 4B R 4C -ONR 4B R 4C -NHC(O)NHNR 4B R 4C -NHC(O)NR 4B R 4C –N(O) m4 –NR 4B R 4C –C(O)R 4D –C(O)OR 4D–C(O)NR 4B R 4C –OR 4A -NR 4B SO2R 4A -NR 4B C(O)R 4D -NR 4B C(O)OR 4D –NR 4B OR 4D –OCX 4.1 3. –OCHX 4.1 2. –OCH2X 4.1 Substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In the embodiments, R 4 It is hydrogen.

[0207] In the implementation plan, R 4 Halogen, –CX 4.1 3. -CHX 4.1 2. -CH2X 4.1 –CN, –N3, –SO n4 R 4A –SO v4 NR 4B R 4C -NHNR 4B R 4C -ONR 4B R 4C -NHC(O)NHNR 4B R 4C -NHC(O)NR 4B R 4C –N(O) m4 –NR 4B R 4C –C(O)R 4D –C(O)OR 4D –C(O)NR 4B R 4C –OR 4A -NR 4B SO2R 4A -NR 4B C(O)R 4D -NR 4B C(O)OR 4D –NR 4B OR 4D –OCX 4.1 3. –OCHX 4.1 2. –OCH2X4.1 R 20 Substituted or unsubstituted alkyl groups (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 20 Substituted or unsubstituted heteroalkyl groups (e.g., 2- to 8-membered heteroalkyl groups, 2- to 6-membered heteroalkyl groups, or 2- to 4-membered heteroalkyl groups), R 20 Substituted or unsubstituted cycloalkyl groups (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R 20 Substituted or unsubstituted heterocyclic alkyl groups (e.g., 3- to 8-membered heterocyclic alkyl groups, 3- to 6-membered heterocyclic alkyl groups, or 5- to 6-membered heterocyclic alkyl groups), R 20 Substituted or unsubstituted aryl groups (e.g., C6-C) 10 Aryl, C 10 (aryl or phenyl) or R 20 Substituted or unsubstituted heteroaryl groups (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In the embodiments, R 4 For –CN. In the implementation plan, R 4 It is -C(O)NH2. In the implementation scheme, R 4 For -CF3. In the implementation plan, R 4 It is –CH3.

[0208] In the implementation plan, R 4 For R 20 Substituted or unsubstituted alkyl groups (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In the embodiments, R 4 For R 20 Substituted alkyl groups (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In the embodiments, R 4 It is an unsubstituted alkyl group (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In the embodiments, R 4 It is an unsubstituted ethyl group. In the embodiments, R 4 It is an unsubstituted C3 alkyl group. In the embodiments, R 4 It is an unsubstituted C4 alkyl group.

[0209] In the implementation plan, R 4 For R 20 Substituted or unsubstituted heteroalkyl groups (e.g., 2- to 8-membered heteroalkyl groups, 2- to 6-membered heteroalkyl groups, or 2- to 4-membered heteroalkyl groups). In the embodiments, R 4 For R 20 Substituted heteroalkyl groups (e.g., 2- to 8-membered heteroalkyl groups, 2- to 6-membered heteroalkyl groups, or 2- to 4-membered heteroalkyl groups). In the embodiments, R 4It is an unsubstituted heteroalkyl group (e.g., 2 to 8-membered heteroalkyl, 2 to 6-membered heteroalkyl, or 2 to 4-membered heteroalkyl).

[0210] In the implementation plan, R 4 For R 20 Substituted or unsubstituted cycloalkyl groups (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In the embodiments, R 4 For R 20 Substituted cycloalkyl groups (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In the embodiments, R 4 It is an unsubstituted cycloalkyl group (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).

[0211] In the implementation plan, R 4 For R 20 Substituted or unsubstituted heterocyclic alkyl groups (e.g., 3- to 8-membered heterocyclic alkyl groups, 3- to 6-membered heterocyclic alkyl groups, or 5- to 6-membered heterocyclic alkyl groups). In the embodiments, R 4 For R 20 Substituted heterocyclic alkyl groups (e.g., 3- to 8-membered heterocyclic alkyl groups, 3- to 6-membered heterocyclic alkyl groups, or 5- to 6-membered heterocyclic alkyl groups). In the embodiments, R 4 It is an unsubstituted heterocyclic alkyl group (e.g., 3- to 8-membered heterocyclic alkyl, 3- to 6-membered heterocyclic alkyl, or 5- to 6-membered heterocyclic alkyl).

[0212] In the implementation plan, R 4 For R 20 Substituted or unsubstituted aryl groups (e.g., C6-C) 10 Aryl, C 10 (aryl or phenyl). In the implementation scheme, R 4 For R 20 Substituted aryl groups (e.g., C6-C) 10 Aryl, C 10 (aryl or phenyl). In the implementation scheme, R 4 For unsubstituted aryl groups (e.g., C6-C) 10 Aryl, C 10 (aryl or phenyl).

[0213] In the implementation plan, R 4 For R 20 Substituted or unsubstituted heteroaryl groups (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In the embodiments, R 4 For R 20 Substituted heteroaryl groups (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In the embodiments, R 4It is an unsubstituted heteroaryl group (e.g., 5 to 10-membered heteroaryl, 5 to 9-membered heteroaryl, or 5 to 6-membered heteroaryl).

[0214] In the implementation plan, R 4 Hydrogen, –CN, halogen, -CF3, -COOH, -COOCH2CH3, -CH3. In the implementation plan, R 4 It is hydrogen. In the implementation scheme, R 4 For –CN. In the implementation plan, R 4 It is a halogen. In the implementation scheme, R 4 For –F. In the implementation plan, R 4 For –Cl. In the implementation scheme, R 4 For –Br. In the implementation scheme, R 4 For –I. In the implementation plan, R 4 For -CF3. In the implementation plan, R 4 For –COOH. In the implementation scheme, R 4 It is -COOCH2CH3. In the implementation scheme, R 4 For –CH3. In the implementation scheme, R 4 For –CHCH2CH2OH. In the implementation scheme, R 4 for In the implementation plan, R 4 It is a substituted or unsubstituted C1-C4 alkyl group. In the embodiments, R 4 The substituted C1-C4 alkyl group. In the embodiments, R 4 It is an unsubstituted C1-C4 alkyl group.

[0215] In the implementation plan, R 4 Halogen, –CF3, -CHF2, -CH2F, –CN, –N3, –SO2CH3, –C(O)R 4D –C(O)OR 4D substituted or unsubstituted alkyl groups, substituted or unsubstituted heteroalkyl groups. In the embodiments, R 4 Halogen, –CF3, -CHF2, -CH2F, –CN, –N3, –SO2CH3, –C(O)R 4D –C(O)OR 4D Substituted or unsubstituted alkyl groups, substituted or unsubstituted heteroalkyl groups.

[0216] In the implementation plan, R 4 For R 20 Substituted or unsubstituted alkyl groups (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In the embodiments, R 4 For R 20Substituted alkyl groups (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In the embodiments, R 4 It is an unsubstituted alkyl group (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).

[0217] In the implementation plan, R 4 For R 20 Substituted or unsubstituted methyl groups. In the embodiments, R 4 For R 20 Substituted or unsubstituted C2 alkyl group. In the embodiments, R 4 For R 20 Substituted or unsubstituted C3 alkyl group. In the embodiments, R 4 For R 20 Substituted or unsubstituted C4 alkyl. In the embodiments, R 4 For R 20 Substituted or unsubstituted C5 alkyl group. In the embodiments, R 4 For R 20 Substituted or unsubstituted C6 alkyl group. In the embodiments, R 4 For R 20 Substituted or unsubstituted C7 alkyl group. In the embodiments, R 4 For R 20 Substituted or unsubstituted C8 alkyl. In the embodiments, R 4 For R 20 Substituted methyl group. In the embodiment, R 4 For R 20 Substituted C2 alkyl group. In the embodiment, R 4 For R 20 Substituted C3 alkyl group. In the embodiment, R 4 For R 20 Substituted C4 alkyl. In the embodiments, R 4 For R 20 Substituted C5 alkyl group. In the embodiment, R 4 For R 20 Substituted C6 alkyl group. In the embodiments, R 4 For R 20 Substituted C7 alkyl group. In the embodiments, R 4 For R 20 Substituted C8 alkyl. In the embodiments, R 4 The methyl group is unsubstituted. In the embodiments, R 4 It is an unsubstituted C2 alkyl group. In the embodiments, R 4 It is an unsubstituted C3 alkyl group. In the embodiments, R 4 It is an unsubstituted C4 alkyl group. In the embodiments, R 4It is an unsubstituted C5 alkyl group. In the embodiments, R 4 It is an unsubstituted C6 alkyl group. In the embodiments, R 4 It is an unsubstituted C7 alkyl group. In the embodiments, R 4 It is an unsubstituted C8 alkyl group.

[0218] In the implementation plan, R 4 For hydrogen, –CX 4.1 3. –CN, –C(O)NR 4B R 4C substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In the embodiments, R 4 Hydrogen, halogen, -CX 4.1 3. -CHX 4.1 2. -CH2X 4.1 -CN, -NR 4B R 4C –C(O)R 4D –C(O)OR 4D –C(O)NR 4B R 4C –OR 4A -NR 4B C(O)R 4D -NR 4B C(O)OR 4D –OCX 4.1 3. –OCHX 4.1 2. –OCH2X 4.1 substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl. In the embodiments, R 4 Hydrogen, halogen, -CX 4.1 3. -CHX 4.1 2. -CH2X 4.1 –CN, –C(O)OR 4D –C(O)NR 4B R 4C substituted or unsubstituted C1-C4 alkyl groups or substituted or unsubstituted 2- to 4-membered heteroalkyl groups. In the embodiments, R 4 It can be –Cl, -Br, -F, –CN, -COOH, -C(O)OCH2CH3, -C(CH3)2OH, –C(O)NH2, -CF3, or –CH3. In the embodiments, R 4 It is hydrogen. In the implementation scheme, R 4 It is a halogen. In the implementation scheme, R 4 For –CX 4.1 3. In the implementation plan, R4 For -CHX 4.1 2. In the implementation plan, R 4 -CH2X 4.1 In the implementation plan, R 4 For –CN. In the implementation plan, R 4 For –NR 4B R 4C In the implementation plan, R 4 For –C(O)R 4D In the implementation plan, R 4 -C(O)OR 4D In the implementation plan, R 4 For –C(O)NR 4B R 4C In the implementation plan, R 4 For –OR 4A In the implementation plan, R 4 For -NR 4B C(O)R 4D In the implementation plan, R 4 For -NR 4B C(O)OR 4D In the implementation plan, R 4 For –OCX 4.1 3. In the implementation plan, R 4 For –OCHX 4.1 2. In the implementation plan, R 4 For –OCH2X 4.1 In the implementation plan, R 4 It is a substituted or unsubstituted alkyl group. In the embodiments, R 4 It is a substituted or unsubstituted heteroalkyl group. In the embodiments, R 4 For –Cl. In the implementation scheme, R 4 For –Br. In the implementation scheme, R 4 For –F. In the implementation plan, R 4 For –CN. In the implementation plan, R 4 For –COOH. In the implementation scheme, R 4 It is -C(O)OCH2CH3. In the implementation scheme, R 4 It is -C(CH3)2OH. In the implementation scheme, R 4 For –C(O)NH2. In the implementation scheme, R 4 For -CF3. In the implementation plan, R 4 It is –CH3.

[0219] In the implementation plan, R 5 Independently halogen, oxo group, –CX 5.1 3. -CHX5.1 2. -CH2X 5.1 –CN, –N3, –SO n5 R 5A –SO v5 NR 5B R 5C -NHNR 5B R 5C -ONR 5B R 5C -NHC(O)NHNR 5B R 5C -NHC(O)NR 5B R 5C –N(O) m5 –NR 5B R 5C –C(O)R 5D –C(O)OR 5D –C(O)NR 5B R 5C –OR 5A -NR 5B SO2R 5A -NR 5B C(O)R 5D -NR 5B C(O)OR 5D –NR 5B OR 5D –OCX 5.1 3. –OCHX 5.1 2. –OCH2X 5.1 Substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

[0220] In the implementation plan, R 5 Independently halogen, –CX 5.1 3. -CHX 5.1 2. -CH2X 5.1 –CN, –N3, –SO n5 R 5A –SO v5 NR 5B R 5C -NHNR 5B R 5C -ONR 5B R 5C -NHC(O)NHNR 5B R 5C -NHC(O)NR 5B R 5C–N(O) m5 –NR 5B R 5C –C(O)R 5D –C(O)OR 5D –C(O)NR 5B R 5C –OR 5A -NR 5B SO2R 5A -NR 5B C(O)R 5D -NR 5B C(O)OR 5D –NR 5B OR 5D –OCX 5.1 3. –OCHX 5.1 2. –OCH2X 5.1 R 23 Substituted or unsubstituted alkyl groups (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 23 Substituted or unsubstituted heteroalkyl groups (e.g., 2- to 8-membered heteroalkyl groups, 2- to 6-membered heteroalkyl groups, or 2- to 4-membered heteroalkyl groups), R 23 Substituted or unsubstituted cycloalkyl groups (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R 23 Substituted or unsubstituted heterocyclic alkyl groups (e.g., 3- to 8-membered heterocyclic alkyl groups, 3- to 6-membered heterocyclic alkyl groups, or 5- to 6-membered heterocyclic alkyl groups), R 23 Substituted or unsubstituted aryl groups (e.g., C6-C) 10 Aryl, C 10 (aryl or phenyl) or R 23 Substituted or unsubstituted heteroaryl groups (e.g., 5 to 10-membered heteroaryl, 5 to 9-membered heteroaryl, or 5 to 6-membered heteroaryl).

[0221] In the implementation plan, R 5 Independently for R 23 Substituted or unsubstituted alkyl groups (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In the embodiments, R 5 Independently for R 23 Substituted alkyl groups (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In the embodiments, R 5 It is independently an unsubstituted alkyl group (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).

[0222] In the implementation plan, R 5 Independently for R 23Substituted or unsubstituted heteroalkyl groups (e.g., 2- to 8-membered heteroalkyl groups, 2- to 6-membered heteroalkyl groups, or 2- to 4-membered heteroalkyl groups). In the embodiments, R 5 Independently for R 23 Substituted heteroalkyl groups (e.g., 2- to 8-membered heteroalkyl groups, 2- to 6-membered heteroalkyl groups, or 2- to 4-membered heteroalkyl groups). In the embodiments, R 5 Independently, it is an unsubstituted heteroalkyl group (e.g., 2 to 8-membered heteroalkyl, 2 to 6-membered heteroalkyl, or 2 to 4-membered heteroalkyl).

[0223] In the implementation plan, R 5 Independently for R 23 Substituted or unsubstituted cycloalkyl groups (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In the embodiments, R 5 Independently for R 23 Substituted cycloalkyl groups (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In the embodiments, R 5 Independently, it is an unsubstituted cycloalkyl group (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).

[0224] In the implementation plan, R 5 Independently for R 23 Substituted or unsubstituted heterocyclic alkyl groups (e.g., 3- to 8-membered heterocyclic alkyl groups, 3- to 6-membered heterocyclic alkyl groups, or 5- to 6-membered heterocyclic alkyl groups). In the embodiments, R 5 Independently for R 23 Substituted heterocyclic alkyl groups (e.g., 3- to 8-membered heterocyclic alkyl groups, 3- to 6-membered heterocyclic alkyl groups, or 5- to 6-membered heterocyclic alkyl groups). In the embodiments, R 5 Independently, it is an unsubstituted heterocyclic alkyl group (e.g., 3- to 8-membered heterocyclic alkyl, 3- to 6-membered heterocyclic alkyl, or 5- to 6-membered heterocyclic alkyl).

[0225] In the implementation plan, R 5 Independently for R 23 Substituted or unsubstituted aryl groups (e.g., C6-C) 10 Aryl, C 10 (aryl or phenyl). In the implementation scheme, R 5 Independently for R 23 Substituted aryl groups (e.g., C6-C) 10 Aryl, C 10 (aryl or phenyl). In the implementation scheme, R 5 Independently unsubstituted aryl group (e.g., C6-C) 10 Aryl, C 10 (aryl or phenyl).

[0226] In the implementation plan, R5 Independently for R 23 Substituted or unsubstituted heteroaryl groups (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In the embodiments, R 5 Independently for R 23 Substituted heteroaryl groups (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In the embodiments, R 5 Independently, it is an unsubstituted heteroaryl group (e.g., 5 to 10-membered heteroaryl, 5 to 9-membered heteroaryl, or 5 to 6-membered heteroaryl).

[0227] In the implementation plan, R 6 Independently halogen, oxo group, –CX 6.1 3. -CHX 6.1 2. -CH2X 6.1 –CN, –N3, –SO n6 R 6A –SO v6 NR 6B R 6C -NHNR 6B R 6C -ONR 6B R 6C -NHC(O)NHNR 6B R 6C -NHC(O)NR 6B R 6C –N(O) m6 –NR 6B R 6C –C(O)R 6D –C(O)OR 6D –C(O)NR 6B R 6C –OR 6A -NR 6B SO2R 6A -NR 6B C(O)R 6D -NR 6B C(O)OR 6D –NR 6B OR 6D –OCX 6.1 3. –OCHX 6.1 2. –OCH2X 6.1 Substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In the embodiments, R 6 It is –COOH.

[0228] In the implementation plan, R 6 Independently halogen, –CX 6.1 3. -CHX 6.1 2. -CH2X 6.1 –CN, –N3, –SO n6 R 6A –SO v6 NR 6B R 6C -NHNR 6B R 6C -ONR 6B R 6C -NHC(O)NHNR 6B R 6C -NHC(O)NR 6B R 6C –N(O) m6 –NR 6B R 6C –C(O)R 6D –C(O)OR 6D –C(O)NR 6B R 6C –OR 6A -NR 6B SO2R 6A -NR 6B C(O)R 6D -NR 6B C(O)OR 6D –NR 6B OR 6D –OCX 6.1 3. –OCHX 6.1 2. –OCH2X 6.1 R 26 Substituted or unsubstituted alkyl groups (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 26 Substituted or unsubstituted heteroalkyl groups (e.g., 2- to 8-membered heteroalkyl groups, 2- to 6-membered heteroalkyl groups, or 2- to 4-membered heteroalkyl groups), R 26 Substituted or unsubstituted cycloalkyl groups (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R 26 Substituted or unsubstituted heterocyclic alkyl groups (e.g., 3- to 8-membered heterocyclic alkyl groups, 3- to 6-membered heterocyclic alkyl groups, or 5- to 6-membered heterocyclic alkyl groups), R 26 Substituted or unsubstituted aryl groups (e.g., C6-C) 10 Aryl, C 10 (aryl or phenyl) or R 26 Substituted or unsubstituted heteroaryl groups (e.g., 5 to 10-membered heteroaryl, 5 to 9-membered heteroaryl, or 5 to 6-membered heteroaryl).

[0229] In the implementation plan, R 6 For R 26 Substituted or unsubstituted alkyl groups. In the embodiments, R 6 It is an unsubstituted phenyl group. In the embodiments, R 6 For –F. In the implementation plan, R 6 For –OH. In the implementation scheme, R 6 For -CH2OH. In the implementation scheme, R 6 It is -(CH2)2OH. In the implementation scheme, R 6 It is -(CH2)3OH. In the implementation scheme, R 6 It is -C(CH3)2OH. In the implementation scheme, R 6 For -CH2SO2NH2. In the implementation scheme, R 6 It is –(CH2)2SO2NH2. In the implementation scheme, R 6 It is -CH2C(O)NH2. In the implementation scheme, R 6 It is -(CH2)2C(O)NH2. In the implementation scheme, R 6 It is -(CH2)3C(O)NH2. In the implementation scheme, R 6 For -CH2NHSO2CF3. In the implementation scheme, R 6 It is -(CH2)2NHSO2CF3. In the implementation scheme, R 6 It is -(CH2)3NHSO2CF3. In the implementation scheme, R 6 It is -CH2NHSO2CH3. In the implementation scheme, R 6 It is -(CH2)2NHSO2CH3. In the implementation scheme, R 6 It is -(CH2)3NHSO2CH3. In the implementation scheme, R 6 It is -CH2SO2CH3. In the implementation scheme, R 6 It is –(CH2)2SO2CH3. In the implementation scheme, R 6 It is -CH2SO2NH2.

[0230] In the implementation plan, R 6 It is –(CH2)2SO2NH2.

[0231] In the implementation plan, R 6 Independently for R 26 Substituted or unsubstituted alkyl groups (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In the embodiments, R 6 Independently for R 26Substituted alkyl groups (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In the embodiments, R 6 It is independently an unsubstituted alkyl group (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).

[0232] In the implementation plan, R 6 Independently for R 26 Substituted or unsubstituted heteroalkyl groups (e.g., 2- to 8-membered heteroalkyl groups, 2- to 6-membered heteroalkyl groups, or 2- to 4-membered heteroalkyl groups). In the embodiments, R 6 Independently for R 26 Substituted heteroalkyl groups (e.g., 2- to 8-membered heteroalkyl groups, 2- to 6-membered heteroalkyl groups, or 2- to 4-membered heteroalkyl groups). In the embodiments, R 6 Independently, it is an unsubstituted heteroalkyl group (e.g., 2 to 8-membered heteroalkyl, 2 to 6-membered heteroalkyl, or 2 to 4-membered heteroalkyl).

[0233] In the implementation plan, R 6 Independently for R 26 Substituted or unsubstituted cycloalkyl groups (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In the embodiments, R 6 Independently for R 26 Substituted cycloalkyl groups (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In the embodiments, R 6 Independently, it is an unsubstituted cycloalkyl group (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).

[0234] In the implementation plan, R 6 Independently for R 26 Substituted or unsubstituted heterocyclic alkyl groups (e.g., 3- to 8-membered heterocyclic alkyl groups, 3- to 6-membered heterocyclic alkyl groups, or 5- to 6-membered heterocyclic alkyl groups). In the embodiments, R 6 Independently for R 26 Substituted heterocyclic alkyl groups (e.g., 3- to 8-membered heterocyclic alkyl groups, 3- to 6-membered heterocyclic alkyl groups, or 5- to 6-membered heterocyclic alkyl groups). In the embodiments, R 6 Independently, it is an unsubstituted heterocyclic alkyl group (e.g., 3- to 8-membered heterocyclic alkyl, 3- to 6-membered heterocyclic alkyl, or 5- to 6-membered heterocyclic alkyl).

[0235] In the implementation plan, R 6 Independently for R 26 Substituted or unsubstituted aryl groups (e.g., C6-C) 10 Aryl, C 10 (aryl or phenyl). In the implementation scheme, R 6 Independently for R 26Substituted aryl groups (e.g., C6-C) 10 Aryl, C 10 (aryl or phenyl). In the implementation scheme, R 6 Independently unsubstituted aryl group (e.g., C6-C) 10 Aryl, C 10 (aryl or phenyl).

[0236] In the implementation plan, R 6 Independently for R 26 Substituted or unsubstituted heteroaryl groups (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In the embodiments, R 6 Independently for R 26 Substituted heteroaryl groups (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In the embodiments, R 6 Independently, it is an unsubstituted heteroaryl group (e.g., 5 to 10-membered heteroaryl, 5 to 9-membered heteroaryl, or 5 to 6-membered heteroaryl).

[0237] In the implementation plan, R 7 Halogen, –CX 7.1 3. -CHX 7.1 2. -CH2X 7.1 –CN, –N3, –SO n7 R 7A –SO v7 NR 7B R 7C -NHNR 7B R 7C -ONR 7B R 7C -NHC(O)NHNR 7B R 7C -NHC(O)NR 7B R 7C –N(O) m7 –NR 7B R 7C –C(O)R 7D –C(O)OR 7D –C(O)NR 7B R 7C –OR 7A -NR 7B SO2R 7A -NR 7B C(O)R 7D -NR 7B C(O)OR 7D –NR 7B OR 7D –OCX 7.13. –OCHX 7.1 2. –OCH2X 7.1 Substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In the embodiments, R 7 It is a halogen. In the implementation scheme, R 7 For –CX 7.1 3. In the implementation plan, R 7 For -CHX 7.1 2. In the implementation plan, R 7 -CH2X 7.1 In the implementation plan, R 7 For -CN. In the implementation plan, R 7 For –N3. In the implementation scheme, R 7 For –SO n7 R 7A In the implementation plan, R 7 For –SO v7 NR 7B R 7C In the implementation plan, R 7 -NHNR 7B R 7C In the implementation plan, R 7 For -ONR 7B R 7C In the implementation plan, R 7 -NHC(O)NHNR 7B R 7C In the implementation plan, R 7 -NHC(O)NR 7B R 7C In the implementation plan, R 7 For –N(O) m7 In the implementation plan, R 7 For –NR 7B R 7C In the implementation plan, R 7 For –C(O)R 7D In the implementation plan, R 7 -C(O)OR 7D In the implementation plan, R 7 For –C(O)NR 7B R 7C In the implementation plan, R 7 For –OR 7A In the implementation plan, R 7 For -NR 7B SO2R 7A In the implementation plan, R7 For -NR 7B C(O)R 7D In the implementation plan, R 7 For -NR 7B C(O)OR 7D In the implementation plan, R 7 For –NR 7B OR 7D In the implementation plan, R 7 For –OCX 7.1 3. In the implementation plan, R 7 For –OCHX 7.1 2. In the implementation plan, R 7 For –OCH2X 7.1 In the implementation plan, R 7 For –CF3. In the implementation plan, R 7 For -CHF2. In the implementation scheme, R 7 For -CH2F. In the implementation scheme, R 7 For –SO2CH3. In the implementation scheme, R 7 For –SO2NH2. In the implementation scheme, R 7 For -NHNH2. In the implementation plan, R 7 For -ONH2. In the implementation scheme, R 7 It is -NHC(O)NHNH2. In the implementation scheme, R 7 It is -NHC(O)NH2. In the implementation scheme, R 7 It is –N(O)2. In the implementation scheme, R 7 For –NH2. In the implementation scheme, R 7 For –C(O)OH. In the implementation scheme, R 7 It is –C(O)OCH3. In the implementation scheme, R 7 For –C(O)NH2. In the implementation scheme, R 7 For –OCH3. In the implementation scheme, R 7 It is -NHSO2CH3. In the implementation scheme, R 7 It is -NHC(O)CH3. In the implementation scheme, R 7 It is -NHC(O)OH. In the implementation scheme, R 7 For –NHOH. In the implementation scheme, R 7 For –OCF3. In the implementation scheme, R 7 For –OCHF2. In the implementation scheme, R 7 For -OCH2F. In the implementation scheme, R 7 It is hydrogen. In the implementation scheme, R 7For –C(O)OH. In the implementation scheme, R 7 For –OH. In the implementation scheme, R 7 For –NH2. In the implementation scheme, R 7 It is –C(O)NH2.

[0238] In the implementation plan, R 7 Halogen, –CX 7.1 3. -CHX 7.1 2. -CH2X 7.1 –CN, –N3, –SO n7 R 7A –SO v7 NR 7B R 7C -NHNR 7B R 7C -ONR 7B R 7C -NHC(O)NHNR 7B R 7C -NHC(O)NR 7B R 7C –N(O) m7 –NR 7B R 7C –C(O)R 7D –C(O)OR 7D –C(O)NR 7B R 7C –OR 7A -NR 7B SO2R 7A -NR 7B C(O)R 7D -NR 7B C(O)OR 7D –NR 7B OR 7D –OCX 7.1 3. –OCHX 7.1 2. –OCH2X 7.1 R 29 Substituted or unsubstituted alkyl groups (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 29 Substituted or unsubstituted heteroalkyl groups (e.g., 2- to 8-membered heteroalkyl groups, 2- to 6-membered heteroalkyl groups, or 2- to 4-membered heteroalkyl groups), R 29 Substituted or unsubstituted cycloalkyl groups (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R 29 Substituted or unsubstituted heterocyclic alkyl groups (e.g., 3- to 8-membered heterocyclic alkyl groups, 3- to 6-membered heterocyclic alkyl groups, or 5- to 6-membered heterocyclic alkyl groups), R 29Substituted or unsubstituted aryl groups (e.g., C6-C) 10 Aryl, C 10 (aryl or phenyl) or R 29 Substituted or unsubstituted heteroaryl groups (e.g., 5 to 10-membered heteroaryl, 5 to 9-membered heteroaryl, or 5 to 6-membered heteroaryl).

[0239] In the implementation plan, R 7 It is –(CH2)3COOH. In the implementation scheme, R 7 It is –(CH2)2COOH. In the implementation scheme, R 7 It is –(CH2)COOH. In the implementation scheme, R 7 It is –(CH2)2CONH2. In the implementation scheme, R 7 It is –(CH2)3CONH2. In the implementation scheme, R 7 It is –(CH2)3OH. In the implementation scheme, R 7 The substituted cyclobutyl group. In the implementation, R 7 It is –(CH2)2SO2CH3. In the implementation scheme, R 7 The form is –CH2CH(CH3)OH. In the implementation scheme, R 7 It is –(CH2)2OH. In the implementation scheme, R 7 It is –(CH2)4OH. In the implementation scheme, R 7 It is –(CH2)OH. In the implementation scheme, R 7 It is –(CH2)2NHSO2CH3. In the implementation scheme, R 7 The form is –(CH2)2NHSO2CH2CH3. In the implementation scheme, R 7 The value is –(CH2)2NHSO2(CH2)2CH3. In the implementation scheme, R 7 The value is –(CH2)2NHSO2CH(CH3)2. In the implementation scheme, R 7 It is –(CH2)2NHC(O)OCH3. In the implementation scheme, R 7 It is –(CH2)3SO2CH3. In the implementation scheme, R 7 It is –(CH2)2NHC(O)CH3. In the implementation scheme, R 7 It is –(CH2)2NHC(O)H. In the embodiment, R7 is –CH2C(O)OCH3. In the embodiment, R 7 It is –CH2C(O)OCH2CH3. In the implementation scheme, R 7 It is –(CH2)3SO2NH2. In the implementation scheme, R 7 It is –(CH2)2SO2NH2. In the implementation scheme, R7 It is –(CH2)1SO2NH2. In the implementation scheme, R 7 It is –(CH2)2NHC(O)CH2CH3. In the implementation scheme, R 7 It is –(CH2)2NHC(O)CH(CH3)2.

[0240] In the implementation plan, R 7 It is hydrogen. In the implementation scheme, R 7 For R 29 Substituted or unsubstituted alkyl groups. In the embodiments, R 7 The phenyl group may be substituted or unsubstituted. In the embodiments, R 7 It is -(CH2)2OH. In the implementation scheme, R 7 The form is -CH2C(CH3)2OH. In the implementation scheme, R 7 It is -(CH2)3OH. In the implementation scheme, R 7 It is -(CH2)2CH(CH3)2OH. In the implementation scheme, R 7 It is –(CH2)2SO2NH2. In the implementation scheme, R 7 It is –(CH2)3SO2NH2. In the implementation scheme, R 7 It is -(CH2)2CONH2. In the implementation scheme, R 7 It is -(CH2)3CONH2. In the implementation scheme, R 7 It is -(CH2)3CON(H)Me. In the implementation scheme, R 7 It is -(CH2)3CON(Me)2. In the implementation scheme, R 7 It is -(CH2)2SO2Me. In the implementation scheme, R 7 It is -(CH2)3SO2Me. In the implementation scheme, R 7 It is -CH2CH(OH)Me. In the implementation scheme, R 7 It is -CH2CO2H. In the implementation scheme, R 7 It is -(CH2)2CO2H. In the implementation scheme, R 7 The form is -CH(CH3)CH2CO2H. In the implementation scheme, R 7 It is -(CH2)3CO2H. In the implementation scheme, R 7 It is -(CH2)2SO2NHCH3. In the implementation scheme, R 7 It is -(CH2)2SO2N(CH3)2. In the implementation scheme, R 7 It is -(CH2)2SO2-(N-morpholinyl). In the embodiments, R 7It is -(CH2)2NHCOCH3. In the implementation scheme, R 7 It is -(CH2)2NHC(O)OCH3. In the implementation scheme, R 7 It is -(CH2)3NHCOCH3. In the implementation scheme, R 7 It is -(CH2)2NHCOCH(CH3)2. In the implementation scheme, R 7 It is -(CH2)2NHSO2CH3. In the implementation scheme, R 7 It is -(CH2)2NHSO2CF3. In the implementation scheme, R 7 The expression is -(CH2)2NHSO2NHCH(CH3)2. In the implementation scheme, R... 7 The derivatives are -CH2CH(CH3)CH2OH (R and S). In the implementation scheme, R... 7 The form is -CH(CH3)(CH2)2OH. In the implementation scheme, R 7 It is -CH2-(2-imidazolyl). In the implementation scheme, R 7 It is -CH2-(4-imidazolyl). In the implementation scheme, R 7 It is -CH2-(3-pyrazolyl). In the embodiments, R 7 It is 4-tetrahydropyranyl. In the embodiments, R... 7 It is a 3-oxetane-butane. In the embodiment, R... 7 The value is -(CH2)2NHCO2Me. In the implementation scheme, R 7 It is -(CH2)3NHCO2Me.

[0241] In the implementation plan, R 7 It is hydrogen. In the implementation scheme, R 7 For –OH. In the implementation scheme, R 7 For –COOH. In the implementation scheme, R 7 The substituted pyrrolidinyl group (e.g., oxo-substituted pyrrolidinyl group). In the embodiments, R 7 It is an oxy group. In the embodiment, R... 7 For –SO2NH2. In the implementation scheme, R 7 For –NH2. In the implementation scheme, R 7 For –CH3. In the implementation scheme, R 7 For –CH2CH3. In the implementation scheme, R 7 For –NHCOCH3. In the implementation scheme, R 7 For –CONHCH3. In the implementation scheme, R 7 It is –NHSO2CH3. In the implementation scheme, R 7 For -NR 7BSO2R 7A In the implementation plan, R 7 It is -NHSO2CH3. In the implementation scheme, R 7 It is -NHSO2CH2CH3. In the implementation scheme, R 7 It is -NHSO2 (C1-C6 alkyl). In the embodiments, R 7 It is –COCH(CH3)2.

[0242] In the implementation plan, R 7 It is -CH2OH. In the implementation plan, R 7 for In the implementation plan, R 7 for In the implementation plan, R 7 for In the implementation plan, R 7 for In the implementation plan, R 7 for

[0243] In the implementation plan, R 7Hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted phenyl, -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, -CH2C(O)OCH2CH3, -SO2CH3, -SO2CH2CH3, -SO2CH(CH3)2, -NHSO2CH3, -N HSO2CH2CH3, -NHSO2CH(CH3)2, -SO2NH2, -SO2NHCH3, -(CH2)2OH, -CH2C(CH3)2OH, -(CH2)3OH, -(CH2)2CH(CH3)2 OH, –(CH2)2SO2NH2, –(CH2)3SO2NH2, –(CH2)2CONH2, –(CH2)3CONH2-(CH2)3CON(H)Me, –(CH2)3CON(Me)2, –(CH2 -2SO2Me, -(CH2)3SO2Me, -CH2CH(OH)Me, -CH2CO2H, -(CH2)2CO2H, -CH(CH3)CH2CO2H, -(CH2)3CO2H, -(CH2)2SO2NHCH3, -(CH2)2SO2N(CH3)2, -(CH2)2SO2-(N-morpholinyl), -(CH2)2NHCOCH3, -(CH2)3NHCOCH3, -(CH2)2NHCOCH(CH3)2, -(CH2)2NHSO2CH3, -(CH2)2NHSO2CF3, -(CH2)2NHSO2NHCH(CH3)2, -CH2CH(CH3)CH2OH (R and S), -CH(CH3)(CH2)2OH, -CH2-(2-imidazolyl), -CH2-(4-imidazolyl), -CH2-(3-pyrazolyl), 4-tetrahydropyranyl, 3-oxacyclobutane, -(CH2)2NHCO2Me, -(CH2)3NHCO2Me, -CH2OH

[0244] In the implementation plan, R 7 The substituted or unsubstituted compounds are aziridinyl, ethylene oxide, thiopropylcycloyl, aziridine, oxacyclobutyl, thiobutyl, pyrrolyl, pyrrolidinyl, imidazolyl, imidazolinyl, pyrazolinyl, tetrahydrofuranyl, thiocyclopentyl, piperidinyl, piperazinyl, pyranyl, morpholinyl, 1,4-dioxyl, tetrahydropyranyl, thiocyclohexyl, or dithiaalkyl. In the embodiments, R 7The substituted or unsubstituted phenyl, thiofuranyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, oxazolyl, isoxazolyl, oxadiazolyl, oxtriazolyl, thiophenyl, thiazolyl, isothiazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, or triazinyl (e.g., 1,3,5-triazinyl, 1,2,3-triazinyl, or 1,2,4-triazinyl). In the embodiments, R 7 The substituted or unsubstituted indole, benzimidazolyl, indazole, benzotriazolyl, pyrrolopyrimidinyl, purine, indoleazinyl, pyrrolopyrazinyl, pyrrolopyrimidinyl, imidazopyridazinyl, imidazopyridinyl, imidazopyrimidinyl, cyclolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, pyridinolpyrazinyl, pteridinyl, pyrazolopyridinyl, quinolinyl, isoquinolinyl, naphridinyl, or carbazoyl.

[0245] In the implementation plan, R 7 The substituted aziridinyl group. In the embodiment, R... 7 The substituted ethylene oxide. In the embodiment, R... 7 The substituted thiopropyl group. In the embodiments, R 7 The substituted nitrogen-containing heterocyclic butyl group. In the embodiment, R... 7 The substituted oxocyclic butyl group. In the embodiment, R... 7 The substituted thioheterobutylene group. In the embodiment, R... 7 The substituted pyrroleyl group. In the embodiments, R 7 The pyrrole group is replaced. In the implementation, R 7 The imidazole group is substituted. In the implementation scheme, R 7 The imidazolinyl group is substituted. In the embodiments, R 7 The substituted pyrazolinyl group is used. In the embodiments, R 7 The tetrahydrofuranyl group is substituted. In the embodiment, R 7 The substituted thiocyclopentane. In the embodiment, R... 7 The piperidinyl group is substituted. In the embodiments, R 7 The piperazine group is substituted. In the embodiments, R 7 The pyran group is replaced. In the implementation, R 7 For substituted morpholino groups. In the embodiments, R 7 The substituted 1,4-dioxane. In the embodiments, R... 7 The tetrahydropyranyl group is substituted. In the embodiments, R 7 The substituted thiohexane. In the embodiment, R... 7 It is a substituted or dithiaalkyl group.

[0246] In the implementation plan, R 7The substituted phenyl group. In the embodiments, R 7 The substituted thiofuran group. In the embodiment, R 7 The imidazole group is substituted. In the implementation scheme, R 7 The substituted pyrazol group. In the embodiments, R 7 The triazole group is substituted. In the implementation scheme, R 7 The tetrazolium group is substituted. In the embodiments, R 7 The furanyl group is substituted. In the implementation scheme, R 7 The substituted oxazolyl group. In the implementation scheme, R 7 The isoxazolyl group is substituted. In the embodiment, R... 7 The substituted oxadiazole group. In the implementation scheme, R 7 The substituted oxalizolate group. In the implementation scheme, R 7 The thiophene group is substituted. In the embodiment, R 7 The substituted thiazole group is used. In the embodiments, R 7 The isothiazol group is substituted. In the embodiment, R... 7 The substituted pyridinyl group is used. In the embodiments, R... 7 The substituted pyrazinyl group is used. In the embodiments, R 7 The substituted pyrimidinyl group. In the embodiments, R 7 For the substituted pyridazinyl group. In the embodiments, R 7 The substituted triazine group (e.g., 1,3,5-triazine, 1,2,3-triazine, or 1,2,4-triazine).

[0247] In the implementation plan, R 7 The indole group is substituted. In the embodiment, R 7 The substituted benzimidazole group is used. In the embodiments, R 7 The indazole group is substituted. In the embodiments, R 7 The substituted benzotriazole group is used. In the embodiments, R 7 The substituted pyrrolopyrimidine group. In the embodiment, R 7 The purine group is replaced. In the implementation, R 7 The indoleazine group is substituted. In the embodiments, R 7 For substituted pyrrolopyrazinyl groups. In the embodiments, R 7 The substituted pyrrolopyrimidine group. In the embodiment, R 7 The substituted imidazopyridazinyl group is used. In the embodiments, R 7 The substituted imidazopyridyl group. In the embodiments, R 7 The substituted imidazopyrimidinyl group is used. In the embodiments, R 7The substituted morpholino group is used. In the embodiments, R 7 The substituted quinazolinyl group is used. In the implementation scheme, R 7 The substituted quinoxalin group. In the implementation, R 7 The substituted phthalazine group is used. In the embodiments, R 7 For substituted pyridinylpyrazinyl groups. In the embodiments, R 7 For substituted pteridyl group. In the embodiment, R 7 The substituted pyrazolopyridyl group. In the embodiments, R 7 The substituted quinolinyl group. In the implementation scheme, R 7 The isoquinolinyl group is substituted. In the embodiment, R 7 For substituted naphthidyl groups. In the embodiments, R 7 The carbazoyl group is substituted.

[0248] In the implementation plan, R 7 It is an unsubstituted aziridinyl group. In the embodiments, R 7 It is an unsubstituted ethylene oxide. In the embodiments, R 7 It is an unsubstituted thiapropylcyclohexyl group. In the embodiments, R 7 It is an unsubstituted nitrogen-containing heterocyclic butyl group. In the embodiments, R 7 It is an unsubstituted oxocyclic butyl group. In the embodiments, R 7 It is an unsubstituted thioheterobutylene. In the embodiments, R 7 It is an unsubstituted pyrrolidinyl compound. In the embodiments, R 7 It is an unsubstituted pyrrole group. In the implementation scheme, R 7 It is an unsubstituted imidazole group. In the embodiments, R 7 It is an unsubstituted imidazolinyl group. In the embodiments, R 7 It is an unsubstituted pyrazolinyl group. In the embodiments, R 7 It is an unsubstituted tetrahydrofuranyl group. In the implementation scheme, R 7 It is an unsubstituted thiocyclopentane. In the embodiments, R 7 It is an unsubstituted piperidinyl group. In the embodiments, R 7 It is an unsubstituted piperazine group. In the embodiments, R 7 It is an unsubstituted pyranyl group. In the implementation scheme, R 7 It is an unsubstituted morpholino group. In the embodiments, R 7 It is an unsubstituted 1,4-dioxane. In the embodiments, R 7 It is an unsubstituted tetrahydropyranyl group. In the embodiments, R 7 It is an unsubstituted thiohexane. In the embodiments, R 7 It is an unsubstituted dithiaalkyl group.

[0249] In the implementation plan, R 7 It is an unsubstituted phenyl group. In the embodiments, R 7 It is an unsubstituted thiofuranyl group. In the embodiments, R 7 It is an unsubstituted imidazole group. In the embodiments, R 7 It is an unsubstituted pyrazolyl group. In the embodiments, R 7 It is an unsubstituted triazole group. In the implementation scheme, R 7 It is an unsubstituted tetrazolium group. In the embodiments, R 7 It is an unsubstituted furanyl group. In the implementation scheme, R 7 It is an unsubstituted oxazolyl group. In the implementation scheme, R 7 It is an unsubstituted isoxazolyl group. In the implementation scheme, R 7 It is an unsubstituted oxadiazole group. In the implementation scheme, R 7 It is an unsubstituted oxalizolate group. In the implementation scheme, R 7 It is an unsubstituted thiophene group. In the embodiments, R 7 It is an unsubstituted thiazole group. In the embodiments, R 7 It is an unsubstituted isothiazol group. In the embodiments, R 7 It is an unsubstituted pyridinyl group. In the embodiments, R 7 It is an unsubstituted pyrazinyl group. In the embodiments, R 7 It is an unsubstituted pyrimidinyl group. In the embodiments, R 7 It is an unsubstituted pyridazinyl group. In the embodiments, R 7 It is an unsubstituted triazine group (e.g., 1,3,5-triazine, 1,2,3-triazine, or 1,2,4-triazine).

[0250] In the implementation plan, R 7 It is an unsubstituted indole group. In the embodiment, R 7 It is an unsubstituted benzimidazole group. In the embodiments, R 7 It is an unsubstituted indazole group. In the embodiments, R 7 It is an unsubstituted benzotriazole group. In the embodiments, R 7 It is an unsubstituted pyrrolopyrimidine group. In the embodiments, R 7 It is an unsubstituted purine group. In the implementation, R 7 It is an unsubstituted indoleazine group. In the embodiments, R 7 It is an unsubstituted pyrrolopyrazinyl group. In the embodiments, R 7 It is an unsubstituted pyrrolopyrimidine group. In the embodiments, R 7 It is an unsubstituted imidazopyridazinyl group. In the embodiments, R 7It is an unsubstituted imidazopyridyl group. In the embodiments, R 7 It is an unsubstituted imidazopyrimidinyl group. In the embodiments, R 7 It is an unsubstituted cenolinyl group. In the embodiments, R 7 It is an unsubstituted quinazolinyl group. In the implementation scheme, R 7 It is an unsubstituted quinoxalinyl group. In the implementation scheme, R 7 It is an unsubstituted phthalazine group. In the embodiments, R 7 It is an unsubstituted pyridinylpyrazinyl group. In the embodiments, R 7 It is an unsubstituted pteridinyl group. In the embodiments, R 7 It is an unsubstituted pyrazolopyridinyl group. In the embodiments, R 7 It is an unsubstituted quinolinyl group. In the implementation scheme, R 7 It is an unsubstituted isoquinolinyl group. In the embodiments, R 7 It is an unsubstituted naphthidyl group. In the embodiments, R 7 It is an unsubstituted carbazoyl group.

[0251] In the implementation plan, R 7 Hydrogen, halogen, -SO n7 R 7A –SO v7 NR 7B R 7C -NHC(O)NR 7B R 7C –NR 7B R 7C –C(O)R 7D –C(O)OR 7D –C(O)NR 7B R 7C –OR 7A -NR 7B SO2R 7A -NR 7B C(O)R 7D -NR 7B C(O)OR 7D 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 the embodiments, R 7 For –OR 7A –C(O)R 7D –C(O)OR 7D –C(O)NR 7B R 7C –SO n7 R 7A –SOv7 NR 7B R 7C 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 the embodiments, R 7 Hydrogen, substituted or unsubstituted alkyl, phenyl, -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, -CH2C(O)OCH2CH3, -SO2CH3, -SO2CH2CH3, -SO2CH(CH3)2, -NHSO2CH3, -NHSO2CH2CH3, -NHSO2CH(CH3)2, -SO2NH2, -SO2NHCH3, -F, -OH, -CH2OH, -(CH2)2OH, -(CH2)3OH, -C(CH3)2OH, -CH2SO2NH2, –(CH2)2SO2NH 2、 -CH2C(O)NH2, -(CH2)2C(O)NH2, -(CH2)3C(O)NH2, -CH2NHSO2CF3, -(CH2)2NHSO2CF3, -(CH2)3NHSO2CF3, -CH2NHSO2CH3, -(CH2)2NHSO2CH3, -(CH2)3NHSO2CH 3、 -CH2SO2CH3, –(CH2)2SO2CH3, -CH2SO2NH2 or –(CH2)2SO2NH2.

[0252] In the implementation plan, R 7 It is hydrogen. In the implementation scheme, R 7 It is a substituted or unsubstituted alkyl group. In the embodiments, R 7 The phenyl group may be substituted or unsubstituted. In the embodiments, R 7 It is -C(O)OH. In the implementation scheme, R 7 It is -C(O)OCH3. In the implementation scheme, R 7 It is -C(O)OCH2CH3. In the implementation scheme, R 7 It is -CH2C(O)OH. In the implementation scheme, R 7 It is -NHC(O)OH. In the implementation scheme, R 7 It is -NHC(O)OCH3. In the implementation scheme, R 7 It is -NHC(O)OCH2CH3. In the implementation scheme, R 7It is -CH2C(O)OH. In the implementation scheme, R 7 It is -CH2C(O)OCH3. In the implementation scheme, R 7 It is -CH2C(O)OCH2CH3. In the implementation scheme, R 7 For -SO2CH3. In the implementation scheme, R 7 It is -SO2CH2CH3. In the implementation scheme, R 7 It is -SO2CH(CH3)2. In the implementation scheme, R 7 It is -NHSO2CH3. In the implementation scheme, R 7 It is -NHSO2CH2CH3. In the implementation scheme, R 7 It is -NHSO2CH(CH3)2. In the implementation scheme, R 7 For -SO2NH2. In the implementation scheme, R 7 It is -SO2NHCH3. In the implementation scheme, R 7 For -F. In the implementation scheme, R 7 It is -OH. In the implementation scheme, R 7 For -CH2OH. In the implementation scheme, R 7 It is -(CH2)2OH. In the implementation scheme, R 7 It is -(CH2)3OH. In the implementation scheme, R 7 It is -C(CH3)2OH. In the implementation scheme, R 7 For -CH2SO2NH2. In the implementation scheme, R 7 It is –(CH2)2SO2NH2. In the implementation scheme, R 7 It is -CH2C(O)NH2. In the implementation scheme, R 7 It is -(CH2)2C(O)NH2. In the implementation scheme, R 7 It is -(CH2)3C(O)NH2. In the implementation scheme, R 7 For -CH2NHSO2CF3. In the implementation scheme, R 7 It is -(CH2)2NHSO2CF3. In the implementation scheme, R 7 It is -(CH2)3NHSO2CF3. In the implementation scheme, R 7 It is -CH2NHSO2CH3. In the implementation scheme, R 7 It is -(CH2)2NHSO2CH3. In the implementation scheme, R 7 It is -(CH2)3NHSO2CH3. In the implementation scheme, R 7 It is -CH2SO2CH3. In the implementation scheme, R 7It is –(CH2)2SO2CH3. In the implementation scheme, R 7 For -CH2SO2NH2. In the implementation scheme, R 7 It is –(CH2)2SO2NH2.

[0253] In the implementation plan, R 7 Hydrogen, substituted or unsubstituted alkyl, phenyl, -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, -CH2C(O)OCH2CH3, -SO2CH3, -SO2CH2CH3, -SO2CH(CH3)2, -NHSO2CH3, -NHSO 2CH2CH3, -NHSO2CH(CH3)2, -SO2NH2, -SO2NHCH3, -(CH2)2OH, -CH2C(CH3)2OH, -(CH2)3OH, -(CH2)2CH(CH3)2O H, –(CH2)2SO2NH2, –(CH2)3SO2NH2, –(CH2)2CONH2, –(CH2)3CONH2-(CH2)3CON(H)Me, –(CH2)3CON(Me)2, –(CH2 -2SO2Me, -(CH2)3SO2Me, -CH2CH(OH)Me, -CH2CO2H, -(CH2)2CO2H, -CH(CH3)CH2CO2H, -(CH2)3CO2H, -(CH2)2SO2NHCH3, -(CH2)2SO2N(CH3)2, -(CH2)2SO2-(N-morpholinyl), -(CH2)2NHCOCH3, -(CH2)3NHCOCH3, -(CH2)2NHCOCH(CH3) )2、-(CH2)2NHSO2CH3、-(CH2)2NHSO2CF3、-(CH2)2NHSO2NHCH(CH3)2、-CH2CH(CH3)CH2OH(R and S),-CH(CH3)(CH2)2OH、-CH2-(2-imidazolyl),-CH2-(4-imidazolyl),-CH2-(3-pyrazolyl),4-tetrahydropyranyl,3-oxacyclobutyl,-(CH2)2NHCO2Me or-(CH2)3NHCO2Me.

[0254] In the implementation plan, R 7 It is hydrogen. In the implementation scheme, R 7 It is a substituted or unsubstituted alkyl group. In the embodiments, R 7 The phenyl group may be substituted or unsubstituted. In the embodiments, R 7It is -C(O)OH. In the implementation scheme, R 7 It is -C(O)OCH3. In the implementation scheme, R 7 It is -C(O)OCH2CH3. In the implementation scheme, R 7 It is -CH2C(O)OH. In the implementation scheme, R 7 It is -NHC(O)OH. In the implementation scheme, R 7 It is -NHC(O)OCH3. In the implementation scheme, R 7 It is -NHC(O)OCH2CH3. In the implementation scheme, R 7 It is -CH2C(O)OH. In the implementation scheme, R 7 It is -CH2C(O)OCH3. In the implementation scheme, R 7 It is -CH2C(O)OCH2CH3. In the implementation scheme, R 7 For -SO2CH3. In the implementation scheme, R 7 It is -SO2CH2CH3. In the implementation scheme, R 7 It is -SO2CH(CH3)2. In the implementation scheme, R 7 It is -NHSO2CH3. In the implementation scheme, R 7 It is -NHSO2CH2CH3. In the implementation scheme, R 7 It is -NHSO2CH(CH3)2. In the implementation scheme, R 7 For -SO2NH2. In the implementation scheme, R 7 It is -SO2NHCH3. In the implementation scheme, R 7 It is -(CH2)2OH. In the implementation scheme, R 7 The form is -CH2C(CH3)2OH. In the implementation scheme, R 7 It is -(CH2)3OH. In the implementation scheme, R 7 It is -(CH2)2CH(CH3)2OH. In the implementation scheme, R 7 It is –(CH2)2SO2NH2. In the implementation scheme, R 7 It is –(CH2)3SO2NH2. In the implementation scheme, R 7 It is -(CH2)2CONH2. In the implementation scheme, R 7 The expression is -(CH2)3CONH2-(CH2)3CON(H)Me. In the implementation scheme, R 7 It is -(CH2)3CON(Me)2. In the implementation scheme, R 7 It is -(CH2)2SO2Me. In the implementation scheme, R 7 It is -(CH2)3SO2Me. In the implementation scheme, R7 It is -CH2CH(OH)Me. In the implementation scheme, R 7 It is -CH2CO2H. In the implementation scheme, R 7 It is -(CH2)2CO2H. In the implementation scheme, R 7 The form is -CH(CH3)CH2CO2H. In the implementation scheme, R 7 It is -(CH2)3CO2H. In the implementation scheme, R 7 It is -(CH2)2SO2NHCH3. In the implementation scheme, R 7 It is -(CH2)2SO2N(CH3)2. In the implementation scheme, R 7 It is -(CH2)2SO2-(N-morpholinyl). In the embodiments, R 7 It is -(CH2)2NHCOCH3. In the implementation scheme, R 7 It is -(CH2)3NHCOCH3. In the implementation scheme, R 7 It is -(CH2)2NHCOCH(CH3)2. In the implementation scheme, R 7 It is -(CH2)2NHSO2CH3. In the implementation scheme, R 7 It is -(CH2)2NHSO2CF3. In the implementation scheme, R 7 The expression is -(CH2)2NHSO2NHCH(CH3)2. In the implementation scheme, R... 7 The derivatives are -CH2CH(CH3)CH2OH (R and S). In the implementation scheme, R... 7 The form is -CH(CH3)(CH2)2OH. In the implementation scheme, R 7 It is -CH2-(2-imidazolyl). In the implementation scheme, R 7 It is -CH2-(4-imidazolyl). In the implementation scheme, R 7 It is -CH2-(3-pyrazolyl). In the embodiments, R 7 It is 4-tetrahydropyranyl. In the embodiments, R... 7 It is a 3-oxetane-butane. In the embodiment, R... 7 The value is -(CH2)2NHCO2Me. In the implementation scheme, R 7 It is -(CH2)3NHCO2Me.

[0255] In the implementation plan, R 7 For R 29 Substituted or unsubstituted C1-C6 alkyl groups. In the embodiments, R 7 For R 29 Substituted C1-C6 alkyl group. In the embodiments, R 7It is an unsubstituted C1-C6 alkyl group. In the embodiments, R 7 For R 29 Substituted or unsubstituted C2-C6 alkyl groups. In the embodiments, R 7 For R 29 Substituted C2-C6 alkyl group. In the embodiments, R 7 It is an unsubstituted C2-C6 alkyl group. In the embodiments, R 7 For R 29 Substituted or unsubstituted C1 alkyl group. In the embodiments, R 7 For R 29 Substituted C1 alkyl group. In the embodiment, R 7 It is an unsubstituted C1 alkyl group. In the embodiments, R 7 For R 29 Substituted or unsubstituted C2 alkyl group. In the embodiments, R 7 For R 29 Substituted C2 alkyl group. In the embodiment, R 7 It is an unsubstituted C2 alkyl group. In the embodiments, R 7 For R 29 Substituted or unsubstituted C3 alkyl group. In the embodiments, R 7 For R 29 Substituted C3 alkyl group. In the embodiment, R 7 It is an unsubstituted C3 alkyl group. In the embodiments, R 7 For R 29 Substituted or unsubstituted C4 alkyl. In the embodiments, R 7 For R 29 Substituted C4 alkyl. In the embodiments, R 7 It is an unsubstituted C4 alkyl group. In the embodiments, R 7 For R 29 Substituted or unsubstituted C5 alkyl group. In the embodiments, R 7 For R 29 Substituted C5 alkyl group. In the embodiment, R 7 It is an unsubstituted C5 alkyl group. In the embodiments, R 7 For R 29 Substituted or unsubstituted C6 alkyl group. In the embodiments, R 7 For R 29 Substituted C6 alkyl group. In the embodiments, R 7 It is an unsubstituted C6 alkyl group.

[0256] In the implementation plan, R 7 For R 29 Substituted or unsubstituted 2- to 8-membered heteroalkyl groups. In the embodiments, R 7 For R 29Substituted 2- to 8-membered heteroalkyl groups. In the embodiments, R 7 It is an unsubstituted 2- to 8-membered heteroalkyl group. In the embodiments, R 7 For R 29 Substituted or unsubstituted dialkyl group. In the embodiments, R 7 For R 29 Substituted dialkyl group. In the embodiment, R 7 It is an unsubstituted dialkyl group. In the embodiments, R 7 For R 29 Substituted or unsubstituted trialkyl group. In the embodiments, R 7 For R 29 Substituted ternary heteroalkyl groups. In the embodiments, R 7 It is an unsubstituted trialkyl group. In the embodiments, R 7 For R 29 Substituted or unsubstituted 4-membered heteroalkyl groups. In the embodiments, R 7 For R 29 Substituted 4-membered heteroalkyl group. In the embodiment, R 7 It is an unsubstituted four-membered heteroalkyl group. In the embodiments, R 7 For R 29 Substituted or unsubstituted 5-membered heteroalkyl group. In the embodiments, R 7 For R 29 Substituted 5-membered heteroalkyl group. In the embodiment, R 7 It is an unsubstituted 5-membered heteroalkyl group. In the embodiments, R 7 For R 29 Substituted or unsubstituted 6-membered heteroalkyl groups. In the embodiments, R 7 For R 29 Substituted 6-membered heteroalkyl group. In the embodiment, R 7 It is an unsubstituted 6-membered heteroalkyl group. In the embodiments, R 7 For R 29 Substituted or unsubstituted 7-membered heteroalkyl group. In the embodiments, R 7 For R 29 Substituted 7-membered heteroalkyl group. In the embodiment, R 7 It is an unsubstituted 7-membered heteroalkyl group.

[0257] In the implementation plan, R 7 For R 29 Substituted or unsubstituted C4-C6 cycloalkyl groups. In the embodiments, R 7 For R 29 Substituted C4-C6 cycloalkyl. In the embodiments, R 7 For R 29 Substituted C4-C6 cycloalkyl. In the embodiments, R 7 For R29 Substituted or unsubstituted C4 cycloalkyl group. In the embodiments, R 7 For R 29 Substituted C4 cycloalkyl group. In the embodiment, R 7 For R 29 Substituted C4 cycloalkyl group. In the embodiment, R 7 For R 29 Substituted or unsubstituted C5 cycloalkyl group. In the embodiments, R 7 For R 29 Substituted C5 cycloalkyl group. In the embodiment, R 7 For R 29 Substituted C5 cycloalkyl groups.

[0258] In the implementation plan, R 7 For R 29 Substituted or unsubstituted 5- to 6-membered heterocyclic alkyl groups. In the embodiments, R 7 For R 29 Substituted 5- to 6-membered heterocyclic alkyl groups. In the embodiments, R 7 It is an unsubstituted 5- to 6-membered heterocyclic alkyl group. In the embodiments, R 7 For R 29 Substituted or unsubstituted 5-membered heterocyclic alkyl group. In the embodiments, R 7 For R 29 Substituted 5-membered heterocyclic alkyl group. In the embodiment, R 7 It is an unsubstituted 5-membered heterocyclic alkyl group. In the embodiments, R 7 For R 29 Substituted or unsubstituted 6-membered heterocyclic alkyl group. In the embodiments, R 7 For R 29 Substituted 6-membered heterocyclic alkyl group. In the embodiment, R 7 It is an unsubstituted 6-membered heterocyclic alkyl group.

[0259] In the implementation plan, R 7 For R 29 Substituted or unsubstituted phenyl groups. In the embodiments, R 7 For R 29 Substituted phenyl group. In the implementation scheme, R 7 It is an unsubstituted phenyl group.

[0260] In the implementation plan, R 7 For R 29 Substituted or unsubstituted 5- to 6-membered heteroaryl groups. In the embodiments, R 7 For R 29 The substituted 5- to 6-membered heteroaryl group. In the implementation scheme, R 7 It is an unsubstituted 5- to 6-membered heteroaryl group. In the implementation scheme, R 7 For R29 Substituted or unsubstituted 5-membered heteroaryl group. In the embodiments, R 7 For R 29 The substituted 5-membered heteroaryl group. In the implementation scheme, R 7 It is an unsubstituted 5-membered heteroaryl group. In the implementation scheme, R 7 For R 29 Substituted or unsubstituted 6-membered heteroaryl group. In the embodiments, R 7 For R 29 The substituted 6-membered heteroaryl group. In the implementation scheme, R 7 It is an unsubstituted 6-membered heteroaryl group.

[0261] In the implementation plan, R 7 It is an oxy group. In the embodiment, R... 7 For –CF3. In the implementation plan, R 7 For -CHF2. In the implementation scheme, R 7 For -CH2F. In the implementation scheme, R 7 For –SO2CH3. In the implementation scheme, R 7 For –SO2NH2. In the implementation scheme, R 7 It is -NHC(O)NH2. In the implementation scheme, R 7 For –NH2. In the implementation scheme, R 7 For –C(O)OH. In the implementation scheme, R 7 It is –C(O)OCH3. In the implementation scheme, R 7 For –C(O)NH2. In the implementation scheme, R 7 For –OCH3. In the implementation scheme, R 7 It is -NHSO2CH3. In the implementation scheme, R 7 It is -NHC(O)CH3. In the implementation scheme, R 7 It is -NHC(O)OH. In the implementation scheme, R 7 For –OCF3. In the implementation scheme, R 7 For –OCHF2. In the implementation scheme, R 7 For -OCH2F. In the implementation scheme, R 7 It is hydrogen. In the implementation scheme, R 7 For –OH. In the implementation scheme, R 7 It is –C(O)OCH2CH3. In the implementation scheme, R 7 It is -SO2CH2CH3. In the implementation scheme, R 7 It is -SO2CH2CH2CH3. In the implementation scheme, R 7 It is -SO2CH(CH3)2. In the implementation scheme, R 7It is –C(O)NHCH3. In the implementation scheme, R 7 It is –C(O)N(CH3)2. In the implementation scheme, R 7 It is -NHC(O)OCH3. In the implementation scheme, R 7 It is -NHC(O)OCH2CH3. In the implementation scheme, R 7 It is -NHC(O)OCH2CH2CH3. In the implementation scheme, R 7 It is -NHC(O)OCH(CH3)2. In the implementation scheme, R 7 It is -NHC(O)CH3. In the implementation scheme, R 7 It is -NHC(O)CH2CH3. In the implementation scheme, R 7 It is -NHC(O)CH2CH2CH3. In the implementation scheme, R 7 It is -NHC(O)CH(CH3)2.

[0262] In the implementation plan, R 29 It is an oxy group. In the embodiment, R... 29 For –CF3. In the implementation plan, R 29 For -CHF2. In the implementation scheme, R 29 For -CH2F. In the implementation scheme, R 29 For –SO2CH3. In the implementation scheme, R 29 For –SO2NH2. In the implementation scheme, R 29 It is -NHC(O)NH2. In the implementation scheme, R 29 For –NH2. In the implementation scheme, R 29 For –C(O)OH. In the implementation scheme, R 29 It is –C(O)OCH3. In the implementation scheme, R 29 For –C(O)NH2. In the implementation scheme, R 29 For –OCH3. In the implementation scheme, R 29 It is -NHSO2CH3. In the implementation scheme, R 29 It is -NHC(O)CH3. In the implementation scheme, R 29 It is -NHC(O)OH. In the implementation scheme, R 29 For –OCF3. In the implementation scheme, R 29 For –OCHF2. In the implementation scheme, R 29 For -OCH2F. In the implementation scheme, R 29 It is hydrogen. In the implementation scheme, R 29 For –OH. In the implementation scheme, R 29 It is –C(O)OCH2CH3. In the implementation scheme, R29 It is -SO2CH2CH3. In the implementation scheme, R 29 It is -SO2CH2CH2CH3. In the implementation scheme, R 29 It is -SO2CH(CH3)2. In the implementation scheme, R 29 It is –C(O)NHCH3. In the implementation scheme, R 29 It is –C(O)N(CH3)2. In the implementation scheme, R 29 It is -NHC(O)OCH3. In the implementation scheme, R 29 It is -NHC(O)OCH2CH3. In the implementation scheme, R 29 It is -NHC(O)OCH2CH2CH3. In the implementation scheme, R 29 It is -NHC(O)OCH(CH3)2. In the implementation scheme, R 29 It is -NHC(O)CH3. In the implementation scheme, R 29 It is -NHC(O)CH2CH3. In the implementation scheme, R 29 It is -NHC(O)CH2CH2CH3. In the implementation scheme, R 29 It is -NHC(O)CH(CH3)2.

[0263] In the implementation plan, R 29 For R 30 Substituted or unsubstituted C1-C6 alkyl groups. In the embodiments, R 29 For R 30 Substituted C1-C6 alkyl group. In the embodiments, R 29 It is an unsubstituted C1-C6 alkyl group. In the embodiments, R 29 For R 30 Substituted or unsubstituted C2-C6 alkyl groups. In the embodiments, R 29 For R 30 Substituted C2-C6 alkyl group. In the embodiments, R 29 It is an unsubstituted C2-C6 alkyl group. In the embodiments, R 29 For R 30 Substituted or unsubstituted C1 alkyl group. In the embodiments, R 29 For R 30 Substituted C1 alkyl group. In the embodiment, R 29 It is an unsubstituted C1 alkyl group. In the embodiments, R 29 For R 30 Substituted or unsubstituted C2 alkyl group. In the embodiments, R 29 For R 30 Substituted C2 alkyl group. In the embodiment, R 29It is an unsubstituted C2 alkyl group. In the embodiments, R 29 For R 30 Substituted or unsubstituted C3 alkyl group. In the embodiments, R 29 For R 30 Substituted C3 alkyl group. In the embodiment, R 29 It is an unsubstituted C3 alkyl group. In the embodiments, R 29 For R 30 Substituted or unsubstituted C4 alkyl. In the embodiments, R 29 For R 30 Substituted C4 alkyl. In the embodiments, R 29 It is an unsubstituted C4 alkyl group. In the embodiments, R 29 For R 30 Substituted or unsubstituted C5 alkyl group. In the embodiments, R 29 For R 30 Substituted C5 alkyl group. In the embodiment, R 29 It is an unsubstituted C5 alkyl group. In the embodiments, R 29 For R 30 Substituted or unsubstituted C6 alkyl group. In the embodiments, R 29 For R 30 Substituted C6 alkyl group. In the embodiments, R 29 It is an unsubstituted C6 alkyl group.

[0264] In the implementation plan, R 29 For R 30 Substituted or unsubstituted 2- to 8-membered heteroalkyl groups. In the embodiments, R 29 For R 30 Substituted 2- to 8-membered heteroalkyl groups. In the embodiments, R 29 It is an unsubstituted 2- to 8-membered heteroalkyl group. In the embodiments, R 29 For R 30 Substituted or unsubstituted dialkyl group. In the embodiments, R 29 For R 30 Substituted dialkyl group. In the embodiment, R 29 It is an unsubstituted dialkyl group. In the embodiments, R 29 For R 30 Substituted or unsubstituted trialkyl group. In the embodiments, R 29 For R 30 Substituted ternary heteroalkyl groups. In the embodiments, R 29 It is an unsubstituted trialkyl group. In the embodiments, R 29 For R 30 Substituted or unsubstituted 4-membered heteroalkyl groups. In the embodiments, R 29 For R 30Substituted 4-membered heteroalkyl group. In the embodiment, R 29 It is an unsubstituted four-membered heteroalkyl group. In the embodiments, R 29 For R 30 Substituted or unsubstituted 5-membered heteroalkyl group. In the embodiments, R 29 For R 30 Substituted 5-membered heteroalkyl group. In the embodiment, R 29 It is an unsubstituted 5-membered heteroalkyl group. In the embodiments, R 29 For R 30 Substituted or unsubstituted 6-membered heteroalkyl groups. In the embodiments, R 29 For R 30 Substituted 6-membered heteroalkyl group. In the embodiment, R 29 It is an unsubstituted 6-membered heteroalkyl group. In the embodiments, R 29 For R 30 Substituted or unsubstituted 7-membered heteroalkyl group. In the embodiments, R 29 For R 30 Substituted 7-membered heteroalkyl group. In the embodiment, R 29 It is an unsubstituted 7-membered heteroalkyl group.

[0265] In the implementation plan, R 29 For R 30 Substituted or unsubstituted C4-C6 cycloalkyl groups. In the embodiments, R 29 For R 30 Substituted C4-C6 cycloalkyl. In the embodiments, R 29 For R 30 Substituted C4-C6 cycloalkyl. In the embodiments, R 29 For R 30 Substituted or unsubstituted C4 cycloalkyl group. In the embodiments, R 29 For R 30 Substituted C4 cycloalkyl group. In the embodiment, R 29 For R 30 Substituted C4 cycloalkyl group. In the embodiment, R 29 For R 30 Substituted or unsubstituted C5 cycloalkyl group. In the embodiments, R 29 For R 30 Substituted C5 cycloalkyl group. In the embodiment, R 29 For R 30 Substituted C5 cycloalkyl groups.

[0266] In the implementation plan, R 29 For R 30 Substituted or unsubstituted 5- to 6-membered heterocyclic alkyl groups. In the embodiments, R 29 For R 30Substituted 5- to 6-membered heterocyclic alkyl groups. In the embodiments, R 29 It is an unsubstituted 5- to 6-membered heterocyclic alkyl group. In the embodiments, R 29 For R 30 Substituted or unsubstituted 5-membered heterocyclic alkyl group. In the embodiments, R 29 For R 30 Substituted 5-membered heterocyclic alkyl group. In the embodiment, R 29 It is an unsubstituted 5-membered heterocyclic alkyl group. In the embodiments, R 29 For R 30 Substituted or unsubstituted 6-membered heterocyclic alkyl group. In the embodiments, R 29 For R 30 Substituted 6-membered heterocyclic alkyl group. In the embodiment, R 29 It is an unsubstituted 6-membered heterocyclic alkyl group.

[0267] In the implementation plan, R 29 For R 30 Substituted or unsubstituted phenyl groups. In the embodiments, R 29 For R 30 Substituted phenyl group. In the implementation scheme, R 29 It is an unsubstituted phenyl group.

[0268] In the implementation plan, R 29 For R 30 Substituted or unsubstituted 5- to 6-membered heteroaryl groups. In the embodiments, R 29 For R 30 The substituted 5- to 6-membered heteroaryl group. In the implementation scheme, R 29 It is an unsubstituted 5- to 6-membered heteroaryl group. In the implementation scheme, R 29 For R 30 Substituted or unsubstituted 5-membered heteroaryl group. In the embodiments, R 29 For R 30 The substituted 5-membered heteroaryl group. In the implementation scheme, R 29 It is an unsubstituted 5-membered heteroaryl group. In the implementation scheme, R 29 For R 30 Substituted or unsubstituted 6-membered heteroaryl group. In the embodiments, R 29 For R 30 The substituted 6-membered heteroaryl group. In the implementation scheme, R 29 It is an unsubstituted 6-membered heteroaryl group.

[0269] In the implementation plan, R 7 for In the implementation plan, R 7 for In the implementation plan, R 7 for In the implementation plan, R7 for In the implementation plan, R 7 for In the implementation plan, R 7 for In the implementation plan, R 7 for In the implementation plan, R 7 for In the implementation plan, R 7 for In the implementation plan, R 7 for In the implementation plan, R 7 for In the implementation plan, R 7 for In the implementation plan, R 7 for In the implementation plan, R 7 for In the implementation plan, R 7 for In the implementation plan, R 7 for In the implementation plan, R 7 for In the implementation plan, R 7 for In the implementation plan, R 7 for In the implementation plan, R 7 for In the implementation plan, R 7 for In the implementation plan, R 7 for In the implementation plan, R 7 for In the implementation plan, R 7 for In the implementation plan, R 7 for In the implementation plan, R 7 for In the implementation plan, R 7 for In the implementation plan, R 7 for In the implementation plan, R 7 for In the implementation plan, R 7 for In the implementation plan, R 7 for In the implementation plan, R 7 for In the implementation plan, R 7 for In the implementation plan, R 7 for In the implementation plan, R 7 for In the implementation plan, R 7 for In the implementation plan, R 7 for In the implementation plan, R 7 for In the implementation plan, R 7 for In the implementation plan, R 7 for In the implementation plan, R 7 for In the implementation plan, R 7 for In the implementation plan, R 7 for In the implementation plan, R 7 for In the implementation plan, R 7 for In the implementation plan, R 7 for In the implementation plan, R 7 for In the implementation plan, R 7 for In the implementation plan, R 7 for In the implementation plan, R 7 for In the implementation plan, R 7 for In the implementation plan, R 7 for In the implementation plan, R 7 for

[0270] In the implementation plan, R 7 It is an oxy group. In the embodiment, R... 7 For –CH3. In the implementation scheme, R 7 For –COOH. In the implementation scheme, R 7 It is -NHC(O)NH2. In the implementation scheme, R 7 For –OH. In the implementation scheme, R 7 For –NH2. In the implementation scheme, R 7 For –CONH2. In the implementation scheme, R 7It is -NHC(O)OH. In the implementation scheme, R 7 For –SO2CH3. In the implementation scheme, R 7 It is –NHSO2CH3. In the implementation scheme, R 7 It is –SO2CH2CH3. In the implementation scheme, R 7 For –SO2R 29 In the implementation plan, R 7 It is –SO2CH(CH3)2. In the implementation scheme, R 7 For –COOEt. In the implementation scheme, R 7 For –NHCOCH3. In the implementation scheme, R 7 The value is –NHSO2CH(CH3)2. In the implementation scheme, R 7 It is –NHCOCH(CH3)2. In the implementation scheme, R 7 For –NHCOOCH3. In the implementation scheme, R 7 For –SO2NHCH3. In the implementation scheme, R 7 For –CONHCH3. In the implementation scheme, R 7 For –CON(CH3)2. In the implementation scheme, R 7 For –SO2NH2. In the implementation scheme, R 7 It is an unsubstituted morpholino group. In the embodiments, R 7 It is an unsubstituted imidazole group. In the embodiments, R 7 It is an unsubstituted thiohexane. In the embodiments, R 7 It is an unsubstituted tetrahydropyranyl group. In the embodiments, R 7 It is an unsubstituted pyrazolyl group. In the embodiments, R 7 It is an unsubstituted pyrrolidinyl compound. In the embodiments, R 7 For R 29 Substituted morpholino group. In the embodiment, R 7 For R 29 The imidazole group is substituted. In the implementation scheme, R 7 For R 29 Substituted thiohexane. In the embodiment, R 7 For R 29 Substituted tetrahydropyranyl group. In the embodiment, R 7 For R 29 Substituted pyrazol group. In the embodiment, R 7 For R 29 Substituted pyrrolidinyl. In the embodiments, R 7 For –CH3. In the implementation scheme, R 7 The methyl group is unsubstituted. In the embodiments, R 7It is an unsubstituted ethyl group. In the embodiments, R 7 It is an unsubstituted propyl group. In the implementation scheme, R 7 It is an unsubstituted n-propyl group. In the implementation scheme, R 7 It is an unsubstituted isopropyl group. In the embodiment, R 7 It is an unsubstituted butyl. In the implementation, R 7 It is an unsubstituted n-butyl. In the implementation scheme, R 7 It is an unsubstituted isobutyl group. In the implementation, R 7 It is unsubstituted tert-butyl. In the implementation, R... 7 It is an unsubstituted pentyl group. In the implementation scheme, R 7 It is an unsubstituted n-pentyl group. In the implementation scheme, R... 7 For unsubstituted hexyl groups. In the implementation scheme, R 7 It is an unsubstituted heptyl group. In the implementation scheme, R... 7 For R 29 Substituted methyl group. In the embodiment, R 7 For R 29 Substituted ethyl. In the embodiment, R 7 For R 29 The substituted propyl group. In the implementation scheme, R... 7 For R 29 The n-propyl group is substituted. In the embodiment, R... 7 For R 29 Substituted isopropyl. In the embodiment, R... 7 For R 29 Replaced butyl. In the implementation, R 7 For R 29 The n-butyl group is substituted. In the implementation, R... 7 For R 29 Substituted isobutyl. In the implementation, R 7 For R 29 Replaced tert-butyl. In the implementation, R... 7 For R 29 Substituted pentyl. In the implementation, R 7 For R 29 Substituted n-pentyl. In the implementation, R 7 For R 29 Replacement of the hexyl group. In the implementation scheme, R 7 For R 29 Replaced heptyl.

[0271] In the implementation plan, R 7 For the phosphine oxide portion. In the implementation scheme, R 7 It is an alkylphosphine moiety, such as -CH2PO(CH3)2 or -CH2CH2PO(CH3)2.

[0272] In the implementation plan, R 7 For hydrogen, R 29 Substituted or unsubstituted alkyl, phenyl, -F, -OH, CH2OH, -(CH2)2OH, -(CH2)3OH, -C(CH3)2OH, -CH2SO2NH2, –(CH2)2SO2NH 2、 -CH2C(O)NH2, -(CH2)2C(O)NH2, -(CH2)3C(O)NH2, -CH2NHSO2CF3, -(CH2)2NHSO2CF3, -(CH2)3NHSO2CF3, -CH2NHSO2CH3, -(CH2)2NHSO2CH3, -(CH2)3NHSO2CH 3、 -CH2SO2CH3, –(CH2)2SO2CH3, -CH2SO2NH2 or –(CH2)2SO2NH2.

[0273] In the implementation plan, R 7 For R 29 Substituted or unsubstituted alkyl groups (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In the embodiments, R 7 For R 29 Substituted alkyl groups (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In the embodiments, R 7 It is an unsubstituted alkyl group (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In the embodiments, R 7 It is an unsubstituted C1-C4 alkyl group. In the embodiments, R 7 It is an unsubstituted C1-C3 alkyl group. In the embodiments, R 7 It is an unsubstituted C1-C2 alkyl group. In the embodiments, R 7 It is an unsubstituted C4 alkyl group. In the embodiments, R 7 It is an unsubstituted C3 alkyl group. In the embodiments, R 7 For R 29 Substituted alkyl groups (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In the embodiments, R 7 For R 29 Substituted C1-C4 alkyl group. In the embodiments, R 7 For R 29 Substituted C1-C3 alkyl group. In the embodiments, R 7 For R 29 Substituted C1-C2 alkyl group. In the embodiments, R 7 For R 29Substituted C4 alkyl. In the embodiments, R 7 For R 29 Substituted C3 alkyl group.

[0274] In the implementation plan, R 7 For R 29 Substituted or unsubstituted heteroalkyl groups (e.g., 2- to 8-membered heteroalkyl groups, 2- to 6-membered heteroalkyl groups, or 2- to 4-membered heteroalkyl groups). In the embodiments, R 7 For R 29 Substituted heteroalkyl groups (e.g., 2- to 8-membered heteroalkyl groups, 2- to 6-membered heteroalkyl groups, or 2- to 4-membered heteroalkyl groups). In the embodiments, R 7 It is an unsubstituted heteroalkyl group (e.g., 2 to 8-membered heteroalkyl, 2 to 6-membered heteroalkyl, or 2 to 4-membered heteroalkyl).

[0275] In the implementation plan, R 7 For R 29 Substituted or unsubstituted cycloalkyl groups (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In the embodiments, R 7 For R 29 Substituted cycloalkyl groups (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In the embodiments, R 7 It is an unsubstituted cycloalkyl group (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In the embodiments, R 7 It is an unsubstituted C3-C6 cycloalkyl group. In the embodiments, R 7 It is an unsubstituted C3-C5 cycloalkyl group. In the embodiments, R 7 It is an unsubstituted C3-C4 cycloalkyl group. In the embodiments, R 7 It is an unsubstituted C4 cycloalkyl group. In the embodiments, R 7 For R 29 Substituted C3-C6 cycloalkyl groups.

[0276] In the implementation plan, R 7 For R 29 Substituted C3-C5 cycloalkyl group. In the embodiments, R 7 For R 29 Substituted C3-C4 cycloalkyl group. In the embodiments, R 7 For R 29 Substituted C4 cycloalkyl groups.

[0277] In the implementation plan, R 7 For R 29 Substituted or unsubstituted heterocyclic alkyl groups (e.g., 3- to 8-membered heterocyclic alkyl groups, 3- to 6-membered heterocyclic alkyl groups, or 5- to 6-membered heterocyclic alkyl groups). In the embodiments, R 7 For R29 Substituted heterocyclic alkyl groups (e.g., 3- to 8-membered heterocyclic alkyl groups, 3- to 6-membered heterocyclic alkyl groups, or 5- to 6-membered heterocyclic alkyl groups). In the embodiments, R 7 It is an unsubstituted heterocyclic alkyl group (e.g., a 3- to 8-membered heterocyclic alkyl group, a 3- to 6-membered heterocyclic alkyl group, or a 5- to 6-membered heterocyclic alkyl group). In the embodiments, R 7 For R 29 Substituted 5- to 6-membered heterocyclic alkyl groups. In the embodiments, R 7 For R 29 Substituted 5-membered heterocyclic alkyl group. In the embodiment, R 7 For R 29 Substituted 6-membered heterocyclic alkyl groups.

[0278] In the implementation plan, R 7 For R 29 Substituted or unsubstituted aryl groups (e.g., C6-C) 10 Aryl, C 10 (aryl or phenyl). In the implementation scheme, R 7 For R 29 Substituted aryl groups (e.g., C6-C) 10 Aryl, C 10 (aryl or phenyl). In the implementation scheme, R 7 For unsubstituted aryl groups (e.g., C6-C) 10 Aryl, C 10 (aryl or phenyl).

[0279] In the implementation plan, R 7 For R 29 Substituted or unsubstituted heteroaryl groups (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In the embodiments, R 7 For R 29 Substituted heteroaryl groups (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In the embodiments, R 7 It is an unsubstituted heteroaryl group (e.g., 5 to 10-membered heteroaryl, 5 to 9-membered heteroaryl, or 5 to 6-membered heteroaryl).

[0280] In the implementation plan, R 8 Halogen, –CX 8.1 3. -CHX 8.1 2. -CH2X 8.1 –CN, –N3, –SO n8 R 8A –SO v8 NR 8B R 8C -NHNR 8B R 8C -ONR 8BR 8C -NHC(O)NHNR 8B R 8C -NHC(O)NR 8B R 8C –N(O) m8 –NR 8B R 8C –C(O)R 8D –C(O)OR 8D –C(O)NR 8B R 8C –OR 8A -NR 8B SO2R 8A -NR 8B C(O)R 8D -NR 8B C(O)OR 8D –NR 8B OR 8D –OCX 8.1 3. –OCHX 8.1 2. –OCH2X 8.1 Substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In the embodiments, R 8 It is hydrogen.

[0281] In the implementation plan, R 8 Halogen, –CX 8.1 3. -CHX 8.1 2. -CH2X 8.1 –CN, –N3, –SO n8 R 8A –SO v8 NR 8B R 8C -NHNR 8B R 8C -ONR 8B R 8C -NHC(O)NHNR 8B R 8C -NHC(O)NR 8B R 8C –N(O) m8 –NR 8B R 8C –C(O)R 8D –C(O)OR 8D –C(O)NR 8B R 8C –OR 8A -NR8B SO2R 8A -NR 8B C(O)R 8D -NR 8B C(O)OR 8D –NR 8B OR 8D –OCX 8.1 3. –OCHX 8.1 2. –OCH2X 8.1 R 32 Substituted or unsubstituted alkyl groups (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 32 Substituted or unsubstituted heteroalkyl groups (e.g., 2- to 8-membered heteroalkyl groups, 2- to 6-membered heteroalkyl groups, or 2- to 4-membered heteroalkyl groups), R 32 Substituted or unsubstituted cycloalkyl groups (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R 32 Substituted or unsubstituted heterocyclic alkyl groups (e.g., 3- to 8-membered heterocyclic alkyl groups, 3- to 6-membered heterocyclic alkyl groups, or 5- to 6-membered heterocyclic alkyl groups), R 32 Substituted or unsubstituted aryl groups (e.g., C6-C) 10 Aryl, C 10 (aryl or phenyl) or R 32 Substituted or unsubstituted heteroaryl groups (e.g., 5 to 10-membered heteroaryl, 5 to 9-membered heteroaryl, or 5 to 6-membered heteroaryl).

[0282] In the implementation plan, R 8 For R 32 Substituted or unsubstituted alkyl groups (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In the embodiments, R 8 For R 32 Substituted alkyl groups (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In the embodiments, R 8 It is an unsubstituted alkyl group (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).

[0283] In the implementation plan, R 8 For R 32 Substituted or unsubstituted heteroalkyl groups (e.g., 2- to 8-membered heteroalkyl groups, 2- to 6-membered heteroalkyl groups, or 2- to 4-membered heteroalkyl groups). In the embodiments, R 8 For R 32 Substituted heteroalkyl groups (e.g., 2- to 8-membered heteroalkyl groups, 2- to 6-membered heteroalkyl groups, or 2- to 4-membered heteroalkyl groups). In the embodiments, R 8 It is an unsubstituted heteroalkyl group (e.g., 2 to 8-membered heteroalkyl, 2 to 6-membered heteroalkyl, or 2 to 4-membered heteroalkyl).

[0284] In the implementation plan, R 8 For R 32 Substituted or unsubstituted cycloalkyl groups (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In the embodiments, R 8 For R 32 Substituted cycloalkyl groups (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In the embodiments, R 8 It is an unsubstituted cycloalkyl group (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).

[0285] In the implementation plan, R 8 For R 32 Substituted or unsubstituted heterocyclic alkyl groups (e.g., 3- to 8-membered heterocyclic alkyl groups, 3- to 6-membered heterocyclic alkyl groups, or 5- to 6-membered heterocyclic alkyl groups). In the embodiments, R 8 For R 32 Substituted heterocyclic alkyl groups (e.g., 3- to 8-membered heterocyclic alkyl groups, 3- to 6-membered heterocyclic alkyl groups, or 5- to 6-membered heterocyclic alkyl groups). In the embodiments, R 8 It is an unsubstituted heterocyclic alkyl group (e.g., 3- to 8-membered heterocyclic alkyl, 3- to 6-membered heterocyclic alkyl, or 5- to 6-membered heterocyclic alkyl).

[0286] In the implementation plan, R 8 For R 32 Substituted or unsubstituted aryl groups (e.g., C6-C) 10 Aryl, C 10 (aryl or phenyl). In the implementation scheme, R 8 For R 32 Substituted aryl groups (e.g., C6-C) 10 Aryl, C 10 (aryl or phenyl). In the implementation scheme, R 8 For unsubstituted aryl groups (e.g., C6-C) 10 Aryl, C 10 (aryl or phenyl).

[0287] In the implementation plan, R 8 For R 32 Substituted or unsubstituted heteroaryl groups (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In the embodiments, R 8 For R 32 Substituted heteroaryl groups (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In the embodiments, R 8 It is an unsubstituted heteroaryl group (e.g., 5 to 10-membered heteroaryl, 5 to 9-membered heteroaryl, or 5 to 6-membered heteroaryl).

[0288] In the implementation plan, R 9 Halogen, –CX 9.1 3. -CHX 9.1 2. -CH2X 9.1 –CN, –N3, –SO n9 R 9A –SO v9 NR 9B R 9C -NHNR 9B R 9C -ONR 9B R 9C -NHC(O)NHNR 9B R 9C -NHC(O)NR 9B R 9C –N(O) m9 –NR 9B R 9C –C(O)R 9D –C(O)OR 9D –C(O)NR 9B R 9C –OR 9A -NR 9B SO2R 9A -NR 9B C(O)R 9D -NR 9B C(O)OR 9D –NR 9B OR 9D –OCX 9.1 3. –OCHX 9.1 2. –OCH2X 9.1 Substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In the embodiments, R 9 It is hydrogen.

[0289] In the implementation plan, R 9 Halogen, –CX 9.1 3. -CHX 9.1 2. -CH2X 9.1 –CN, –N3, –SO n9 R 9A –SO v9 NR 9B R 9C -NHNR 9B R 9C -ONR 9B R 9C-NHC(O)NHNR 9B R 9C -NHC(O)NR 9B R 9C –N(O) m9 –NR 9B R 9C –C(O)R 9D –C(O)OR 9D –C(O)NR 9B R 9C –OR 9A -NR 9B SO2R 9A -NR 9B C(O)R 9D -NR 9B C(O)OR 9D –NR 9B OR 9D –OCX 9.1 3. –OCHX 9.1 2. –OCH2X 9.1 R 35 Substituted or unsubstituted alkyl groups (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 35 Substituted or unsubstituted heteroalkyl groups (e.g., 2- to 8-membered heteroalkyl groups, 2- to 6-membered heteroalkyl groups, or 2- to 4-membered heteroalkyl groups), R 35 Substituted or unsubstituted cycloalkyl groups (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R 35 Substituted or unsubstituted heterocyclic alkyl groups (e.g., 3- to 8-membered heterocyclic alkyl groups, 3- to 6-membered heterocyclic alkyl groups, or 5- to 6-membered heterocyclic alkyl groups), R 35 Substituted or unsubstituted aryl groups (e.g., C6-C) 10 Aryl, C 10 (aryl or phenyl) or R 35 Substituted or unsubstituted heteroaryl groups (e.g., 5 to 10-membered heteroaryl, 5 to 9-membered heteroaryl, or 5 to 6-membered heteroaryl).

[0290] In the implementation plan, R 9 For R 35 Substituted or unsubstituted alkyl groups (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In the embodiments, R 9 For R 35 Substituted alkyl groups (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In the embodiments, R 9 It is an unsubstituted alkyl group (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).

[0291] In the implementation plan, R 9 For R 35 Substituted or unsubstituted heteroalkyl groups (e.g., 2- to 8-membered heteroalkyl groups, 2- to 6-membered heteroalkyl groups, or 2- to 4-membered heteroalkyl groups). In the embodiments, R 9 For R 35 Substituted heteroalkyl groups (e.g., 2- to 8-membered heteroalkyl groups, 2- to 6-membered heteroalkyl groups, or 2- to 4-membered heteroalkyl groups). In the embodiments, R 9 It is an unsubstituted heteroalkyl group (e.g., 2 to 8-membered heteroalkyl, 2 to 6-membered heteroalkyl, or 2 to 4-membered heteroalkyl).

[0292] In the implementation plan, R 9 For R 35 Substituted or unsubstituted cycloalkyl groups (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In the embodiments, R 9 For R 35 Substituted cycloalkyl groups (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In the embodiments, R 9 It is an unsubstituted cycloalkyl group (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).

[0293] In the implementation plan, R 9 For R 35 Substituted or unsubstituted heterocyclic alkyl groups (e.g., 3- to 8-membered heterocyclic alkyl groups, 3- to 6-membered heterocyclic alkyl groups, or 5- to 6-membered heterocyclic alkyl groups). In the embodiments, R 9 For R 35 Substituted heterocyclic alkyl groups (e.g., 3- to 8-membered heterocyclic alkyl groups, 3- to 6-membered heterocyclic alkyl groups, or 5- to 6-membered heterocyclic alkyl groups). In the embodiments, R 9 It is an unsubstituted heterocyclic alkyl group (e.g., 3- to 8-membered heterocyclic alkyl, 3- to 6-membered heterocyclic alkyl, or 5- to 6-membered heterocyclic alkyl).

[0294] In the implementation plan, R 9 For R 35 Substituted or unsubstituted aryl groups (e.g., C6-C) 10 Aryl, C 10 (aryl or phenyl). In the implementation scheme, R 9 For R 35 Substituted aryl groups (e.g., C6-C) 10 Aryl, C 10 (aryl or phenyl). In the implementation scheme, R 9 For unsubstituted aryl groups (e.g., C6-C) 10 Aryl, C 10 (aryl or phenyl).

[0295] In the implementation plan, R 9 For R 35 Substituted or unsubstituted heteroaryl groups (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In the embodiments, R 9 For R 35 Substituted heteroaryl groups (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In the embodiments, R 9 It is an unsubstituted heteroaryl group (e.g., 5 to 10-membered heteroaryl, 5 to 9-membered heteroaryl, or 5 to 6-membered heteroaryl).

[0296] In the implementation plan, R 9 Hydrogen, –CN, halogen, -CF3, -COOH, -COOCH2CH3, -CH3. In the implementation plan, R 9 It is hydrogen. In the implementation scheme, R 9 For –CN. In the implementation plan, R 9 It is a halogen. In the implementation scheme, R 9 For –F. In the implementation plan, R 9 For –Cl. In the implementation scheme, R 9 For –Br. In the implementation scheme, R 9 For –I. In the implementation plan, R 9 For -CF3. In the implementation plan, R 9 For –COOH. In the implementation scheme, R 9 It is -COOCH2CH3. In the implementation scheme, R 9 For –CH3. In the implementation scheme, R 9 For –CHCH2CH2OH. In the implementation scheme, R 9 for In the implementation plan, R 9 It is a substituted or unsubstituted C1-C4 alkyl group. In the embodiments, R 9 The substituted C1-C4 alkyl group. In the embodiments, R 9 It is an unsubstituted C1-C4 alkyl group.

[0297] In the implementation plan, R 9 Halogen, –CF3, -CHF2, -CH2F, –CN, –N3, –SO2CH3, –C(O)R 9D –C(O)OR 9D substituted or unsubstituted alkyl groups, substituted or unsubstituted heteroalkyl groups. In the embodiments, R 9 Halogen, –CF3, -CHF2, -CH2F, –CN, –N3, –SO2CH3, –C(O)R 9D –C(O)OR9D Substituted or unsubstituted alkyl groups, substituted or unsubstituted heteroalkyl groups.

[0298] In the implementation plan, R 9 For R 35 Substituted or unsubstituted alkyl groups (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In the embodiments, R 9 For R 35 Substituted alkyl groups (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In the embodiments, R 9 It is an unsubstituted alkyl group (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).

[0299] In the implementation plan, R 9 For R 35 Substituted or unsubstituted methyl groups. In the embodiments, R 9 For R 35 Substituted or unsubstituted C2 alkyl group. In the embodiments, R 9 For R 35 Substituted or unsubstituted C3 alkyl group. In the embodiments, R 9 For R 35 Substituted or unsubstituted C4 alkyl. In the embodiments, R 9 For R 35 Substituted or unsubstituted C5 alkyl group. In the embodiments, R 9 For R 35 Substituted or unsubstituted C6 alkyl group. In the embodiments, R 9 For R 35 Substituted or unsubstituted C7 alkyl group. In the embodiments, R 9 For R 35 Substituted or unsubstituted C8 alkyl. In the embodiments, R 9 For R 35 Substituted methyl group. In the embodiment, R 9 For R 35 Substituted C2 alkyl group. In the embodiment, R 9 For R 35 Substituted C3 alkyl group. In the embodiment, R 9 For R 35 Substituted C4 alkyl. In the embodiments, R 9 For R 35 Substituted C5 alkyl group. In the embodiment, R 9 For R 35 Substituted C6 alkyl group. In the embodiments, R 9 For R 35 Substituted C7 alkyl group. In the embodiments, R 9 For R35 Substituted C8 alkyl. In the embodiments, R 9 The methyl group is unsubstituted. In the embodiments, R 9 It is an unsubstituted C2 alkyl group. In the embodiments, R 9 It is an unsubstituted C3 alkyl group. In the embodiments, R 9 It is an unsubstituted C4 alkyl group. In the embodiments, R 9 It is an unsubstituted C5 alkyl group. In the embodiments, R 9 It is an unsubstituted C6 alkyl group. In the embodiments, R 9 It is an unsubstituted C7 alkyl group. In the embodiments, R 9 It is an unsubstituted C8 alkyl group.

[0300] In the implementation plan, X 2 For CR 9 And R 9 For hydrogen, –CX 9.1 3. -CHX 9.1 2. -CH2X 9.1 –CN or substituted or unsubstituted C1-C4 alkyl groups. In the embodiments, X 2 For CR 9 And R 9 It is hydrogen. In the implementation scheme, X 2 For CR 9 And R 9 For –CX 9.1 3. In the implementation plan, X 2 For CR 9 And R 9 For -CHX 9.1 2. In the implementation plan, X 2 For CR 9 And R 9 -CH2X 9.1 In the implementation plan, X 2 For CR 9 And R 9 For –CN. In the implementation scheme, X 2 For CR 9 And R 9 It is a substituted or unsubstituted C1-C4 alkyl group. In the embodiments, R 9 It can be hydrogen, -CF3, or an unsubstituted methyl group.

[0301] In the implementation plan, R 4 and R 9Optionally, they can be linked to form substituted or unsubstituted cycloalkyl groups (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), substituted or unsubstituted heterocycloalkyl groups (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), or substituted or unsubstituted aryl groups (e.g., C6-C...). 10 Aryl, C 10 Aryl or phenyl) or substituted or unsubstituted heteroaryl (e.g., 5 to 10-membered heteroaryl, 5 to 9-membered heteroaryl or 5 to 6-membered heteroaryl).

[0302] In the implementation plan, R 4 and R 9 Optionally, they can be linked to form substituted or unsubstituted C5-C7 cycloalkyl groups. In an embodiment, R 4 and R 9 Optionally, it can be linked to form a substituted C5-C7 cycloalkyl group. In an embodiment, R 4 and R 9 They can be optionally linked to form unsubstituted C5-C7 cycloalkyl groups.

[0303] In the implementation plan, R 4 and R 9 Optionally, they can be linked to form substituted or unsubstituted 5- to 7-membered heterocyclic alkyl groups. In an embodiment, R 4 and R 9 Optio...

Claims

1. A compound having structural formula (I): or a pharmaceutically acceptable salt thereof, wherein: X 1 CR 8 or N; X 2 CR 9 or N; X 3 CR 10 or N; X 1 , X 2 and X 3 At least one of is N; n1, n2, n3, n4, n5, n6, n7, n8, n9, n10 and n44 are independently integers from 0 to 4; 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 4; z3 is an integer from 0 to 11; z4 is an integer from 0 to 2; z5 is an integer from 1 to 2; L 7 for bonds, –O–, –S–, –NR 7.2B –, –C(O)–, -C(O)O–, –S(O)–, –S(O)2–, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; R 1 For hydrogen, halogen, –CX 1.1 3. -CHX 1.1 2. -CH2X 1.1 , –CN, –N3, –SO n1 R 1A ,–SO v1 NR 1B R 1C 、-NHNR 1B R 1C 、-ONR 1B R 1C 、-NHC(O)NHNR 1B R 1C 、-NHC(O)NR 1B R 1C 、–N(O) m1 ,–NR 1B R 1C , –C(O)R 1D , –C(O)OR 1D , –C(O)NR 1B R 1C ,–OR 1A 、-NR 1B S02R 1A 、-NR 1B C(O)R 1D 、-NR 1B C(O)OR 1D ,–NR 1B OR 1D 、–OCX 1.1 3. –OCHX 1.1 2. –OCH2X 1.1 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 For hydrogen, halogen, –CX 2.1 3. -CHX 2.1 2. -CH2X 2.1 , –CN, –N3, –SO n2 R 2A ,–SO v2 NR 2B R 2C 、-NHNR 2B R 2C 、-ONR 2B R 2C 、-NHC(O)NHNR 2B R 2C 、-NHC(O)NR 2B R 2C 、–N(O) m2 ,–NR 2B R 2C , –C(O)R 2D , –C(O)OR 2D , –C(O)NR 2B R 2C ,–OR 2A 、-NR 2B S02R 2A 、-NR 2B C(O)R 2D 、-NR 2B C(O)OR 2D ,–NR 2B OR 2D 、–OCX 2.1 3. –OCHX 2.1 2. –OCH2X 2.1 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 3 independently halogen, –CX 3.1 3. -CHX 3.1 2. -CH2X 3.1 , –CN, –N3, –SO n3 R 3A ,–SO v3 NR 3B R 3C , -NHNR 3B R 3C 、-ONR 3B R 3C 、-NHC(O)NHNR 3B R 3C 、-NHC(O)NR 3B R 3C 、–N(O) m3 ,–NR 3B R 3C , –C(O)R 3D , –C(O)OR 3D , –C(O)NR 3B R 3C ,–OR 3A 、-NR 3B S02R 3A 、-NR 3B C(O)R 3D 、-NR 3B C(O)OR 3D ,–NR 3B OR 3D 、–OCX 3.1 3. –OCHX 3.1 2. –OCH2X 3.1 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 4 For hydrogen, halogen, –CX 4.1 3. -CHX 4.1 2. -CH2X 4.1 , –CN, –N3, –SO n4 R 4A ,–SO v4 NR 4B R 4C 、-NHNR 4B R 4C 、-ONR 4B R 4C 、-NHC(O)NHNR 4B R 4C 、-NHC(O)NR 4B R 4C 、–N(O) m4 ,–NR 4B R 4C , –C(O)R 4D , –C(O)OR 4D , –C(O)NR 4B R 4C ,–OR 4A 、-NR 4B S02R 4A 、-NR 4B C(O)R 4D 、-NR 4B C(O)OR 4D ,–NR 4B OR 4D 、–OCX 4.1 3. –OCHX 4.1 2. –OCH2X 4.1 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, or when X 2 CR 9 When R 4 and R 9 can be optionally linked to form a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl; R 5 are independently halogen, oxo, –CX 5.1 3. -CHX 5.1 2. -CH2X 5.1 , –CN, –N3, –SO n5 R 5A ,–SO v5 NR 5B R 5C 、-NHNR 5B R 5C 、-ONR 5B R 5C 、-NHC(O)NHNR 5B R 5C 、-NHC(O)NR 5B R 5C 、–N(O) m5 ,–NR 5B R 5C , –C(O)R 5D , –C(O)OR 5D , –C(O)NR 5B R 5C ,–OR 5A 、-NR 5B S02R 5A 、-NR 5B C(O)R 5D 、-NR 5B C(O)OR 5D ,–NR 5B OR 5D 、–OCX 5.1 3. –OCHX 5.1 2. –OCH2X 5.1 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 6 are independently halogen, oxo, –CX 6.1 3. -CHX 6.1 2. -CH2X 6.1 , –CN, –N3, –SO n6 R 6A ,–SO v6 NR 6B R 6C 、-NHNR 6B R 6C 、-ONR 6B R 6C 、-NHC(O)NHNR 6B R 6C 、-NHC(O)NR 6B R 6C 、–N(O) m6 ,–NR 6B R 6C , –C(O)R 6D , –C(O)OR 6D , –C(O)NR 6B R 6C ,–OR 6A 、-NR 6B S02R 6A 、-NR 6B C(O)R 6D 、-NR 6B C(O)OR 6D ,–NR 6B OR 6D 、–OCX 6.1 3. –OCHX 6.1 2. –OCH2X 6.1 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 7 For hydrogen, halogen, –CX 7.1 3. -CHX 7.1 2. -CH2X 7.1 , –CN, –N3, –SO n7 R 7A ,–SO v7 NR 7B R 7C 、-NHNR 7B R 7C 、-ONR 7B R 7C 、-NHC(O)NHNR 7B R 7C 、-NHC(O)NR 7B R 7C 、–N(O) m7 ,–NR 7B R 7C , –C(O)R 7D , –C(O)OR 7D , –C(O)NR 7B R 7C ,–OR 7A 、-NR 7B S02R 7A 、-NR 7B C(O)R 7D 、-NR 7B C(O)OR 7D ,–NR 7B OR 7D 、–OCX 7.1 3. –OCHX 7.1 2. –OCH2X 7.1 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 8 For hydrogen, halogen, –CX 8.1 3. -CHX 8.1 2. -CH2X 8.1 , –CN, –N3, –SO n8 R 8A ,–SO v8 NR 8B R 8C 、-NHNR 8B R 8C 、-ONR 8B R 8C 、-NHC(O)NHNR 8B R 8C 、-NHC(O)NR 8B R 8C 、–N(O) m8 ,–NR 8B R 8C , –C(O)R 8D , –C(O)OR 8D , –C(O)NR 8B R 8C ,–OR 8A 、-NR 8B S02R 8A 、-NR 8B C(O)R 8D 、-NR 8B C(O)OR 8D ,–NR 8B OR 8D 、–OCX 8.1 3. –OCHX 8.1 2. –OCH2X 8.1 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 9 For hydrogen, halogen, –CX 9.1 3. -CHX 9.1 2. -CH2X 9.1 , –CN, –N3, –SO n9 R 9A ,–SO v9 NR 9B R 9C 、-NHNR 9B R 9C 、-ONR 9B R 9C 、-NHC(O)NHNR 9B R 9C 、-NHC(O)NR 9B R 9C 、–N(O) m9 ,–NR 9B R 9C , –C(O)R 9D , –C(O)OR 9D , –C(O)NR 9B R 9C ,–OR 9A 、-NR 9B S02R 9A 、-NR 9B C(O)R 9D 、-NR 9B C(O)OR 9D ,–NR 9B OR 9D 、–OCX 9.1 3. –OCHX 9.1 2. –OCH2X 9.1 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, or when X 2 CR 9 When R 4 and R 9 can be optionally linked to form a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl; or when X 2 CR 9 And X 3 CR 10 When R 9 and R 10 can be optionally linked to form a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, or an unsubstituted aryl or a substituted or unsubstituted heteroaryl; R 10 For hydrogen, halogen, –CX 10.1 3. -CHX 10.1 2. -CH2X 10.1 , –CN, –N3, –SO n10 R 10A ,–SO v10 NR 10B R 10C 、-NHNR 10B R 10C 、-ONR 10B R 10C 、-NHC(O)NHNR 10B R 10C 、-NHC(O)NR 10B R 10C 、–N(O) m10 ,–NR 10B R 10C , –C(O)R 10D , –C(O)OR 10D , –C(O)NR 10B R 10C ,–OR 10A 、-NR 10B S02R 10A 、-NR 10B C(O)R 10D 、-NR 10B C(O)OR 10D ,–NR 10B OR 10D 、–OCX 10.1 3. –OCHX 10.1 2. –OCH2X 10.1 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; or when X 2 CR 9 And X 3 CR 10 When R 9 and R 10 can be optionally linked to form a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, or an unsubstituted aryl or a substituted or unsubstituted heteroaryl; R 44 For hydrogen, –CX 44.1 3. -CHX 44.1 2. -CH2X 44.1 ,–SO n44 R 44A ,–SO v44 NR 44B R 44C , –C(O)R 44D , –C(O)OR 44D , –C(O)NR 44B R 44C , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 1A , R 1B , R 1C , R 1D , R 2A , R 2B , R 2C , R 2D , R 3A , R 3B , R 3C , R 3D , R 4A , R 4B , R 4C , R 4D , R 5A , R 5B , R 5C , R 5D , R 6A , R 6B , R 6C , R 6D , R 7A , R 7B , R 7C , R 7D , R 7.2B , R 8A , R 8B , R 8C , R 8D , R 9A , R 9B , R 9C , R 9D , R 10A , R 10B , R 10C , R 10D , R 44A , R 44B , R 44C and R 44D R is independently hydrogen, halogen, -CF3, -CCl3, -CBr3, -CI3, -COOH, -CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R bonded to the same nitrogen atom 1B , R 1C , R 2B , R 2C , R 3B , R 3C , R 4B , R 4C , R 5B , R 5C , R 6B , R 6C , R 7B , R 7C , R 8B , R 8C , R 9B , R 9C , R 10B , R 10C , R 44B and R 44C The substituents can be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; and X 1.1 , X 2.1 , X 3.1 , X 4.1 , X 5.1 , X 6.1 , X 7.1 , X 8.1 , X 9.1 , X 10.1 and X 44.1 is independently –Cl, –Br, –I or –F.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein z2 is 0.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein z4 is 1.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein z1 is 2.

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has structural formula (II): in R 4 For hydrogen, halogen, –CX 4.1 3. –CN, –C(O)NR 4B R 4C , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 3.2 For hydrogen, halogen, –CX 3.2 3. -CHX 3.2 2. -CH2X 3.2 , –CN, –N3, –SO n3.2 R 3.2A ,–SO v3.2 NR 3.2B R 3.2C 、-NHNR 3.2B R 3.2C 、-ONR 3.2B R 3.2C 、-NHC(O)NHNR 3.2B R 3.2C 、-NHC(O)NR 3.2B R 3.2C 、–N(O) m3.2 ,–NR 3.2B R 3.2C , –C(O)R 3.2D , –C(O)OR 3.2D , –C(O)NR 3.2B R 3.2C ,–OR 3.2A 、-NR 3.2B S02R 3.2A 、-NR 3.2B C(O)R 3.2D 、-NR 3.2B C(O)OR 3.2D ,–NR 3.2B OR 3.2D 、–OCX 3.2 3. –OCHX 3.2 2. –OCH2X 3.2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 3.3 For hydrogen, halogen, –CX 3.3 3. -CHX 3.3 2. -CH2X 3.3 , –CN, –N3, –SO n3.3 R 3.3A ,–SO v3.3 NR 3.3B R 3.3C 、-NHNR 3.3B R 3.3C 、-ONR 3.3B R 3.3C 、-NHC(O)NHNR 3.3B R 3.3C 、-NHC(O)NR 3.3B R 3.3C 、–N(O) m3.3 ,–NR 3.3B R 3.3C , –C(O)R 3.3D , –C(O)OR 3.3D , –C(O)NR 3.3B R 3.3C ,–OR 3.3A 、-NR 3.3B S02R 3.3A 、-NR 3.3B C(O)R 3.3D 、-NR 3.3B C(O)OR 3.3D ,–NR 3.3B OR 3.3D 、–OCX 3.3 3. –OCHX 3.3 2. –OCH2X 3.3 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 3.2A , R 3.2B , R 3.2C , R 3.2D , R 3.3A , R 3.3B , R 3.3C and R 3.3D R is independently hydrogen, halogen, -CF3, -CCl3, -CBr3, -CI3, -COOH, -CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R bonded to the same nitrogen atom 3.2B , R 3.2C , R 3.3B and R 3.3C The substituents can be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; n3.2 and n3.3 are independently integers from 0 to 4; m3.2, m3.3, v3.2 and v3.3 are independently 1 or 2; and X 3.2 and X 3.3 is independently –Cl, –Br, –I or –F.

6. The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein the compound has structural formula (IIb):

7. The compound according to claim 6 or a pharmaceutically acceptable salt thereof, wherein: X 2 CR 9 ;and R 9 For hydrogen, –CX 9.1 3. -CHX 9.1 2. -CH2X 9.1 , –CN or substituted or unsubstituted C1-C4 alkyl.

8. The compound according to claim 7 or a pharmaceutically acceptable salt thereof, wherein R 9 It is hydrogen, -CF3 or unsubstituted methyl.

9. The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein the compound has structural formula (IIa):

10. The compound according to claim 9 or a pharmaceutically acceptable salt thereof, wherein: X 3 CR 10 ;and R 10 For hydrogen, –CX 10.1 3. -CHX 10.1 2. -CH2X 10.1 , –CN or substituted or unsubstituted C1-C4 alkyl.

11. The compound according to claim 10 or a pharmaceutically acceptable salt thereof, wherein R 10 It is hydrogen or -CN.

12. The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein the compound has one of the structural formulas (IIIa), (IIIb) and (IIIc): in: X 2 CR 9 ;and R 9 For hydrogen, –CX 9.1 3. -CHX 9.1 2. -CH2X 9.1 , –CN or substituted or unsubstituted C1-C4 alkyl.

13. The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein the compound has structural formula (IVa), (IVb) or (IVc):

14. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 4 For hydrogen, halogen, –CX 4.1 3. -CHX 4.1 2. -CH2X 4.1 , –CN, –NR 4B R 4C , –C(O)R 4D , –C(O)OR 4D , –C(O)NR 4B R 4C ,–OR 4A 、-NR 4B C(O)R 4D 、-NR 4B C(O)OR 4D 、–OCX 4.1 3. –OCHX 4.1 2. –OCH2X 4.1 , substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.

15. The compound according to claim 14 or a pharmaceutically acceptable salt thereof, wherein R 4 For hydrogen, halogen, –CX 4.1 3. -CHX 4.1 2. -CH2X 4.1 、–CN、–C(O)OR 4D , –C(O)NR 4B R 4C , substituted or unsubstituted C1-C4 alkyl, or substituted or unsubstituted 2- to 4-membered heteroalkyl.

16. The compound according to claim 15 or a pharmaceutically acceptable salt thereof, wherein R 4 is –Cl, –Br, –F, –CN, –COOH, –C(O)OCH2CH3, –C(CH3)2OH, –C(O)NH2, –CF3 or –CH3.

17. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: X 2 CR 9 ;and R 4 and R 9 are connected to form 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.

18. The compound according to claim 17 or a pharmaceutically acceptable salt thereof, wherein R 4 and R 9 Connected to form a substituted or unsubstituted C5-C7 cycloalkyl group, a substituted or unsubstituted 5- to 7-membered heterocycloalkyl group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted 5- to 6-membered heteroaryl group.

19. The compound according to claim 17 or a pharmaceutically acceptable salt thereof, wherein R 4 and R 9 Connected to form an unsubstituted C5-C7 cycloalkyl group, an unsubstituted 5- to 7-membered heterocycloalkyl group, an unsubstituted phenyl group, or an unsubstituted 5- to 6-membered heteroaryl group.

20. The compound according to claim 17 or a pharmaceutically acceptable salt thereof, wherein R 4 and R 9 Connected to form an unsubstituted C5 cycloalkyl group, an unsubstituted thienyl group or an unsubstituted phenyl group.

21. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 44 For hydrogen.

22. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 and R is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.

23. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 is a substituted or unsubstituted alkyl group.

24. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 is –CH3.

25. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 For hydrogen.

26. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 is a substituted or unsubstituted alkyl group.

27. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 is –CH3.

28. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 For hydrogen.

29. The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein R 3.2 and R 3.3 are independently halogen.

30. The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein R 3.2 and R 3.3 are independently chlorine.

31. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein L 7 is a bond, a substituted or unsubstituted alkylene group, or a substituted or unsubstituted cycloalkylene group.

32. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein L 7 It is a substituted or unsubstituted C4-C6 cycloalkylene group.

33. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein L 7 It is an unsubstituted C4-C6 cycloalkylene group.

34. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein L 7 is a substituted or unsubstituted cyclobutylene group.

35. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein L 7 is a substituted or unsubstituted alkylene group.

36. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein L 7 is a substituted or unsubstituted C1-C6 alkylene group.

37. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein L 7 is the key.

38. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 7 For hydrogen, halogen, –SO n7 R 7A ,–SO v7 NR 7B R 7C 、-NHC(O)NR 7B R 7C ,–NR 7B R 7C , –C(O)R 7D , –C(O)OR 7D , –C(O)NR 7B R 7C ,–OR 7A , -NR 7B S02R 7A 、-NR 7B C(O)R 7D 、-NR 7B C(O)OR 7D , 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.

39. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 7 For –OR 7A , –C(O)R 7D , –C(O)OR 7D , –C(O)NR 7B R 7C ,–SO n7 R 7A ,–SO v7 NR 7B R 7C , 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.

40. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 7 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted phenyl, -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, -CH2C(O)OCH2CH3, -SO2CH3, -SO2CH2CH3, -SO2CH(CH3)2, -NHSO2CH3, -NHSO2CH2CH3, -NHSO2CH(CH3)2, -SO2NH2, -SO2NHCH3, -F, -OH, -CH2OH, -(CH2)2OH, -(CH2)3OH, -C(CH3)2OH, -CH2SO2NH2, -(CH2)2SO2NH 2、 -CH2C(O)NH2, -(CH2)2C(O)NH2, -(CH2)3C(O)NH2, -CH2NHSO2CF3, -(CH2)2NHSO2CF3, -(CH2)3NHSO2CF3, -CH2NHSO2CH3, -(CH2)2NHSO2CH3, -(CH2)3NHSO2CH 3、 -CH2SO2CH3, –(CH2)2SO2CH3, -CH2SO2NH2 or –(CH2)2SO2NH2.

41. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 7 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted phenyl, -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, -CH2C(O)OCH2CH3, -SO2CH3, -SO2CH2CH3, -SO2CH(CH3)2, -NHSO2CH3, -N HSO2CH2CH3, -NHSO2CH(CH3)2, -SO2NH2, -SO2NHCH3, -(CH2)2OH, -CH2C(CH3)2OH, -(CH2)3OH, -(CH2)2CH(CH3)2 OH, –(CH2)2SO2NH2, –(CH2)3SO2NH2, –(CH2)2CONH2, –(CH2)3CONH2-(CH2)3CON(H)Me, –(CH2)3CON(Me)2, –(CH2 )2SO2Me, -(CH2)3SO2Me, -CH2CH(OH)Me, -CH2CO2H, -(CH2)2CO2H, -CH(CH3)CH2CO2H, -(CH2)3CO2H, -(CH2)2SO2NHCH3, -(CH2)2SO2N(CH3)2, -(CH2)2SO2-(N-morpholinyl), -(CH2)2NHCOCH3, -(CH2)3NHCOCH3, -(CH2)2NHCOCH(CH3)2, -(CH2)2NHSO2CH3, -(CH2)2NHSO2CF3, -(CH2)2NHSO2NHCH(CH3)2, -CH2CH(CH3)CH2OH(R and S), -CH(CH3)(CH2)2OH, -CH2-(2-imidazolyl), -CH2-(4-imidazolyl), -CH2-(3-pyrazolyl), 4-tetrahydropyranyl, 3-oxetanyl, -(CH2)2NHCO2Me, -(CH2)3NHCO2Me, -CH2OH, 42. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein -L 7 -R 7 is carboxylic acid substituted cyclobutyl, carboxylic acid substituted cyclopentyl or hydroxy substituted ethyl; all groups are optionally further substituted by substituted or unsubstituted alkyl.

43. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has the following structure:

44. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has the following structure:

45. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

46. ​​A method for treating or preventing a disease or condition mediated by CCR4, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.

47. A method for treating or preventing a disease or condition mediated by CCR4, the method comprising administering a therapeutically effective amount of the pharmaceutical composition of claim 45 to a subject in need thereof.

48. A method of inhibiting CC chemokine receptor type 4 (CCR4), the method comprising contacting CCR4 with a compound according to claim 1 or a pharmaceutically acceptable salt thereof.

49. The method of claim 46, wherein the disease or disorder is an immune or inflammatory disease or disorder.

50. The method of claim 49, further comprising co-administering an anti-inflammatory agent to the subject.

51. The method of claim 50, wherein the anti-inflammatory agent is thalidomide or a derivative thereof, a retinoid, anthracene, calcipotriol, a nonsteroidal anti-inflammatory agent (NSAID), a cyclooxygenase inhibiting nitric oxide donor (CINOD), a glucocorticoid, methotrexate, leflunomide, hydroxychloroquine, d-penicillamine, auranofin, an analgesic, diacerein, a hyaluronic acid derivative, or a nutritional supplement.

52. The method of claim 46, wherein the disease or disorder is a cardiovascular or metabolic disease or disorder.

53. The method of claim 52, further comprising co-administering a cardiovascular agent or a metabolic disorder agent to the subject.

54. The method of claim 53, wherein the cardiovascular agent is a calcium channel blocker, a beta-adrenergic receptor blocker, an angiotensin converting enzyme (ACE) inhibitor, an angiotensin-2 receptor antagonist, a lipid-lowering agent, a blood cell morphology regulator, a thrombolytic agent, or an anticoagulant.

55. The method of claim 46, wherein the disease or disorder is cancer.

56. The method of claim 55, further comprising co-administering a chemotherapeutic or anti-cancer agent to the subject.

57. The method of claim 56, wherein the chemotherapeutic or anticancer agent is an antiproliferative / antineoplastic agent, an antimetabolite, an antitumor antibiotic, an antimitotic agent, a topoisomerase inhibitor, a cytostatic agent, an estrogen receptor downregulator, an antiandrogen, an LHRH antagonist or an LHRH agonist, a progestin, an aromatase inhibitor, a 5α-reductase inhibitor, an agent that inhibits cancer cell invasion, a growth factor function inhibitor, a farnesyl transferase inhibitor, a tyrosine kinase inhibitor, a serine / threonine kinase inhibitor, an epidermal growth factor family inhibitor, a platelet-derived growth factor family inhibitor, a hepatocyte growth factor family inhibitor; an anti-angiogenic agent, a vascular damaging agent, an agent for antisense therapy, an anti-ras antisense agent, an agent for gene therapy, an immunotherapeutic agent, or an antibody.

58. The method of claim 57, wherein the chemotherapeutic or anticancer agent is an inhibitor of the PD-L1 / PD-1 pathway, an inhibitor of CTLA-4, or an agonistic antibody to CD137 (4-1BB).

59. The method of claim 57, wherein the chemotherapeutic or anticancer agent is an agent from Table 1.

60. The method of claim 55, wherein the cancer is colon cancer or pancreatic cancer.

61. The method of claim 46, wherein the disease or disorder is allergy related.

62. The method of claim 46, wherein the disease or condition is inflammation.

63. The method of claim 46, wherein the disease or condition is asthma, urticaria, rhinitis, or dermatitis.

64. The method of claim 63, wherein the disease or condition is allergic asthma, autoimmune urticaria, allergic rhinitis, or contact dermatitis.

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