JP2024517340A - Compounds that degrade alpha-synuclein aggregates and uses thereof - Google Patents

Abstract

The present disclosure provides compounds comprising an E3 ubiquitin ligase binding moiety and an alpha-synuclein protein binding moiety for use in the treatment of neurodegenerative diseases, particularly synucleinopathies.

Description

Neurodegenerative diseases affect an estimated 50 million Americans each year and impose a tremendous human toll and economic costs of hundreds of billions of dollars annually in medical expenses and lost productivity. Synucleinopathies are neurodegenerative diseases characterized by the abnormal accumulation of α-synuclein (α-Syn) aggregates in neurons and glial cells.

α-synuclein is a 140 amino acid protein expressed preferentially in neurons at presynaptic terminals where it is thought to play a role in regulating synaptic transmission (Bendor et al., Neuron 2013; 79:1044-66). α-synuclein can form pathological aggregates known as Lewy bodies in neurons, which are characteristic of both Parkinson's disease (PD) and dementia with Lewy bodies (DLB). The pathological aggregates consist of aggregated, insoluble deposits of misfolded α-synuclein protein in neurons, nerve fibers or glial cells and are the hallmark of synucleinopathies. Synucleinopathies include Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA), Lewy body variant of Alzheimer's disease (LBVAD), combined Parkinson's disease (PD) and Alzheimer's disease (AD), and brain iron deposition neurodegeneration type 1 (NBIA-1). In PD and DLB, α-Syn aggregates are located in neuronal cytoplasm and axonal processes, forming Lewy bodies and Lewy neurites, respectively, whereas α-Syn inclusions in oligodendrocytes are a recognized neuropathological hallmark of MSA.

Currently, there are no therapies that target synucleinopathy in terms of α-synuclein aggregation. Strategies aimed at reducing α-synuclein aggregation possess therapeutic potential in the treatment of patients with synucleinopathy.

The present disclosure arises from the recognition of bispecific conjugate compounds that contain an E3 ubiquitin ligase binding moiety based on an imide drug (e.g., lenalidomide, thalidomide, VHL ligand) and also contain a binder of α-synuclein that can induce proteasomal degradation of α-synuclein aggregates. The present disclosure thus provides compounds, compositions and methods for treating various neurodegenerative diseases associated with α-synuclein aggregates based on this discovery. The bispecific conjugate compounds described herein degrade α-synuclein aggregates by eliminating or reducing the extent of α-synuclein aggregation to low levels in cell and/or animal models, thereby possessing therapeutic potential in the treatment of patients with synucleinopathies, including, but not limited to, Parkinson's disease (PD), dementia with Lewy bodies (DLB) or multiple system atrophy (MSA).

The present disclosure also provides methods for removing α-synuclein aggregates or reducing Lewy bodies or α-synuclein aggregates in patients with Lewy body disease or at risk for Lewy body disease, as well as methods for reducing dementia with Lewy bodies (DLB) or multiple system atrophy (MSA) or other synucleinopathies.

One aspect of the present disclosure is a compound of formula A
EBM-L-SBM (Formula A)
[wherein EBM is an E3 ubiquitin ligase binding moiety;
L is a linker covalently connecting the EBM and SBM;
SBM has the formula:

のα-シヌクレインタンパク質結合部分であり、

is the alpha-synuclein protein-binding portion of

はLに共有結合し、
(i)

is covalently bonded to L,
(i)

は、O、S及びNから選択される少なくとも1個の環ヘテロ原子を含有する置換若しくは非置換二環式縮合芳香族環であり、

is a substituted or unsubstituted bicyclic fused aromatic ring containing at least one ring heteroatom selected from O, S and N;

は、O、S及びNから選択される0～2個の環ヘテロ原子を含有する置換若しくは非置換単環式芳香族環であり、

is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S and N;

は、O、S及びNから選択される0～2個の環ヘテロ原子を含有する置換若しくは非置換単環式芳香族環であり、又は
(ii)

is a substituted or unsubstituted monocyclic aromatic ring containing 0-2 ring heteroatoms selected from O, S and N; or
(ii)

は、O、S及びNから選択される0～2個の環ヘテロ原子を含有する置換若しくは非置換単環式芳香族環であり、

is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S and N;

は、O、S及びNから選択される0～2個の環ヘテロ原子を含有する置換若しくは非置換単環式芳香族環であり、

is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S and N;

は、O、S及びNから選択される少なくとも1個の環ヘテロ原子を含有する置換若しくは非置換二環式縮合芳香族環である]の化合物又はその薬学的に許容される塩、鏡像異性体、非鏡像異性体、互変異性体、ラセミ化合物、溶媒和物、代謝前駆体、プロドラッグである。

is a substituted or unsubstituted bicyclic fused aromatic ring containing at least one ring heteroatom selected from O, S, and N, or a pharma- ceutically acceptable salt, enantiomer, non-enantiomer, tautomer, racemate, solvate, metabolic precursor, or prodrug thereof.

Another aspect of the present disclosure is a compound represented by formula (I) to (VI):

のいずれか1つの化合物又はその薬学的に許容される塩、溶媒和物、水和物、多形体、共結晶、互変異性体、立体異性体、同位体標識誘導体若しくはプロドラッグであり、L₁、L₂、L3、X、Y、J、Q、K、T、U、V、Z、Y₁、R'、R''、R'''、R^2'、R^3'、n、m、k及びm6は、本明細書に定義されている通りである。

or a pharma- ceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative or prodrug thereof, wherein _L1 , _L2 , L3, X, Y, J, Q, K, T, U, V, Z, _Y1 , R', R'', R''', R2 ^' , R3 ^' , n, m, k and m6 are as defined herein.

Another aspect of the present disclosure is a composition comprising a compound of the present disclosure and a pharma- ceutically acceptable excipient.

Another aspect of the present disclosure is a method of treating, reducing the severity, slowing the progression, reducing the risk of development, and/or delaying the onset of a disease characterized by the presence of Lewy bodies or pathological aggregates of α-synuclein, comprising administering to a subject in need thereof an effective amount of a compound or composition of the present disclosure.

Another aspect of the present disclosure is a method for synthesizing the compounds of the present disclosure.

The foregoing summary is merely illustrative and is not intended to be in any way limiting. In addition to the exemplary embodiments and features described herein, further aspects, embodiments, objects and features of the present disclosure will become more fully apparent from the drawings and detailed description and claims.

Figure 1 shows quantification of high content of aggregated α-synuclein species combined with determination of nuclei count (% remaining cells) in differentiated ReNcell VM cells. Results showed that 24 hour treatment with test compounds 166362, 170357, 162640 and 180948, respectively, induced a concentration-dependent inhibition of MJFR14 immunoreactivity indicative of reduced α-synuclein aggregation. Figure 2A shows immunocytochemistry images of cells treated with vehicle (0.1% DMSO) and test compounds 132168, 166362 and 170357 and immunostained for MJFR14 illustrating the reduction of α-synuclein expression after treatment with compounds 132168 and 166362. Figure 2A: DMSO (0.1%). Figure 2B shows immunocytochemistry images of cells treated with vehicle (0.1% DMSO) and test compounds 132168, 166362 and 170357 and immunostained for MJFR14 illustrating the reduction of α-synuclein expression after treatment with compounds 132168 and 166362. Figure 2B: Compound 132168 (3 μM). Figure 2C shows immunocytochemistry images of cells treated with vehicle (0.1% DMSO) and test compounds 132168, 166362 and 170357 and immunostained for MJFR14 illustrating the reduction of α-synuclein expression after treatment with compounds 132168 and 166362. Figure 2C: Compound 166362 (3 μM). Figure 2D: Immunocytochemistry images of cells treated with vehicle (0.1% DMSO) and test compounds 132168, 166362 and 170357 and immunostained for MJFR14 illustrating the reduction of α-synuclein expression after treatment with compounds 132168 and 166362. Figure 2D: Compound 170357 (10 μM). Figure 1 shows the results of an in vivo α-synuclein degradation study: Treatment with compound 132168 reduced the insoluble α-synuclein fraction by 30% compared to the DMSO vehicle control, indicating a reduction in insoluble α-synuclein aggregates.

The present disclosure provides compounds, compositions and methods useful for removing α-synuclein aggregates or reducing the extent of α-synuclein aggregation to low levels, thereby possessing therapeutic potential in treating patients with synucleinopathies.

Provided herein are bispecific conjugate compounds capable of simultaneously binding to a target protein (i.e., aggregated α-synuclein) and an E3 ubiquitin ligase. The bispecific conjugate compounds exhibit desirable functional properties, including preferentially binding to α-synuclein aggregates and positioning α-synuclein adjacent to E3 ubiquitin ligase, thereby facilitating selective ubiquitination and ultimately proteasome-mediated degradation of α-synuclein aggregates.

The methods described herein include administering a compound or composition of the present disclosure to a subject to treat, alleviate, or prevent a neurodegenerative disease or disorder characterized by the presence of Lewy bodies or pathological aggregates of α-synuclein.

Compounds One aspect of the present disclosure is a compound of formula A:
EBM-L-SBM (Formula A)
[Wherein,
EBM is an E3 ubiquitin ligase binding moiety
L is a linker covalently connecting the EBM and SBM;
SBM has the formula:

のα-シヌクレインタンパク質結合部分であり、

is the alpha-synuclein protein-binding portion of

はLに共有結合し、
(i)

is covalently bonded to L,
(i)

は、O、S及びNから選択される少なくとも1個の環ヘテロ原子を含有する置換若しくは非置換二環式縮合芳香族環であり、

is a substituted or unsubstituted bicyclic fused aromatic ring containing at least one ring heteroatom selected from O, S and N;

は、O、S及びNから選択される0～2個の環ヘテロ原子を含有する置換若しくは非置換単環式芳香族環であり、

is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S and N;

は、O、S及びNから選択される0～2個の環ヘテロ原子を含有する置換若しくは非置換単環式芳香族環であり、又は
(ii)

is a substituted or unsubstituted monocyclic aromatic ring containing 0-2 ring heteroatoms selected from O, S and N; or
(ii)

は、O、S及びNから選択される0～2個の環ヘテロ原子を含有する置換若しくは非置換単環式芳香族環であり、

is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S and N;

は、O、S及びNから選択される0～2個の環ヘテロ原子を含有する置換若しくは非置換単環式芳香族環であり、

is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S and N;

は、O、S及びNから選択される少なくとも1個の環ヘテロ原子を含有する置換若しくは非置換二環式縮合芳香族環である]の化合物又はその薬学的に許容される塩、鏡像異性体、非鏡像異性体、互変異性体、ラセミ化合物、溶媒和物、代謝前駆体、プロドラッグである。

is a substituted or unsubstituted bicyclic fused aromatic ring containing at least one ring heteroatom selected from O, S, and N, or a pharma- ceutically acceptable salt, enantiomer, non-enantiomer, tautomer, racemate, solvate, metabolic precursor, or prodrug thereof.

In some embodiments, the substituted or unsubstituted bicyclic fused aromatic ring is a substituted or unsubstituted bicyclic 5-6 system. Non-limiting examples include:

を含む。

including.

In some embodiments, the SBM is of formula B or formula C.

[式中、
ZはC又はNであり、UはO、S又はCHであり、VはN又はNHであり、
KはCH又はNであり、QはCH又はNであり、ここでK及びQは同時にNであることはなく、
各出現のR'''はH、OH、NH₂、C_1～6アルキル、C_1～6アルキルアミノ、C_1～6アルコキシ及びハロゲンからなる群から独立して選択され、kは0、1、2又は3であり、
各出現のR'はH、ハロゲン、OH、C_1～6アルキル、C_1～6ハロアルキル及びC_1～6アルコキシからなる群から独立して選択され、mは0、1、2、3又は4であり、
各出現のR''はH、ハロ、OH、NH₂、C_1～6アルキル、C_1～6アルコキシ、C_1～6ハロアルキル、C_1～6アルキルアミノ、C_3～6シクロアルキルアミノ、C_3～6シクロアルキル及びC_3～6ヘテロシクロアルキルからなる群から独立して選択され、nは0、1又は2であり、
JはCR⁶又はNであり、XはCR⁶又はNであり、YはCR⁶又はNであり、ここでJ、X及びYのうちの少なくとも1つはNであるが、J及びYは同時にNであることはなく、X及びYは同時にNであることはなく、
R⁶はH、NH₂、C_1～6アルキル及びC_1～6アルコキシからなる群から独立して選択され、NH₂、C_1～6アルキル又はC_1～6アルコキシは、C_1～3アルキル、C_3～6シクロアルキル及び/又はハロのうちの1～3つで場合により置換されており、
式Bにおいて、VはNであり、ここでZ及びUは同時にヘテロ原子であることはなく、
式Cにおいて、VはN又はNHであり、TはCH又はNであり、ここでU、Z、V及びTのうちの2つまではヘテロ原子を含有する]のSBMである。

[Wherein,
Z is C or N, U is O, S or CH, V is N or NH;
K is CH or N and Q is CH or N, where K and Q are not both N;
each occurrence of R''' is independently selected from the group consisting of H, OH, _NH2 , _C1-6 alkyl, _C1-6 alkylamino, _C1-6 alkoxy, and halogen; k is 0, 1, 2, or 3;
each occurrence of R' is independently selected from the group consisting of H, halogen, OH, _C1-6 alkyl, _C1-6 haloalkyl, and _C1-6 alkoxy; and m is 0, 1, 2, 3, or 4;
each occurrence of R'' is independently selected from the group consisting of H, halo, OH, NH2, _C1-6 alkyl, _C1-6 alkoxy _{, C1-6} haloalkyl, _C1-6 alkylamino, _C3-6 cycloalkylamino, _C3-6 cycloalkyl, and _C3-6 heterocycloalkyl; n is 0, 1, or 2;
J is ^CR6 or N, X is ^CR6 or N, and Y is ^CR6 or N, where at least one of J, X, and Y is N, but J and Y are not both N, and X and Y are not both N;
R ⁶ is independently selected from the group consisting of H, NH ₂ , C _1-6 alkyl, and C _1-6 alkoxy, wherein NH ₂ , C _1-6 alkyl, or C _1-6 alkoxy is optionally substituted with one to three of C _1-3 alkyl, C _3-6 cycloalkyl, and/or halo;
In formula B, V is N, where Z and U are not both heteroatoms;
In formula C, V is N or NH, T is CH or N, where up to two of U, Z, V and T contain heteroatoms.

In some embodiments, EBM is

であり、
R^3'はH又はC_1～6アルキルであり、
各出現のR^2'はH、OH、C_1～6アルキル、C_1～6アルコキシ、C_1～6アルキルアミノ及びNH₂からなる群から独立して選択され、
m6は0、1、2、3又は4であり、
Y₁はCH₂又は

and
R ^3' is H or C _1-6 alkyl;
each occurrence of R2 ^' is independently selected from the group consisting of H, OH, _C1-6 alkyl, _C1-6 alkoxy, _C1-6 alkylamino, and _NH2 ;
m6 is 0, 1, 2, 3 or 4;
_Y1 is _CH2 or

である。

It is.

In some embodiments, the compound has formula (I)-(VI)

のいずれか1つの化合物であり、式Iにおいて、R^3'はH又はC_1～6アルキルであり、Y₁はCH₂又は

In the compound of formula I, R ^3' is H or C _1-6 alkyl, and Y ₁ is CH ₂ or

であり、L₁は結合、-C(=O)-、-NR-、-O-又は-S-であり、Rは水素、場合により置換されているアシル、場合により置換されているアルキル又は窒素保護基であり、L₃は結合、-NR-、-O-又は-S-であり、Rは水素、場合により置換されているアシル、場合により置換されているアルキル又は窒素保護基であり、L₂は置換又は非置換C_1～50炭化水素鎖であり、ZはC又はNであり、UはO、S又はCHであり、VはNであり、ここでZ及びUは同時にヘテロ原子であることはなく、KはCH又はNであり、QはCH又はNであり、ここでK及びQは同時にNであることはなく、各出現のR'''はH、OH、NH₂、C_1～6アルキル、C_1～6アルキルアミノ、C_1～6アルコキシ及びハロゲンからなる群から独立して選択され、kは0、1、2又は3であり、各出現のR'はH、ハロゲン、OH、C_1～6アルキル、C_1～6ハロアルキル及びC_1～6アルコキシからなる群から独立して選択され、mは0、1、2、3又は4であり、各出現のR''はH、ハロ、OH、NH₂、C_1～6アルキル、C_1～6アルコキシ、C_1～6ハロアルキル、C_1～6アルキルアミノ、C_3～6シクロアルキルアミノ、C_3～6シクロアルキル及びC_3～6ヘテロシクロアルキルからなる群から独立して選択され、nは0、1又は2であり、JはCR⁶又はNであり、XはCR⁶又はNであり、YはCR⁶又はNであり、ここでJ、X及びYのうちの少なくとも1つはNであるが、J及びYは同時にNであることはなく、X及びYは同時にNであることはなく、R⁶はH、NH₂、C_1～6アルキル及びC_1～6アルコキシからなる群から独立して選択され、NH₂、C_1～6アルキル又はC_1～6アルコキシは、C_1～3アルキル、C_3～6シクロアルキル及び/又はハロのうちの1～3つで場合により置換されており、
式IIにおいて、各出現のR^2'はH、OH、C_1～6アルキル、C_1～6アルコキシ、C_1～6アルキルアミノ及びNH₂からなる群から独立して選択され、m6は0、1、2、3又は4であり、Y₁はCH₂又は

wherein L ₁ is a bond, -C(═O)-, -NR-, -O- or -S-; R is hydrogen, optionally substituted acyl, optionally substituted alkyl or a nitrogen protecting group; L ₃ is a bond, -NR-, -O- or -S-; R is hydrogen, optionally substituted acyl, optionally substituted alkyl or a nitrogen protecting group; L ₂ is a substituted or unsubstituted C _1-50 hydrocarbon chain; Z is C or N; U is O, S or CH; V is N, where Z and U are not simultaneously heteroatoms; K is CH or N; Q is CH or N, where K and Q are not simultaneously N; each occurrence of R′″ is independently selected from the group consisting of H, OH, NH ₂ , C _1-6 alkyl, C _1-6 alkylamino, C _1-6 alkoxy and halogen; k is 0, 1, 2 or 3; and each occurrence of R′ is H, halogen, OH, C _1-6 alkyl, C m is 0, 1, 2, 3 or 4; each occurrence of R″ is independently selected from the group consisting of H, halo, OH, NH ₂ , C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl _{, C 1-6 alkylamino, C 3-6 cycloalkylamino, C 3-6 cycloalkyl and C 3-6 heterocycloalkyl ; n is} 0, 1 or 2; J is CR ⁶ or N, X is CR ₆ or N and Y is CR ⁶ or N, where at least one of J, X and Y is N, but J and Y are ^not both N and X and Y are not both N; R ⁶ is independently selected from the group consisting of H, NH ₂ , C _1-6 alkyl and C _1-6 alkoxy; NH ₂ , C _1-6 alkyl or C _1-6 alkoxy is selected from the group consisting of C _1-3 alkyl, C optionally substituted with 1 to 3 of _{3 to 6} cycloalkyl and/or halo;
In formula II, R2 ^' at each occurrence is independently selected from the group consisting of H, OH, _C1-6 alkyl, _C1-6 alkoxy, _C1-6 alkylamino, and _NH2 ; m6 is 0, 1, 2, 3, or 4; _Y1 is _CH2 or

であり、L₁は結合、-C(=O)-、-NR-、-O-又は-S-であり、Rは水素、場合により置換されているアシル、場合により置換されているアルキル又は窒素保護基であり、L₂は置換又は非置換C_1～50炭化水素鎖であり、ZはC又はNであり、UはO、S又はCHであり、VはNであり、ここでZ及びUは同時にヘテロ原子であることはなく、KはCH又はNであり、QはCH又はNであり、ここでK及びQは同時にNであることはなく、各出現のR'''はH、OH、NH₂、C_1～6アルキル、C_1～6アルキルアミノ、C_1～6アルコキシ及びハロゲンからなる群から独立して選択され、kは0、1、2又は3であり、各出現のR'はH、ハロゲン、OH、C_1～6アルキル、C_1～6ハロアルキル及びC_1～6アルコキシからなる群から独立して選択され、mは0、1、2、3又は4であり、各出現のR''はH、ハロ、OH、NH₂、C_1～6アルキル、C_1～6アルコキシ、C_1～6ハロアルキル、C_1～6アルキルアミノ、C_3～6シクロアルキル及びC_3～6ヘテロシクロアルキルからなる群から独立して選択され、nは0、1又は2であり、JはCR⁶又はNであり、XはCR⁶又はNであり、YはCR⁶又はNであり、ここでJ、X及びYのうちの少なくとも1つはNであるが、J及びYは同時にNであることはなく、X及びYは同時にNであることはなく、R⁶はH、NH₂、C_1～6アルキル及びC_1～6アルコキシからなる群から独立して選択され、NH₂、C_1～6アルキル又はC_1～6アルコキシは、C_1～3アルキル、C_3～6シクロアルキル及び/又はハロのうちの1～3つで場合により置換されており、
式IIIにおいて、L₁は結合、-C(=O)-、-NR-、-O-又は-S-であり、Rは水素、場合により置換されているアシル、場合により置換されているアルキル又は窒素保護基であり、L₂は置換又は非置換C_1～50炭化水素鎖であり、ZはC又はNであり、UはO、S又はCHであり、VはNであり、ここでZ及びUは同時にヘテロ原子であることはなく、KはCH又はNであり、QはCH又はNであり、ここでK及びQは同時にNであることはなく、各出現のR'''はH、OH、NH₂、C_1～6アルキル、C_1～6アルキルアミノ、C_1～6アルコキシ及びハロゲンからなる群から独立して選択され、kは0、1、2又は3であり、各出現のR'はH、ハロゲン、OH、C_1～6アルキル、C_1～6ハロアルキル及びC_1～6アルコキシからなる群から独立して選択され、mは0、1、2、3又は4であり、各出現のR''はH、ハロ、OH、NH₂、C_1～6アルキル、C_1～6アルコキシ、C_1～6ハロアルキル、C_1～6アルキルアミノ、C_3～6シクロアルキル、C_3～6シクロアルキルアミノ及びC_3～6ヘテロシクロアルキルからなる群から独立して選択され、nは0、1又は2であり、JはCR⁶又はNであり、XはCR⁶又はNであり、YはCR⁶又はNであり、ここでJ、X及びYのうちの少なくとも1つはNであるが、J及びYは同時にNであることはなく、X及びYは同時にNであることはなく、R⁶はH、NH₂、C_1～6アルキル及びC_1～6アルコキシからなる群から独立して選択され、NH₂、C_1～6アルキル又はC_1～6アルコキシは、C_1～3アルキル、C_3～6シクロアルキル及び/又はハロのうちの1～3つで場合により置換されており、
式IVにおいて、R^3'はH又はC_1～6アルキルであり、Y₁はCH₂又は

wherein L ₁ is a bond, -C(═O)-, -NR-, -O- or -S-; R is hydrogen, optionally substituted acyl, optionally substituted alkyl or a nitrogen protecting group; L ₂ is a substituted or unsubstituted C _1-50 hydrocarbon chain; Z is C or N; U is O, S or CH; V is N, where Z and U are not both heteroatoms; K is CH or N; Q is CH or N, where K and Q are not both N; each occurrence of R′″ is independently selected from the group consisting of H, OH, NH ₂ , C _1-6 alkyl, C _1-6 alkylamino, C _1-6 alkoxy and halogen; k is 0, 1, 2 or 3; and each occurrence of R′ is H, halogen, OH, C _1-6 alkyl, C _1-6 haloalkyl and C R" is independently selected from the group consisting of H, halo, OH, _NH2 , C1-6 alkyl, _C1-6 alkoxy, _C1-6 haloalkyl, _C1-6 alkylamino, _C3-6 cycloalkyl, and _C3-6 heterocycloalkyl; n is 0, ₁ , or 2; J is ^CR6 or N; X is CR6 or _N ; and Y is ^CR6 or N, where at least one of J, X, and Y is N, but J and Y are not both N, and X and Y are not both N; ^R6 is independently selected from the group ^consisting of H, _NH2 , _C1-6 alkyl, and _{C1-6 alkoxy, where NH2, C1-6 alkyl, or C1-6 alkoxy is optionally} substituted with 1-3 of _C1-3 alkyl, _C3-6 cycloalkyl, and/or halo;
In formula III, L ₁ is a bond, -C(═O)-, -NR-, -O- or -S-; R is hydrogen, optionally substituted acyl, optionally substituted alkyl or a nitrogen protecting group; L ₂ is a substituted or unsubstituted C _1-50 hydrocarbon chain; Z is C or N; U is O, S or CH; V is N, where Z and U are not both heteroatoms; K is CH or N; Q is CH or N, where K and Q are not both N; each occurrence of R′″ is independently selected from the group consisting of H, OH, NH ₂ , C _1-6 alkyl, C _1-6 alkylamino, C _1-6 alkoxy and halogen; k is 0, 1, 2 or 3; and each occurrence of R′ is H, halogen, OH, C _1-6 alkyl, C _1-6 haloalkyl and C R″ is independently selected from the group consisting of H, halo, OH, NH ₂ , C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _{1-6 alkylamino, C 3-6} cycloalkyl, C _3-6 cycloalkylamino, and C _3-6 heterocycloalkyl, n is 0, 1, or 2, J is CR ^{6 or N, X is CR 6} _or N, and Y is CR ₆ or N, where at least one of J, ^X , and Y is N, but J and Y are not both N, and X and Y ^{are not both N, and R 6 is} independently selected from the group consisting of H, NH ₂ , C _1-6 alkyl, and C 1-6 alkoxy _, where NH ₂ , C _1-6 alkyl, or C _1-6 alkoxy is selected from the group consisting of C _1-3 alkyl, C optionally substituted with 1 to 3 of _{3 to 6} cycloalkyl and/or halo;
In formula IV, R ^3' is H or C _1-6 alkyl and Y ₁ is CH ₂ or

であり、L₁は結合、-C(=O)-、-NR-、-O-又は-S-であり、Rは水素、場合により置換されているアシル、場合により置換されているアルキル又は窒素保護基であり、L₃は結合、-NR-、-O-又は-S-であり、Rは水素、場合により置換されているアシル、場合により置換されているアルキル又は窒素保護基であり、L₂は置換又は非置換C_1～50炭化水素鎖であり、ZはC又はNであり、UはO、S又はCHであり、VはN又はNHであり、TはCH又はNであり、ここでU、Z、V及びTのうちの2つまではヘテロ原子を含有し、KはCH又はNであり、QはCH又はNであり、ここでK及びQは同時にNであることはなく、各出現のR'''はH、OH、NH₂、C_1～6アルキル、C_1～6アルキルアミノ、C_1～6アルコキシ及びハロゲンからなる群から独立して選択され、kは0、1、2又は3であり、各出現のR'はH、ハロゲン、OH、C_1～6アルキル、C_1～6ハロアルキル及びC_1～6アルコキシからなる群から独立して選択され、mは0、1、2、3又は4であり、各出現のR''はH、ハロ、OH、NH₂、C_1～6アルキル、C_1～6アルコキシ、C_1～6ハロアルキル、C_1～6アルキルアミノ、C_3～6シクロアルキル、C_3～6シクロアルキルアミノ及びC_3～6ヘテロシクロアルキルからなる群から独立して選択され、nは0、1又は2であり、JはCR⁶又はNであり、XはCR⁶又はNであり、YはCR⁶又はNであり、ここでJ、X及びYのうちの少なくとも1つはNであるが、J及びYは同時にNであることはなく、X及びYは同時にNであることはなく、R⁶はH、NH₂、C_1～6アルキル及びC_1～6アルコキシからなる群から独立して選択され、NH₂、C_1～6アルキル又はC_1～6アルコキシは、C_1～3アルキル、C_3～6シクロアルキル及び/又はハロのうちの1～3つで場合により置換されており、
式Vにおいて、各出現のR^2'はH、OH、C_1～6アルキル、C_1～6アルコキシ、C_1～6アルキルアミノ及びNH₂からなる群から独立して選択され、m6は0、1、2、3又は4であり、Y₁はCH₂又は

wherein L ₁ is a bond, -C(═O)-, -NR-, -O- or -S-; R is hydrogen, optionally substituted acyl, optionally substituted alkyl or a nitrogen protecting group; L ₃ is a bond, -NR-, -O- or -S-; R is hydrogen, optionally substituted acyl, optionally substituted alkyl or a nitrogen protecting group; L ₂ is a substituted or unsubstituted C _1-50 hydrocarbon chain; Z is C or N; U is O, S or CH; V is N or NH; T is CH or N, where up to two of U, Z, V and T contain a heteroatom; K is CH or N; Q is CH or N, where K and Q are not both N; and each occurrence of R′″ is H, OH, NH ₂ , C _1-6 alkyl, C _1-6 alkylamino, C and R is independently selected from the group consisting of H, halogen, OH, _C1-6 alkyl, C1-6 haloalkyl, and C1-6 alkoxy; k is 0, 1 _{, 2} , or 3; each occurrence of R' is independently selected from the group consisting of H, halogen, OH, C1-6 alkyl, _C1-6 haloalkyl, and _C1-6 alkoxy; m is 0, 1, 2, 3, or 4; each occurrence of R'' is independently selected from the group consisting of H, halo, OH, _NH2 , _C1-6 alkyl, _C1-6 alkoxy, _C1-6 haloalkyl, _C1-6 alkylamino, _C3-6 cycloalkyl, _C3-6 cycloalkylamino, and _C3-6 heterocycloalkyl; n is 0, 1, or 2; J is ^CR6 or N; X is CR6 or N; and Y is ^CR6 or N, where at least one of J, X, and Y is N, but J and Y are not both N, and X and Y are not both N; ^R6 is H, NH2, _{C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 alkylamino, C3-6 cycloalkyl, C3-6} cycloalkylamino, and ^C3-6 heterocycloalkyl; independently selected from the group consisting of _1-6 alkyl and C _1-6 alkoxy, wherein NH ₂ , C _1-6 alkyl or C _1-6 alkoxy is optionally substituted with 1-3 of C _1-3 alkyl, C _3-6 cycloalkyl and/or halo;
In formula V, each occurrence of R2 ^' is independently selected from the group consisting of H, OH, _C1-6 alkyl, _C1-6 alkoxy, _C1-6 alkylamino, and _NH2 ; m6 is 0, 1, 2, 3, or 4; and _Y1 is _CH2 or

であり、L₁は結合、-C(=O)-、-NR-、-O-又は-S-であり、Rは水素、場合により置換されているアシル、場合により置換されているアルキル又は窒素保護基であり、L₂は置換又は非置換C_1～50炭化水素鎖であり、ZはC又はNであり、UはO、S又はCHであり、VはN又はNHであり、TはCH又はNであり、ここでU、Z、V及びTのうちの2つまではヘテロ原子を含有し、KはCH又はNであり、QはCH又はNであり、ここでK及びQは同時にNであることはなく、各出現のR'''はH、OH、NH₂、C_1～6アルキル、C_1～6アルキルアミノ、C_1～6アルコキシ及びハロゲンからなる群から独立して選択され、kは0、1、2又は3であり、各出現のR'はH、ハロゲン、OH、C_1～6アルキル、C_1～6ハロアルキル及びC_1～6アルコキシからなる群から独立して選択され、mは0、1、2、3又は4であり、各出現のR''はH、ハロ、OH、NH₂、C_1～6アルキル、C_1～6アルコキシ、C_1～6ハロアルキル、C_1～6アルキルアミノ、C_3～6シクロアルキル、C_3～6シクロアルキルアミノ及びC_3～6ヘテロシクロアルキルからなる群から独立して選択され、nは0、1又は2であり、JはCR⁶又はNであり、XはCR⁶又はNであり、YはCR⁶又はNであり、ここでJ、X及びYのうちの少なくとも1つはNであるが、J及びYは同時にNであることはなく、X及びYは同時にNであることはなく、R⁶はH、NH₂、C_1～6アルキル及びC_1～6アルコキシからなる群から独立して選択され、NH₂、C_1～6アルキル又はC_1～6アルコキシは、C_1～3アルキル、C_3～6シクロアルキル及び/又はハロのうちの1～3つで場合により置換されており、
式VIにおいて、L₁は結合、-C(=O)-、-NR-、-O-又は-S-であり、Rは水素、場合により置換されているアシル、場合により置換されているアルキル又は窒素保護基であり、L₂は置換又は非置換C_1～50炭化水素鎖であり、ZはC又はNであり、UはO、S又はCHであり、VはNであり、TはCH又はNであり、ここでU、Z、V及びTのうちの2つまではヘテロ原子を含有し、KはCH又はNであり、QはCH又はNであり、ここでK及びQは同時にNであることはなく、各出現のR'''はH、OH、NH₂、C_1～6アルキル、C_1～6アルキルアミノ、C_1～6アルコキシ及びハロゲンからなる群から独立して選択され、kは0、1、2又は3であり、各出現のR'はH、ハロゲン、OH、C_1～6アルキル、C_1～6ハロアルキル及びC_1～6アルコキシからなる群から独立して選択され、mは0、1、2、3又は4であり、各出現のR''はH、ハロ、OH、NH₂、C_1～6アルキル、C_1～6アルコキシ、C_1～6ハロアルキル、C_1～6アルキルアミノ、C_3～6シクロアルキル、C_3～6シクロアルキルアミノ及びC_3～6ヘテロシクロアルキルからなる群から独立して選択され、nは0、1又は2であり、JはCR⁶又はNであり、XはCR⁶又はNであり、YはCR⁶又はNであり、ここでJ、X及びYのうちの少なくとも1つはNであるが、J及びYは同時にNであることはなく、X及びYは同時にNであることはなく、R⁶はH、NH₂、C_1～6アルキル及びC_1～6アルコキシからなる群から独立して選択され、NH₂、C_1～6アルキル又はC_1～6アルコキシが、C_1～3アルキル、C_3～6シクロアルキル及び/又はハロのうちの1～3つで場合により置換されている。場合により置換又は非置換C_1～50炭化水素鎖の1個以上の鎖原子は、-C(=O)-、-O-、-NR^a1-、-S-又は環状部分で独立して置き換えられており、R^a1は独立して水素、置換又は非置換C_1～6アルキル(例えば、置換又は非置換メチル又はエチル)又は窒素保護基(例えば、ベンジル(Bn)、炭酸t-ブチル(BOC又はBoc)、カルバミン酸ベンジル(Cbz)、炭酸9-フルオレニルメチル(Fmoc)、トリフルオロアセチル、トリフェニルメチル、アセチル又はp-トルエンスルホンアミド(Ts))である。

wherein L ₁ is a bond, -C(═O)-, -NR-, -O- or -S-; R is hydrogen, optionally substituted acyl, optionally substituted alkyl or a nitrogen protecting group; L ₂ is a substituted or unsubstituted C _1-50 hydrocarbon chain; Z is C or N; U is O, S or CH; V is N or NH; T is CH or N, where up to two of U, Z, V and T contain a heteroatom; K is CH or N; Q is CH or N, where K and Q are not both N; each occurrence of R′″ is independently selected from the group consisting of H, OH, NH ₂ , C _1-6 alkyl, C _1-6 alkylamino, C _1-6 alkoxy and halogen; k is 0, 1, 2 or 3; and each occurrence of R′ is H, halogen, OH, C _1-6 alkyl, C _1-6 haloalkyl and C R″ is independently selected from the group consisting of H, halo, OH, NH ₂ , C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _{1-6 alkylamino, C 3-6} cycloalkyl, C _3-6 cycloalkylamino, and C _3-6 heterocycloalkyl, n is 0, 1, or 2, J is CR ^{6 or N, X is CR 6} _or N, and Y is CR ₆ or N, where at least one of J, ^X , and Y is N, but J and Y are not both N, and X and Y ^{are not both N, and R 6 is} independently selected from the group consisting of H, NH ₂ , C _1-6 alkyl, and C 1-6 alkoxy _, where NH ₂ , C _1-6 alkyl, or C _1-6 alkoxy is selected from the group consisting of C _1-3 alkyl, C optionally substituted with 1 to 3 of _{3 to 6} cycloalkyl and/or halo;
In formula VI, L ₁ is a bond, -C(═O)-, -NR-, -O- or -S-; R is hydrogen, optionally substituted acyl, optionally substituted alkyl or a nitrogen protecting group; L ₂ is a substituted or unsubstituted C _1-50 hydrocarbon chain; Z is C or N; U is O, S or CH; V is N; T is CH or N, where up to two of U, Z, V and T contain a heteroatom; K is CH or N; Q is CH or N, where K and Q are not both N; each occurrence of R′″ is independently selected from the group consisting of H, OH, NH ₂ , C _1-6 alkyl, C _1-6 alkylamino, C _1-6 alkoxy and halogen; k is 0, 1, 2 or 3; and each occurrence of R′ is H, halogen, OH, C _1-6 alkyl, C 1-6 haloalkyl and C _1-6 haloalkyl. R″ is independently selected from the group consisting of H, halo, OH, NH ₂ , C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _{1-6 alkylamino, C 3-6} cycloalkyl, C _3-6 cycloalkylamino, and C _3-6 heterocycloalkyl, n is 0, 1, or 2, J is CR ^{6 or N, X is CR 6} _or N, and Y is CR ₆ or N, where at least one of J, ^X , and Y is N, but J and Y are not both N, and X and Y are not both N, R ⁶ is independently selected from the group consisting of H, NH ₂ , C _1-6 alkyl, and C 1-6 alkoxy, where NH ₂ , C _1-6 alkyl, or C _1-6 alkoxy is selected from the group _{consisting of C 1-3 alkyl} , ^C Optionally substituted with one to three of _3-6 cycloalkyl and/or halo. One or more chain atoms of the optionally substituted or unsubstituted C _1-50 hydrocarbon chain are independently replaced with -C(=O)-, -O-, -NR ^a1 -, -S-, or a cyclic moiety, where R ^a1 is independently hydrogen, substituted or unsubstituted C _1-6 alkyl (e.g., substituted or unsubstituted methyl or ethyl) or a nitrogen protecting group (e.g., benzyl (Bn), t-butyl carbonate (BOC or Boc), benzyl carbamate (Cbz), 9-fluorenylmethyl carbonate (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl, or p-toluenesulfonamide (Ts)).

In certain embodiments, the compound has the structure of formula I.

In certain embodiments, the compound has the structure of formula II.

In certain embodiments, the compound has the structure of formula III.

In certain embodiments, the compound has the structure of formula IV.

In certain embodiments, the compound has the structure of formula V.

In certain embodiments, the compound has the structure of formula VI.

In certain embodiments, the moieties of formulae (I), (II) and (III):

は、

teeth,

である。

It is.

In certain embodiments, the moieties of formulae (IV), (V) and (VI):

は、

teeth,

である。

It is.

In certain embodiments, the moieties of formulae (I) to (VI):

は、

teeth,

である。

It is.

In certain embodiments, the moieties of formula (I) and (IV):

は、

teeth,

である。

It is.

In certain embodiments, the moieties of formula (II) and (V):

は、

teeth,

である。

It is.

In one embodiment of the present disclosure, L1 is a bond.

In one embodiment of the present disclosure, L1 is -C(=O)-, -NH-, -O-, or -S-.

In one embodiment of the present disclosure, L3 is a bond.

In one embodiment of the present disclosure, L3 is -NH-, -O-, or -S-.

In one embodiment of the present disclosure, L2 is a substituted or unsubstituted _C1-30 hydrocarbon chain, optionally wherein one or more chain atoms of the hydrocarbon chain are independently replaced with -C(=O)-, -O-, -NR ^a1 -, -S-, or a cyclic moiety, and R ^a1 is independently hydrogen, substituted or unsubstituted C _1-6 alkyl, or a nitrogen protecting group.

In certain embodiments, L2 is an unsubstituted C _1-30 hydrocarbon chain, optionally wherein one or more chain atoms of the hydrocarbon chain are independently replaced with -C(=O)-, -O-, -NR ^a1 -, -S-, or a cyclic moiety, and R ^a1 is independently hydrogen, substituted or unsubstituted C _1-6 alkyl, or a nitrogen protecting group.

In certain embodiments, L2 is a substituted or unsubstituted C _1-24 hydrocarbon chain, optionally wherein one or more chain atoms of the hydrocarbon chain are independently replaced with -C(=O)-, -O-, -NR ^a1 -, -S-, or a cyclic moiety, and R ^a1 is independently hydrogen, substituted or unsubstituted C _1-6 alkyl, or a nitrogen protecting group.

In certain embodiments, L2 is an unsubstituted C _1-24 hydrocarbon chain, optionally wherein one or more chain atoms of the hydrocarbon chain are independently replaced with -C(=O)-, -O-, -NR ^a1 -, -S-, or a cyclic moiety, and R ^a1 is independently hydrogen, substituted or unsubstituted C _1-6 alkyl, or a nitrogen protecting group.

In certain embodiments, L2 is a substituted or unsubstituted _C1-20 hydrocarbon chain, optionally wherein one or more chain atoms of the hydrocarbon chain are independently replaced with -C(=O)-, -O-, -NR ^a1 -, -S-, or a cyclic moiety, and R ^a1 is independently hydrogen, substituted or unsubstituted C _1-6 alkyl, or a nitrogen protecting group.

In certain embodiments, L2 is an unsubstituted _C1-20 hydrocarbon chain, optionally wherein one or more chain atoms of the hydrocarbon chain are independently replaced with -C(=O)-, -O-, -NR ^a1 -, -S-, or a cyclic moiety, and R ^a1 is independently hydrogen, substituted or unsubstituted C _1-6 alkyl, or a nitrogen protecting group.

In certain embodiments, at least one chain atom of the hydrocarbon chain of L2 is independently replaced with -O-.

In certain embodiments, the chain of L2 comprises a length of up to 50 contiguous covalently bonded atoms, excluding hydrogen atoms and substituents.

In certain embodiments, L2 includes a length of up to, for example, 46, 45, 40, 35, 32, 30, 25, 23, 20, 15, 14, 12, 11, 10, 9, 8, 7, 6, 5, or 3 consecutive covalently bonded atoms, excluding hydrogen atoms and substituents.

In certain embodiments, any atom of L2 may be substituted. In certain embodiments, none of the atoms in the linker L2 are substituted. In certain embodiments, none of the carbon atoms of the linker are substituted.

In certain embodiments, L2 is a linker that contains an asymmetric carbon/stereocenter, i.e., contains an sp3 hybridized carbon atom with four different groups attached. In certain embodiments, a compound containing such an L2 group is enantiomerically enriched or substantially enantiomerically enriched. In certain embodiments, a compound containing such an L2 group is enantiomerically pure. In certain embodiments, a compound containing such an L2 group is a racemate.

In certain embodiments, L2 comprises a substituted or unsubstituted carbocyclylene, a substituted or unsubstituted heterocyclylene, a substituted or unsubstituted arylene, a substituted or unsubstituted heteroarylene, or a substituted or unsubstituted heteroalkylene, or a combination thereof. In certain embodiments, L2 is a substituted or unsubstituted carbocyclylene, a substituted or unsubstituted heterocyclylene, a substituted or unsubstituted arylene, a substituted or unsubstituted heteroarylene, or a substituted or unsubstituted heteroalkylene. In certain embodiments, L2 is a linker selected from the group consisting of substituted and unsubstituted alkylene, substituted and unsubstituted alkenylene, substituted and unsubstituted alkynylene, substituted and unsubstituted heteroalkylene, substituted and unsubstituted heteroalkenylene, substituted and unsubstituted heteroalkynylene, substituted and unsubstituted heterocyclylene, substituted and unsubstituted carbocyclylene, substituted and unsubstituted arylene, substituted and unsubstituted heteroarylene, and combinations thereof.

Reference to L2, which is a combination of at least two examples of a divalent moiety described herein, refers to a linker consisting of at least one example of a first divalent moiety and at least one example of a second divalent moiety, where the first and second divalent moieties are the same or different and are within the scope of the divalent moieties described herein, and where the first and second divalent moiety examples are contiguous covalently linked to each other. For example, when L2 is a combination of alkylene and heteroalkylene linkers, -alkylene-heteroalkylene-, -alkylene-(heteroalkylene) ₂ -, and -heteroalkylene-alkylene-heteroalkylene- are all within the scope of L2, where the alkylene in each instance in any one of the linkers can be the same or different, and the heteroalkylene in each instance in any one of the linkers can be the same or different.

In certain embodiments, L2 includes at least one example of a substituted or unsubstituted alkylene, such as substituted or unsubstituted _C1-6 alkylene, substituted or unsubstituted _C1-2 alkylene, substituted or unsubstituted _C1-3 alkylene, substituted or unsubstituted _C3-4 alkylene, substituted or unsubstituted _C4-5 alkylene, substituted or unsubstituted _C5-6 alkylene, substituted or unsubstituted _C3-6 alkylene, or substituted or unsubstituted _C4-6 alkylene. Representative alkylene groups include unsubstituted alkylene groups, such as methylene ( _-CH2- ), ethylene (-( _CH2 ) _2- ), n-propylene ( _- (CH2) _3- ), n-butylene (-( _CH2 ) _4- ), n-pentylene (-( _CH2 ) _5- ), and n-hexylene (-( _CH2 ) _6- ).

In certain embodiments, L2 includes at least one example of substituted or unsubstituted alkenylene, such as substituted or unsubstituted _C2-6 alkenylene, substituted or unsubstituted _C1-3 alkenylene, substituted or unsubstituted _{C3-4 alkenylene, substituted or unsubstituted C4-5 alkenylene} , or substituted or unsubstituted _C5-6 alkenylene.

In certain embodiments, L2 includes at least one example of substituted or unsubstituted alkynylene, such as substituted or unsubstituted _C2-6 alkynylene, substituted or unsubstituted _C2-3 alkynylene, substituted or unsubstituted _C3-4 alkynylene, substituted or unsubstituted _C4-5 alkynylene, or substituted or unsubstituted _C5-6 alkynylene.

In certain embodiments, L2 includes at least one example of substituted or unsubstituted heteroalkylene, e.g., substituted or unsubstituted heteroC _1-6 alkylene, substituted or unsubstituted heteroC _1-2 alkylene, substituted or unsubstituted heteroC _2-3 alkylene, substituted or unsubstituted heteroC _3-4 alkylene, substituted or unsubstituted heteroC _4-5 alkylene, or substituted or unsubstituted heteroC _5-6 alkylene. Representative heteroalkylene groups include unsubstituted heteroalkylene groups, such as, -( _CH2 ) ₂ -O( _CH2 ) _2- , _{-OCH2- ,} -CH2O-, -O( _CH2 ) _2- , -(CH2)2O-, -O( _CH2 ) _3- , -( _CH2 ) _3O- , -O(CH2) _4- , -( _CH2 ) _4O- , -O( _CH2 ) _5- , _- ( _CH2 ) _{5O- ,} -O( _CH2 ) _6- , and -O( _CH2 ) _6O- , as well _as amide groups (e.g., -NH-C(=O)- and -C(=O)NH-).

In certain embodiments, L2 includes at least one example of substituted or unsubstituted heteroalkenylene, such as substituted or unsubstituted heteroC _2-6 alkenylene, substituted or unsubstituted heteroC _1-3 alkenylene, substituted or unsubstituted heteroC _3-4 alkenylene, substituted or unsubstituted heteroC _4-5 alkenylene, or substituted or unsubstituted heteroC _5-6 alkenylene.

In certain embodiments, L2 includes at least one example of substituted or unsubstituted heteroalkynylene, such as substituted or unsubstituted heteroC _2-6 alkynylene _, substituted or unsubstituted heteroC _{2-3 alkynylene, substituted or unsubstituted heteroC 3-4} alkynylene, substituted or unsubstituted heteroC _4-5 alkynylene, or substituted or unsubstituted heteroC _5-6 alkynylene.

In certain embodiments, L2 includes at least one example of a substituted or unsubstituted carbocyclylene, such as a substituted or unsubstituted _C3-6 carbocyclylene, a substituted or unsubstituted _C3-4 carbocyclylene, a substituted or unsubstituted _C4-5 carbocyclylene, or a substituted or unsubstituted _C5-6 carbocyclylene.

In certain embodiments, L2 includes at least one example of a substituted or unsubstituted heterocyclylene, such as a substituted or unsubstituted 3- to 6-membered heterocyclylene, a substituted or unsubstituted 3- to 4-membered heterocyclylene, a substituted or unsubstituted 4- to 5-membered heterocyclylene, or a substituted or unsubstituted 5- to 6-membered heterocyclylene. In certain embodiments, at least one chain atom of the hydrocarbon chain of L2 is independently replaced with a 5- to 8-membered heterocyclyl group having 1-4 ring heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In certain embodiments, at least one chain atom of the hydrocarbon chain of L2 is independently replaced with a 6-membered heterocyclyl group having 1-3 ring heteroatoms selected from the group consisting of nitrogen and oxygen. In certain embodiments, at least one chain atom of the hydrocarbon chain of L2 is independently replaced with piperidine, piperazine, or morpholine.

In certain embodiments, L2 includes at least one example of a substituted or unsubstituted arylene, such as a substituted or unsubstituted phenylene. In certain embodiments, at least one chain atom of the hydrocarbon chain of L2 is independently replaced with an optionally substituted phenyl group.

In certain embodiments, L2 includes at least one example of a substituted or unsubstituted heteroarylene, e.g., a substituted or unsubstituted 5- to 6-membered heteroarylene.

In certain embodiments, L2 is an unsubstituted hydrocarbon chain, optionally one or more chain atoms of the hydrocarbon chain are independently replaced with -NR ^a1 -, and each instance of R ^a1 is independently hydrogen, substituted or unsubstituted C _1-6 alkyl, or a nitrogen protecting group, or optionally two instances of R ^a1 together with an intervening atom form a substituted or unsubstituted heterocyclic ring or a substituted or unsubstituted heteroaryl ring. In certain embodiments, at least one instance of R ^a1 is hydrogen. In certain embodiments, at least one instance of R ^a1 is substituted or unsubstituted C _1-6 alkyl (e.g., substituted or unsubstituted methyl or ethyl). In certain embodiments, at least one instance of R ^a1 is a nitrogen protecting group (e.g., benzyl (Bn), t-butyl carbonate (BOC or Boc), benzyl carbamate (Cbz), 9-fluorenylmethyl carbonate (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl, or p-toluenesulfonamide (Tts)).

In certain embodiments, L2 is an optionally substituted C _1-45 hydrocarbon chain, optionally wherein one or more chain atoms of the hydrocarbon chain are independently replaced with -C(=O)-, -O-, -NR ^a1 -, -S-, or a cyclic moiety, and R ^a1 is independently hydrogen, substituted or unsubstituted C _1-6 alkyl, or a nitrogen protecting group. In certain embodiments, L2 is an unsubstituted C _1-45 hydrocarbon chain, optionally wherein one or more chain atoms of the hydrocarbon chain are independently replaced with -C(=O)-, -O-, -NR ^a1 -, -S-, or a cyclic moiety, and R ^a1 is independently hydrogen, substituted or unsubstituted C _1-6 alkyl, or a nitrogen protecting group. In certain embodiments, L2 is an optionally substituted C _1-24 hydrocarbon chain, optionally wherein one or more chain atoms of the hydrocarbon chain are independently replaced with -C(=O)-, -O-, -NR ^a1 -, -S-, or a cyclic moiety, and R ^a1 is independently hydrogen, substituted or unsubstituted C _1-6 alkyl, or a nitrogen protecting group. In certain embodiments, L2 is an unsubstituted C _1-24 hydrocarbon chain, optionally wherein one or more chain atoms of the hydrocarbon chain are independently replaced with -C(=O)-, -O-, -NR ^a1 -, -S-, or a cyclic moiety, and R ^a1 is independently hydrogen, substituted or unsubstituted C _1-6 alkyl, or a nitrogen protecting group. In certain embodiments, L2 is an optionally substituted C _1-20 hydrocarbon chain, where one or more chain atoms of the hydrocarbon chain are independently replaced with -C(=O)-, -O-, -NR ^a1 -, -S-, or a cyclic moiety, and R ^a1 is independently hydrogen, substituted or unsubstituted C _1-6 alkyl, or a nitrogen protecting group. In certain embodiments, L2 is an unsubstituted C _1-20 hydrocarbon chain, where one or more chain atoms of the hydrocarbon chain are independently replaced with -C(=O)-, -O-, -NR ^a1 -, -S-, or a cyclic moiety, and R ^a1 is independently hydrogen, substituted or unsubstituted C _1-6 alkyl, or a nitrogen protecting group. In certain embodiments, L2 is an optionally substituted C _1-30 hydrocarbon chain, where one or more chain atoms of the hydrocarbon chain are independently replaced with -O- or -NR ^a1 -. In certain embodiments, L2 is an unsubstituted C _1-30 hydrocarbon chain, wherein one or more chain atoms of the hydrocarbon chain are independently replaced with -O- or -NR ^a1 -. In certain embodiments, L2 is an unsubstituted C _1-30 hydrocarbon chain, wherein at least one chain atom of the hydrocarbon chain is independently replaced with -O-. In certain embodiments, L2 is an unsubstituted C _1-26 hydrocarbon chain, wherein one or more chain atoms of the hydrocarbon chain are independently replaced with -C(=O)-, -O-, or -NR ^a1 -. In certain embodiments, L2 is an unsubstituted C _1-20 hydrocarbon chain, wherein one or more chain atoms of the hydrocarbon chain are independently replaced with -O-. In certain embodiments, L2 is an unsubstituted C _5-26 hydrocarbon chain, wherein one or more chain atoms of the hydrocarbon chain are independently replaced with -C(=O)-, -O-, or -NR ^a1 -. In certain embodiments, L2 is an unsubstituted C _5-26 hydrocarbon chain, where one or more chain atoms of the hydrocarbon chain are independently replaced with -O-. In certain embodiments, L2 is an unsubstituted C _5-20 hydrocarbon chain, where one or more chain atoms of the hydrocarbon chain are independently replaced with -C(=O)-, -O-, or -NR a1 -. In certain embodiments, L2 is an unsubstituted C _5-20 hydrocarbon chain, where one or more chain atoms of the hydrocarbon chain are independently replaced with -O- or -NR ^a1 -. In certain embodiments, L2 is an unsubstituted C _5-15 hydrocarbon chain, where one or more chain atoms of the hydrocarbon chain are independently replaced with -C(=O) ^- , -O-, or -NR ^a1 -. In certain embodiments, L2 is an unsubstituted C _15-20 hydrocarbon chain, where one or more chain atoms of the hydrocarbon chain are independently replaced with -C(=O)-, -O-, or -NR ^a1 -. In certain embodiments, L2 is an unsubstituted _C20-25 hydrocarbon chain, where one or more chain atoms of the hydrocarbon chain are independently replaced with -C(=O)-, -O-, or -NR ^a1 -. In certain embodiments, L2 is a substituted or unsubstituted _C1-45 hydrocarbon chain. In certain embodiments, L2 is a substituted or unsubstituted _C5-40 hydrocarbon chain. In certain embodiments, one or more chain atoms of the hydrocarbon chain of L2 are independently replaced with -C(=O)-, -O-, -S-, -NR ^a1 -, -N=, or =N-. In certain embodiments, one or more chain atoms of the hydrocarbon chain of L2 are independently replaced with -C(=O)-, -O-, or -NR ^a1 -, where R ^a1 is independently hydrogen, substituted or unsubstituted _C1-6 alkyl, or a nitrogen protecting group. In certain embodiments, L2 is an unsubstituted _C1-26 hydrocarbon chain, where at least one chain atom of the hydrocarbon chain is independently replaced with -O-. Cyclic moieties herein include cycloalkylene or heterocycloalkylene, e.g.

を指す。

Refers to...

In certain embodiments, L2 is an all-carbon substituted or unsubstituted C _1-45 hydrocarbon chain. In certain embodiments, L2 is an all-carbon substituted or unsubstituted C _1-30 hydrocarbon chain. In certain embodiments, L2 is an all-carbon substituted or unsubstituted C _{1-26 hydrocarbon chain. In certain embodiments, L2 is an all-carbon substituted or unsubstituted C 1-24} hydrocarbon chain. In certain embodiments, L2 is an all-carbon substituted or unsubstituted C _1-20 hydrocarbon chain. In certain embodiments, L2 is an all _{-carbon substituted or unsubstituted C 1-20 hydrocarbon} chain.

In a particular embodiment, L2 is

であり、gは1、2、3、4、5又は6である。ある特定の実施形態において、gは1である。ある特定の実施形態において、gは2である。ある特定の実施形態において、gは3である。ある特定の実施形態において、gは4である。ある特定の実施形態において、gは5である。ある特定の実施形態において、gは6である。

and g is 1, 2, 3, 4, 5 or 6. In certain embodiments, g is 1. In certain embodiments, g is 2. In certain embodiments, g is 3. In certain embodiments, g is 4. In certain embodiments, g is 5. In certain embodiments, g is 6.

In certain embodiments, L2 comprises at least one example selected from the group consisting of substituted or unsubstituted methylene, ethylene, _n -propylene, n-butylene _, n-pentylene, n-hexylene, -( _CH2 ) _{2 -} O( _CH2 ) _2- , -OCH2-, -CH2O-, -O( _CH2 ) _2- , _- ( _CH2 ) _2O- , -O( _CH2 ) _3- , -( _CH2 ) _3O- , -O( _CH2 ) _4- , -( _CH2 ) _4O- , -O( _CH2 ) _5- , -( _CH2 )5O-, -O( _CH2 ) _6- , -O(CH2) _6O- , -C(=O)O-, -OC(=O)-, -NH-C(=O)-, and -C(=O)NH-.

In certain embodiments, L2 comprises at least one example selected from the group consisting of substituted or unsubstituted methylene, ethylene, _n -propylene, n-butylene _, n-pentylene, n-hexylene, -( _CH2 ) _{2 -} O( _CH2 ) _2- , -OCH2-, -CH2O-, -O( _CH2 ) _2- , _- ( _CH2 ) _2O- , -O( _CH2 ) _3- , -( _CH2 ) _3O- , -O( _CH2 ) _4- , -( _CH2 )4O-, -O( _CH2 ) _5- , -( _CH2 ) _5O- , -O( _CH2 ) _6- , -O(CH2 ₎ 6O-, -NH-C(=O)-, and -C(=O)NH-.

In certain embodiments, L2 comprises the moiety -NHC(=O)-.

In certain embodiments, L2 includes the moiety -NH-.

Examples of L2 in this disclosure are:

を含むが、それらに限定されず、各gは独立して1、2、3、4、5又は6であり、fは1、2、3、4、5又は6であり、hは1、2、3、4、5又は6である。

wherein each g is independently 1, 2, 3, 4, 5, or 6; f is 1, 2, 3, 4, 5, or 6; and h is 1, 2, 3, 4, 5, or 6.

In certain embodiments, L2 has the formula:

のものである。

belongs to.

In certain embodiments, L2 has the formula:

のものである。

belongs to.

In certain embodiments, L2 has the formula:

のものであり、式中、gは1、2、3、4又は5であり、hは0、1、2、3、4又は5であり、fは1、2、3、4、5、6、7又は8である。

wherein g is 1, 2, 3, 4 or 5; h is 0, 1, 2, 3, 4 or 5; and f is 1, 2, 3, 4, 5, 6, 7 or 8.

In certain embodiments, L2 has the formula:

のものであり、式中、gは1、2、3、4、5、6、7又は8であり、fは1、2、3、4、5、6、7又は8である。

wherein g is 1, 2, 3, 4, 5, 6, 7 or 8; and f is 1, 2, 3, 4, 5, 6, 7 or 8.

In certain embodiments, L2 has the formula:

のものであり、式中、gは1、2、3、4、5、6、7又は8である。

wherein g is 1, 2, 3, 4, 5, 6, 7 or 8.

In certain embodiments, L2 has the formula:

のものであり、式中、gは1、2、3、4、5、6、7又は8であり、fは1、2、3、4、5、6、7又は8である。

wherein g is 1, 2, 3, 4, 5, 6, 7 or 8; and f is 1, 2, 3, 4, 5, 6, 7 or 8.

In certain embodiments, L2 has the formula:

のものであり、式中、gは1、2、3、4、5、6、7又は8であり、fは1、2、3、4、5、6、7又は8である。

wherein g is 1, 2, 3, 4, 5, 6, 7 or 8; and f is 1, 2, 3, 4, 5, 6, 7 or 8.

In certain embodiments, L2 has the formula:

のものであり、式中、gは1、2、3、4、5、6、7又は8である。

wherein g is 1, 2, 3, 4, 5, 6, 7 or 8.

In certain embodiments, the compounds disclosed herein have the following structure:

のうちのいずれか1つの化合物であり、式I-1において、R^3'はH又はC_1～6アルキルであり、Y₁はCH₂又は

In the formula I-1, R ^3' is H or C _1-6 alkyl, and Y ₁ is CH ₂ or

であり、L₁は結合、-C(=O)-、-NR-、-O-又は-S-であり、Rは水素、場合により置換されているアシル、場合により置換されているアルキル又は窒素保護基であり、L₃は結合、-NR-、-O-又は-S-であり、Rは水素、場合により置換されているアシル、場合により置換されているアルキル又は窒素保護基であり、L₂は置換又は非置換C_1～50炭化水素鎖であり、ZはC又はNであり、UはO、S又はCHであり、ここでZ及びUは同時にヘテロ原子であることはなく、QはCH又はNであり、KはCH又はNであり、Q及びKは同時にNであることはなく、各出現のR'''はH、OH、NH₂、C_1～6アルキル、C_1～6アルキルアミノ、C_1～6アルコキシ及びハロゲンからなる群から独立して選択され、kは0、1、2又は3であり、各出現のR'はH、ハロゲン、OH、C_1～6アルキル、C_1～6ハロアルキル及びC_1～6アルコキシからなる群から独立して選択され、mは0、1、2、3又は4であり、各出現のR''はH、ハロ、OH、NH₂、C_1～6アルキル、C_1～6アルコキシ、C_1～6ハロアルキル、C_1～6アルキルアミノ、C_3～6シクロアルキル、C_3～6シクロアルキルアミノ及びC_3～6ヘテロシクロアルキルからなる群から独立して選択され、nは0、1又は2であり、
式II-1において、各出現のR^2'はH、OH、C_1～6アルキル、C_1～6アルコキシ、C_1～6アルキルアミノ及びNH₂からなる群から独立して選択され、m6は0、1、2、3又は4であり、Y₁はCH₂又は

wherein L ₁ is a bond, -C(═O)-, -NR-, -O- or -S-; R is hydrogen, optionally substituted acyl, optionally substituted alkyl or a nitrogen protecting group; L ₃ is a bond, -NR-, -O- or -S-; R is hydrogen, optionally substituted acyl, optionally substituted alkyl or a nitrogen protecting group; L ₂ is a substituted or unsubstituted C _1-50 hydrocarbon chain; Z is C or N; U is O, S or CH, where Z and U are not simultaneously heteroatoms; Q is CH or N; K is CH or N, where Q and K are not simultaneously N; each occurrence of R′″ is independently selected from the group consisting of H, OH, NH ₂ , C _1-6 alkyl, C _{1-6 alkylamino, C 1-6 alkoxy} and halogen; k is 0, 1, 2 or 3; and each occurrence of R′ is H, halogen, OH, C _1-6 alkyl, C _1-6 haloalkyl and C _1-6 alkoxy, m is 0, 1, 2, 3 or 4, each occurrence of R'' is independently selected from the group consisting of H, halo, OH, NH2, _C1-6 alkyl, _C1-6 alkoxy, _{C1-6 haloalkyl} , _C1-6 alkylamino, _C3-6 cycloalkyl, _C3-6 cycloalkylamino and _C3-6 heterocycloalkyl, and n is 0, 1 or 2;
In formula II-1, R2 ^' at each occurrence is independently selected from the group consisting of H, OH, _C1-6 alkyl, _C1-6 alkoxy, _C1-6 alkylamino, and NH2; m6 is 0, 1, 2, 3, or ₄ ; _Y1 is _CH2 or

であり、L₁は結合、-C(=O)-、-NR-、-O-又は-S-であり、Rは水素、場合により置換されているアシル、場合により置換されているアルキル又は窒素保護基であり、L₃は結合、-NR-、-O-又は-S-であり、Rは水素、場合により置換されているアシル、場合により置換されているアルキル又は窒素保護基であり、L₂は置換又は非置換C_1～50炭化水素鎖であり、ZはC又はNであり、UはO、S又はCHであり、ここでZ及びUは同時にヘテロ原子であることはなく、QはCH又はNであり、KはCH又はNであり、ここでQ及びKは同時にNであることはなく、各出現のR'''はH、OH、NH₂、C_1～6アルキル、C_1～6アルキルアミノ、C_1～6アルコキシ及びハロゲンからなる群から独立して選択され、kは0、1、2又は3であり、各出現のR'はH、ハロゲン、OH、C_1～6アルキル、C_1～6ハロアルキル及びC_1～6アルコキシからなる群から独立して選択され、mは0、1、2、3又は4であり、各出現のR''はH、ハロ、OH、NH₂、C_1～6アルキル、C_1～6アルコキシ、C_1～6ハロアルキル、C_1～6アルキルアミノ、C_3～6シクロアルキル、C_3～6シクロアルキルアミノ及びC_3～6ヘテロシクロアルキルからなる群から独立して選択され、nは0、1又は2であり、
式III-1において、L₁は結合、-C(=O)-、-NR-、-O-又は-S-であり、Rは水素、場合により置換されているアシル、場合により置換されているアルキル又は窒素保護基であり、L₃は結合、-NR-、-O-又は-S-であり、Rは水素、場合により置換されているアシル、場合により置換されているアルキル又は窒素保護基であり、L₂は置換又は非置換C_1～50炭化水素鎖であり、ZはC又はNであり、UはO、S又はCHであり、ここでZ及びUは同時にヘテロ原子であることはなく、QはCH又はNであり、KはCH又はNであり、ここでQ及びKは同時にNであることはなく、各出現のR'''はH、OH、NH₂、C_1～6アルキル、C_1～6アルキルアミノ、C_1～6アルコキシ及びハロゲンからなる群から独立して選択され、kは0、1、2又は3であり、各出現のR'はH、ハロゲン、OH、C_1～6アルキル、C_1～6ハロアルキル及びC_1～6アルコキシからなる群から独立して選択され、mは0、1、2、3又は4であり、各出現のR''はH、ハロ、OH、NH₂、C_1～6アルキル、C_1～6アルコキシ、C_1～6ハロアルキル、C_1～6アルキルアミノ、C_3～6シクロアルキル、C_3～6シクロアルキルアミノ及びC_3～6ヘテロシクロアルキルからなる群から独立して選択され、nは0、1又は2であり、
式IV-1において、R^3'はH又はC_1～6アルキルであり、Y₁はCH₂又は

wherein L ₁ is a bond, -C(═O)-, -NR-, -O- or -S-; R is hydrogen, optionally substituted acyl, optionally substituted alkyl or a nitrogen protecting group; L ₃ is a bond, -NR-, -O- or -S-; R is hydrogen, optionally substituted acyl, optionally substituted alkyl or a nitrogen protecting group; L ₂ is a substituted or unsubstituted C _1-50 hydrocarbon chain; Z is C or N; U is O, S or CH, where Z and U are not simultaneously heteroatoms; Q is CH or N; K is CH or N, where Q and K are not simultaneously N; each occurrence of R′″ is independently selected from the group consisting of H, OH, NH ₂ , C _1-6 alkyl, C _1-6 alkylamino, C _1-6 alkoxy and halogen; k is 0, 1, 2 or 3; and each occurrence of R′ is H, halogen, OH, C _1-6 alkyl, C _1-6 haloalkyl and C _1-6 alkoxy, m is 0, 1, 2, 3 or 4, each occurrence of R'' is independently selected from the group consisting of H, halo, OH, NH2, _C1-6 alkyl, _C1-6 alkoxy, _{C1-6 haloalkyl} , _C1-6 alkylamino, _C3-6 cycloalkyl, _C3-6 cycloalkylamino and _C3-6 heterocycloalkyl, and n is 0, 1 or 2;
In formula III-1, L ₁ is a bond, -C(═O)-, -NR-, -O-, or -S-; R is hydrogen, optionally substituted acyl, optionally substituted alkyl, or a nitrogen protecting group; L ₃ is a bond, -NR-, -O-, or -S-; R is hydrogen, optionally substituted acyl, optionally substituted alkyl, or a nitrogen protecting group; L ₂ is a substituted or unsubstituted C _1-50 hydrocarbon chain; Z is C or N; U is O, S, or CH, where Z and U are not simultaneously heteroatoms; Q is CH or N; K is CH or N, where Q and K are not simultaneously N; each occurrence of R′″ is independently selected from the group consisting of H, OH, NH ₂ , C _1-6 alkyl, C _1-6 alkylamino, C _1-6 alkoxy, and halogen; k is 0, 1, 2, or 3; each occurrence of R′ is H, halogen, OH, C _1-6 alkyl, C R'' is independently selected from the group consisting of H, halo, OH, NH2, _C1-6 alkyl, _C1-6 alkoxy, _C1-6 haloalkyl _{, C1-6 alkylamino, C3-6 cycloalkyl, C3-6 cycloalkylamino , and C3-6} heterocycloalkyl; and n is 0 _, 1, or ₂ ;
In formula IV-1, R ^3' is H or C _1-6 alkyl, and Y ₁ is CH ₂ or

であり、L₁は結合、-C(=O)-、-NR-、-O-又は-S-であり、Rは水素、場合により置換されているアシル、場合により置換されているアルキル又は窒素保護基であり、L₃は結合、-NR-、-O-又は-S-であり、Rは水素、場合により置換されているアシル、場合により置換されているアルキル又は窒素保護基であり、L₂は置換又は非置換C_1～50炭化水素鎖であり、ZはC又はNであり、UはO、S又はCHであり、TはCH又はNであり、ここでU、Z及びTのうちの1つのみがヘテロ原子であり、QはCH又はNであり、KはCH又はNであり、ここでQ及びKは同時にNであることはなく、各出現のR'''はH、OH、NH₂、C_1～6アルキル、C_1～6アルキルアミノ、C_1～6アルコキシ及びハロゲンからなる群から独立して選択され、kは0、1、2又は3であり、各出現のR'はH、ハロゲン、OH、C_1～6アルキル、C_1～6ハロアルキル及びC_1～6アルコキシからなる群から独立して選択され、mは0、1、2、3又は4であり、各出現のR''はH、ハロ、OH、NH₂、C_1～6アルキル、C_1～6アルコキシ、C_1～6ハロアルキル、C_1～6アルキルアミノ、C_3～6シクロアルキル、C_3～6シクロアルキルアミノ及びC_3～6ヘテロシクロアルキルからなる群から独立して選択され、nは0、1又は2であり、XはCR⁶又はNであり、YはCR⁶又はNであり、ここでX及びYのうちの一方はNであり、他方はCR⁶であり、R⁶はH、NH₂、C_1～6アルキル及びC_1～6アルコキシからなる群から独立して選択され、NH₂、C_1～6アルキル又はC_1～6アルコキシは、C_1～3アルキル、C_3～6シクロアルキル及び/又はハロのうちの1～3つで場合により置換されており、
式V-1において、各出現のR^2'はH、OH、C_1～6アルキル、C_1～6アルコキシ、C_1～6アルキルアミノ及びNH₂からなる群から独立して選択され、m6は0、1、2、3又は4であり、Y₁はCH₂又は

wherein L ₁ is a bond, -C(═O)-, -NR-, -O- or -S-; R is hydrogen, optionally substituted acyl, optionally substituted alkyl or a nitrogen protecting group; L ₃ is a bond, -NR-, -O- or -S-; R is hydrogen, optionally substituted acyl, optionally substituted alkyl or a nitrogen protecting group; L ₂ is a substituted or unsubstituted C _1-50 hydrocarbon chain; Z is C or N; U is O, S or CH; T is CH or N, where only one of U, Z and T is a heteroatom; Q is CH or N; K is CH or N, where Q and K are not both N; each occurrence of R′″ is independently selected from the group consisting of H, OH, NH ₂ , C _1-6 alkyl, C _1-6 alkylamino, C _1-6 alkoxy and halogen; k is 0, 1, 2 or 3; and each occurrence of R′ is H, halogen, OH, C _1-6 alkyl, C m is 0, 1, 2, 3 or 4; each occurrence of R'' is independently selected from the group consisting of H, halo, OH, _NH2 , _C1-6 alkyl, _C1-6 alkoxy, _{C1-6 haloalkyl, C1-6 alkylamino, C3-6 cycloalkyl , C3-6} cycloalkylamino and _C3-6 heterocycloalkyl; n is 0, 1 or 2; X is ^CR6 or N and Y is _CR6 or N, where one of X and Y is N and the other is ^CR6 ; ^R6 is independently selected from the group consisting of H, _NH2 , ^C1-6 alkyl and _{C1-6 alkoxy, where NH2, C1-6 alkyl or C1-6} alkoxy are optionally substituted with 1 _{to 3 of C1-3 alkyl} , _C3-6 cycloalkyl and/or halo;
In formula V-1, R2 ^' at each occurrence is independently selected from the group consisting of H, OH, _C1-6 alkyl, _C1-6 alkoxy, _C1-6 alkylamino, and NH2; m6 is 0, 1, 2, 3, or ₄ ; _Y1 is _CH2 or

であり、L₁は結合、-C(=O)-、-NR-、-O-又は-S-であり、Rは水素、場合により置換されているアシル、場合により置換されているアルキル又は窒素保護基であり、L₃は結合、-NR-、-O-又は-S-であり、Rは水素、場合により置換されているアシル、場合により置換されているアルキル又は窒素保護基であり、L₂は置換又は非置換C_1～50炭化水素鎖であり、ZはC又はNであり、UはO、S又はCHであり、TはCH又はNであり、ここでU、Z及びTのうちの1つのみがヘテロ原子であり、QはCH又はNであり、KはCH又はNであり、ここでQ及びKは同時にNであることはなく、各出現のR'''はH、OH、NH₂、C_1～6アルキル、C_1～6アルキルアミノ、C_1～6アルコキシ及びハロゲンからなる群から独立して選択され、kは0、1、2又は3であり、各出現のR'はH、ハロゲン、OH、C_1～6アルキル、C_1～6ハロアルキル及びC_1～6アルコキシからなる群から独立して選択され、mは0、1、2、3又は4であり、各出現のR''はH、ハロ、OH、NH₂、C_1～6アルキル、C_1～6アルコキシ、C_1～6ハロアルキル、C_1～6アルキルアミノ、C_3～6シクロアルキル、C_3～6シクロアルキルアミノ及びC_3～6ヘテロシクロアルキルからなる群から独立して選択され、nは0、1又は2であり、XはCR⁶又はNであり、YはCR⁶又はNであり、ここでX及びYのうちの一方はNであり、他方はCR⁶であり、R⁶はH、NH₂、C_1～6アルキル及びC_1～6アルコキシからなる群から独立して選択され、NH₂、C_1～6アルキル又はC_1～6アルコキシは、C_1～3アルキル、C_3～6シクロアルキル及び/又はハロのうちの1～3つで場合により置換されており、
式VI-1において、L₁は結合、-C(=O)-、-NR-、-O-又は-S-であり、Rは水素、場合により置換されているアシル、場合により置換されているアルキル又は窒素保護基であり、L₃は結合、-NR-、-O-又は-S-であり、Rは水素、場合により置換されているアシル、場合により置換されているアルキル又は窒素保護基であり、L₂は置換又は非置換C_1～50炭化水素鎖であり、ZはC又はNであり、UはO、S又はCHであり、TはCH又はNであり、ここでU、Z及びTのうちの1つのみがヘテロ原子であり、QはCH又はNであり、KはCH又はNであり、ここでQ及びKは同時にNであることはなく、各出現のR'''はH、OH、NH₂、C_1～6アルキル、C_1～6アルキルアミノ、C_1～6アルコキシ及びハロゲンからなる群から独立して選択され、kは0、1、2又は3であり、各出現のR'はH、ハロゲン、OH、C_1～6アルキル、C_1～6ハロアルキル及びC_1～6アルコキシからなる群から独立して選択され、mは0、1、2、3又は4であり、各出現のR''はH、ハロ、OH、NH₂、C_1～6アルキル、C_1～6アルコキシ、C_1～6ハロアルキル、C_1～6アルキルアミノ、C_3～6シクロアルキル、C_3～6シクロアルキルアミノ及びC_3～6ヘテロシクロアルキルからなる群から独立して選択され、nは0、1又は2であり、XはCR⁶又はNであり、YはCR⁶又はNであり、ここでX及びYのうちの一方はNであり、他方はCR⁶であり、R⁶はH、NH₂、C_1～6アルキル及びC_1～6アルコキシからなる群から独立して選択され、NH₂、C_1～6アルキル又はC_1～6アルコキシが、C_1～3アルキル、C_3～6シクロアルキル及び/又はハロのうちの1～3つで場合により置換されている。

wherein L ₁ is a bond, -C(═O)-, -NR-, -O- or -S-; R is hydrogen, optionally substituted acyl, optionally substituted alkyl or a nitrogen protecting group; L ₃ is a bond, -NR-, -O- or -S-; R is hydrogen, optionally substituted acyl, optionally substituted alkyl or a nitrogen protecting group; L ₂ is a substituted or unsubstituted C _1-50 hydrocarbon chain; Z is C or N; U is O, S or CH; T is CH or N, where only one of U, Z and T is a heteroatom; Q is CH or N; K is CH or N, where Q and K are not both N; each occurrence of R′″ is independently selected from the group consisting of H, OH, NH ₂ , C _1-6 alkyl, C _1-6 alkylamino, C _1-6 alkoxy and halogen; k is 0, 1, 2 or 3; and each occurrence of R′ is H, halogen, OH, C _1-6 alkyl, C m is 0, 1, 2, 3 or 4; each occurrence of R'' is independently selected from the group consisting of H, halo, OH, _NH2 , _C1-6 alkyl, _C1-6 alkoxy, _{C1-6 haloalkyl, C1-6 alkylamino, C3-6 cycloalkyl , C3-6} cycloalkylamino and _C3-6 heterocycloalkyl; n is 0, 1 or 2; X is ^CR6 or N and Y is _CR6 or N, where one of X and Y is N and the other is ^CR6 ; ^R6 is independently selected from the group consisting of H, _NH2 , ^C1-6 alkyl and _{C1-6 alkoxy, where NH2, C1-6 alkyl or C1-6} alkoxy are optionally substituted with 1 _{to 3 of C1-3 alkyl} , _C3-6 cycloalkyl and/or halo;
In formula VI-1, L ₁ is a bond, -C(═O)-, -NR-, -O-, or -S-; R is hydrogen, optionally substituted acyl, optionally substituted alkyl, or a nitrogen protecting group; L ₃ is a bond, -NR-, -O-, or -S-; R is hydrogen, optionally substituted acyl, optionally substituted alkyl, or a nitrogen protecting group; L ₂ is a substituted or unsubstituted C _1-50 hydrocarbon chain; Z is C or N; U is O, S, or CH; T is CH or N, where only one of U, Z, and T is a heteroatom; Q is CH or N; K is CH or N, where Q and K are not simultaneously N; each occurrence of R′″ is independently selected from the group consisting of H, OH, NH ₂ , C _1-6 alkyl, C _1-6 alkylamino, C _1-6 alkoxy, and halogen; k is 0, 1, 2, or 3; and each occurrence of R′ is H, halogen, OH, C R″ is independently selected from the group consisting of H, halo, OH, NH2, _C1-6 alkyl, _C1-6 alkoxy, _{C1-6 haloalkyl, C1-6} alkylamino, _C3-6 cycloalkyl, _C3-6 cycloalkylamino, and _C3-6 heterocycloalkyl, n is ₀ , ₁ , or ₂ , X is CR6 or N, Y _is CR6 or N, where one of X and Y is N and _the other is ^CR6 , and ^R6 is independently selected from the group consisting of H, _NH2 , ^C1-6 alkyl, and _{C1-6 alkoxy, where NH2, C1-6 alkyl ,} or _C1-6 alkoxy is optionally substituted with 1 to 3 of _C1-3 alkyl, _C3-6 cycloalkyl _, and/ ^or halo.

In certain embodiments, the compound of formula I-1 is represented by the following formula 1, 5, 6, 8, 10 or 13:

の化合物であり、
各Aは独立してO、NH、

is a compound of
Each A is independently O, NH,

であり、m2は1、2、3、4、5、6又は7であり、
m3は1、2、3、4、5又は6であり、
m4は0、1、2又は3であり、
m5は0、1、2又は3であり、
R^1'はO、NH、

and m2 is 1, 2, 3, 4, 5, 6 or 7;
m3 is 1, 2, 3, 4, 5 or 6;
m4 is 0, 1, 2 or 3;
m5 is 0, 1, 2 or 3;
R ^1' is O, NH,

である。

It is.

One embodiment of the present disclosure is a compound of formula 1, wherein R' is H, _C1-3 haloalkyl or _C1-3 alkoxy, preferably H, _CF3 , _CCl3 , methoxy or ethoxy, more preferably H, _CF3 or methoxy.

One embodiment of the present disclosure is a compound of formula 1, where m is 0, 1, 2, 3 or 4, preferably 0 or 1.

One embodiment of the present disclosure is a compound of formula 1, wherein R'' is H, halo, OH, _NH2 , _C1-3 alkoxy, _C1-3 alkylamino, _C3-5 cycloalkyl, _{C3-5 cycloalkylamino and C3-5 heterocycloalkyl} , preferably H, F, Cl, _NH2 , methoxy, ethoxy, methylamino, dimethylamino, ethylamino, diethylamino, cyclopropyl, cyclobutyl or cyclopentyl, more preferably H, F, dimethylamino or cyclopropyl.

One embodiment of the present disclosure is a compound of formula 1, where n is 0, 1 or 2, preferably 0 or 1.

One embodiment of the present disclosure is a compound of formula 1, where R''' is H, OH or halogen, preferably H, OH, F or Cl, more preferably H.

One embodiment of the present disclosure is a compound of formula 1, where k is 0, 1, 2 or 3, preferably 0 or 1.

In one embodiment of the present disclosure, R ^1′ is O, NH,

である式1の化合物である。本開示の一実施形態は、R^1'がO、NH、

One embodiment of the present disclosure is a compound of formula 1, wherein R ^1' is O, NH,

である式1の化合物である。

is a compound of formula 1,

In one embodiment of the present disclosure, A is O, NH,

、好ましくはO又は

, preferably O or

である式1の化合物である。

is a compound of formula 1,

One embodiment of the present disclosure is a compound of formula 1, where m2 is 2, 3, 4 or 6, preferably 2 or 6.

One embodiment of the present disclosure is a compound of formula 1, wherein R ^3′ is H or C _1-3 alkyl, preferably H or methyl, and more preferably H.

One embodiment of the present disclosure is a compound represented by formula 1-1:

に示されている構造を有する式1の化合物である。

The compound is of formula 1 having the structure shown in

In formula 1-1, R ^3' is H or C _1-3 alkyl, and Y ₁ is CH ₂ or

であり、AはO、NH、

where A is O, NH,

であり、m2は1、2、3、4、5、6及び7であり、R^1'はO、NH、

m2 is 1, 2, 3, 4, 5, 6, or 7; R ^1′ is O, NH,

であり、UはO、S又はCHであり、ZはC又はNであり、ここでU及びZは同時にヘテロ原子であることはなく、R'はH、C_1～3ハロアルキル又はC_1～3アルコキシであり、R''はH、F、Cl、OH、NH₂、C_1～3アルコキシ、メチルアミノ、ジメチルアミノ、ジエチルアミノ又はシクロプロピルアミノであり、nは0、1又は2である。

wherein U is O, S or CH, Z is C or N, where U and Z are not both heteroatoms, R' is H, _C1-3 haloalkyl or _C1-3 alkoxy, R'' is H, F, Cl, OH, _NH2 , _C1-3 alkoxy, methylamino, dimethylamino, diethylamino or cyclopropylamino, and n is 0, 1 or 2.

One embodiment of the present disclosure is a compound of formula 1-1, where m2 is 2, 3, 4 or 6, preferably 2 or 6.

One embodiment of the disclosure is a compound of formula 1-1 where R ^3' is H or methyl.

In one embodiment of the present disclosure, A is O or

である式1-1の化合物である。

is a compound of formula 1-1,

One embodiment of the present disclosure is where R ^1′ is O, NH or

である式1-1の化合物である。本開示の一実施形態は、R^1'がO、NH、

One embodiment of the present disclosure is a compound of formula 1-1, wherein R ^1' is O, NH,

である式1-1の化合物である。

is a compound of formula 1-1,

One embodiment of the present disclosure is a compound of formula 1-1 where Z is N and U is CH.

One embodiment of the present disclosure is a compound of formula 1-1, where Z is C and U is S or O.

One embodiment of the disclosure is a compound of formula 1-1, where R'' is H, F, Cl, OH, _NH2 , methoxy, methylamino, dimethylamino, diethylamino, cyclopropyl or cyclopropylamino, preferably H, F, methylamino, dimethylamino or cyclopropylamino.

One embodiment of the present disclosure is a compound of formula 1-1, where R' is H, _C1-3 fluoroalkyl, methoxy or ethoxy, preferably R' is H, methoxy or _CF3 .

One embodiment of the present disclosure is a compound of formula 5, where R ^3' is H or C _1-3 alkyl, preferably H or methyl.

One embodiment of the present disclosure is a compound of formula 5, where A is O, NH or

、好ましくはOである。本開示の一実施形態は式5の化合物であり、各Aは独立してO、NH、

and preferably O. One embodiment of the present disclosure is a compound of formula 5, wherein each A is independently O, NH,

である。

It is.

One embodiment of the present disclosure is a compound of formula 5, where m4 is 0, 1, 2 or 3, preferably 0 or 3.

One embodiment of the present disclosure is a compound of formula 5, where m5 is 0, 1, 2 or 3, preferably 0 or 1.

One embodiment of the present disclosure is a compound of formula 5, where m3 is 1, 2, 3, 4, 5 or 6, preferably 3 or 5.

One embodiment of the present disclosure is where R ^1′ is O, NH or

である式5の化合物である。

is a compound of formula 5,

An embodiment of the present disclosure is a compound of formula 5, wherein R''' is H, OH, C _1-3 alkyl, C _1-3 alkoxy or halogen, preferably H, methyl, methoxy or F, more preferably H.

One embodiment of the present disclosure is a compound of formula 5, where k is 0, 1, 2 or 3, preferably 0 or 1.

One embodiment of the present disclosure is a compound of formula 5 where Z is C and U is O or S.

One embodiment of the present disclosure is a compound of formula 5 where Z is N and U is CH.

One embodiment of the present disclosure is a compound of formula 5, wherein R' is H, halogen, OH, _C1-3 alkyl, _C1-3 haloalkyl or _C1-3 alkoxy, preferably H, F, _CF3 , _CCl3 , methyl or methoxy, more preferably H or _CF3 .

One embodiment of the present disclosure is a compound of formula 5, where m is 0, 1, 2 or 3, preferably 0 or 1.

One embodiment of the present disclosure is a compound of formula 5, wherein R'' is H, halo, OH, NH2, _C1-3 alkyl, _C1-3 alkoxy, _C1-3 haloalkyl, _C1-3 alkylamino, _C3-5 cycloalkyl, _C3-5 cycloalkylamino or _C3-5 heterocycloalkyl, preferably H, F, OH, _NH2 , methyl, methoxy, _{CF3 , CCl3} , methylamino, cyclopropyl or dimethylamino, more preferably H, F, _CF3 , cyclopropyl, cyclopropylamino or dimethylamino.

One embodiment of the present disclosure is a compound of formula 5, where n is 0, 1 or 2, preferably 0 or 1.

One embodiment of the present disclosure is represented by formula 5-1:

に示されている構造を有する式5の化合物である。

The compound is of formula 5 having the structure shown in

In formula 5-1, R ^3' is H or C _1-3 alkyl, and Y ₁ is CH ₂ or

であり、AはO、NH、

where A is O, NH,

であり、m5は0又は1であり、m4は0、1、2、3又は4であり、m3は1、2、3、4、5又は6であり、R^1'はO、NH、

m5 is 0 or 1, m4 is 0, 1, 2, 3 or 4, m3 is 1, 2, 3, 4, 5 or 6, and R ^1′ is O, NH,

であり、ZはC又はNであり、UはO、S又はCHであり、ここでZ及びUは同時にヘテロ原子であることはなく、R'''はH、OH、C_1～3アルキル、C_1～3アルコキシ又はハロゲンであり、R'はH、ハロゲン、OH、C_1～3アルキル、C_1～3ハロアルキル又はC_1～3アルコキシであり、R''はH、ハロ、OH、NH₂、C_1～3アルキル、C_1～3アルコキシ、C_1～3ハロアルキル、C_1～3アルキルアミノ、C_3～5シクロアルキル、C_3～5シクロアルキルアミノ及びC_3～5ヘテロシクロアルキルであり、nは0、1又は2である。

wherein Z is C or N, U is O, S or CH, where Z and U are not both heteroatoms, R''' is H, OH, _{C1-3 alkyl, C1-3} alkoxy or halogen, R' is H, halogen, OH, C1-3 alkyl, _C1-3 haloalkyl or _C1-3 alkoxy, R'' is H, halo, OH, NH2, _C1-3 alkyl _{, C1-3 alkoxy, C1-3 haloalkyl, C1-3 alkylamino , C3-5 cycloalkyl} , _C3-5 cycloalkylamino and _C3-5 heterocycloalkyl, and n is 0 _, 1 or ₂ .

One embodiment of the present disclosure is a compound of formula 5-1, where A is O.

One embodiment of the present disclosure is a compound of formula 5-1, where m5 is 0 or 1.

One embodiment of the present disclosure is a compound of formula 5-1, where m4 is 0 or 3.

One embodiment of the present disclosure is a compound of formula 5-1, where m3 is 3 or 5.

One embodiment of the present disclosure is where R ^1′ is O, NH or

である式5-1の化合物である。

is a compound of formula 5-1,

One embodiment of the present disclosure is a compound of formula 5-1, where Z is C and U is O or S.

One embodiment of the present disclosure is a compound of formula 5-1, where Z is N and U is CH.

One embodiment of the present disclosure is a compound of formula 5-1, where R' is H, halogen, C _1-3 alkyl, C _1-3 fluoroalkyl or C _1-3 alkoxy, preferably H, methyl, CF ₃ , methyl or methoxy, more preferably H or CF ₃ .

One embodiment of the disclosure is a compound of formula 5-1, wherein R'' is H, halo, OH, NH2, _C1-3 alkyl, _C1-3 alkoxy, _{C1-3 haloalkyl} , _C1-3 alkylamino, _C3-5 cycloalkyl, _C3-5 cycloalkylamino or _C3-5 heterocycloalkyl, preferably H, F, _CF3 , amino, methylamino, dimethylamino, cyclopropyl or cyclopropylamino, more preferably H, F, _CF3 , dimethylamino, cyclopropylamino or cyclopropyl.

One embodiment of the present disclosure is a compound of formula 6, where R ^3' is H or C _1-3 alkyl, preferably H or methyl.

In one embodiment of the present disclosure, A is O, NH or

、好ましくはO又はNHである式6の化合物である。

, preferably O or NH.

One embodiment of the present disclosure is a compound of formula 6, where m2 is 1, 2, 3, 4, 5, 6 or 7, preferably 2 or 6.

One embodiment of the present disclosure is where R ^1′ is O, NH or

、好ましくはO又はNHである式6の化合物である。

, preferably O or NH.

One embodiment of the present disclosure is a compound of formula 6, where Z is C or N and U is O, S or CH, where Z and U are not both heteroatoms, preferably Z is C and U is S.

An embodiment of the present disclosure is a compound of formula 6, wherein R''' is H, OH, C _1-3 alkyl, C _1-3 alkoxy or halogen, preferably H, methyl, methoxy or F, more preferably H.

One embodiment of the present disclosure is a compound of formula 6, wherein R' is H, halogen, OH, _C1-3 alkyl, _C1-3 haloalkyl or _C1-3 alkoxy, preferably H, F, _CF3 , _CCl3 , methyl or methoxy, more preferably H or _CF3 .

One embodiment of the present disclosure is a compound of formula 6, where m is 0, 1, 2 or 3, preferably 0 or 1.

One embodiment of the present disclosure is a compound of formula 6, wherein R'' is H, halo, OH, NH2, _C1-3 alkyl, _C1-3 alkoxy, _C1-3 haloalkyl, _C1-3 alkylamino, _C3-5 cycloalkyl, _C3-5 cycloalkylamino or _C3-5 heterocycloalkyl, preferably H, F, OH, _NH2 , methyl, methoxy, CF3 _{, CCl3} , _methylamino , cyclopropyl, cyclopropylamino or dimethylamino, more preferably H, F, _CF3 , dimethylamino, cyclopropyl or cyclopropylamino.

One embodiment of the present disclosure is a compound of formula 6, where n is 0 or 1.

One embodiment of the present disclosure is represented by formula 6-1:

に示されている構造を有する式6の化合物である。

The compound is of formula 6 having the structure shown in

In formula 6-1, R ^3' is H or C _1-3 alkyl, and Y ₁ is CH ₂ or

であり、AはO、NH、

where A is O, NH,

であり、m2は1、2、3、4、5、6又は7であり、R^1'はO、NH、

m2 is 1, 2, 3, 4, 5, 6 or 7; R ^1′ is O, NH,

であり、R'''はH、OH、C_1～3アルキル、C_1～3アルコキシ又はハロゲンであり、kは0、1、2又は3であり、ZはC又はNであり、UはO、S又はCHであり、ここでZ及びUは同時にヘテロ原子であることはなく、R'はH、ハロゲン、OH、C_1～3アルキル、C_1～3ハロアルキル又はC_1～3アルコキシであり、mは0、1、2又は3であり、R''はH、ハロ、OH、NH₂、C_1～3アルキル、C_1～3アルコキシ、C_1～3ハロアルキル、C_1～3アルキルアミノ、C_3～5シクロアルキル、C_3～5シクロアルキルアミノ又はC_3～5ヘテロシクロアルキルであり、nは0、1又は2である。

wherein R''' is H, OH, _C1-3 alkyl, _C1-3 alkoxy or halogen, k is 0, 1, 2 or 3, Z is C or N, U is O, S or CH, where Z and U are not both heteroatoms, R' is H, halogen, OH, _C1-3 alkyl, _C1-3 haloalkyl or _C1-3 alkoxy, m is 0, 1, 2 or 3, R'' is H, halo, OH, NH2, _C1-3 alkyl, _C1-3 alkoxy _{, C1-3} haloalkyl, _C1-3 alkylamino, _C3-5 cycloalkyl, _C3-5 cycloalkylamino or _C3-5 heterocycloalkyl, and n is 0, 1 or 2.

In some embodiments of formula 6-1, R ^3' is H or C _1-3 alkyl and Y ₁ is CH ₂ or

であり、AはO、NH、

where A is O, NH,

であり、m2は1、2、3、4、5、6又は7であり、R^1'はO、NH、

m2 is 1, 2, 3, 4, 5, 6 or 7; R ^1′ is O, NH,

であり、R'''はH、OH、C_1～3アルキル、C_1～3アルコキシ又はハロゲンであり、kは0、1、2又は3であり、ZはC又はNであり、UはO、S又はCHであり、ここでZ及びUは同時にヘテロ原子であることはなく、R'はH、ハロゲン、OH、C_1～3アルキル、C_1～3ハロアルキル又はC_1～3アルコキシであり、mは0、1、2又は3であり、R''はH、ハロ、OH、NH₂、C_1～3アルキル、C_1～3アルコキシ、C_1～3ハロアルキル、C_1～3アルキルアミノ、C_3～5シクロアルキル、C_3～5シクロアルキルアミノ又はC_3～5ヘテロシクロアルキルであり、nは0、1又は2である。

wherein R''' is H, OH, _C1-3 alkyl, _C1-3 alkoxy or halogen, k is 0, 1, 2 or 3, Z is C or N, U is O, S or CH, where Z and U are not both heteroatoms, R' is H, halogen, OH, _C1-3 alkyl, _C1-3 haloalkyl or _C1-3 alkoxy, m is 0, 1, 2 or 3, R'' is H, halo, OH, NH2, _C1-3 alkyl, _C1-3 alkoxy _{, C1-3} haloalkyl, _C1-3 alkylamino, _C3-5 cycloalkyl, _C3-5 cycloalkylamino or _C3-5 heterocycloalkyl, and n is 0, 1 or 2.

One embodiment of the disclosure is a compound of formula 6-1 where R ^3' is H or methyl.

One embodiment of the present disclosure is a compound of formula 6-1, where A is O or NH.

One embodiment of the present disclosure is a compound of formula 6-1, where m2 is 2 or 6.

One embodiment of the disclosure is a compound of formula 6-1, where R ^1' is O or NH.

One embodiment of the present disclosure is a compound of formula 6-1, where R' is H or _CF3 .

One embodiment of the present disclosure is a compound of formula 6-1, where m is 0, 1, 2 or 3, preferably 0 or 1.

One embodiment of the disclosure is a compound of formula 6-1, wherein R'' is H, halo, OH, NH2, _C1-3 alkyl, _C1-3 alkoxy, _C1-3 haloalkyl, _C1-3 alkylamino, _C3-5 cycloalkyl, _C3-5 cycloalkylamino or _C3-5 heterocycloalkyl, preferably H, F, _CF3 , methoxy, methyl, dimethylamino, cyclopropyl _, cyclopropylamino or methylamino, more preferably H, _CF3 , F, dimethylamino, cyclopropyl or cyclopropylamino, most preferably H, dimethylamino, cyclopropyl or cyclopropylamino.

One embodiment of the present disclosure is a compound of formula 6-1, where n is 0 or 1.

One embodiment of the present disclosure is a compound of formula 6-1, in which R'' is substituted at the adjacent position to the N atom.

One embodiment of the present disclosure is a compound of formula 8, where R ^3' is H or C _1-3 alkyl, preferably H or methyl.

In one embodiment of the present disclosure, Y ₁ is CH ₂ or

、好ましくはCH₂である式8の化合物である。

, preferably a compound of formula 8, where _CH2 is

In one embodiment of the present disclosure, A is O, NH,

、好ましくはOである式8の化合物である。

, preferably O.

One embodiment of the present disclosure is a compound of formula 8, where m2 is 1, 2, 3 or 4, preferably 2.

In one embodiment of the present disclosure, R ^1′ is O, NH,

、好ましくはOである式8の化合物である。

, preferably O.

An embodiment of the present disclosure is a compound of formula 8, wherein R''' is H, OH, C _1-3 alkyl, C _1-3 alkoxy or halogen, preferably H, methyl, methoxy or F, more preferably H.

One embodiment of the present disclosure is a compound of formula 8, where k is 0 or 1.

One embodiment of the present disclosure is a compound of formula 8, where Z is C or N and U is O, S or CH, where Z and U are not both heteroatoms, preferably Z is N and U is CH, and preferably Z is C and U is S.

One embodiment of the present disclosure is a compound of formula 8, wherein R' is H, halogen, OH, _C1-3 alkyl, _C1-3 haloalkyl or _C1-3 alkoxy, preferably H, F, _CF3 , _CCl3 , methyl or methoxy, more preferably H or _CF3 .

One embodiment of the present disclosure is a compound of formula 8, where m is 0, 1, or 2.

One embodiment of the present disclosure is a compound of formula 8, wherein R'' is H, halo, OH, NH2, _C1-3 alkyl, _C1-3 alkoxy, _C1-3 haloalkyl, _C1-3 alkylamino, _C3-5 cycloalkyl, _C3-5 cycloalkylamino or _C3-5 heterocycloalkyl, preferably H, F, OH, _NH2 , methyl, methoxy, CF3 _{, CCl3} , _methylamino , dimethylamino, cyclopropyl or cyclopropylamino, more preferably H, F, _CF3 , cyclopropyl or cyclopropylamino.

One embodiment of the present disclosure is a compound of formula 8, where n is 0, 1, or 2.

One embodiment of the present disclosure is a compound of formula 10, where R ^3' is H or C _1-3 alkyl, preferably H or methyl.

In one embodiment of the present disclosure, Y ₁ is CH ₂ or

、好ましくはCH₂である式10の化合物である。

, preferably a compound of formula 10, where _CH2 is

In one embodiment of the present disclosure, each A is independently O, NH,

である式10の化合物である。本開示の一実施形態は、AがO、NH、

One embodiment of the present disclosure is a compound of formula 10, wherein A is O, NH,

、好ましくは

,Preferably

である、式10の化合物である。

is a compound of formula 10,

One embodiment of the present disclosure is a compound of formula 10, where m5 is 0 or 1.

One embodiment of the present disclosure is a compound of formula 10, where m4 is 0 or 1.

One embodiment of the present disclosure is a compound of formula 10, where m3 is 1, 2, 3, 4 or 5, preferably 4.

In one embodiment of the present disclosure, R ^1′ is O, NH,

、好ましくはOである式10の化合物である。

, preferably O.

An embodiment of the present disclosure is a compound of formula 10, wherein R''' is H, OH, C _1-3 alkyl, C _1-3 alkoxy or halogen, preferably H, methyl, methoxy or F, more preferably H.

One embodiment of the present disclosure is a compound of formula 10, where k is 0 or 1.

One embodiment of the present disclosure is a compound of formula 10, where Z is C and U is S or O.

One embodiment of the present disclosure is a compound of formula 10 where Z is N and U is CH.

One embodiment of the present disclosure is a compound of formula 10, wherein R' is H, halogen, OH, _C1-3 alkyl, _C1-3 haloalkyl or _C1-3 alkoxy, preferably H, F, _CF3 , _CCl3 , methyl or methoxy, more preferably H or _CF3 .

One embodiment of the present disclosure is a compound of formula 10, where m is 0 or 1.

One embodiment of the present disclosure is a compound of formula 10, wherein R'' is H, halo, OH, NH2, _C1-3 alkyl, _C1-3 alkoxy, _C1-3 haloalkyl, _C1-3 alkylamino, _C3-5 cycloalkyl, _C3-5 cycloalkylamino or _C3-5 heterocycloalkyl, preferably H, F, OH, _NH2 , methyl, methoxy, CF3, _CCl3 , _methylamino , cyclopropyl, cyclopropylamino or dimethylamino, more preferably H, F _{or CF3} .

One embodiment of the present disclosure is a compound of formula 10, where n is 0 or 1.

One embodiment of the present disclosure is a compound of formula 13, where R ^3' is H or C _1-3 alkyl, preferably H or methyl.

In one embodiment of the present disclosure, Y ₁ is CH ₂ or

、好ましくはCH₂である式13の化合物である。

, preferably a compound of formula 13, where _CH2 is

In one embodiment of the present disclosure, A is O, NH,

、好ましくは

,Preferably

である式13の化合物である。

is a compound of formula 13,

One embodiment of the present disclosure is a compound of formula 13, where m2 is 1, 2, 3 or 4, preferably 1.

In one embodiment of the present disclosure, R ^1′ is O, NH,

、好ましくはNHである式13の化合物である。

, preferably NH.

An embodiment of the present disclosure is a compound of formula 13, wherein R''' is H, OH, C _1-3 alkyl, C _1-3 alkoxy or halogen, preferably H, methyl, methoxy or F, more preferably H.

One embodiment of the present disclosure is a compound of formula 13, where k is 0, 1, 2 or 3, preferably 0 or 1.

One embodiment of the present disclosure is a compound of formula 13, where Z is C and U is S or O.

One embodiment of the present disclosure is a compound of formula 13 where Z is N and U is CH.

One embodiment of the present disclosure is a compound of formula 13, wherein R' is H, halogen, OH, _C1-3 alkyl, _C1-3 haloalkyl or _C1-3 alkoxy, preferably H, F, _CF3 , _CCl3 , methyl or methoxy, more preferably H or _CF3 .

One embodiment of the present disclosure is a compound of formula 13, where m is 0, 1, 2 or 3, preferably 0 or 1.

One embodiment of the present disclosure is a compound of formula 13, wherein R'' is H, halo, OH, NH2, _C1-3 alkyl, _C1-3 alkoxy, _C1-3 haloalkyl, _C1-3 alkylamino, _C3-5 cycloalkyl, _C3-5 cycloalkylamino or _C3-5 heterocycloalkyl, preferably H, F, OH, _NH2 , methyl, methoxy, CF3 _{, CCl3} , _methylamino , cyclopropyl, cyclopropylamino or dimethylamino, more preferably H, F, _CF3 , dimethylamino, cyclopropyl or cyclopropylamino, most preferably dimethylamino.

One embodiment of the present disclosure is a compound of formula 13, where n is 0, 1 or 2, preferably 0 or 1.

One embodiment of the compound of formula II-1 is represented by the following formula 3:

の化合物であり、R^1'はO、NH、

where R ^1' is O, NH,

である。

It is.

One embodiment of the present disclosure is a compound of formula 3, where R ^2' is H, OH, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 alkylamino or NH ₂ , preferably H, OH or NH ₂ .

One embodiment of the present disclosure is a compound of formula 3, where m6 is 0, 1, 2 or 3, preferably 0 or 1.

One embodiment of the present disclosure is a compound of formula 3, where R ^1′ is O or NH.

One embodiment of the present disclosure is a compound of formula 3, wherein R' is H, halogen, OH, _C1-3 alkyl, _C1-3 haloalkyl or _C1-3 alkoxy, preferably H, halogen or _C1-3 fluoroalkyl, more preferably H or F.

One embodiment of the present disclosure is a compound of formula 3, where m is 0, 1, 2, 3 or 4, preferably 0 or 1.

One embodiment of the present disclosure is _{a compound of formula 3, wherein R″ is H, halo, OH, NH2, C1-3 alkoxy, C3-5 cycloalkyl, C3-5 cycloalkylamino or C1-3 alkylamino , preferably H} , halo, methylamino, dimethylamino, cyclopropylamino or cyclopropyl, more preferably H, F or dimethylamino.

One embodiment of the present disclosure is a compound of formula 3, where n is 0, 1, 2 or 3, preferably 0, 1 or 2.

One embodiment of the present disclosure is a compound of formula 3 where Z is C and U is O or S.

One embodiment of the present disclosure is a compound of formula 3 where Z is N and U is CH.

An embodiment of the present disclosure is a compound of formula 3, wherein R''' is H, OH, C _1-3 alkyl, C _1-3 alkoxy or halogen, preferably H, F, methyl or methoxy, more preferably H.

One embodiment of the present disclosure is represented by formula 3-1:

に示されている構造を有する式3の化合物であり、R^2'はH、OH、C_1～3アルキル、C_1～3アルコキシ、C_1～3アルキルアミノ又はNH₂であり、m6は0、1、2又は3であり、Y₁はCH₂又は

wherein R2 ^' is H, OH, _C1-3 alkyl, _C1-3 alkoxy, C1-3 alkylamino or _NH2 ; m6 is 0, 1 _{, 2} or 3; and _Y1 is _CH2 or

であり、R^1'はO、NH、

and R ^1′ is O, NH,

であり、ZはC又はNであり、UはO、S又はCHであり、ここでZ及びUは同時にヘテロ原子であることはなく、R''はH、ハロ、OH、NH₂、C_1～3アルコキシ、C_1～3ハロアルキル、C_3～5シクロアルキル、C_3～5シクロアルキルアミノ又はC_1～3アルキルアミノであり、nは0、1又は2である。

wherein Z is C or N, U is O, S or CH, where Z and U are not both heteroatoms, R″ is H, halo, OH, _NH2 , _C1-3 alkoxy, _C1-3 haloalkyl, _C3-5 cycloalkyl, _C3-5 cycloalkylamino or _C1-3 alkylamino, and n is 0, 1 or 2.

One embodiment of the present disclosure is a compound of formula 3-1, where R2 ^' is H, _NH2 , or OH.

One embodiment of the present disclosure is a compound of formula 3-1, where m6 is 0 or 1.

One embodiment of the present disclosure is when m6 is 1, R ^2′ at the following position of phenyl:

が置換されている、式3-1の化合物である。

is a compound of formula 3-1, wherein

One embodiment of the disclosure is a compound of formula 3-1, where R ^1' is O or NH.

One embodiment of the present disclosure is a compound of formula 3-1, where R'' is F, dimethylamino, methylamino, cyclopropyl, or cyclopropylamino.

One embodiment of the present disclosure is a compound of formula 3-1, where n is 0, 1, or 2.

One embodiment of the compound of formula III-1 is represented by the following formula 15:

の化合物であり、m2が1、2、3、4、5、6又は7であり、R^1'がO、NH、

wherein m2 is 1, 2, 3, 4, 5, 6 or 7; R ^1′ is O, NH,

である。

It is.

One embodiment of the present disclosure is a compound of formula 15, where m2 is 1, 2, 3, 4, 5, 6 or 7, preferably 1, 2, 3, 4, 5 or 6, more preferably 2 or 5.

In one embodiment of the present disclosure, R ^1′ is O, NH,

、好ましくはO又はNHである式15の化合物である。

, preferably O or NH.

An embodiment of the present disclosure is a compound of formula 15, wherein R''' is H, OH, C _1-3 alkyl, C _1-3 alkoxy or halogen, preferably H, F, methyl or methoxy, more preferably H.

One embodiment of the present disclosure is a compound of formula 15, where Z is C and U is O or S.

One embodiment of the present disclosure is a compound of formula 15 where Z is N and U is CH.

One embodiment of the present disclosure is a compound of formula 15, wherein R' is H, halogen, OH, _C1-3 alkyl, _C1-3 haloalkyl or _C1-3 alkoxy, preferably H, halogen or _C1-3 fluoroalkyl, more preferably H, _CF3 or F.

One embodiment of the present disclosure is a compound of formula 15, where m is 0, 1, 2 or 3, preferably 0, 1 or 2, more preferably 0 or 1.

One embodiment of the present disclosure is _{a compound of formula 15, wherein R″ is H, halo, OH, NH2, C1-3 alkoxy, C3-5 cycloalkyl, C3-5 cycloalkylamino or C1-3 alkylamino , preferably H} , halo, methylamino, dimethylamino, cyclopropylamino or cyclopropyl, more preferably H, F, methylamino, cyclopropylamino or dimethylamino, most preferably H or dimethylamino.

One embodiment of the present disclosure is a compound of formula 15, where n is 0, 1 or 2, preferably 0 or 1.

One embodiment of the compound of formula IV-1 is represented by the following formula 2, 7, 9, 11, 12 or 14:

の化合物であり、各Aは独立してO、NH、

where each A is independently O, NH,

であり、
m2が2、3、4、5又は6であり、
m3が1、2、3、4、5又は6であり、
m4が0、1、2、3又は4であり、
m5が0、1、2又は3であり、
R^1'がO、NH、

and
m2 is 2, 3, 4, 5 or 6;
m3 is 1, 2, 3, 4, 5 or 6;
m4 is 0, 1, 2, 3 or 4;
m5 is 0, 1, 2 or 3;
R ^1' is O, NH,

である。

It is.

One embodiment of the present disclosure is a compound of formula 2, where R ^3' is H or C _1-3 alkyl, preferably H or methyl.

In one embodiment of the present disclosure, Y ₁ is CH ₂ or

である式2の化合物である。

is a compound of formula 2,

In one embodiment of the present disclosure, A is O, NH,

、好ましくはOである式2の化合物である。

, preferably O.

One embodiment of the present disclosure is a compound of formula 2, where m2 is 2, 3, 4, 5 or 6, preferably 2 or 6.

In one embodiment of the present disclosure, R ^1′ is O, NH,

、好ましくはNHである式2の化合物である。

, preferably NH.

One embodiment of the present disclosure is a compound of formula ₂ , wherein R'' is H, halo, OH, NH2, _C1-3 alkyl, C1-3 alkoxy, _C1-3 haloalkyl, _C1-3 alkylamino, _C3-5 cycloalkyl, _C3-5 cycloalkylamino or _C3-5 heterocycloalkyl, preferably H, F, OH, _NH2 , methyl, methoxy, CF3 _{, CCl3} , _methylamino , dimethylamino, cyclopropyl or cyclopropylamino, more preferably H, F, _CF3 , cyclopropyl or cyclopropylamino.

One embodiment of the present disclosure is a compound of formula 2, where n is 0, 1 or 2, preferably 0 or 1.

One embodiment of the present disclosure is a compound of formula 2, wherein R' is H, halogen, OH, _C1-3 alkyl, _C1-3 haloalkyl or _C1-3 alkoxy, preferably H, F, _CF3 , _CCl3 , methyl or methoxy, more preferably H or _CF3 .

One embodiment of the present disclosure is a compound of formula 2, where m is 0, 1, 2 or 3, preferably 0, 1 or 2.

One embodiment of the present disclosure is a compound of formula 2 where Z is C, U is O or S, and W is CH.

One embodiment of the present disclosure is a compound of formula 2 where Z is N, U is CH, and W is CH.

One embodiment of the present disclosure is a compound of formula 2 where Z is C, W is N, and U is CH.

An embodiment of the present disclosure is a compound of formula 2, where R''' is H, OH, NH ₂ , C _1-3 alkyl, C _1-3 alkylamino, C _1-3 alkoxy or halogen, preferably H, F, methoxy, methylamino or dimethylamino.

One embodiment of the present disclosure is a compound of formula 2, where k is 0, 1, 2 or 3, preferably 0, 1 or 2, more preferably 0 or 1.

One embodiment of the present disclosure is a compound of formula 7, where R ^3' is H or C _1-3 alkyl, preferably H or methyl.

In one embodiment of the present disclosure, Y ₁ is CH ₂ or

である式7の化合物である。

is a compound of formula 7,

In one embodiment of the present disclosure, A is O, NH,

、好ましくはOである式7の化合物である。

, preferably O.

One embodiment of the present disclosure is a compound of formula 7, where m2 is 2, 3, 4, 5 or 6, preferably 2 or 3.

In one embodiment of the present disclosure, R ^1′ is O, NH,

、好ましくはNHである式7の化合物である。

, preferably NH.

One embodiment of the present disclosure is a compound of formula 7, wherein R'' is H, halo, OH, NH2, _C1-3 alkyl, _C1-3 alkoxy, _C1-3 haloalkyl, _C1-3 alkylamino, _C3-5 cycloalkyl, _C3-5 cycloalkylamino or _C3-5 heterocycloalkyl, preferably H, F, OH, _NH2 , methyl, methoxy, CF3 _{, CCl3} , _methylamino , dimethylamino, cyclopropyl or cyclopropylamino, more preferably H, F, _CF3 , cyclopropyl or cyclopropylamino.

One embodiment of the present disclosure is a compound of formula 7, where n is 0, 1 or 2, preferably 0 or 1.

One embodiment of the present disclosure is a compound of formula 7, wherein R' is H, halogen, OH, _C1-3 alkyl, _C1-3 haloalkyl or _C1-3 alkoxy, preferably H, F, _CF3 , _CCl3 , methyl or methoxy, more preferably H or _CF3 .

One embodiment of the present disclosure is a compound of formula 7, where m is 0, 1, 2 or 3, preferably 0, 1 or 2.

One embodiment of the present disclosure is a compound of formula 7 where Z is C, U is O or S, and W is CH.

One embodiment of the present disclosure is a compound of formula 7 where Z is N, U is CH, and W is CH.

One embodiment of the present disclosure is a compound of formula 7 where Z is C, W is N, and U is CH.

An embodiment of the present disclosure is a compound of formula 7, where R''' is H, OH, NH ₂ , C _1-3 alkyl, C _{1-3 alkylamino, C 1-3 alkoxy} or halogen, preferably H, F, methoxy, methylamino or dimethylamino.

One embodiment of the present disclosure is a compound of formula 7, where k is 0, 1, 2 or 3, preferably 0, 1 or 2, more preferably 0 or 1.

One embodiment of the present disclosure is a compound of formula 9, where R ^3' is H or C _1-3 alkyl, preferably H or methyl.

In one embodiment of the present disclosure, Y ₁ is CH ₂ or

である式9の化合物である。

is a compound of formula 9,

In one embodiment of the present disclosure, A is O, NH,

、好ましくはOである式9の化合物である。

, preferably O.

One embodiment of the present disclosure is a compound of formula 9, where m2 is 2, 3, 4, 5 or 6, preferably 2 or 3.

In one embodiment of the present disclosure, R ^1′ is O, NH,

、好ましくはNHである式9の化合物である。

, preferably NH.

One embodiment of the present disclosure is a compound of formula 9, wherein R'' is H, halo, OH, NH2, _C1-3 alkyl, _C1-3 alkoxy, _C1-3 haloalkyl, _C1-3 alkylamino, _C3-5 cycloalkyl, _C3-5 cycloalkylamino or _C3-5 heterocycloalkyl, preferably H, F, OH, _NH2 , methyl, methoxy, CF3 _{, CCl3} , _methylamino , dimethylamino, cyclopropyl or cyclopropylamino, more preferably H, F, _CF3 , cyclopropyl or cyclopropylamino.

One embodiment of the present disclosure is a compound of formula 9, where n is 0, 1 or 2, preferably 0 or 1.

One embodiment of the present disclosure is a compound of formula 9, wherein R' is H, halogen, OH, _C1-3 alkyl, _C1-3 haloalkyl or _C1-3 alkoxy, preferably H, F, _CF3 , _CCl3 , methyl or methoxy, more preferably H or _CF3 .

One embodiment of the present disclosure is a compound of formula 9, where m is 0, 1, 2 or 3, preferably 0, 1 or 2.

One embodiment of the present disclosure is a compound of formula 9 where Z is C, U is O or S, and W is CH.

One embodiment of the present disclosure is a compound of formula 9 where Z is N, U is CH, and W is CH.

One embodiment of the present disclosure is a compound of formula 9 where Z is C, W is N, and U is CH.

One embodiment of the present disclosure is a compound of formula 9, where R''' is H, OH, NH ₂ , C _1-3 alkyl, C _1-3 alkylamino, C _1-3 alkoxy or halogen, preferably H, F, methoxy, methylamino or dimethylamino.

One embodiment of the present disclosure is a compound of formula 9, where k is 0, 1, 2 or 3, preferably 0, 1 or 2, more preferably 0 or 1.

One embodiment of the present disclosure is a compound of formula 11, where R ^3' is H or C _1-3 alkyl, preferably H or methyl.

In one embodiment of the present disclosure, Y ₁ is CH ₂ or

である式11の化合物である。

is a compound of formula 11,

In one embodiment of the present disclosure, A is O, NH,

、好ましくはOである式11の化合物である。

, preferably O.

One embodiment of the present disclosure is a compound of formula 11, where m2 is 2, 3, 4, 5 or 6, preferably 2 or 3.

In one embodiment of the present disclosure, R ^1′ is O, NH,

、好ましくはNHである式11の化合物である。

, preferably NH.

One embodiment of the present disclosure is a compound of formula 11, wherein R'' is H, halo, OH, NH2, _C1-3 alkyl, _C1-3 alkoxy, _C1-3 haloalkyl, _C1-3 alkylamino, _C3-5 cycloalkyl, _C3-5 cycloalkylamino or _C3-5 heterocycloalkyl, preferably H, F, OH, _NH2 , methyl, methoxy, CF3 _{, CCl3} , _methylamino , dimethylamino, cyclopropyl or cyclopropylamino, more preferably H, F, _CF3 , cyclopropyl or cyclopropylamino.

One embodiment of the present disclosure is a compound of formula 11, where n is 0, 1 or 2, preferably 0 or 1.

One embodiment of the present disclosure is a compound of formula 11, wherein R' is H, halogen, OH, _C1-3 alkyl, _C1-3 haloalkyl or _C1-3 alkoxy, preferably H, F, _CF3 , _CCl3 , methyl or methoxy, more preferably H or _CF3 .

One embodiment of the present disclosure is a compound of formula 11, where m is 0, 1, 2 or 3, preferably 0, 1 or 2.

One embodiment of the present disclosure is a compound of formula 11, where Z is C, U is O or S, and W is CH.

One embodiment of the present disclosure is a compound of formula 11, where Z is N, U is CH, and W is CH.

One embodiment of the present disclosure is a compound of formula 11 where Z is C, W is N, and U is CH.

One embodiment of the present disclosure is a compound of formula 11, where R''' is H, OH, NH ₂ , C _1-3 alkyl, C _{1-3 alkylamino, C 1-3 alkoxy} or halogen, preferably H, F, methoxy, methylamino or dimethylamino.

One embodiment of the present disclosure is a compound of formula 11, where k is 0, 1, 2 or 3, preferably 0, 1 or 2, more preferably 0 or 1.

One embodiment of the present disclosure is a compound of formula 12, where R ^3' is H or C _1-3 alkyl, preferably H or methyl.

In one embodiment of the present disclosure, Y ₁ is CH ₂ or

、好ましくはCH₂である式12の化合物である。

, preferably a compound of formula 12, where _CH2 is

In one embodiment of the present disclosure, each A is independently O, NH,

である式12の化合物である。本開示の一実施形態は、AがO、NH、

One embodiment of the present disclosure is a compound of formula 12, wherein A is O, NH,

、好ましくはOである式12の化合物である。

, preferably O.

One embodiment of the present disclosure is a compound of formula 12, where m3 is 1, 2, 3, 4, 5 or 6, preferably 2 or 3.

One embodiment of the present disclosure is a compound of formula 12, where m4 is 0 or 1, 2 or 3, preferably 0 or 3.

One embodiment of the present disclosure is a compound of formula 12, where m5 is 0 or 1, 2 or 3, preferably 0 or 1.

In one embodiment of the present disclosure, R ^1′ is O, NH,

、好ましくはNHである式12の化合物である。

, preferably NH.

One embodiment of the present disclosure is a compound of formula 12, wherein R'' is H, halo, OH, NH2, _C1-3 alkyl, _C1-3 alkoxy, _C1-3 haloalkyl, _C1-3 alkylamino, _C3-5 cycloalkyl, _C3-5 cycloalkylamino or _C3-5 heterocycloalkyl, preferably H, F, OH, _NH2 , methyl, methoxy, CF3 _{, CCl3} , _methylamino , dimethylamino, cyclopropyl or cyclopropylamino, more preferably H, F, _CF3 , cyclopropyl or cyclopropylamino.

One embodiment of the present disclosure is a compound of formula 12, where n is 0, 1 or 2, preferably 0 or 1.

One embodiment of the present disclosure is a compound of formula 12, wherein R' is H, halogen, OH, _C1-3 alkyl, _C1-3 haloalkyl or _C1-3 alkoxy, preferably H, F, _CF3 , _CCl3 , methyl or methoxy, more preferably H or _CF3 .

One embodiment of the present disclosure is a compound of formula 12, where m is 0, 1, 2 or 3, preferably 0, 1 or 2.

One embodiment of the present disclosure is a compound of formula 12 where Z is C, U is O or S, and W is CH.

One embodiment of the present disclosure is a compound of formula 12 where Z is N, U is CH, and W is CH.

One embodiment of the present disclosure is a compound of formula 12 where Z is C, W is N, and U is CH.

An embodiment of the present disclosure is a compound of formula 12, where R''' is H, OH, NH ₂ , C _1-3 alkyl, C _{1-3 alkylamino, C 1-3 alkoxy} or halogen, preferably H, F, methoxy, methylamino or dimethylamino.

One embodiment of the present disclosure is a compound of formula 12, where k is 0, 1, 2 or 3, preferably 0, 1 or 2, more preferably 0 or 1.

One embodiment of the present disclosure is a compound of formula 14, where R ^3' is H or C _1-3 alkyl, preferably H or methyl.

In one embodiment of the present disclosure, Y ₁ is CH ₂ or

、好ましくはCH₂である式14の化合物である。

, preferably a compound of formula 14, where _CH2 is

In one embodiment of the present disclosure, each A is independently O, NH,

である式14の化合物である。本開示の一実施形態は、AがO、NH、

One embodiment of the present disclosure is a compound of formula 14, wherein A is O, NH,

、好ましくはOである式14の化合物である。

, preferably O.

One embodiment of the present disclosure is a compound of formula 14, where m3 is 1, 2, 3, 4, 5 or 6, preferably 2, 3 or 4.

One embodiment of the present disclosure is a compound of formula 14, where m4 is 0, 1, 2, 3 or 4, preferably 0 or 3.

One embodiment of the present disclosure is a compound of formula 14, where m5 is 0 or 1, 2 or 3, preferably 0 or 1.

In one embodiment of the present disclosure, R ^1′ is O, NH,

、好ましくは

,Preferably

である式14の化合物である。

is a compound of formula 14,

One embodiment of the present disclosure is a compound of formula 14, wherein R'' is H, halo, OH, NH2, _C1-3 alkyl, _C1-3 alkoxy, _C1-3 haloalkyl, _C1-3 alkylamino, _C3-5 cycloalkyl, _C3-5 cycloalkylamino or _C3-5 heterocycloalkyl, preferably H, F, OH, _NH2 , methyl, methoxy, CF3 _{, CCl3} , _methylamino , dimethylamino, cyclopropyl or cyclopropylamino, more preferably H, F, _CF3 , cyclopropyl or cyclopropylamino.

One embodiment of the present disclosure is a compound of formula 14, where n is 0, 1 or 2, preferably 0 or 1.

One embodiment of the present disclosure is a compound of formula 14, wherein R' is H, halogen, OH, _C1-3 alkyl, _C1-3 haloalkyl or _C1-3 alkoxy, preferably H, F, _CF3 , _CCl3 , methyl or methoxy, more preferably H or _CF3 .

One embodiment of the present disclosure is a compound of formula 14, where m is 0, 1, 2 or 3, preferably 0, 1 or 2.

One embodiment of the present disclosure is a compound of formula 14, where Z is C, U is O or S, and W is CH.

One embodiment of the present disclosure is a compound of formula 14 where Z is N, U is CH, and W is CH.

One embodiment of the present disclosure is a compound of formula 14 where Z is C, W is N, and U is CH.

An embodiment of the present disclosure is a compound of formula 14, where R''' is H, OH, NH ₂ , C _1-3 alkyl, C _{1-3 alkylamino, C 1-3 alkoxy} or halogen, preferably H, F, methoxy, methylamino or dimethylamino.

One embodiment of the present disclosure is a compound of formula 14, where k is 0, 1, 2 or 3, preferably 0, 1 or 2, more preferably 0 or 1.

One embodiment of the compound of formula V-1 is represented by the following formula 4:

の化合物であり、R^1'がO、NH、

wherein R ^1' is O, NH,

である。

It is.

One embodiment of the present disclosure is a compound of formula 4, where R ^2' is H, OH, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 alkylamino or NH ₂ , preferably H, OH or NH ₂ .

One embodiment of the present disclosure is a compound of formula 4, where m6 is 0, 1, 2 or 3, preferably 0 or 1.

In one embodiment of the present disclosure, R ^1′ is O, NH,

、好ましくはO又はNHである式4の化合物である。

, preferably O or NH.

One embodiment of the present disclosure is a compound of formula 4, wherein R' is H, halogen, OH, _C1-3 alkyl, _C1-3 haloalkyl or _C1-3 alkoxy, preferably H, halogen or _C1-3 fluoroalkyl, more preferably H or F.

One embodiment of the present disclosure is a compound of formula 4, where m is 0, 1, 2, 3 or 4, preferably 0 or 1.

One embodiment of the present disclosure is a compound of formula _{4, wherein R″ is H, halo, OH, NH2, C1-3 alkoxy, C3-5 cycloalkyl, C3-5 cycloalkylamino or C1-3 alkylamino , preferably H} , halo, methylamino, dimethylamino, cyclopropylamino or cyclopropyl, more preferably H, F or dimethylamino.

One embodiment of the present disclosure is a compound of formula 4, where n is 0, 1 or 2, preferably 0 or 1.

One embodiment of the present disclosure is a compound of formula 4 where Z is C, U is O or S, and W is CH.

One embodiment of the present disclosure is a compound of formula 4 where Z is N, U is CH, and W is CH.

One embodiment of the present disclosure is a compound of formula 4 where Z is C, U is CH, and W is N.

One embodiment of the present disclosure is a compound of formula 4, where R''' is H, OH, NH ₂ , C _1-3 alkyl, C _1-3 alkylamino, C _1-3 alkoxy or halogen, preferably H, F, methoxy, methylamino or dimethylamino.

One embodiment of the present disclosure is a compound of formula 4, where k is 0, 1, 2 or 3, preferably 0, 1 or 2, more preferably 0 or 1.

One embodiment of the present disclosure is represented by formula 4-1:

に示されている構造を有する式4の化合物である。

The compound is of formula 4 having the structure shown in

In formula 4-1, R2 ^' is H, OH, _C1-3 alkyl, _C1-3 alkoxy, _C1-3 alkylamino or _NH2 , and _Y1 is _CH2 or

であり、R^1'はO、NH、

and R ^1′ is O, NH,

であり、R''はH、ハロ、OH、NH₂、C_1～3アルコキシ、C_1～3ハロアルキル、C_1～3アルキルアミノ又はC_3～5ヘテロシクロアルキルであり、nは0、1又は2であり、R'はH、ハロゲン、OH、C_1～3アルキル、C_1～3ハロアルキル又はC_1～3アルコキシであり、mは、nは0、1又は2であり、UはO又はSであり、R'''はH、OH、NH₂、C_1～3アルキル、C_1～3アルキルアミノ、C_1～3アルコキシ又はハロゲンであり、kは0、1、2、3又は4である。

wherein R″ is H, halo, OH, NH2, _C1-3 alkoxy, _C1-3 haloalkyl, _C1-3 alkylamino or _C3-5 heterocycloalkyl, n is 0, 1 or 2, R' is H, halogen, OH, _{C1-3 alkyl, C1-3 haloalkyl} or C1-3 alkoxy, m is, n is 0, 1 or 2, U is O or S, R′″ is H, OH, _NH2 , _C1-3 alkyl, _C1-3 alkylamino, _C1-3 alkoxy or halogen and k is 0, _{1, 2 ,} 3 or 4.

One embodiment of the disclosure is a compound of formula 4-1, where R ^1' is NH.

One embodiment of the present disclosure is a compound of formula 4-1, where R'' is H.

One embodiment of the present disclosure is a compound of formula 4-1, where R' is H.

One embodiment of the present disclosure is a compound of formula 4-1 where R ^2′ is OH.

One embodiment of the disclosure is a compound of formula 4-1, where R''' is H, OH, NH ₂ , C _1-3 alkyl, C _1-3 alkylamino, C _1-3 alkoxy or halogen, preferably H, F, methoxy, methylamino or dimethylamino.

One embodiment of the present disclosure is a compound of formula 4, where k is 0, 1, 2 or 3, preferably 0, 1 or 2, more preferably 0 or 1.

One embodiment of the present disclosure is a compound of formula 4 where U is S.

One embodiment of the compound of formula VI-1 is represented by the following formula 16 or 17:

の化合物であり、m2が1、2、3、4、5、6又は7であり、R^1'がO、NH、

wherein m2 is 1, 2, 3, 4, 5, 6 or 7; and R ^1′ is O, NH,

である。

It is.

One embodiment of the present disclosure is a compound of formula 16, where m2 is 1, 2, 3, 4, 5 or 6, preferably 2 or 5.

In one embodiment of the present disclosure, R ^1′ is O, NH,

、好ましくはNHである式16の化合物である。

, preferably NH.

An embodiment of the present disclosure is a compound of formula 16, wherein R' is H, halogen, OH, C _1-3 alkyl, C _1-3 haloalkyl or C _1-3 alkoxy, preferably H, halogen or C _1-3 fluoroalkyl, more preferably H or F.

One embodiment of the present disclosure is a compound of formula 16, where m is 0, 1, 2, 3 or 4, preferably 0 or 1.

One embodiment of the present disclosure is a compound of formula _{16, wherein R″ is H, halo, OH, NH2, C1-3 alkoxy, C3-5 cycloalkyl, C3-5 cycloalkylamino or C1-3 alkylamino , preferably H} , halo, methylamino, dimethylamino, cyclopropylamino or cyclopropyl, more preferably H, F or dimethylamino.

One embodiment of the present disclosure is a compound of formula 16, where n is 0, 1 or 2, preferably 0 or 1.

One embodiment of the present disclosure is a compound of formula 16 where Z is C, U is O or S, and W is CH.

One embodiment of the present disclosure is a compound of formula 16 where Z is N, U is CH, and W is CH.

One embodiment of the present disclosure is a compound of formula 16 where Z is C, U is CH, and W is N.

An embodiment of the present disclosure is a compound of formula 16, where R''' is H, OH, NH ₂ , C _1-3 alkyl, C _{1-3 alkylamino, C 1-3 alkoxy} or halogen, preferably H, F, methoxy, methylamino or dimethylamino.

One embodiment of the present disclosure is a compound of formula 16, where k is 0, 1, 2 or 3, preferably 0, 1 or 2, more preferably 0 or 1.

One embodiment of the present disclosure is a compound of formula 17, where m2 is 1, 2, 3, 4, 5 or 6, preferably 2 or 5.

In one embodiment of the present disclosure, R ^1′ is O, NH,

、好ましくはNHである式17の化合物である。

, preferably NH.

An embodiment of the present disclosure is a compound of formula 17, wherein R' is H, halogen, OH, C _1-3 alkyl, C _1-3 haloalkyl or C _1-3 alkoxy, preferably H, halogen or C _1-3 fluoroalkyl, more preferably H or F.

One embodiment of the present disclosure is a compound of formula 17, where m is 0, 1, 2, 3 or 4, preferably 0 or 1.

One embodiment of the present disclosure is a compound of formula _{17, wherein R″ is H, halo, OH, NH2, C1-3 alkoxy, C3-5 cycloalkyl, C3-5 cycloalkylamino or C1-3 alkylamino , preferably H} , halo, methylamino, dimethylamino, cyclopropylamino or cyclopropyl, more preferably H, F or dimethylamino.

One embodiment of the present disclosure is a compound of formula 17, where n is 0, 1 or 2, preferably 0 or 1.

One embodiment of the present disclosure is a compound of formula 17, where Z is C, U is O or S, and W is CH.

One embodiment of the present disclosure is a compound of formula 17 where Z is N, U is CH, and W is CH.

One embodiment of the present disclosure is a compound of formula 17, where Z is C, U is CH, and W is N.

An embodiment of the present disclosure is a compound of formula 17, where R''' is H, OH, NH ₂ , C _1-3 alkyl, C _{1-3 alkylamino, C 1-3 alkoxy} or halogen, preferably H, F, methoxy, methylamino or dimethylamino.

One embodiment of the present disclosure is a compound of formula 17, where k is 0, 1, 2 or 3, preferably 0, 1 or 2, more preferably 0 or 1.

Some embodiments of the present disclosure are compounds having the structures depicted in Table 2, or pharma- ceutically acceptable salts, enantiomers, non-enantiomers, tautomers, racemates, solvates, metabolic precursors, or prodrugs thereof.

In some embodiments, provided herein are solvates, hydrates, salts, or esters of the compounds disclosed herein.

Certain compounds of the present disclosure are further discussed in International Patent Application No. PCT/US2020/060459, filed November 13, 2020, which claims priority to U.S. Provisional Application No. 62/935,017, filed November 13, 2019, the contents of each of which are incorporated herein by reference in their entirety.

One aspect of the present disclosure is a composition comprising a compound disclosed herein and at least one pharma- ceutically acceptable excipient.

DEFINITIONS Unless otherwise defined, all terms, designations and other scientific or technical terms of the art used herein have the meaning commonly understood by those skilled in the art to which this application pertains. In some cases, commonly understood terms are defined herein for clarity and/or ease of reference, and the inclusion of such definitions herein should not necessarily be construed as representing a substantially different meaning than that commonly understood in the art. Many of the techniques and procedures described or referenced herein are well understood and commonly employed using conventional methods by those skilled in the art.

When a range of values is provided, it is understood that each intervening value between the upper and lower limits of that range, to one-tenth of the unit of the lower limit unless otherwise clearly dictated by context, as well as any other stated or intervening values in that stated range, are encompassed within the scope of the disclosure. The upper and lower limits of these smaller ranges may be independently included in the smaller ranges and are encompassed within the scope of the disclosure, subject to any specific excluded limits in the stated ranges. When a stated range includes one or both limits, ranges excluding either or both of those included limits are also included in the disclosure.

It is understood that certain features of the present disclosure, which are described for clarity in the context of separate embodiments, can also be provided in combination with a single embodiment. Conversely, various features of the present disclosure, which are described for simplicity in the context of a single embodiment, can also be provided separately or in any suitable subcombination. All combinations of the embodiments of the present disclosure are specifically included in the present disclosure and disclosed herein as if each and every combination were individually and explicitly disclosed. In addition, all subcombinations of the various embodiments and elements thereof are specifically included in the present disclosure and disclosed herein as if each and every subcombination were individually and explicitly disclosed herein. When a range of values is listed, it is intended to encompass each value and subrange within the range. For example, " _C1-6 " is intended to include _{C1 , C2} , _C3 , C4, _C5 , _{C6 , C1-6} , _{C1-5 , C1-4, C1-3 ,} C1-2, C2-6, _C2-5 , _C2-4 , C2-3 _{, C3-6} , _{C3-5, C3-4 ,} C4-6, _C4-5 and _C5-6 .

"Alkyl" refers to the radical of a straight or branched chain saturated hydrocarbon group having the indicated number of carbon atoms. In some embodiments, an alkyl group has 1 to 6 carbon atoms ("C _1-6 alkyl"). In some embodiments, an alkyl group has 1 to 5 carbon atoms ("C _1-5 alkyl"). In some embodiments, an alkyl group has 1 to 4 carbon atoms ("C _1-4 alkyl"). In some embodiments, an alkyl group has 1 to 3 carbon atoms ("C _1-3 alkyl"). In some embodiments, an alkyl group has 1 to 2 carbon atoms ("C _1-2 alkyl"). In some embodiments, an alkyl group has 1 carbon atom ("C ₁ alkyl"). In some embodiments, an alkyl group has 2 to 6 carbon atoms ("C _2-6 alkyl"). Examples of _C1-6 alkyl groups include methyl ( _C1 ), ethyl ( _C2 ), n-propyl ( _C3 ), iso-propyl ( _C3 ), n-butyl ( _C4 ), tert-butyl ( _C4 ), sec-butyl ( _C4 ), iso-butyl ( _C4 ), n-pentyl ( _C5 ), 3-pentyl ( _C5 ), amyl ( _C5 ), neopentyl ( _C5 ), 3-methyl-2-butyl ( _C5 ), tertiary amyl ( _C5 ), and n-hexyl ( _C6 ).

"Alkenyl" refers to an alkyl group having one or more carbon-carbon double bonds anywhere in the chain, and can be mono- or polysubstituted and mono-, di- or polyvalent. Examples of alkenyl groups include vinyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, and the like.

"Alkynyl" refers to an alkyl group having one or more carbon-carbon triple bonds anywhere in the chain, and can be mono- or polysubstituted and mono-, di- or polyvalent. Examples of alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, and the like.

"Cycloalkyl" refers to any stable cyclic or polycyclic hydrocarbon group and may be saturated with any carbon atom, may be mono- or polysubstituted, and may be mono-, di- or polyvalent. Examples of such cycloalkyl groups include, but are not limited to, cyclopropyl, norbornyl, [2.2.2]bicyclooctane, [4.4.0]bicyclononane, and the like.

"Optionally" means that the subsequently described event or circumstance may, but need not, occur, and the description includes the occurrence of the event or circumstance described above as well as the absence of the described event or circumstance.

"Substituted" means that any one or more hydrogen atoms at a particular atom are replaced with a substituent, including deuterium and hydrogen variants, so long as the valence of the particular atom is normal and the substituted compound is stable. When the substituent is keto (i.e., =O), it means that two hydrogen atoms are replaced. Ketone substitution does not occur in aromatic groups. The term "optionally substituted" means that it may or may not be substituted. Unless specified, the type and number of substituents can be any based on chemical achievability.

When any variable (e.g., R) occurs more than one time in any constituent or formula of a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R, said group may be optionally substituted with up to 2 R groups, where R is selected independently of the definition of R at each occurrence. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

When the number of bonding groups is zero, for example -(A) ₀ -, the bonding group is a single bond.

"Alkoxy" refers to an alkyl group as defined above having the specified number of carbon atoms attached through an oxygen bridge. Unless specified, _C1-6 alkoxy includes _C1 , _C2 , _C3 , C4, _C5 and _C6 alkoxy groups. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy and S-pentyloxy.

"Aryl" refers to a polyvalent unsaturated aromatic hydrocarbon substituent that may be mono- or polysubstituted, monovalent, divalent or polyvalent, and monocyclic or polycyclic (e.g., 1 to 3 rings, at least one of which is aromatic), that are fused together or covalently linked.

"Halo" or "halogen" by itself or as part of another substituent refers to a fluorine, chlorine, bromine, or iodine atom.

"Haloalkyl" includes both monohaloalkyl and polyhaloalkyl. For example, the term "halo(C _1-4 )alkyl" includes, but is not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. Unless specified, examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl.

"Heterocyclo" refers to a 3-10 membered non-aromatic ring or aromatic ring system having the indicated ring carbon atoms (e.g., 2-6 ring carbon atoms) and 1-4 ring heteroatoms, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("C _2-6 heterocyclo"). In heterocyclo groups containing one or more nitrogen atoms, the point of attachment may be at a carbon or nitrogen atom, where valence allows. Heterocyclo groups are either monocyclic ("monocyclic heterocyclo") or fused, bridged, or spiro ring systems, e.g., bicyclic systems (bicyclic heterocyclo"), and may be saturated or partially unsaturated. Heterocyclobicyclic ring systems contain one or more heteroatoms in one or both rings. "Heterocyclo" also includes ring systems in which a heterocyclic ring as defined above is fused to one or more carbocyclic groups, where the point of attachment is at either the carbocyclic or heterocyclic ring, or in which a heterocyclic ring as defined above is fused to one or more aryl or heteroaryl groups, where the point of attachment is at the heterocyclic ring, in such cases the number of ring members continues to specify the number of ring members of the heterocyclic ring system.

"Nitrogen protecting group" refers to a protecting group that prevents side reactions at the amino nitrogen position. Representative amino protecting groups include, but are not limited to, formyl; acyl, such as alkanoyl (e.g., acetyl, trichloroacetyl, or trifluoroacetyl); alkoxycarbonyl, such as tert-butoxycarbonyl (Boc); arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-di-(4'-methoxyphenyl)methyl; silyl groups, such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS), and the like.

In some embodiments, a heterocyclo group is a 5-10 membered non-aromatic or aromatic ring system having the indicated ring carbon atoms and 1-4 ring heteroatoms, each heteroatom being independently selected from nitrogen, oxygen, and sulfur. In some embodiments, a heterocyclo group is a 5-6 membered non-aromatic or aromatic ring system having the indicated ring carbon atoms and 1-4 ring heteroatoms, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heterocyclo"). In some embodiments, a 5-6 membered heterocyclo has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5-6 membered heterocyclo has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5-6 membered heterocyclo has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

Representative 3-membered heterocyclo groups containing one heteroatom include, but are not limited to, aziridinyl, oxiranyl, and thiorenyl. Representative 4-membered heterocyclo groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Representative 5-membered heterocyclo groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Representative 5-membered heterocyclo groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Representative 5-membered heterocyclo groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Representative 6-membered heterocyclo groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Representative 6-membered heterocyclo groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Representative 6-membered heterocyclo groups containing two heteroatoms include, but are not limited to, triazinanyl. Representative 7-membered heterocyclo groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Representative 8-membered heterocyclo groups containing one heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl. Representative 5-membered heterocyclo groups (also referred to as 5,6-bicyclic heterocyclic rings) fused to a _C6 aryl ring include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Representative 6-membered heterocyclo groups (also referred to as 6,6-bicyclic heterocyclic rings) fused to an aryl ring include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

The term "pharmaceutically acceptable salt" means a salt that is not harmful to mammals, especially humans. Pharmaceutically acceptable salts can be formed using non-toxic acids or bases, including mineral acids or inorganic bases, or organic acids or bases. Examples of pharmaceutically acceptable salts include metal salts formed with aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, etc., and organic salts formed with lysine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), procaine, etc. Pharmaceutically acceptable salts also include acid addition salts and base addition salts.

The term "solvate" refers to a compound containing a solvent formed by the association of one or more solvent molecules with a compound of the present disclosure. Solvates include, for example, monosolvates, disolvates, trisolvates, and tetrasolvates. Solvates also include hydrates. The term "hydrate" refers to a compound or a salt thereof that further contains a stoichiometric or nonstoichiometric amount of water bound by noncovalent intermolecular forces. Hydrates include monohydrates, dihydrates, trihydrates, tetrahydrates, etc.

Certain ranges are presented herein with numerical values preceded by the term "about." The term "about" is used herein to provide literal support for the exact number it precedes, as well as a number that is near or approximately the number it precedes. In determining whether a number is near or approximately a specifically stated number, the near or approximately unstated number may be a number that, in the context in which it is presented, provides substantial equivalence to the specifically stated number. If there are any uses of the term that are not clear to one of ordinary skill in the art, given the context in which it is used, "about" means up to plus or minus 10% of the particular term.

"Subjects" to which administration is contemplated include, but are not limited to, humans (i.e., male or female of any age group, e.g., pediatric subjects (e.g., infants, toddlers, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or geriatric adults)) and/or other non-human animals, e.g., mammals (e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys), commercially relevant mammals such as cows, pigs, horses, sheep, goats, cats, and/or dogs) and birds (e.g., commercially relevant birds such as chickens, ducks, geese, and/or turkeys). In certain embodiments, the animal is a mammal. The animal may be male or female and at any stage of development. The non-human animal may be a transgenic animal.

The terms "administer," "administering," or "administration" refer to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound of the present invention or a pharmaceutical composition thereof.

The terms "treatment," "treat," and "treating" refer to reversing, alleviating, delaying the onset of, or inhibiting the progression of a "pathological condition" (e.g., a disease, disorder, or condition, or one or more signs or symptoms thereof) as described herein. In some embodiments, treatment may be administered after one or more signs or symptoms of a disease have occurred or been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of a disease or condition. For example, treatment may be administered to a susceptible subject before symptoms develop (e.g., in light of a history of the condition and/or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, e.g., to delay or prevent recurrence.

The terms "condition," "disease," and "disorder" are used interchangeably.

An "effective amount" of a compound or composition refers to an amount sufficient to elicit a desired biological response, i.e., to treat a condition. As will be recognized by one of skill in the art, an effective amount of a compound or composition may vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the condition to be treated, the mode of administration, and the age and health of the subject. Effective amounts encompass therapeutic and prophylactic treatments.

A "therapeutically effective amount" of a compound or composition is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to delay or minimize one or more symptoms associated with a condition. A therapeutically effective amount of a compound or composition means an amount of a therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in the treatment of a condition. The term "therapeutically effective amount" can include an amount that improves treatment overall, or reduces or avoids the symptoms or causes of a condition, or improves the therapeutic efficacy of another therapeutic agent.

The terms "alpha-synuclein", "α-synuclein" and "α-Syn" are used interchangeably herein and refer to a 140 amino acid polypeptide (wild-type human α-synuclein) having the following amino acid sequence:

The terms "aggregated alpha-synuclein," "alpha-synuclein aggregates," and "alpha-synuclein aggregates" are used interchangeably herein.

For E3 ubiquitin ligases, representative amino acid sequences are shown in Table 2.

For E3 ubiquitin ligases, other representative amino acid sequences are shown in Table 3.

The term "binding agent" refers to a compound that binds to a protein. A binding agent binds to a protein with a Kd of less than 50,000nM, less than 20,000nM, less than 10,000nM, less than 5,000nM, less than 2,500nM, less than 1,000nM, less than 900nM, less than 800nM, less than 700nM, less than 600nM, less than 500nM, less than 400nM, less than 300nM, less than 200nM, less than 100nM, less than 90nM, less than 80nM, less than 70nM, less than 60nM, less than 50nM, less than 40nM, less than 30nM, less than 20nM, less than 10nM, less than 5nM, less than 4nM, less than 3nM, less than 2nM, or less than 1nM.

The term "proteasome" refers to a protease complex that carries out the degradation of proteins. Specifically, the proteasome is a multisubunit enzyme complex that may also play an important role in regulating proteins that control cell cycle progression and apoptosis. The proteasome carries out the proteolysis of selected proteins.

The term "pharmaceutical acceptable excipient" means a pharmaceutically acceptable substance, composition, or vehicle, such as saline solution, liquid or solid fillers, diluents, solvents, or encapsulating materials. Examples of pharmaceutically acceptable excipients include water, saline, normal saline or phosphate buffered saline (PBS), sodium chloride injection, Ringer's injection, isotonic dextrose injection, sterile water injection, dextrose, and lactated Ringer's injection.

Synthesis of Compounds The compounds of the present disclosure can be prepared by a variety of synthetic methods known to those of skill in the art, including the embodiments listed below, combinations of these with other chemical synthesis methods, and equivalent alternatives known to those of skill in the art.

The following synthetic procedures are provided as examples that will enable one of ordinary skill in the art to synthesize the compounds of the present disclosure.

Compound of formula (I)

Compounds of general formula (I) are prepared as described in the following scheme:

Compound of formula (II)

Compounds of general formula (II) are prepared as described in the following scheme:

Compound of formula (III)

Compounds of general formula (III) are prepared as described in the following scheme:

Compound of formula (IV)

Compounds of general formula (IV) are prepared as described in the following scheme:

Compound of formula (V)

Compounds of general formula (V) are prepared as described in the following scheme:

Compound of formula (VI)

Compounds of general formula (VI) are prepared as described in the following scheme:

Other compounds within the scope of the present disclosure are synthesized by methods such as these and by analogy with the methods described in the Examples below. Additional synthetic methods can be found in WO2019214681, WO2018102067, and WO2019014429, all of which are incorporated herein by reference in their entirety.

Methods of Treatment Another aspect of the present disclosure is a method of aiding in the treatment of a synucleinopathy in a subject comprising, consisting essentially of, or consisting of administering to the subject an effective amount of a compound disclosed herein, or a composition disclosed herein.

Another aspect of the present disclosure is a method of treating a subject (e.g., a human) suffering from a disease characterized by the presence of Lewy bodies or pathological aggregates of α-synuclein, comprising, consisting essentially of, or consisting of administering to the subject an effective amount of a compound disclosed herein, or a composition disclosed herein.

Another aspect of the present disclosure is a method of preventing a disease characterized by the presence of Lewy bodies or pathological aggregates of α-synuclein in a subject, comprising, consisting essentially of, or consisting of administering to the subject an effective amount of a compound or composition disclosed herein.

In another aspect, provided herein is a method of treating a disease characterized by the presence of Lewy bodies or pathological aggregates of α-synuclein in a subject, comprising, consisting essentially of, or consisting of administering to the subject an effective amount of a compound or pharmaceutical composition described herein.

In another aspect, provided herein is a method for reducing the severity of a disease characterized by the presence of Lewy bodies or pathological aggregates of α-synuclein in a subject, comprising, consisting essentially of, or consisting of administering to the subject an effective amount of a compound or pharmaceutical composition described herein.

In another aspect, provided herein is a method for slowing the progression of a disease characterized by the presence of Lewy bodies or pathological aggregates of α-synuclein in a subject, comprising, consisting essentially of, or consisting of administering to the subject an effective amount of a compound or pharmaceutical composition described herein.

In another aspect, provided herein is a method for reducing the risk of developing a disease in a subject characterized by the presence of Lewy bodies or pathological aggregates of α-synuclein, comprising, consisting essentially of, or consisting of administering to a subject at risk of developing the disease an effective amount of a compound or pharmaceutical composition described herein.

In another aspect, provided herein is a method of delaying the onset of a disease characterized by the presence of Lewy bodies or pathological aggregates of α-synuclein in a subject at risk of developing the disease, comprising, consisting essentially of, or consisting of administering to the subject an effective amount of a compound or pharmaceutical composition described herein.

In some embodiments, the subject being treated exhibits one or more symptoms (signs) of a synucleinopathy, such as neuropsychiatric manifestations (depression, dementia, hallucinations, anxiety, anhedonia, anhedonia), autonomic nervous system changes (orthostatic hypotension, bladder disorders, constipation, fecal incontinence, salivation, dysphagia, sexual dysfunction, altered cerebral blood flow), sensory changes (smell, pain, color discrimination paresthesia), sleep disorders (REM sleep behavior disorder (RBD), restless legs syndrome/periodic extremity movements, hypersomnia, insomnia) or other signs and symptoms (fatigue, diplopia, blurred vision, seborrhea, weight loss/gain).

In some embodiments, the subject to be treated does not exhibit one or more symptoms of a synucleinopathy, but has a known genetic risk of developing a disease characterized by the presence of Lewy bodies or pathological aggregates of α-synuclein in the brain. For example, such individuals, who may have one or more relatives with the disease or at risk, are determined by analysis of genetic or biochemical markers. For example, mutations in SNCA (PARK1, encoding α-synuclein), including A30P, E46K, H50Q, G51D, and A53T, as well as duplications and triplications of the entire SNCA gene, cause autosomal dominant forms of PD. Mutations in LRRK2 (PARKS, leucine-rich repeat kinase 2) and VPS35 (PARK17, vacuolar protein sorting 35) also cause autosomal dominant forms of PD (Hernandez et al., (2016) Genetics in Parkinson disease: Mendelian versus non-Mendelian inheritance. Journal of Neurochemistry 10.1111/jnc.13593). Mutations in PINK1 (PARK6, PTEN-induced kinase 1), DJ-1 (PARK7), Parkin (PARK2), ATP13A2 (PARK9, ATPase type 13A2), FBXO7 (PARK15, F-box-only protein 7) and PLA2 GB (PARK14, phospholipase A2, group VI) have been shown to cause autosomal recessive PD/parkinsonism. In addition, 28 different genetic risk loci associated with PD and related synucleinopathies have been identified, including SNCA, LRRK2, GBA/SYT11, MAPT, HLA-DRB5, GAK, GCH1, NUCKS1/RAB7L1, SLC41A1, BST1, SIPA1L2, ACMSD/TMEM163, STK39, MCCC1, TMEM175/GAK/DGKQ, FAM47E/SCARB2, GPNMB, FGF20, INPP5F, MIR4697, CCDC62, GCH1, VPS13C, BCKDK/STX1B, SREBF/RAI1, RIT2, and DDRGK1 (Nails et al. (2014) Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson's disease. Nature Genetics 46(9): 989-993). Thus, in prophylactic applications, the antibodies described herein, or pharmaceutical compositions comprising same, are administered to a patient susceptible to or otherwise at risk of a disease in a regime (dosage, frequency and route of administration) effective to reduce the risk, reduce the severity, or delay the onset of at least one sign or symptom of the disease. In some prophylactic applications, the regime is effective to inhibit or delay accumulation of alpha-synuclein in the brain, and/or inhibit or delay its toxic effects, and/or inhibit or delay the development of behavioral deficits in the patient.

In some embodiments, the methods described above produce a beneficial therapeutic response in the subject patient (e.g., reduction of α-synuclein aggregates in the brain, improved cognitive function, and/or reversal, treatment, or prevention of cognitive decline in the subject). Thus, in some embodiments, the compounds or pharmaceutical compositions described herein are administered to a patient suspected of or already suffering from a disease characterized by the presence of Lewy bodies or pathological aggregates of α-synuclein in a regime (dosage, frequency, and route of administration) effective to ameliorate or at least inhibit further worsening of at least one sign or symptom of the disease. In some therapeutic applications, the regime is effective to reduce or at least inhibit further increases in the levels of α-synuclein, associated toxicity, and/or behavioral deficits. In certain embodiments, the treatment can result in, for example, a reduction in α-synuclein aggregates in the brain by 10% or more, 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, or 90% or more relative to before the start of treatment or compared to a population of untreated control patients.

In some embodiments, the disease characterized by the presence of Lewy bodies or pathological aggregates of α-synuclein in the brain is Parkinson's disease (including idiopathic Parkinson's disease), DLB, DLBD, LBVAD, pure autonomic failure, Lewy body dysphagia, incident LBD, hereditary LBD (e.g., mutations in SNCA (PARK1), LRRK2 (PARK8), VPS35 (PARK17), PINK1 (PARK6), DJ-1 (PARK7), Parkin (PARK2), ATP13A2 (PARK9), FBXO7 (PARK15), and PLA2 GB (PARK14)) or multiple system atrophy (MSA, e.g., olivopontocerebellar atrophy, striatonigral degeneration, and Shy-Drageri syndrome).

Also provided are methods of preserving or increasing synaptic and/or dendritic density as measured using markers of synaptogenesis (synaptophysin) and/or dendrites (MAP2). Thus, in some embodiments, subjects treated with a compound or composition described herein exhibit an increase in synaptic or dendritic density of 10% or more, 20% or more, 30% or more, 40% or more, or 50% or more relative to before the start of treatment or compared to a population of untreated control patients.

A. Administration The pharmaceutical compositions of the present disclosure can be formulated in a desired dosage with appropriate pharma- ceutically acceptable excipients and then administered orally, parenterally, intracisternally, intraperitoneally, intrathecally, intraventricularly, topically, bucally, etc., to humans and other animals depending on the disease or condition to be treated.

In certain embodiments, pharmaceutical compositions comprising compounds of the present disclosure are administered orally or parenterally at dosage levels sufficient to deliver from about 0.001 mg/kg to about 200 mg/kg in one or more administrations over a period of one or more days. In some embodiments, the effective amount per administration ranges from about 0.001 mg/kg to about 200 mg/kg, about 0.001 mg/kg to about 100 mg/kg, about 0.01 mg/kg to about 100 mg/kg, about 0.01 mg/kg to about 50 mg/kg, about 0.1 mg/kg to about 40 mg/kg, about 0.5 mg/kg to about 30 mg/kg, about 0.01 mg/kg to about 10 mg/kg, about 0.1 mg/kg to about 10 mg/kg, one or more times per day to obtain the desired treatment and/or prophylactic effect. In some embodiments, the compounds described herein are in a dosage sufficient to deliver from about 0.001 mg/kg to about 200 mg/kg, from about 0.001 mg/kg to about 100 mg/kg, from about 0.01 mg/kg to about 100 mg/kg, from about 0.01 mg/kg to about 50 mg/kg, from about 0.1 mg/kg to about 40 mg/kg, from about 0.5 mg/kg to about 30 mg/kg, from about 0.01 mg/kg to about 10 mg/kg, from about 0.1 mg/kg to about 10 mg/kg, or from about 1 mg/kg to about 25 mg/kg of subject body weight per day, one or more times per day, to obtain the desired treatment and/or prophylactic effect. The desired dosage may be delivered three times per day, twice per day, once per day, every other day, every third day, every week, every two weeks, every three weeks, or every four weeks. In some embodiments, the dosage is delivered using multiple administrations (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or more administrations). In some embodiments, the compositions described herein are administered at a dose below the dose at which the agent causes non-specific effects.

B. Compositions The pharmaceutical compositions described herein can be prepared by methods generally known in the art of pharmacology.In general, such methods include combining the disclosed compound with carrier and/or one or more other accessory ingredients, and then shaping and/or packaging the product into the desired single or multiple dose unit.

Pharmaceutical compositions can be prepared, packaged, and/or sold in bulk, as a single unit dose, and/or as a plurality of single unit doses. As used herein, a "unit dose" is a discrete amount of a pharmaceutical composition comprising a predetermined amount of an active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient that would be administered to a subject and/or a convenient fraction of such a dosage, e.g., one-half or one-third of such a dosage.

Pharmaceutically acceptable excipients used in the preparation of pharmaceutical compositions include inert diluents, dispersing and/or granulating agents, surfactants and/or emulsifying agents, disintegrating agents, binders, preservatives, stabilizers, buffers, lubricants, and/or oils. Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening agents, flavoring agents, and perfuming agents may also be present in the composition.

Suitable diluents include calcium carbonate, sodium carbonate, calcium phosphate, calcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate, lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, corn starch, powdered sugar, and mixtures thereof.

Suitable granulating and/or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clay, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose, and wood products, natural sponges, cation exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethylcellulose, cross-linked sodium carboxymethylcellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethylcellulose, and magnesium aluminum silicate.

All publications and patent applications mentioned in this disclosure are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

None of the references cited herein are admitted to constitute prior art. The discussion of the references states what their authors assert, and the inventors reserve the right to challenge the accuracy and pertinence of the cited documents. Although this specification refers to a number of sources, including scientific journal articles, patent documents, and textbooks, it will be expressly understood that such references do not constitute an admission that any of these documents form part of the common general knowledge in the art.

The discussion of the general methods presented herein is intended for illustrative purposes only. Other alternative methods and substitutes will be apparent to those of skill in the art upon review of this disclosure. They are intended to be included within the spirit and scope of this application.

[Example]
The following examples are provided as a further guide to the practitioner of ordinary skill in the art and are not intended to limit the scope of the claimed invention in any way.

In general, chemicals in the following examples were purchased from Sinopharm Chemical Reagent Co. (SCRC), Sigma-Aldrich, Alfa, or other suppliers. ¹ H NMR and ¹⁹ F NMR spectra were recorded on a Bruker AVIII 400 or Bruker AVIII 500 spectrometer.

LCMS measurements were performed on an Agilent 1200 HPLC/6100 SQ System using the following conditions: Method A: Mobile phase: A: Water (0.01% TFA) B: CAN (0.01% TFA); Gradient phase: 5% B increasing to 95% B within 1.4 min, 1.6 min at 95% B (total runtime: 3 min); Flow rate: 2.3 mL/min; Column: SunFire C18, 4.6×50 mm, 3.5 μm; Column temperature: 50° C. Detectors: ADC ELSD, DAD (214 nm and 254 nm), ES-API. Method B: Mobile phase: A: Water (10 _{mM NH4HCO3} ) B: Acetonitrile; Gradient phase: 5% B to 95% B in 1.5 min, 1.5 min at 95% B (total runtime: 3 min); Flow rate: 2.0 mL/min; Column: XBridge C18, 4.6 x 50 mm, 3.5 μm; Column temperature: 40°C. Detectors: ADC ELSD, DAD (214 nm and 254 _nm ), MSD (ES-API). Method C: Mobile phase: A: Water (10 mM _NH4HCO3 ) B: Acetonitrile; Gradient phase: 5% B to 95% B in 1.5 min, 1.5 min at 95% B (total runtime: 3 min); Flow rate: 2.0 mL/min; Column: XBridge C18, 4.6 x 50 mm, 3.5 μm; Column temperature: 40°C. Detectors: ADC ELSD, DAD (214nm and 254nm), MSD (ES-API).

Abbreviations: THF-tetrahydrofuran; DMF-N,N-dimethylformamide; EtOAc-ethyl acetate; DCM-dichloromethane; MeOH-methanol; EtOH-ethanol; TEA-triethanolamine; TFA-trifluoroacetic acid; RT-room temperature.

Additional embodiments are disclosed in more detail in the following examples, which are provided by way of example and are not intended to limit the scope of the disclosure or claims in any way. Although specific options of the disclosure have been disclosed, it should be understood that various modifications and combinations are possible and are contemplated to be within the true spirit and scope of the appended claims. Thus, it is not intended to limit the precise summary and disclosure presented herein.

[Example 1]
Synthesis of compound 159985

(A) 2-[2-[2-[2-[2-[2-[[2-[4-[6-(ジメチルアミノ)ピリジン-3-イル]フェニル]-1,3-ベンゾチアゾール-6-イル]-[(2-メチルプロパン-2-イル)オキシカルボニル]アミノ]エトキシ]エトキシ]エトキシ]エトキシ]エトキシ]エチル4-メチルベンゼンスルホネート: tert-ブチルN-[2-[4-[6-(ジメチルアミノ)ピリジン-3-イル]フェニル]-1,3-ベンゾチアゾール-6-イル]カルバメート(500mg、1.12mmol)のDMF(10mL)中溶液に、0℃でNaH(107.49mg、4.48mmol)を添加し、RTで1時間撹拌した。DMF(10mL)中の2-[2-[2-[2-[2-[2-(4-メチルフェニル)スルホニルオキシエトキシ]エトキシ]エトキシ]エトキシ]エトキシ]エチル4-メチルベンゼンスルホネート(2.65g、4.48mmol)を反応混合物に添加し、RTで14時間撹拌した。0℃で水を添加することによって混合物をクエンチし、次いでEtOAc(200mL)で抽出した。有機層を水(100mL)、ブライン(100mL)で洗浄し、Na₂SO₄で乾燥させ、濃縮し、カラムクロマトグラフィー(DCM:MeOH=10:1、Rf=0.7)によって精製して、2-[2-[2-[2-[2-[2-[[2-[4-[6-(ジメチルアミノ)ピリジン-3-イル]フェニル]-1,3-ベンゾチアゾール-6-イル]-[(2-メチルプロパン-2-イル)オキシカルボニル]アミノ]エトキシ]エトキシ]エトキシ]エトキシ]エトキシ]エチル4-メチルベンゼンスルホネート(化合物159835、603mg、0.70mmol、収率62%)を淡黄色の固体として得た。

(A) 2-[2-[2-[2-[2-[2-[2-[[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl 4-methylbenzenesulfonate: To a solution of tert-butyl N-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]carbamate (500 mg, 1.12 mmol) in DMF (10 mL) was added NaH (107.49 mg, 4.48 mmol) at 0° C. and stirred at RT for 1 h. 2-[2-[2-[2-[2-[2-[2-(4-methylphenyl)sulfonyloxyethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl 4-methylbenzenesulfonate (2.65 g, 4.48 mmol) in DMF (10 mL) was added to the reaction mixture and stirred at RT for 14 h. The mixture was quenched by adding water at 0° C. and then extracted with EtOAc (200 mL). The organic layer was washed with water (100 mL), brine ( ₁₀₀ mL), dried over _Na2SO4 , concentrated and purified by column chromatography (DCM:MeOH=10:1, Rf=0.7) to give 2-[2-[2-[2-[2-[2-[2-[[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl 4-methylbenzenesulfonate (compound 159835, 603 mg, 0.70 mmol, 62% yield) as a pale yellow solid.

(B) tert-Butyl N-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]-N-[2-[2-[2-[2-[2-(2-iodoethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate: A mixture of 2-[2-[2-[2-[2-[2-[2-[[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl 4-methylbenzenesulfonate (200 mg, 0.23 mmol) and NaI (42 mg, 0.28 mmol) in _CH3CN (5 mL) was heated at 80° C. for 20 h. The residue was dissolved in DCM (50 mL) and water (50 mL). The organic layer was washed with water (50 mL), brine ( ₅₀ mL), dried over _Na2SO4 , and concentrated to give tert-butyl N-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]-N-[2-[2-[2-[2-[2-(2-iodoethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate (compound 159890, 185.1 mg, 0.23 mmol, 98% yield) as a yellow solid.

(C) tert-Butyl N-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2,6-bis(oxo)piperidin-3-yl]-1,3-bis(oxo)isoindol-5-yl]oxyethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]-N-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]carbamate: 2-[2,6-bis(oxo)piperidin- ₃ -yl]-5-hydroxy-isoindole-1,3-dione (67 mg, 0.24 mmol), _K2CO3 A mixture of (51 mg, 0.37 mmol) and tert-butyl N-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]-N-[2-[2-[2-[2-[2-(2-iodoethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate (100 mg, 0.12 mmol) in DMF (5 mL) was heated at 50° C. for 5 h. The mixture was quenched with water and then extracted with DCM (200 mL). The organic layer was dried _{over Na2SO4} , concentrated and purified by column chromatography on silica gel (DCM:MeOH=20:1, Rf=0.52) to give tert-butyl N-[2-[2-[2-[2-[2-[2-[2-[2-[2,6-bis(oxo)piperidin-3-yl]-1,3-bis(oxo)isoindol-5-yl]oxyethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]-N-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]carbamate (53 mg, 0.05 mmol, 45% yield) as a pale yellow solid.

(D) 2-[2,6-bis(oxo)piperidin-3-yl]-5-[2-[2-[2-[2-[2-[2-[2-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]isoindole-1,3-dione: To a solution of tert-butyl N-[2-[2-[2-[2-[2-[2-[2-[2-[2,6-bis(oxo)piperidin-3-yl]-1,3-bis(oxo)isoindol-5-yl]oxyethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]-N-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]carbamate (52 mg, 0.05 mmol) in DCM (5 mL) was added TFA (0.08 mL, 1.08 mmol) and stirred at RT for 20 h. The mixture was poured into ice water and neutralized to pH 8 with saturated NaHCO ₃ solution. The residue was dissolved in DCM (20 mL) and water (10 mL). The organic layer was washed with water (10 mL), brine ( ₁₀ mL), dried over _Na2SO4 , and concentrated to dryness to give 2-[2,6-bis(oxo)piperidin-3-yl]-5-[2-[2-[2-[2-[2-[2-[2-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]isoindole-1,3-dione (compound 159985, 41 mg, 0.05 mmol, 83% yield) as a yellow solid. ^1H NMR (400 MHz, DMSO- _d6 ). MS (ESI) m/z 867 (M+H) ⁺ .

[Example 2]
Synthesis of compound 160219

(A) 化合物160087: tert-ブチルN-[2-[4-[6-(ジメチルアミノ)ピリジン-3-イル]フェニル]-1,3-ベンゾチアゾール-6-イル]カルバメート(500mg、1.12mmol)のDMF(10mL)中溶液に、0℃でNaH(107mg、4.48mmol)を添加し、室温で1時間撹拌した。DMF(10mL)中の2-[2-(4-メチルフェニル)スルホニルオキシエトキシ]エチル4-メチルベンゼンスルホネート(1.86g、4.48mmol)を反応混合物に添加し、室温で14時間撹拌した。混合物を0℃に冷却し、水でクエンチした。沈殿物を濾過によって収集し、水で洗浄し、カラムクロマトグラフィー(DCM:MeOH=20:1、Rf=0.68)によって精製して、2-[2-[[2-[4-[6-(ジメチルアミノ)ピリジン-3-イル]フェニル]-1,3-ベンゾチアゾール-6-イル]-[(2-メチルプロパン-2-イル)オキシカルボニル]アミノ]エトキシ]エチル4-メチルベンゼンスルホネート(595mg、0.86mmol、収率77%)を黄色の固体として得た。

(A) Compound 160087: To a solution of tert-butyl N-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]carbamate (500 mg, 1.12 mmol) in DMF (10 mL) was added NaH (107 mg, 4.48 mmol) at 0° C. and stirred at room temperature for 1 h. 2-[2-(4-methylphenyl)sulfonyloxyethoxy]ethyl 4-methylbenzenesulfonate (1.86 g, 4.48 mmol) in DMF (10 mL) was added to the reaction mixture and stirred at room temperature for 14 h. The mixture was cooled to 0° C. and quenched with water. The precipitate was collected by filtration, washed with water and purified by column chromatography (DCM:MeOH=20:1, Rf=0.68) to give 2-[2-[[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethyl 4-methylbenzenesulfonate (595 mg, 0.86 mmol, 77% yield) as a yellow solid.

(B) Compound 160150: A mixture of 2-[2-[[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethyl 4-methylbenzenesulfonate (595 mg, 0.86 mmol), NaI (156 mg, 1.04 mmol) in MeCN (15 mL) was heated at 80° C. for 17 h. The residue was dissolved in DCM (50 mL) and water (50 mL). The organic layer was washed with water (50 mL), brine (50 mL), dried _{over Na2SO4} and concentrated to give tert-butyl N-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]-N-[2-(2-iodoethoxy)ethyl]carbamate (449 mg, 0.70 mmol, 81% yield) as a yellow solid.

(C) Compound 160159: A mixture of 2-[2,6-bis(oxo)piperidin-3-yl]-5-hydroxy-isoindole-1,3-dione (96 mg, 0.35 mmol), _K2CO3 (96 mg, 0.70 mmol), tert-butyl N-[2-[4-[6-(dimethylamino)pyridin-3 _- yl]phenyl]-1,3-benzothiazol-6-yl]-N-[2-(2-iodoethoxy)ethyl]carbamate (150 mg, 0.23 mmol) in DMF (5 mL) was heated at 50° C. for 5 h. Water (10 mL) was added to the mixture and the resulting precipitate was collected by filtration. The residue was purified by column chromatography (DCM: EtOAc = 5: 2, Rf = 0.32) to give tert-butyl N-[2-[2-[2-[2,6-bis(oxo)piperidin-3-yl]-1,3-bis(oxo)isoindol-5-yl]oxyethoxy]ethyl]-N-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]carbamate (121 mg, 0.15 mmol, 66% yield) as a yellow solid.

(D) Compound 160219: tert-butyl N-[2-[2-[2-[2,6-bis(oxo)piperidin-3-yl]-1,3-bis(oxo)isoindol-5-yl]oxyethoxy]ethyl]-N-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]carbamate (120 mg, 0.15 mmol) in DCM (5 mL) was added with TFA (0.23 mL, 3.03 mmol) and the mixture was stirred at room temperature for 20 hours. The mixture was poured into ice water and neutralized to pH 8 with saturated NaHCO _3. The residue was dissolved in DCM (20 mL) and water (10 mL). The organic layer was washed with water (10 mL), brine (10 mL), dried _{over Na2SO4} and concentrated to dryness to give 2-[2,6-bis(oxo)piperidin-3-yl]-5-[2-[2-[[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]amino]ethoxy]ethoxy]isoindole-1,3-dione (21 mg, 0.03 mmol, 18% yield) as a yellow solid.

[Example 3]
Synthesis of compound 160939

(A) 化合物160812: tert-ブチルN-[2-[4-[6-(ジメチルアミノ)ピリジン-3-イル]フェニル]-1,3-ベンゾチアゾール-6-イル]カルバメート(500mg、1.12mmol)のDMF(10mL)中溶液に、0℃でNaH(107mg、4.48mmol)を添加し、RTで1時間撹拌した。DMF(5mL)中の2-[2-[2-[2-(4-メチルフェニル)スルホニルオキシエトキシ]エトキシ]エトキシ]エチル4-メチルベンゼンスルホネート(1125mg、2.24mmol)を反応混合物に添加し、RTで22時間撹拌した。混合物を水(50mL)及びDCM(50mL)に溶解させた。有機層を水(50mL)、ブライン(50mL)で洗浄し、Na₂SO₄で乾燥させ、濃縮し、シリカゲルでのカラムクロマトグラフィー(EtOAc:DCM=1:5、Rf=0.13)によって精製して、2-[2-[2-[2-[[2-[4-[6-(ジメチルアミノ)ピリジン-3-イル]フェニル]-1,3-ベンゾチアゾール-6-イル]-[(2-メチルプロパン-2-イル)オキシカルボニル]アミノ]エトキシ]エトキシ]エトキシ]エチル4-メチルベンゼンスルホネート(733mg、0.94mmol、収率84%)を黄色の固体として得た。

(A) Compound 160812: To a solution of tert-butyl N-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]carbamate (500 mg, 1.12 mmol) in DMF (10 mL) was added NaH (107 mg, 4.48 mmol) at 0° C. and stirred at RT for 1 h. 2-[2-[2-[2-(4-methylphenyl)sulfonyloxyethoxy]ethoxy]ethoxy]ethyl 4-methylbenzenesulfonate (1125 mg, 2.24 mmol) in DMF (5 mL) was added to the reaction mixture and stirred at RT for 22 h. The mixture was dissolved in water (50 mL) and DCM (50 mL). The organic layer was washed with water (50 mL), brine ( ₅₀ mL), dried over _Na2SO4 , concentrated and purified by column chromatography on silica gel (EtOAc:DCM=1:5, Rf=0.13) to give 2-[2-[2-[2-[[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethoxy]ethoxy]ethyl 4-methylbenzenesulfonate (733 mg, 0.94 mmol, 84% yield) as a yellow solid.

(B) Compound 160829: A mixture of 2-[2-[2-[2-[[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethoxy]ethoxy]ethyl 4-methylbenzenesulfonate (333 mg, 0.43 mmol) and NaI (109 mg, 0.73 mmol) in _CH3CN (10 mL) was heated at 80° C. for 15 h. The solvent was removed under reduced pressure and the residue was redissolved in EtOAc. The mixture was washed with water (50 mL), brine (50 mL), dried over _MgSO4 and concentrated to give tert-butyl N-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]-N-[2-[2-[2-(2-iodoethoxy)ethoxy]ethoxy]ethyl]carbamate (112 mg, 0.15 mmol, 36% yield) as a yellow solid.

(C) Compound 160889: A mixture of tert-butyl N-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-3a,7a-dihydro-1,3-benzothiazol-6-yl]-N-[2-[2-[2-(2-iodoethoxy)ethoxy]ethoxy]ethyl]carbamate (112 mg, 0.15 mmol), _Cs2CO3 (149.09 mg, 0.46 mmol), and dimethyl ₄ -hydroxybenzene-1,2-dicarboxylate (64 mg, 0.30 mmol) in DMF (2 mL) was stirred at 50° C. for 1 h. The mixture was cooled to RT and water was added. The precipitate was collected by filtration and then purified by column chromatography (EtOAc:DCM=1:1, Rf=0.33) to give dimethyl 4-[2-[2-[2-[2-[[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]benzene-1,2-dicarboxylate (102 mg, 0.13 mmol, 82% yield) as a yellow solid.

(D) Compound 160901: To a solution of dimethyl 4-[2-[2-[2-[2-[[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]benzene-1,2-dicarboxylate (102 mg, 0.13 mmol) in EtOH (2 mL) was added NaOH (40 mg, 1 mmol) in water (2 mL). The resulting mixture was stirred at RT for 40 h. The reaction was diluted with EtOAc (10 mL) and acidified to pH 1 with 1N HCl solution. The organic layer was washed with water (10 mL), brine (10 mL), dried _{over Na2SO4} and concentrated to dryness to give 4-[2-[2-[2-[2-[[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]phthalic acid (86 mg, 0.13 mmol, 99.9% yield) as an orange solid.

(E) Compound 160939: A mixture of 4-[2-[2-[2-[2-[[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]phthalic acid (122 mg, 0.18 mmol) and 3-aminopiperidine-2,6-dione hydrochloride (32 mg, 0.20 mmol) in pyridine (5 mL) was heated at 120° C. for 19 h. The mixture was cooled to RT, diluted with DCM (100 mL) and washed with water (50 mL) and brine (50 mL). _The organic layer was collected, dried over _Na2SO4 , concentrated and purified by column chromatography (MeOH:DCM=1:10, Rf=0.73) to give 2-[2,6-bis(oxo)piperidin-3-yl]-5-[2-[2-[2-[2-[[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]isoindole-1,3-dione (49 mg, 0.06 mmol, 35% yield) as a yellow solid.

[Example 4]
Synthesis of compound 161103

(A) 化合物160891: tert-ブチルN-[2-[4-[6-(ジメチルアミノ)ピリジン-3-イル]フェニル]-1,3-ベンゾチアゾール-6-イル]カルバメート(500mg、1.12mmol)のDMF(10mL)中溶液に、0℃でNaH(107mg、4.48mmol)を添加し、RTで1時間撹拌した。DMF(10mL)中の5-(4-メチルフェニル)スルホニルオキシペンチル4-メチルベンゼンスルホネート(1.85g、4.48mmol)を反応混合物に添加し、RTで17時間撹拌した。混合物を0℃に冷却し、水でクエンチした。得られた沈殿物を濾過によって収集し、カラムクロマトグラフィー(DCM:EtOAc=4:1、Rf=0.7)によって精製して、5-[[2-[4-[6-(ジメチルアミノ)ピリジン-3-イル]フェニル]-1,3-ベンゾチアゾール-6-イル]-[(2-メチルプロパン-2-イル)オキシカルボニル]アミノ]ペンチル4-メチルベンゼンスルホネート(604mg、0.88mmol、収率79%)を黄色の固体として得た。

(A) Compound 160891: To a solution of tert-butyl N-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]carbamate (500 mg, 1.12 mmol) in DMF (10 mL) was added NaH (107 mg, 4.48 mmol) at 0° C. and stirred at RT for 1 h. 5-(4-methylphenyl)sulfonyloxypentyl 4-methylbenzenesulfonate (1.85 g, 4.48 mmol) in DMF (10 mL) was added to the reaction mixture and stirred at RT for 17 h. The mixture was cooled to 0° C. and quenched with water. The resulting precipitate was collected by filtration and purified by column chromatography (DCM:EtOAc=4:1, Rf=0.7) to give 5-[[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]pentyl 4-methylbenzenesulfonate (604 mg, 0.88 mmol, 79% yield) as a yellow solid.

(B) Compound 160938: A mixture of dimethyl 4-hydroxybenzene-1,2-dicarboxylate (122 mg, 0.58 mmol), _Cs2CO3 ( ₂₈₅ mg, 0.87 mmol), KI (5 mg, 0.03 mmol), and 5-[[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]pentyl 4-methylbenzenesulfonate (200 mg, 0.29 mmol) in DMF (2 mL) was heated at 50° C. for 2 h. The reaction was quenched with water. The resulting solid was collected by filtration and washed with water to give dimethyl 4-[5-[[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]pentoxy]benzene-1,2-dicarboxylate (206 mg, 0.28 mmol, 98% yield) as a yellow solid.

(C) Compound 160999: To a solution of dimethyl 4-[5-[[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]pentoxy]benzene-1,2-dicarboxylate (100 mg, 0.14 mmol) in EtOH (2 mL) was added NaOH (110 mg, 2.76 mmol) in water (2 mL) and stirred at RT for 40 h. The reaction was neutralized to pH 1 with 1N HCl solution. The precipitate was collected by filtration and washed with water to give 4-[5-[[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]pentoxy]phthalic acid (93 mg, 0.13 mmol, 97% yield) as a yellow solid.

(D) Compound 161054: A mixture of 4-[5-[[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]pentoxy]phthalic acid (93 mg, 0.13 mmol) and 3-aminopiperidine-2,6-dione hydrochloride (48 mg, 0.29 mmol) in pyridine (3 mL) was heated at 120 °C for 40 hours. Water was then added to the mixture. The precipitate was collected by filtration and purified by column chromatography (DCM: EtOAc = 4: 1, Rf = 0.28) to give tert-butyl N-[5-[2-[2,6-bis(oxo)piperidin-3-yl]-1,3-bis(oxo)isoindol-5-yl]oxypentyl]-N-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]carbamate (61 mg, 0.08 mmol, 58% yield) as a yellow solid.

(E) Compound 161103: tert-Butyl N-[5-[2-[2,6-bis(oxo)piperidin-3-yl]-1,3-bis(oxo)isoindol-5-yl]oxypentyl]-N-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]carbamate (61 mg, 0.08 mmol) in DCM (5 mL) was added with TFA (0.12 mL, 1.55 mmol) and stirred at RT for 6 h. The mixture was poured into ice water and neutralized to pH 8 with saturated NaHCO ₃ solution. The residue was dissolved in DCM (20 mL) and water (10 mL). The organic layer was washed with water (10 mL), brine (10 mL), dried _{over Na2SO4} and concentrated to dryness to give 2-[2,6-bis(oxo)piperidin-3-yl]-5-[5-[[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]amino]pentoxy]isoindole-1,3-dione (44 mg, 0.06 mmol, 80% yield) as a yellow solid.

[Example 5]
Synthesis of compound 160273

(A) 化合物160210: 3-(6-ヒドロキシ-3-オキソ-1H-イソインドール-2-イル)ピペリジン-2,6-ジオン(95mg、0.37mmol)、K₂CO₃(101mg、0.73mmol)、tert-ブチルN-[2-[4-[6-(ジメチルアミノ)ピリジン-3-イル]フェニル]-1,3-ベンゾチアゾール-6-イル]-N-[2-[2-[2-[2-[2-(2-ヨードエトキシ)エトキシ]エトキシ]エトキシ]エトキシ]エチル]カルバメート(200mg、0.24mmol)のDMF(5mL)中混合物を50℃で5時間加熱した。混合物を水でクエンチし、DCM(200mL)で抽出した。有機層を収集し、Na₂SO₄で乾燥させ、濃縮し、カラムクロマトグラフィー(DCM:MeOH=20:1、Rf=0.48)によって精製して、tert-ブチルN-[2-[2-[2-[2-[2-[2-[[2-[2,6-ビス(オキソ)ピペリジン-3-イル]-1-オキソ-3H-イソインドール-5-イル]オキシ]エトキシ]エトキシ]エトキシ]エトキシ]エトキシ]エチル]-N-[2-[4-[6-(ジメチルアミノ)ピリジン-3-イル]フェニル]-1,3-ベンゾチアゾール-6-イル]カルバメート(83mg、0.09mmol、収率36%)を淡黄色の固体として得た。

(A) Compound 160210: A mixture of 3-(6-hydroxy-3-oxo-1H-isoindol-2-yl)piperidine-2,6 _- dione (95 mg, 0.37 mmol), _K2CO3 (101 mg, 0.73 mmol), tert-butyl N-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]-N-[2-[2-[2-[2-[2-(2-iodoethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate (200 mg, 0.24 mmol) in DMF (5 mL) was heated at 50° C. for 5 h. The mixture was quenched with water and extracted with DCM (200 mL). The organic layer was collected, dried over _Na2SO4 , concentrated and purified by column chromatography (DCM:MeOH=20: ₁ , Rf=0.48) to give tert-butyl N-[2-[2-[2-[2-[2-[2-[2-[[2-[2,6-bis(oxo)piperidin-3-yl]-1-oxo-3H-isoindol-5-yl]oxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]-N-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]carbamate (83 mg, 0.09 mmol, 36% yield) as a pale yellow solid.

(B) Compound 160273: To a solution of tert-butyl N-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2,6-bis(oxo)piperidin-3-yl]-1-oxo-3H-isoindol-5-yl]oxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]-N-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]carbamate (83 mg, 0.09 mmol) in DCM (5 mL) was added TFA (0.13 mL, 1.74 mmol) and stirred at RT for 7 h. The mixture was poured into ice water and neutralized to pH 8 with saturated NaHCO ₃ solution. The residue was dissolved in DCM (20 mL) and water (10 mL). The organic layer was washed with water (10 mL), brine (10 mL), dried over _Na2SO4 and concentrated to dryness to give _3- [6-[2-[2-[2-[2-[2-[2-[2-[2-[[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]-3-oxo-1H-isoindol-2-yl]piperidine-2,6-dione (73 mg, 0.08 mmol, 92% yield) as a yellow solid.

[Example 6]
Synthesis of compound 160313

(A) 化合物160284: 3-(6-ヒドロキシ-3-オキソ-1H-イソインドール-2-イル)ピペリジン-2,6-ジオン(58mg、0.22mmol)、K₂CO₃(61mg、0.44mmol)、tert-ブチルN-[2-[4-[6-(ジメチルアミノ)ピリジン-3-イル]フェニル]-1,3-ベンゾチアゾール-6-イル]-N-[2-(2-ヨードエトキシ)エチル]カルバメート(95mg、0.15mmol)のDMF(2mL)中混合物を50℃で5時間加熱した。水(10mL)を混合物に添加した。得られた沈殿物を濾過によって収集し、次いでカラムクロマトグラフィー(DCM:MeOH=20:1、Rf=0.52)によって精製して、tert-ブチルN-[2-[2-[[2-[2,6-ビス(オキソ)ピペリジン-3-イル]-1-オキソ-3H-イソインドール-5-イル]オキシ]エトキシ]エチル]-N-[2-[4-[6-(ジメチルアミノ)ピリジン-3-イル]フェニル]-1,3-ベンゾチアゾール-6-イル]カルバメート(57mg、0.07mmol、収率50%)を黄色の固体として得た。

(A) Compound 160284: A mixture of 3-(6-hydroxy-3-oxo-1H-isoindol-2-yl)piperidine- _2,6 -dione (58 mg, 0.22 mmol), _K2CO3 (61 mg, 0.44 mmol), tert-butyl N-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]-N-[2-(2-iodoethoxy)ethyl]carbamate (95 mg, 0.15 mmol) in DMF (2 mL) was heated at 50° C. for 5 h. Water (10 mL) was added to the mixture. The resulting precipitate was collected by filtration and then purified by column chromatography (DCM:MeOH=20:1, Rf=0.52) to afford tert-butyl N-[2-[2-[[2-[2,6-bis(oxo)piperidin-3-yl]-1-oxo-3H-isoindol-5-yl]oxy]ethoxy]ethyl]-N-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]carbamate (57 mg, 0.07 mmol, 50% yield) as a yellow solid.

(B) Compound 160313: To a solution of tert-butyl N-[2-[2-[[2-[2,6-bis(oxo)piperidin-3-yl]-1-oxo-3H-isoindol-5-yl]oxy]ethoxy]ethyl]-N-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]carbamate (54 mg, 0.07 mmol) in DCM (5 mL), TFA (0.11 mL, 1.39 mmol) was added and the mixture was stirred at room temperature for 20 hours. The mixture was poured into ice water and neutralized to pH 8 with saturated NaHCO ₃ solution. The residue was dissolved in DCM (20 mL) and water (10 mL). The organic layer was washed with water (10 mL), brine (10 mL), dried _{over Na2SO4} and concentrated to dryness to give 3-[6-[2-[2-[[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]amino]ethoxy]ethoxy]-3-oxo-1H-isoindol-2-yl]piperidine-2,6-dione (39 mg, 0.05 mmol, 77% yield) as a yellow solid.

[Example 7]
Synthesis of compound 162640

化合物162640は、実施例6と同様の方法に従って合成した。
¹H NMR (600 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.36 (s, 1H), 8.24 (d, J = 2.3 Hz, 1H), 8.01-8.05 (m, 4H), 7.72 (d, J = 8.4 Hz, 2H), 7.62 (d, J = 8.4 Hz, 1H), 7.52 (d, J = 9.7 Hz, 1H), 7.17 (d, J = 1.7 Hz, 1H), 7.05-7.09 (m, 2H), 6.81-6.85 (m, 2H), 6.61 (t, J = 5.8 Hz, 1H), 5.07 (dd, J = 13.2, 5.1 Hz, 1H), 4.36 (d, J = 17.2 Hz, 1H), 4.19-4.27 (m, 4H), 3.79-3.85 (m, 7H), 3.66 (t, J = 5.8 Hz, 3H), 3.48-3.54 (m, 3H), 2.85-2.93 (m, 1H), 1.92-1.99 (m, 1H).

Compound 162640 was synthesized according to a similar method to Example 6.
^1H NMR (600 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.36 (s, 1H), 8.24 (d, J = 2.3 Hz, 1H), 8.01-8.05 (m, 4H), 7.72 (d, J = 8.4 Hz, 2H), 7.62 (d, J = 8.4 Hz, 1H), 7.52 (d, J = 9.7 Hz, 1H), 7.17 (d, J = 1.7 Hz, 1H), 7.05-7.09 (m, 2H), 6.81-6.85 (m, 2H), 6.61 (t, J = 5.8 Hz, 1H), 5.07 (dd, J = 13.2, 5.1 Hz, 1H), 4.36 (d, J = 17.2 Hz, 1H), 4.19-4.27 (m, 4H), 3.79-3.85 (m, 7H), 3.66 (t, J = 5.8 Hz, 3H), 3.48-3.54 (m, 3H), 2.85-2.93 (m, 1H), 1.92-1.99 (m, 1H).

[Example 8]
Synthesis of compound 162842

化合物162842は、実施例6と同様の方法に従って合成した。
¹H NMR (600 MHz, DMSO-d6) δ 10.96 (s, 1H), 8.50 (d, J = 2.5 Hz, 1H), 8.40 (s, 1H), 8.13 (d, J = 6.6 Hz, 1H), 7.99 (d, J = 8.2 Hz, 2H), 7.89 (dd, J = 8.9, 2.5 Hz, 1H), 7.68 (d, J = 8.2 Hz, 2H), 7.60 (d, J = 8.4 Hz, 1H), 7.19 (s, 1H), 7.08 (d, J = 8.4 Hz, 1H), 6.79 (t, J = 7.4 Hz, 1H), 6.75 (d, J = 8.9 Hz, 1H), 6.70 (d, J = 7.4 Hz, 1H), 5.06 (dd, J = 13.2, 5.1 Hz, 1H), 4.35-4.38 (m, 2H), 4.32 (d, J = 17.2 Hz, 1H), 4.28 (dd, J = 8.2, 4.5 Hz, 2H), 4.20 (d, J = 17.2 Hz, 1H), 3.96-3.99 (m, 2H), 3.92-3.95 (m, 2H), 3.08 (s, 7H), 2.85-2.93 (m, 1H), 2.26-2.37 (m, 2H), 1.91-1.98 (m, 2H).

Compound 162842 was synthesized according to a similar method to Example 6.
^1H NMR (600 MHz, DMSO-d6) δ 10.96 (s, 1H), 8.50 (d, J = 2.5 Hz, 1H), 8.40 (s, 1H), 8.13 (d, J = 6.6 Hz, 1H), 7.99 (d, J = 8.2 Hz, 2H), 7.89 (dd, J = 8.9, 2.5 Hz, 1H), 7.68 (d, J = 8.2 Hz, 2H), 7.60 (d, J = 8.4 Hz, 1H), 7.19 (s, 1H), 7.08 (d, J = 8.4 Hz, 1H), 6.79 (t, J = 7.4 Hz, 1H), 6.75 (d, J = 8.9 Hz, 1H), 6.70 (d, J = 7.4 Hz, 1H), 5.06 (dd, J = 13.2, 5.1 Hz, 1H), 4.35-4.38 (m, 2H), 4.32 (d, J = 17.2 Hz, 1H), 4.28 (dd, J = 8.2, 4.5 Hz, 2H), 4.20 (d, J = 17.2 Hz, 1H), 3.96-3.99 (m, 2H), 3.92-3.95 (m, 2H), 3.08 (s, 7H), 2.85-2.93 (m, 1H), 2.26-2.37 (m, 2H), 1.91-1.98 (m, 2H).

[Example 9]
Synthesis of compound 162903

化合物162903は、実施例6と同様の方法に従って合成した。
¹H NMR (600 MHz, DMS-d6) δ 10.97 (s, 1H), 8.63 (d, J = 2.4 Hz, 1H), 8.12 (s, 1H), 8.08 (d, J = 8.0 Hz, 1H), 8.03 (dd, J = 8.9, 2.6 Hz, 1H), 7.99 (d, J = 8.9 Hz, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.78 (d, J = 2.4 Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.18-7.21 (m, 1H), 7.08 (dd, J = 8.4, 2.4 Hz, 1H), 6.79 (d, J = 8.8 Hz, 1H), 5.08 (dd, J = 13.4, 5.1 Hz, 1H), 4.38 (d, J = 17.2 Hz, 1H), 4.22-4.29 (m, 4H), 3.89 (dd, J = 9.2, 5.0 Hz, 3H), 3.11 (s, 3H), 2.56-2.63 (m, 1H), 2.33-2.40 (m, 1H).

Compound 162903 was synthesized according to a similar method to Example 6.
^1H NMR (600 MHz, DMS-d6) δ 10.97 (s, 1H), 8.63 (d, J = 2.4 Hz, 1H), 8.12 (s, 1H), 8.08 (d, J = 8.0 Hz, 1H), 8.03 (dd, J = 8.9, 2.6 Hz, 1H), 7.99 (d, J = 8.9 Hz, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.78 (d, J = 2.4 Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.18-7.21 (m, 1H), 7.08 (dd, J = 8.4, 2.4 Hz, 1H), 6.79 (d, J = 8.8 Hz, 1H), 5.08 (dd, J = 13.4, 5.1 Hz, 1H), 4.38 (d, J = 17.2 Hz, 1H), 4.22-4.29 (m, 4H), 3.89 (dd, J = 9.2, 5.0 Hz, 3H), 3.11 (s, 3H), 2.56-2.63 (m, 1H), 2.33-2.40 (m, 1H).

[Example 10]
Synthesis of compound 163123

化合物163123は、実施例6と同様の方法に従って合成した。
¹H NMR (600 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.56 (d, J = 2.5 Hz, 1H), 8.06 (d, J = 8.4 Hz, 2H), 7.92-7.96 (m, 2H), 7.82 (d, J = 8.4 Hz, 2H), 7.74 (d, J = 2.5 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.13-7.18 (m, 2H), 7.07 (dd, J = 8.4, 2.1 Hz, 1H), 6.77 (d, J = 9.0 Hz, 1H), 5.07 (dd, J = 13.4, 5.2 Hz, 1H), 4.35 (d, J = 17.1 Hz, 1H), 4.22-4.27 (m, 6H), 3.85-3.91 (m, 5H), 3.10 (s, 7H), 2.85-2.96 (m, 1H), 2.55-2.63 (m, 2H), 2.31-2.42 (m, 2H).

Compound 163123 was synthesized according to a similar method to Example 6.
^1H NMR (600 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.56 (d, J = 2.5 Hz, 1H), 8.06 (d, J = 8.4 Hz, 2H), 7.92-7.96 (m, 2H), 7.82 (d, J = 8.4 Hz, 2H), 7.74 (d, J = 2.5 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.13-7.18 (m, 2H), 7.07 (dd, J = 8.4, 2.1 Hz, 1H), 6.77 (d, J = 9.0 Hz, 1H), 5.07 (dd, J = 13.4, 5.2 Hz, 1H), 4.35 (d, J = 17.1 Hz, 1H), 4.22-4.27 (m, 6H), 3.85-3.91 (m, 5H), 3.10 (s, 7H), 2.85-2.96 (m, 1H), 2.55-2.63 (m, 2H), 2.31-2.42 (m, 2H).

[Example 11]
Synthesis of compound 163365

化合物163365は、実施例6と同様の方法に従って合成した。
¹H NMR (600 MHz, DMSO-d6) δ 10.96 (s, 1H), 8.57 (d, J = 2.5 Hz, 1H), 8.16 (d, J = 8.4 Hz, 2H), 8.09 (s, 1H), 7.96 (dd, J = 8.9, 2.4 Hz, 1H), 7.86 (d, J = 8.4 Hz, 2H), 7.68 (d, J = 8.7 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.45 (d, J = 2.1 Hz, 1H), 7.18 (s, 1H), 7.08 (d, J = 8.3 Hz, 1H), 7.02 (dd, J = 8.7, 2.2 Hz, 1H), 6.77 (d, J = 8.9 Hz, 1H), 5.07 (dd, J = 13.3, 5.2 Hz, 1H), 4.36 (d, J = 17.2 Hz, 1H), 4.22-4.28 (m, 5H), 3.86-3.91 (m, 3H), 3.10 (s, 5H), 2.84-2.94 (m, 2H).

Compound 163365 was synthesized according to a similar method to Example 6.
^1H NMR (600 MHz, DMSO-d6) δ 10.96 (s, 1H), 8.57 (d, J = 2.5 Hz, 1H), 8.16 (d, J = 8.4 Hz, 2H), 8.09 (s, 1H), 7.96 (dd, J = 8.9, 2.4 Hz, 1H), 7.86 (d, J = 8.4 Hz, 2H), 7.68 (d, J = 8.7 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.45 (d, J = 2.1 Hz, 1H), 7.18 (s, 1H), 7.08 (d, J = 8.3 Hz, 1H), 7.02 (dd, J = 8.7, 2.2 Hz, 1H), 6.77 (d, J = 8.9 Hz, 1H), 5.07 (dd, J = 13.3, 5.2 Hz, 1H), 4.36 (d, J = 17.2 Hz, 1H), 4.22-4.28 (m, 5H), 3.86-3.91 (m, 3H), 3.10 (s, 5H), 2.84-2.94 (m, 2H).

[Example 12]
Synthesis of compound 161247

(A) 化合物161084: tert-ブチルN-[2-[4-[6-(ジメチルアミノ)ピリジン-3-イル]フェニル]-1,3-ベンゾチアゾール-6-イル]カルバメート(200mg、0.45mmol)のDMF(3mL)中溶液に、0℃でNaH(32mg、1.34mmol)を添加した。得られた混合物をRTで1時間撹拌した。2-[2-[2-[2-[2-[tert-ブチル(ジメチル)シリル]オキシエトキシ]エトキシ]エトキシ]エトキシ]エチル4-メチルベンゼンスルホネート(454mg、0.90mmol)を反応混合物に添加し、RTで22時間撹拌した。混合物を水でクエンチした。沈殿物を濾過によって収集し、カラムクロマトグラフィー(EtOAC:DCM=2:3、Rf=0.48)によって精製して、tert-ブチルN-[2-[2-[2-[2-[2-[tert-ブチル(ジメチル)シリル]オキシエトキシ]エトキシ]エトキシ]エトキシ]エチル]-N-[2-[4-[6-(ジメチルアミノ)ピリジン-3-イル]フェニル]-1,3-ベンゾチアゾール-6-イル]カルバメート(235mg、0.30mmol、収率67%)を黄色の固体として得た。

(A) Compound 161084: To a solution of tert-butyl N-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]carbamate (200 mg, 0.45 mmol) in DMF (3 mL) was added NaH (32 mg, 1.34 mmol) at 0° C. The resulting mixture was stirred at RT for 1 h. 2-[2-[2-[2-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]ethoxy]ethoxy]ethyl 4-methylbenzenesulfonate (454 mg, 0.90 mmol) was added to the reaction mixture and stirred at RT for 22 h. The mixture was quenched with water. The precipitate was collected by filtration and purified by column chromatography (EtOAC:DCM=2:3, Rf=0.48) to give tert-butyl N-[2-[2-[2-[2-[2-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]ethoxy]ethoxy]ethyl]-N-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]carbamate (235 mg, 0.30 mmol, 67% yield) as a yellow solid.

(B) Compound 161112: To a solution of tert-butyl N-[2-[2-[2-[2-[2-[2-[tert-butyl-(dimethyl)silyl]oxyethoxy]ethoxy]ethoxy]ethoxy]ethyl]-N-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]carbamate (235 mg, 0.30 mmol) in THF (5 mL) was added dropwise 1 M TBAF solution in THF (1.81 mL, 1.81 mmol). The reaction mixture was stirred at RT for 7 h. The reaction mixture was concentrated to dryness and the residue was dissolved in EtOAc (100 mL). The mixture was washed with water (100 mL) and brine (100 mL). _The organic layer was collected, dried over _Na2SO4 , and concentrated to give tert-butyl N-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]-N-[2-[2-[2-[2-(2-hydroxyethyloxy)ethoxy]ethoxy]ethoxy]ethyl]carbamate (200 mg, 0.30 mmol, 99.7% yield) as a yellow solid.

(C) Compound 161181: To a solution of tert-butyl N-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]-N-[2-[2-[2-[2-(2-hydroxyethyloxy)ethoxy]ethoxy]ethoxy]ethyl]carbamate (120 mg, 0.18 mmol) in THF (3 mL) was added NaH (9 mg, 0.36 mmol) at 0 °C and stirred for 30 min. Then tert-butyl 2-bromoethanoate (0.08 mL, 0.54 mmol) was added and the mixture was heated at 50 °C for 8 h. The solvent was removed under reduced pressure. The residue was purified by column chromatography (EtOAc:DCM=2:3, Rf=0.35) to give tert-butyl 2-[2-[2-[2-[2-[2-[2-[[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanoate (84 mg, 0.11 mmol, 60% yield) as a yellow solid.

(D) Compound 161218: A mixture of tert-butyl 2-[2-[2-[2-[2-[2-[2-[[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanoate (84 mg, 0.11 mmol) and TFA (0.12 mL, 1.61 mmol) in DCM (2 mL) was stirred at RT for 23 h. The mixture was acidified to pH 1 with 1N HCl solution. The mixture was extracted with DCM. The organic layer was washed with _brine , dried over _Na2SO4 and concentrated to dryness to give 2-[2-[2-[2-[2-[2-[2-[2-[[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanoic acid (60 mg, 0.10 mmol, 89% yield) as a yellow solid.

(E) Compound 161247: A mixture of (2S,4R)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]-4-hydroxy-pyrrolidine-2-carboxamide (45 mg, 0.11 mmol), 2-[2-[2-[2-[2-[2-[[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]amino]ethoxy ... The mixture was diluted with DCM, washed with water and _brine , dried over _Na2SO4 , concentrated and purified by column chromatography on NH silica gel (MeOH:DCM=97:3, Rf=0.48) to give rac-(2R,4S)-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]-4-hydroxy-1-[rac-(2R)-2-[2-[2-[2-[2-[2-[2-[2-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanoylamino]-3,3-dimethyl-butanoyl]pyrrolidine-2-carboxamide (16 mg, 0.01 mmol, 14% yield) as a yellow solid.

[Example 13]
Synthesis of compound 160275

(A) 化合物160161: NaH(81mg、2.02mmol)のDMF(1mL)中溶液に、DMF(6mL)中のtert-ブチルN-[5-[4-[6-(ジメチルアミノ)-1,3-ベンゾチアゾール-2-イル]フェニル]ピリジン-2-イル]カルバメート(300mg、0.67mmol)を0℃で添加し、25℃で30分間撹拌した。DMF(3mL)中の2-[2-[2-[2-[2-[2-(4-メチルフェニル)スルホニルオキシエトキシ]エトキシ]エトキシ]エトキシ]エトキシ]エチル4-メチルベンゼンスルホネート(794mg、1.34mmol)を反応混合物に添加し、50℃で2時間加熱した。混合物を飽和NH₄Cl溶液でクエンチし、DCMで抽出した。有機層をブラインで洗浄し、MgSO₄で乾燥させ、濃縮し、カラムクロマトグラフィー(MeOH:DCM=3:97、Rf=0.3)によって精製して、2-[2-[2-[2-[2-[2-[[5-[4-[6-(ジメチルアミノ)-1,3-ベンゾチアゾール-2-イル]フェニル]ピリジン-2-イル]-[(2-メチルプロパン-2-イル)オキシカルボニル]アミノ]エトキシ]エトキシ]エトキシ]エトキシ]エトキシ]エチル4-メチルベンゼンスルホネート(273mg、0.32mmol、収率47%)を黄色の油状物として得た。

(A) Compound 160161: To a solution of NaH (81 mg, 2.02 mmol) in DMF (1 mL) was added tert-butyl N-[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]carbamate (300 mg, 0.67 mmol) in DMF (6 mL) at 0° C. and stirred at 25° C. for 30 min. 2-[2-[2-[2-[2-[2-[2-(4-methylphenyl)sulfonyloxyethoxy]ethoxy]ethoxy]ethoxy]ethyl 4-methylbenzenesulfonate (794 mg, 1.34 mmol) in DMF (3 mL) was added to the reaction mixture and heated at 50° C. for 2 h. The mixture was quenched with saturated NH ₄ Cl solution and extracted with DCM. The organic layer was washed with brine, dried over _MgSO4 , concentrated and purified by column chromatography (MeOH:DCM=3:97, Rf=0.3) to give 2-[2-[2-[2-[2-[2-[[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl 4-methylbenzenesulfonate (273 mg, 0.32 mmol, 47% yield) as a yellow oil.

(B) Compound 160244: A mixture of 2-[2-[2-[2-[2-[2-[[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl 4-methylbenzenesulfonate (270 mg, 0.31 mmol) and NaI (56.18 mg, 0.37 mmol) in _CH3CN (5 mL) was heated at 80° C. for 19 h. The mixture was diluted with DCM and extracted with water (50 mL) and brine (50 mL). The organic layer was dried over _MgSO4 and concentrated to dryness to give tert-butyl N-[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]-N-[2-[2-[2-[2-[2-(2-iodoethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate (256 mg, 0.31 mmol, 99.9% yield) as an orange oil.

(C) Compound 160252: A mixture of 2-[2,6-bis(oxo)piperidin-3-yl]-5-hydroxy-isoindole-1,3-dione (102 mg, 0.37 mmol), _K2CO3 ( ₇₇ mg, 0.56 mmol) and tert-butyl N-[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]-N-[2-[2-[2-[2-[2-(2-iodoethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate (153 mg, 0.19 mmol) in DMF (4 mL) was heated at 50° C. for 18 h. The mixture was diluted with DCM (200 mL) and extracted with water. The organic layer was collected, dried over _MgSO4 , concentrated and purified by column chromatography (MeOH:DCM=5:95, Rf=0.3) to give tert-butyl N-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2,6-bis(oxo)piperidin-3-yl]-1,3-bis(oxo)isoindol-5-yl]oxyethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]-N-[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]carbamate (61 mg, 0.06 mmol, 34% yield) as a yellow solid.

(D) Compound 160275: To a solution of tert-butyl N-[2-[2-[2-[2-[2-[2-[2-[2-[2,6-bis(oxo)piperidin-3-yl]-1,3-bis(oxo)isoindol-5-yl]oxyethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]-N-[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]carbamate (61 mg, 0.06 mmol) in DCM (1 mL) was added TFA (0.5 mL, 6.53 mmol) at 0° C. The resulting mixture was stirred at RT for 5 h. The solution was neutralized with saturated NaHCO ₃ solution at 0° C. and extracted with DCM. The organic layer was washed with brine, dried over _MgSO4 , concentrated and purified by column chromatography on NH silica gel (MeOH:DCM=99:1, Rf=0.3) to give 2-[2,6-bis(oxo)piperidin-3-yl]-5-[2-[2-[2-[2-[2-[2-[[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]isoindole-1,3-dione (51 mg, 0.05 mmol, 86% yield) as a yellow solid.

[Example 14]
Synthesis of compound 161177

(A) 化合物161026: ジメチル4-ヒドロキシフタレート(139mg、0.62mmol)、Cs₂CO₃(303mg、0.93mmol)、tert-ブチルN-[5-[4-[6-(ジメチルアミノ)-1,3-ベンゾチアゾール-2-イル]フェニル]ピリジン-2-イル]-N-[2-(2-ヨードエトキシ)エチル]カルバメート(200mg、0.31mmol)のDMF(5mL)中混合物を50℃で1時間加熱した。混合物を水でクエンチし、DCMで抽出した。有機層をMgSO₄で乾燥させ、濃縮し、カラムクロマトグラフィー(EtOAc:Hex=1:1、Rf=0.4)によって精製して、ジメチル4-[2-[2-[[5-[4-[6-(ジメチルアミノ)-1,3-ベンゾチアゾール-2-イル]フェニル]ピリジン-2-イル]-[(2-メチルプロパン-2-イル)オキシカルボニル]アミノ]エトキシ]エトキシ]ベンゼン-1,2-ジカルボキシレート(148mg、0.20mmol、収率66%)を黄色の固体として得た。

(A) Compound 161026: A _mixture of dimethyl 4-hydroxyphthalate (139 mg, 0.62 mmol), _Cs2CO3 (303 mg, 0.93 mmol), tert-butyl N-[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]-N-[2-(2-iodoethoxy)ethyl]carbamate (200 mg, 0.31 mmol) in DMF (5 mL) was heated at 50° C. for 1 h. The mixture was quenched with water and extracted with DCM. The organic layer was dried over _MgSO4 , concentrated and purified by column chromatography (EtOAc:Hex=1:1, Rf=0.4) to give dimethyl 4-[2-[2-[[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethoxy]benzene-1,2-dicarboxylate (148 mg, 0.20 mmol, 66% yield) as a yellow solid.

(B) Compound 161083: To a solution of dimethyl 4-[2-[2-[[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethoxy]benzene-1,2-dicarboxylate (148 mg, 0.20 mmol) in MeOH (1 mL) and water (1 mL) was added LiOH (39 mg, 1.63 mmol). The reaction mixture was stirred at RT for 5 days. The solution was acidified to pH 4-5 with 1 N HCl. The resulting precipitate was collected by filtration, washed with water, and dried under reduced pressure to give 4-[2-[2-[[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethoxy]phthalic acid (119 mg, 0.17 mmol, 84% yield) as a yellow solid.

(C) Compound 161115: A mixture of 4-[2-[2-[[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethoxy]phthalic acid (119 mg, 0.17 mmol) and 3-aminopiperidine-2,6-dione hydrochloride (31 mg, 0.19 mmol) in pyridine (2 mL) was heated at 120 °C for 2 days. The mixture was concentrated to dryness and purified by column chromatography (MeOH:DCM=5:95, Rf=0.3) to give tert-butyl N-[2-[2-[2-[2,6-bis(oxo)piperidin-3-yl]-1,3-bis(oxo)isoindol-5-yl]oxyethoxy]ethyl]-N-[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]carbamate (39 mg, 0.05 mmol, 29% yield) as a yellow solid.

(D) Compound 161177: To a solution of tert-butyl N-[2-[2-[2-[2,6-bis(oxo)piperidin-3-yl]-1,3-bis(oxo)isoindol-5-yl]oxyethoxy]ethyl]-N-[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]carbamate (39 mg, 0.05 mmol) in DCM (1 mL) was added TFA (1 mL, 13.06 mmol) at 0° C. The resulting mixture was stirred at RT for 2 h. The solution was neutralized with saturated NaHCO ₃ solution and extracted with DCM. The organic layer was washed with brine, dried over MgSO4, concentrated and purified by chromatography (MeOH:DCM=1:99, Rf=0.1) to give 2-[2,6-bis(oxo)piperidin-3-yl]-5-[2-[2-[[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]amino]ethoxy]ethoxy]isoindole-1,3-dione (11 mg, 0.02 mmol, 31% yield) as a yellow solid.

[Example 15]
Synthesis of compound 160383

(A) 化合物160366: 3-(6-ヒドロキシ-3-オキソ-1H-イソインドール-2-イル)ピペリジン-2,6-ジオン(63mg、0.24mmol)、K₂CO₃(51mg、0.37mmol)、tert-ブチルN-[5-[4-[6-(ジメチルアミノ)-1,3-ベンゾチアゾール-2-イル]フェニル]ピリジン-2-イル]-N-[2-[2-[2-[2-[2-(2-ヨードエトキシ)エトキシ]エトキシ]エトキシ]エトキシ]エチル]カルバメート(100mg、0.12mmol)のDMF(2mL)中混合物を50℃で3時間加熱した。混合物を水でクエンチし、DCM(200mL)で抽出し、MgSO₄で乾燥させ、濃縮し、クロマトグラフィー(MeOH:DCM=5:95、Rf=0.3)によって精製して、tert-ブチルN-[2-[2-[2-[2-[2-[2-[[2-[2,6-ビス(オキソ)ピペリジン-3-イル]-1-オキソ-3H-イソインドール-5-イル]オキシ]エトキシ]エトキシ]エトキシ]エトキシ]エトキシ]エチル]-N-[5-[4-[6-(ジメチルアミノ)-1,3-ベンゾチアゾール-2-イル]フェニル]ピリジン-2-イル]カルバメート(26mg、0.03mmol、収率22%)を黄色の固体として得た。

(A) Compound 160366: A mixture of 3-(6-hydroxy-3-oxo-1H-isoindol-2-yl)piperidine-2,6 _- dione (63 mg, 0.24 mmol), _K2CO3 (51 mg, 0.37 mmol), tert-butyl N-[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]-N-[2-[2-[2-[2-[2-(2-iodoethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate (100 mg, 0.12 mmol) in DMF (2 mL) was heated at 50° C. for 3 h. The mixture was quenched with water, extracted with DCM (200 mL), dried over _MgSO4 , concentrated and purified by chromatography (MeOH:DCM=5:95, Rf=0.3) to give tert-butyl N-[2-[2-[2-[2-[2-[2-[2-[[2-[2,6-bis(oxo)piperidin-3-yl]-1-oxo-3H-isoindol-5-yl]oxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]-N-[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]carbamate (26 mg, 0.03 mmol, 22% yield) as a yellow solid.

(B) Compound 160383: To a solution of tert-butyl N-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2,6-bis(oxo)piperidin-3-yl]-1-oxo-3H-isoindol-5-yl]oxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]-N-[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]carbamate (26 mg, 0.03 mmol) in DCM (1 mL) was added TFA (0.5 mL, 6.53 mmol) at 0° C. and the mixture was stirred at RT for 3 h. The solution was neutralized with saturated NaHCO ₃ solution at 0° C. and then extracted with DCM. The organic layer was washed with brine, dried over _MgSO4 , concentrated and purified by chromatography (MeOH:DCM=5:95, Rf=0.2) to give 3-[6-[2-[2-[2-[2-[2-[2-[2-[[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]-3-oxo-1H-isoindol-2-yl]piperidine-2,6-dione (9 mg, 0.01 mmol, 33% yield) as a yellow solid.

[Example 16]
Synthesis of compound 160744

(A) 化合物160690: 2-[4-[6-(ジメチルアミノ)-2-フルオロ-ピリジン-3-イル]フェニル]イミダゾ[1,2-a]ピリジン-6-オール(400mg、1.15mmol)のDMF(10mL)中溶液に0℃でNaH(184mg、4.59mmol)を添加し、RTで1時間撹拌した。2-[2-[2-[2-[2-[2-(4-メチルフェニル)スルホニルオキシエトキシ]エトキシ]エトキシ]エトキシ]エトキシ]エチル4-メチルベンゼンスルホネート(2mL、4.13mmol)を混合物に添加し、RTで14時間、アルゴン下で撹拌した。混合物をDCM(10mL)で希釈し、水(10mL)及びブライン(10mL)で洗浄した。有機層を収集し、Na₂SO₄で乾燥させ、濃縮し、カラムクロマトグラフィー(DCM:MeOH=50:1、Rf=0.29)によって精製して、2-[2-[2-[2-[2-[2-[2-[4-[6-(ジメチルアミノ)-2-フルオロ-ピリジン-3-イル]フェニル]イミダゾ[1,2-a]ピリジン-6-イル]オキシエトキシ]エトキシ]エトキシ]エトキシ]エトキシ]エチル4-メチルベンゼンスルホネート(520mg、0.68mmol、収率59%)を淡黄色の固体として得た。

(A) Compound 160690: To a solution of 2-[4-[6-(dimethylamino)-2-fluoro-pyridin-3-yl]phenyl]imidazo[1,2-a]pyridin-6-ol (400 mg, 1.15 mmol) in DMF (10 mL) was added NaH (184 mg, 4.59 mmol) at 0° C. and stirred at RT for 1 h. 2-[2-[2-[2-[2-[2-(4-methylphenyl)sulfonyloxyethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl 4-methylbenzenesulfonate (2 mL, 4.13 mmol) was added to the mixture and stirred at RT for 14 h under argon. The mixture was diluted with DCM (10 mL) and washed with water (10 mL) and brine (10 mL). _The organic layer was collected, dried over _Na2SO4 , concentrated and purified by column chromatography (DCM:MeOH=50:1, Rf=0.29) to give 2-[2-[2-[2-[2-[2-[2-[2-[4-[6-(dimethylamino)-2-fluoro-pyridin-3-yl]phenyl]imidazo[1,2-a]pyridin-6-yl]oxyethoxy]ethoxy]ethoxy]ethoxy]ethyl 4-methylbenzenesulfonate (520 mg, 0.68 mmol, 59% yield) as a pale yellow solid.

(B) Compound 160707: A mixture of 2-[2-[2-[2-[2-[2-[2-[2-[4-[6-(dimethylamino)-2-fluoro-pyridin-3-yl]phenyl]imidazo[1,2-a]pyridin-6-yl]oxyethoxy]ethoxy]ethoxy]ethoxy]ethyl 4-methylbenzenesulfonate (520 mg, 0.68 mmol) and NaI (122 mg, 0.81 mmol) in _CH3CN (6 mL) was heated at 80° C. for 5 h. Water was added to the mixture and it was extracted with DCM. The organic layer was washed with water (20 mL), brine ( ₂₀ mL), dried over _Na2SO4 , concentrated and purified by chromatography (MeOH:DCM=1:50, Rf=0.39) to give 6-fluoro-5-[4-[6-[2-[2-[2-[2-[2-[2-(2-iodoethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]imidazo[1,2-a]pyridin-2-yl]phenyl]-N,N-dimethyl-pyridin-2-amine (427 mg, 0.59 mmol, 87% yield) as a pale yellow solid.

(C) Compound 160744: A mixture of 2-[2,6-bis(oxo)piperidin-3-yl]-5-hydroxy-isoindole-1,3-dione (114 mg, 0.41 mmol), _Cs2CO3 ( ₂₀₂ mg, 0.62 mmol), and 6-fluoro-5-[4-[6-[2-[2-[2-[2-[2-[2-(2-iodoethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]-3,8a-dihydroimidazo[1,2-a]pyridin-2-yl]phenyl]-N,N-dimethyl-pyridin-2-amine (150 mg, 0.21 mmol) in DMF (3 mL) was heated at 50° C. for 20 h. The mixture was quenched with water and the resulting precipitate was collected by filtration. The residue was purified by column chromatography (MeOH:DCM=1:20, Rf=0.34) to give 2-[2,6-bis(oxo)piperidin-3-yl]-5-[2-[2-[2-[2-[2-[2-[2-[2-[4-[6-(dimethylamino)-2-fluoro-pyridin-3-yl]phenyl]imidazo[1,2-a]pyridin-6-yl]oxyethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]isoindole-1,3-dione (28 mg, 0.03 mmol, 15% yield) as a brown solid.
^1H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 8.28 (s, 1H), 8.23 (d, J = 2.3Hz, 1H), 7.97 (d, J = 7.8, 2H), 7.87 (dd, J = 10.8, 8.4Hz, 1H), 7.81 (d, J = 8.4Hz, 1H), 7.57 (d, J = 7.8Hz, 2H), 7.50 (d, J = 9.7 Hz, 1H), 7.43 (d, J = 2.3Hz, 1H), 7.34 (dd, J = 8.4, 2.3 Hz, 1H), 7.05 (dd, J = 9.7, 2.3 Hz, 1H), 6.63 (dd, J = 8.4, 2.0 Hz, 1H), 5.11 (dd, J = 12.9, 5.5 Hz, 1H), 4.25-4.32 (m, 2H), 4.06-4.14 (m, 2H), 3.74-3.79 (m, 4H), 3.47-3.63 (m, 18H), 3.06 (s, 6H), 2.80-2.96 (m, 2H).

[Example 17]
Synthesis of compound 161111

(A) 化合物160947: 2-[4-[6-(ジメチルアミノ)-2-フルオロ-ピリジン-3-イル]フェニル]イミダゾ[1,2-a]ピリジン-6-オール(400mg、1.15mmol)の乾燥DMF(8mL)中溶液に、0℃でNaH(0.14g、3.44mmol)を添加し、RTで1時間撹拌した。2-[2-(4-メチルフェニル)スルホニルオキシエトキシ]エチル4-メチルベンゼンスルホネート(1.43g、3.44mmol)を混合物に添加し、同じ温度で16時間撹拌した。反応物を水でクエンチし、DCMで抽出した。有機層を水、ブラインで洗浄し、Na₂SO₄で乾燥させ、濃縮し、シリカゲルでのカラムクロマトグラフィー(EtOAc:DCM=1:5、Rf=0.33)によって精製して、2-[2-[2-[4-[6-(ジメチルアミノ)-2-フルオロ-ピリジン-3-イル]フェニル]イミダゾ[1,2-a]ピリジン-6-イル]オキシエトキシ]エチル4-メチルベンゼンスルホネート(227mg、0.38mmol、収率33%)を橙色の固体として得た。

(A) Compound 160947: To a solution of 2-[4-[6-(dimethylamino)-2-fluoro-pyridin-3-yl]phenyl]imidazo[1,2-a]pyridin-6-ol (400 mg, 1.15 mmol) in dry DMF (8 mL), NaH (0.14 g, 3.44 mmol) was added at 0° C. and stirred at RT for 1 h. 2-[2-(4-methylphenyl)sulfonyloxyethoxy]ethyl 4-methylbenzenesulfonate (1.43 g, 3.44 mmol) was added to the mixture and stirred at the same temperature for 16 h. The reaction was quenched with water and extracted with DCM. The organic layer was washed with water, _brine , dried over _Na2SO4 , concentrated and purified by column chromatography on silica gel (EtOAc:DCM=1:5, Rf=0.33) to give 2-[2-[2-[4-[6-(dimethylamino)-2-fluoro-pyridin-3-yl]phenyl]imidazo[1,2-a]pyridin-6-yl]oxyethoxy]ethyl 4-methylbenzenesulfonate (227 mg, 0.38 mmol, 33% yield) as an orange solid.

(B) Compound 160997: A mixture of dimethyl 4-hydroxybenzene-1,2-dicarboxylate (161 mg, 0.77 mmol), _Cs2CO3 ( _374.2 mg, 1.15 mmol), KI (6 mg, 0.04 mmol), and 2-[2-[2-[4-[6-(dimethylamino)-2-fluoro-pyridin-3-yl]phenyl]imidazo[1,2-a]pyridin-6-yl]oxyethoxy]ethyl 4-methylbenzenesulfonate (226 mg, 0.38 mmol) in DMF (4 mL) was heated at 50° C. for 4 h. The mixture was quenched with water and the resulting precipitate was collected by filtration and washed with water to give dimethyl 4-[2-[2-[2-[4-[6-(dimethylamino)-2-fluoro-pyridin-3-yl]phenyl]imidazo[1,2-a]pyridin-6-yl]oxyethoxy]ethoxy]benzene-1,2-dicarboxylate (212 mg, 0.34 mmol, 88% yield) as an orange solid.

(C) Compound 161006: To a solution of dimethyl 4-[2-[2-[2-[4-[6-(dimethylamino)-2-fluoropyridin-3-yl]phenyl]imidazo[1,2-a]pyridin-6-yl]oxyethoxy]ethoxy]benzene-1,2-dicarboxylate (211 mg, 0.34 mmol) in MeOH (2 mL) was added NaOH (443 mg, 11.08 mmol) in water (2 mL) and stirred at RT for 5 days. The reaction was diluted with EtOAc (50 mL) and acidified to pH 1 with 1N HCl solution. The organic layer was washed with water (50 mL), brine (50 mL), dried _{over Na2SO4} and concentrated to give 4-[2-[2-[2-[4-[6-(dimethylamino)-2-fluoro-pyridin-3-yl]phenyl]imidazo[1,2-a]pyridin-6-yl]oxyethoxy]ethoxy]phthalic acid (185 mg, 0.31 mmol, 92% yield) as a yellow solid.

(D) Compound 161111: A mixture of 4-[2-[2-[2-[4-[6-(dimethylamino)-2-fluoro-pyridin-3-yl]phenyl]imidazo[1,2-a]pyridin-6-yl]oxyethoxy]ethoxy]phthalic acid (67 mg, 0.11 mmol) and 3-aminopiperidine-2,6-dione hydrochloride (20 mg, 0.15 mmol) in pyridine (3 mL) was heated at 120 °C for 14 h. The solvent was removed under reduced pressure. The residue was redissolved in DCM and water was added. The resulting precipitate was collected by filtration and purified by column chromatography (MeOH:DCM=1:100, Rf=0.19) to give 2-[2,6-bis(oxo)piperidin-3-yl]-5-[2-[2-[2-[4-[6-(dimethylamino)-2-fluoro-pyridin-3-yl]phenyl]imidazo[1,2-a]pyridin-6-yl]oxyethoxy]ethoxy]isoindole-1,3-dione (18 mg, 0.02 mmol, 22% yield) as a yellow solid.

[Example 18]
Synthesis of compound 161215

(A) 化合物160806: NaH(138mg、3.45mmol)のDMF(2mL)中溶液に、DMF(10mL)中のtert-ブチルN-[6-フルオロ-5-[4-(6-メトキシイミダゾ[1,2-a]ピリジン-2-イル)フェニル]ピリジン-2-イル]カルバメート(500mg、1.15mmol)を0℃で添加した。得られた混合物を室温で30分間撹拌した。DMF(3mL)中の2-[2-(4-メチルフェニル)スルホニルオキシエトキシ]エチル4-メチルベンゼンスルホネート(954mg、2.30mmol)を反応混合物に添加し、室温で21時間撹拌した。混合物を飽和NH₄Cl溶液でクエンチし、EtOAcで抽出した。有機層をブラインで洗浄し、MgSO₄で乾燥させ、濃縮し、カラムクロマトグラフィー(EtOAc:DCM=3:17、Rf=0.3)によって精製して、2-[2-[[6-フルオロ-5-[4-(6-メトキシイミダゾ[1,2-a]ピリジン-2-イル)フェニル]ピリジン-2-イル]-[(2-メチルプロパン-2-イル)オキシカルボニル]アミノ]エトキシ]エチル4-メチルベンゼンスルホネート(339mg、0.50mmol、収率44%)を黄色の固体として得た。

(A) Compound 160806: To a solution of NaH (138 mg, 3.45 mmol) in DMF (2 mL) was added tert-butyl N-[6-fluoro-5-[4-(6-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl]pyridin-2-yl]carbamate (500 mg, 1.15 mmol) in DMF (10 mL) at 0° C. The resulting mixture was stirred at room temperature for 30 min. 2-[2-(4-methylphenyl)sulfonyloxyethoxy]ethyl 4-methylbenzenesulfonate (954 mg, 2.30 mmol) in DMF (3 mL) was added to the reaction mixture and stirred at room temperature for 21 h. The mixture was quenched with saturated NH ₄ Cl solution and extracted with EtOAc. The organic layer was washed with brine, dried over _MgSO4 , concentrated and purified by column chromatography (EtOAc:DCM=3:17, Rf=0.3) to give 2-[2-[[6-fluoro-5-[4-(6-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl]pyridin-2-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethyl 4-methylbenzenesulfonate (339 mg, 0.50 mmol, 44% yield) as a yellow solid.

(B) Compound 160814: A mixture of 2-[2-[[6-fluoro-5-[4-(6-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl]pyridin-2-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethyl 4-methylbenzenesulfonate (339 mg, 0.50 mmol) and NaI (90 mg, 0.60 mmol) in MeCN (10 mL) was heated at 80° C. for 19 h. The mixture was added to water and extracted with EtOAc. The organic layer was washed with water (50 mL), brine (50 mL), dried over _MgSO4 , concentrated and purified by column chromatography (EtOAc:DCM=1:9, Rf=0.3) to give tert-butyl N-[6-fluoro-5-[4-(6-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl]pyridin-2-yl]-N-[2-(2-iodoethoxy)ethyl]carbamate (197 mg, 0.31 mmol, 62% yield) as a yellow solid.

(C) Compound 161091: A mixture of dimethyl 4-oxobenzene-1,2-dicarboxylate (131 mg, 0.62 mmol), _Cs2CO3 ( ₃₀₅ mg, 0.93 mmol), tert-butyl N-[6-fluoro-5-[4-(6-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl]pyridin-2-yl]-N-[2-(2-iodoethoxy)ethyl]carbamate (197 mg, 0.31 mmol) in DMF (5 mL) was heated at 50°C for 1 h. The mixture was quenched with water, extracted with DCM, and purified by filtration with MgSO. It was dried over ₄ , concentrated and purified by column chromatography (EtOAc:Hexanes=1:1, Rf=0.3) to give dimethyl 4-[2-[2-[[6-fluoro-5-[4-(6-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl]pyridin-2-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethoxy]benzene-1,2-dicarboxylate (147 mg, 0.21 mmol, 66% yield) as a yellow solid.

(D) Compound 161105: To a solution of dimethyl 4-[2-[2-[[6-fluoro-5-[4-(6-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl]pyridin-2-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethoxy]benzene-1,2-dicarboxylate (147 mg, 0.21 mmol) in MeOH (2 mL) was added NaOH (66 mg, 1.65 mmol) in water (2 mL) and the mixture was stirred at room temperature for 3 days. The reaction was neutralized to pH 1 with 1N HCl solution. The precipitate was collected by filtration and washed with water to give 4-[2-[2-[[6-fluoro-5-[4-(6-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl]pyridin-2-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethoxy]phthalic acid (135 mg, 0.20 mmol, 96% yield) as a white solid.

(E) Compound 161183: A mixture of 4-[2-[2-[[6-fluoro-5-[4-(6-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl]pyridin-2-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethoxy]phthalic acid (135 mg, 0.20 mmol) and 3-aminopiperidine-2,6-dione hydrochloride (49 mg, 0.29 mmol) in pyridine (2 mL) was heated at 120 °C for 20 hours. The mixture was concentrated to dryness and purified by column chromatography on NH silica gel (MeOH:DCM=1:99, Rf=0.1) to give tert-butyl N-[2-[2-[2-[2,6-bis(oxo)piperidin-3-yl]-1,3-bis(oxo)isoindol-5-yl]oxyethoxy]ethyl]-N-[6-fluoro-5-[4-(6-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl]pyridin-2-yl]carbamate (47 mg, 0.06 mmol, 30% yield) as a yellow solid.

(F) Compound 161215: tert-butyl N-[2-[2-[2-[2,6-bis(oxo)piperidin-3-yl]-1,3-bis(oxo)isoindol-5-yl]oxyethoxy]ethyl]-N-[6-fluoro-5-[4-(6-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl]pyridin-2-yl]carbamate (47 mg, 0.06 mmol) in DCM (1 mL) was added with TFA (1 mL, 13 mmol) at 0° C., and the mixture was stirred at room temperature for 2 hours. The solution was neutralized with saturated NaHCO ₃ solution and extracted with DCM. The organic layer was washed with brine, dried over MgSO4, concentrated and purified by chromatography on NH silica gel (MeOH:DCM=1:99, Rf=0.1) to give 2-[2,6-bis(oxo)piperidin-3-yl]-5-[2-[2-[[6-fluoro-5-[4-(6-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl]pyridin-2-yl]amino]ethoxy]ethoxy]isoindole-1,3-dione (17 mg, 0.02 mmol, 38% yield) as a yellow solid. ^1H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 8.28 (s, 1H), 8.19 (d, J = 2.3 Hz, 1H), 7.92 (d, J = 8.3 Hz, 2H), 7.79 (d, J = 8.3 Hz, 1H), 7.70 (dd, J = 10.3, 8.2 Hz, 1H), 7.46-7.52 (m, 3H), 7.43 (d, J = 2.2 Hz, 1H), 7.34 (dd, J = 8.2, 2.3 Hz, 1H), 7.14 (t, J = 5.7 Hz, 1H), 7.01 (dd, J = 10.3, 2.2 Hz, 1H), 6.49 (d, J = 8.5 Hz, 1H), 5.08 (dd, J = 13.1, 5.3 Hz, 1H), 4.34-4.28 (m, 2H), 3.75-3.83 (m, 5H), 3.62 (t, J = 5.5 Hz, 2H), 3.39-3.44 (m, 2H), 2.77-2.91 (m, 1H), 2.49-2.66 (m, 2).

[Example 19]
Synthesis of compound 161409

化合物161409は、実施例19と同様の方法に従って合成することが可能であった。
¹H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 8.27 (s, 1H), 8.19 (d, J = 2.5 Hz, 1H), 7.92 (d, J = 8.0 Hz, 2H), 7.78 (d, J = 8.4 Hz, 1H), 7.71 (dd, J = 10.2, 8.6 Hz, 1H), 7.45-7.53 (m, 3H), 7.41 (d, J = 2.0 Hz, 1H), 7.32 (dd, J = 8.6, 2.1 Hz, 1H), 7.13 (t, J = 5.3 Hz, 1H), 7.00 (dd, J = 9.7, 1.6 Hz, 1H), 6.49 (d, J = 9.2 Hz, 1H), 5.07 (dd, J = 12.8, 5.3 Hz, 1H), 4.24-4.29 (m, 2H), 3.77 (s, 3H), 3.72-3.76 (m, 2H), 3.44-3.58 (m, 20H), 3.34-3.41 (m, 3H), 2.77-2.91 (m, 2H).

Compound 161409 could be synthesized according to a similar method to Example 19.
^1H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 8.27 (s, 1H), 8.19 (d, J = 2.5 Hz, 1H), 7.92 (d, J = 8.0 Hz, 2H), 7.78 (d, J = 8.4 Hz, 1H), 7.71 (dd, J = 10.2, 8.6 Hz, 1H), 7.45-7.53 (m, 3H), 7.41 (d, J = 2.0 Hz, 1H), 7.32 (dd, J = 8.6, 2.1 Hz, 1H), 7.13 (t, J = 5.3 Hz, 1H), 7.00 (dd, J = 9.7, 1.6 Hz, 1H), 6.49 (d, J = 9.2 Hz, 1H), 5.07 (dd, J = 12.8, 5.3 Hz, 1H), 4.24-4.29 (m, 2H), 3.77 (s, 3H), 3.72-3.76 (m, 2H), 3.44-3.58 (m, 20H), 3.34-3.41 (m, 3H), 2.77-2.91 (m, 2H).

[Example 20]
Synthesis of compound 161104

(A) 化合物160937: tert-ブチル2-[4-[6-[(2-メチルプロパン-2-イル)オキシカルボニルアミノ]ピリジン-3-イル]フェニル]ピロロ[2,3-c]-ピリジン-1-カルボキシレート(500mg、1.03mmol)のDMF(10mL)中溶液に0℃でNaH(49mg、1.23mmol)を添加し、RTで30分間撹拌した。2-[2-[2-[2-[2-[2-(4-メチルフェニル)スルホニルオキシエトキシ]エトキシ]エトキシ]エトキシ]エトキシ]エチル4-メチルベンゼンスルホネート(789mg、1.34mmol)を反応混合物に添加し、RTで6時間撹拌した。混合物を飽和NH₄Cl溶液でクエンチし、DCMで抽出した。有機層をブラインで洗浄し、MgSO₄で乾燥させ、濃縮し、カラムクロマトグラフィー(EtOAc:DCM=1:4、Rf=0.33)によって精製して、tert-ブチル2-[4-[6-[2-[2-[2-[2-[2-[2-(4-メチルフェニル)スルホニルオキシエトキシ]エトキシ]エトキシ]エトキシ]エトキシ]エチル-[(2-メチルプロパン-2-イル)オキシカルボニル]アミノ]ピリジン-3-イル]フェニル]ピロロ[2,3-c]ピリジン-1-カルボキシレート(280mg、0.31mmol、収率30%)を淡黄色の油状物として得た。

(A) Compound 160937: To a solution of tert-butyl 2-[4-[6-[(2-methylpropan-2-yl)oxycarbonylamino]pyridin-3-yl]phenyl]pyrrolo[2,3-c]-pyridine-1-carboxylate (500 mg, 1.03 mmol) in DMF (10 mL) was added NaH (49 mg, 1.23 mmol) at 0° C. and stirred at RT for 30 min. 2-[2-[2-[2-[2-[2-[2-(4-methylphenyl)sulfonyloxyethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl 4-methylbenzenesulfonate (789 mg, 1.34 mmol) was added to the reaction mixture and stirred at RT for 6 h. The mixture was quenched with saturated NH ₄ Cl solution and extracted with DCM. The organic layer was washed with brine, dried over _MgSO4 , concentrated and purified by column chromatography (EtOAc:DCM=1:4, Rf=0.33) to give tert-butyl 2-[4-[6-[2-[2-[2-[2-[2-[2-[2-(4-methylphenyl)sulfonyloxyethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]pyridin-3-yl]phenyl]pyrrolo[2,3-c]pyridine-1-carboxylate (280 mg, 0.31 mmol, 30% yield) as a pale yellow oil.

(B) Compound 160987: A solution of dimethyl 4-hydroxybenzene-1,2-dicarboxylate (130.05 mg, 0.62 mmol), _Cs2CO3 ( ₃₀₃ mg, 0.93 mmol), and tert-butyl 2-[4-[6-[2-[2-[2-[2-[2-[2-[2-(4-methylphenyl)sulfonyloxyethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]pyridin-3-yl]phenyl]pyrrolo[2,3-c]pyridine-1-carboxylate (280 mg, 0.31 mmol) in DMF (3 mL) was heated at 50° C. for 3 h. The mixture was quenched with water and the resulting precipitate was collected by filtration. The solid was then purified by column chromatography (EtOAc:DCM=4:1, Rf=0.32) to give dimethyl 4-[2-[2-[2-[2-[2-[2-[(2-methylpropan-2-yl)oxycarbonyl-[5-[4-[1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolo[2,3-c]pyridin-2-yl]phenyl]pyridin-2-yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]benzene-1,2-dicarboxylate (98 mg, 0.10 mmol, 34% yield) as a pale yellow oil.

(C) Compound 161004: To a solution of dimethyl 4-[2-[2-[2-[2-[2-[2-[2-[(2-methylpropan-2-yl)oxycarbonyl-[5-[4-[1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolo[2,3-c]pyridin-2-yl]phenyl]pyridin-2-yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]benzene-1,2-dicarboxylate (98 mg, 0.10 mmol) in EtOH (5 mL) was added NaOH (33 mg, 0.83 mmol) in water (5 mL) and stirred at RT for 4 days. The reaction was diluted with DCM (10 mL) and acidified to pH 1 with 1N HCl solution. The organic layer was washed with water (10 mL), brine (10 mL), dried _{over Na2SO4} and concentrated to dryness to give 4-[2-[2-[2-[2-[2-[2-[2-[[5-[4-[1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolo[2,3-c]pyridin-2-yl]phenyl]pyridin-2-yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]phthalic acid (79 mg, 0.10 mmol, 93% yield) as a pale yellow solid.

(D) Compound 161045: A mixture of 4-[2-[2-[2-[2-[2-[2-[2-[[5-[4-[1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolo[2,3-c]pyridin-2-yl]phenyl]pyridin-2-yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]phthalic acid (79 mg, 0.10 mmol) and 3-aminopiperidine-2,6-dione HCl (18 mg, 0.11 mmol) in pyridine (3 mL) was heated at 120° C. for 42 hours. The solvent was removed under reduced pressure. The residue was redissolved in DCM (10 mL), washed with _brine , dried over _Na2SO4 , concentrated and purified by column chromatography (MeOH:DCM=1:19, Rf=0.3) to give tert-butyl 2-[4-[6-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2,6-bis(oxo)piperidin-3-yl]-1,3-bis(oxo)isoindol-5-yl]oxyethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethylamino]pyridin-3-yl]phenyl]pyrrolo[2,3-c]pyridine-1-carboxylate (22 mg, 0.02 mmol, 25% yield) as a yellow solid.

(E) Compound 161104: To a solution of tert-butyl 2-[4-[6-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2,6-bis(oxo)piperidin-3-yl]-1,3-bis(oxo)isoindol-5-yl]oxyethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethylamino]pyridin-3-yl]phenyl]pyrrolo[2,3-c]pyridine-1-carboxylate (22 mg, 0.02 mmol) in DCM (3 mL) was added TFA (0.03 mL, 0.36 mmol) and the mixture was stirred at RT for 42 h. The mixture was neutralized to pH 8 with saturated NaHCO ₃ and extracted with DCM (10 mL). The organic layer was washed with _brine , dried over _Na2SO4 and concentrated to dryness to give 2-[2,6-bis(oxo)piperidin-3-yl]-5-[2-[2-[2-[2-[2-[2-[2-[[5-[4-(1H-pyrrolo[2,3-c]pyridin-2-yl)phenyl]pyridin-2-yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]isoindole-1,3-dione (15 mg, 0.02 mmol, 73% yield) as a yellow solid.

[Example 21]
Synthesis of compound 160624

化合物160557: 3-(6-オキシダニル-3-オキシダニリデン-1H-イソインドール-2-イル)ピペリジン-2,6-ジオン(169mg、0.65mmol)、Cs₂CO₃(317mg、0.97mmol)、tert-ブチルN-[5-[4-[6-(ジメチルアミノ)-1,3-ベンゾチアゾール-2-イル]フェニル]ピリジン-2-イル]-N-[2-(2-ヨーダニルエトキシ)エチル]カルバメート(209mg、0.32mmol)のDMF(5mL)中混合物を50℃で1時間加熱した。混合物を水でクエンチし、DCMで抽出し、MgSO₄で乾燥させ、濃縮し、カラムクロマトグラフィー(溶媒勾配DCM中0%から3% MeOH、Rf=0.2)によって精製して、tert-ブチル(5-(4-(6-(ジメチルアミノ)ベンゾ[d]チアゾール-2-イル)フェニル)ピリジン-2-イル)(2-(2-(3-(5-ヒドロキシ-1-オキソイソインドリン-2-イル)-2,6-ジオキソピペリジン-1-イル)エトキシ)エチル)カルバメート(68mg、0.09mmol、収率27%)を黄色の固体として得た。

Compound 160557: A mixture of 3-(6-oxidanyl-3-oxidanylidene-1H-isoindol-2-yl)piperidine-2,6- _dione (169 mg, 0.65 mmol), _Cs2CO3 (317 mg, 0.97 mmol), tert-butyl N-[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]-N-[2-(2-iodanylethoxy)ethyl]carbamate (209 mg, 0.32 mmol) in DMF (5 mL) was heated at 50° C. for 1 h. The mixture was quenched with water, extracted with DCM, dried over _MgSO4 , concentrated and purified by column chromatography (solvent gradient 0% to 3% MeOH in DCM, Rf=0.2) to give tert-butyl (5-(4-(6-(dimethylamino)benzo[d]thiazol-2-yl)phenyl)pyridin-2-yl)(2-(2-(3-(5-hydroxy-1-oxoisoindolin-2-yl)-2,6-dioxopiperidin-1-yl)ethoxy)ethyl)carbamate (68 mg, 0.09 mmol, 27% yield) as a yellow solid.

Compound 160624: To a solution of tert-butyl (5-(4-(6-(dimethylamino)benzo[d]thiazol-2-yl)phenyl)pyridin-2-yl)(2-(2-(3-(5-hydroxy-1-oxoisoindolin-2-yl)-2,6-dioxopiperidin-1-yl)ethoxy)ethyl)carbamate (68 mg, 0.09 mmol) in DCM (2 mL) was added TFA (1 mL, 13.06 mmol) at 0° C. and stirred at room temperature for 6 h. The solution was neutralized with saturated NaHCO ₃ solution at 0° C. and the solution was extracted with DCM. The organic layer was washed with brine, dried over _MgSO4 and concentrated to dryness to give 1-(2-(2-((5-(4-(6-(dimethylamino)benzo[d]thiazol-2-yl)phenyl)pyridin-2-yl)amino)ethoxy)ethyl)-3-(5-hydroxy-1-oxoisoindolin-2-yl)piperidine-2,6-dione (51 mg, 0.07 mmol, 85% yield) as a yellow solid.

[Example 22]
Synthesis of compound 162641

化合物162586: tert-ブチルN-[2-[4-[6-(ジメチルアミノ)ピリジン-3-イル]フェニル]-1,3-ベンゾチアゾール-6-イル]-N-[2-(2-ヨーダニルエトキシ)エチル]カルバメート(100mg、0.16mmol)のDMF(5mL)中溶液に、3-(7-アザニル-3-オキシダニリデン-1H-イソインドール-2-イル)ピペリジン-2,6-ジオン(48mg、0.19mmol)及びK₂CO₃(101mg、0.31mmol)を添加し、80℃で3時間加熱した。混合物をDCMで希釈し、水及びブラインで洗浄し、Na₂SO₄で乾燥させ、濃縮し、カラムクロマトグラフィー(MeOH:DCM=1:20、Rf=0.3)によって精製して、tert-ブチルN-[2-[2-[3-(7-アザニル-3-オキシダニリデン-1H-イソインドール-2-イル)-2,6-ビス(オキシダニリデン)ピペリジン-1-イル]エトキシ]エチル]-N-[2-[4-[6-(ジメチルアミノ)ピリジン-3-イル]フェニル]-1,3-ベンゾチアゾール-6-イル]カルバメート(70mg、0.09mmol、収率58%)を黄色の固体として得た。

Compound 162586: To a solution of tert-butyl N-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]-N-[2-(2-iodanylethoxy)ethyl]carbamate (100 mg, 0.16 mmol) in DMF (5 mL) was added 3-(7-azanyl-3-oxidanylidene-1H-isoindol-2-yl)piperidine-2,6 _- dione (48 mg, 0.19 mmol) and _K2CO3 (101 mg, 0.31 mmol) and heated at 80° C. for 3 h. The mixture was diluted with DCM, washed with water and _brine , dried over _Na2SO4 , concentrated and purified by column chromatography (MeOH:DCM=1:20, Rf=0.3) to give tert-butyl N-[2-[2-[3-(7-azanyl-3-oxidanylidene-1H-isoindol-2-yl)-2,6-bis(oxidanylidene)piperidin-1-yl]ethoxy]ethyl]-N-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]carbamate (70 mg, 0.09 mmol, 58% yield) as a yellow solid.

Compound 162641: tert-Butyl N-[2-[2-[3-(7-azanyl-3-oxidanylidene-1H-isoindol-2-yl)-2,6-bis(oxidanylidene)piperidin-1-yl]ethoxy]ethyl]-N-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]carbamate (70 mg, 0.09 mmol) in DCM (2 mL) was added with TFA (0.1 mL, 1.35 mmol) and stirred at room temperature for 20 hours. The mixture was neutralized to pH 8 with saturated NaHCO ₃ solution. The residue was dissolved in DCM (20 mL) and water (10 mL). The organic layer was washed with water (10 mL) and brine (10 mL), dried _{over Na2SO4} and concentrated to give 3-(7-azanyl-3-oxidanylidene-1H-isoindol-2-yl)-1-[2-[2-[[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]amino]ethoxy]ethyl]piperidine-2,6-dione (30 mg, 0.04 mmol, 46% yield) as a yellow solid.

[Example 23]
Synthesis of compound 161598

化合物161444: tert-ブチルN-[5-[4-[6-(ジメチルアミノ)-1,3-ベンゾチアゾール-2-イル]フェニル]ピリジン-2-イル]カルバメート(200mg、0.45mmol)のDMF(5mL)中溶液に0℃でNaH(43mg、1.79mmol)を添加し、室温で1時間撹拌した。混合物に2-[2-[2-[2-[2-[tert-ブチル(ジメチル)シリル]オキシエトキシ]エトキシ]エトキシ]エトキシ]エチル4-メチルベンゼンスルホネート(681mg、1.34mmol)を添加し、同じ温度で24時間撹拌した。水を添加することによって反応物をクエンチした。得られた固体を濾過によって収集し、カラムクロマトグラフィー(EtOAc:DCM=7:3、Rf=0.4)によって精製して、tert-ブチルN-[2-[2-[2-[2-[2-[tert-ブチル(ジメチル)シリル]オキシエトキシ]エトキシ]エトキシ]エトキシ]エチル]-N-[5-[4-[6-(ジメチルアミノ)-1,3-ベンゾチアゾール-2-イル]フェニル]ピリジン-2-イル]カルバメート(252mg、0.32mmol、収率72%)を黄色の油状物として得た。

Compound 161444: To a solution of tert-butyl N-[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]carbamate (200 mg, 0.45 mmol) in DMF (5 mL) was added NaH (43 mg, 1.79 mmol) at 0° C. and stirred at room temperature for 1 h. To the mixture was added 2-[2-[2-[2-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]ethoxy]ethoxy]ethoxy]ethyl 4-methylbenzenesulfonate (681 mg, 1.34 mmol) and stirred at the same temperature for 24 h. The reaction was quenched by adding water. The resulting solid was collected by filtration and purified by column chromatography (EtOAc:DCM=7:3, Rf=0.4) to afford tert-butyl N-[2-[2-[2-[2-[2-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]ethoxy]ethoxy]ethyl]-N-[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]carbamate (252 mg, 0.32 mmol, 72% yield) as a yellow oil.

Compound 161467: To a solution of tert-butyl N-[2-[2-[2-[2-[2-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]ethoxy]ethoxy]ethoxy]ethyl]-N-[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]carbamate (252 mg, 0.32 mmol) in THF (5 mL), TBAF (1 M in THF, 1.94 mL, 1.94 mmol) was added dropwise and stirred at room _temperature for 19 hours. The reaction mixture was concentrated to dryness and the residue was dissolved in EtOAc (50 mL). The mixture was washed with water (50 mL) and brine (50 mL) and dried over _Na2SO4 . Concentration to dryness afforded tert-butyl N-[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]-N-[2-[2-[2-[2-(2-hydroxyethyloxy)ethoxy]ethoxy]ethoxy]ethyl]carbamate (214 mg, 0.32 mmol, 99% yield) as a yellow oil.

Compound 161530: To a mixture of tert-butyl N-[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]-N-[2-[2-[2-[2-(2-hydroxyethyloxy)ethoxy]ethoxy]ethoxy]ethyl]carbamate (214 mg, 0.32 mmol) and tert-butyl 2-bromanyl ethanoate (0.14 mL, 0.96 mmol) in THF (3 mL) was added NaH (19 mg, 0.80 mmol) at 0° C. and stirred at room temperature for 42 hours. The reaction was quenched by adding water. The mixture was diluted with _DCM (50 mL), washed with water (50 mL) and brine (50 mL), dried over _Na2SO4 , concentrated to dryness and purified by column chromatography (EtOAc:Hex=1:1, Rf=0.35) to give tert-butyl 2-[2-[2-[2-[2-[2-[[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanoate (130 mg, 0.17 mmol, 52% yield) as a yellow oil.

Compound 161586: To a solution of tert-butyl 2-[2-[2-[2-[2-[2-[2-[[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanoate (130 mg, 0.17 mmol) in DCM (2 mL) was added TFA (0.38 mL, 4.99 mmol) and stirred at room temperature for 22 hours. The mixture was concentrated to dryness to give the TFA salt of 2-[2-[2-[2-[2-[2-[[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanoic acid (179 mg, 0.29 mmol, >99% yield) as an orange oil.

Compound 161598: A mixture of (2S,4R)-1-[(2S)-2-azanyl-3,3-dimethyl-butanoyl]-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]-4-oxidanyl-pyrrolidine-2-carboxamide (79 mg, 0.18 mmol), 2-[2-[2-[2-[2-[2-[[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]amino]ethoxy ... The mixture was dissolved in DCM, washed with water and _brine , dried over anhydrous _Na2SO4 , concentrated and purified by column chromatography (MeOH:DCM=3:100, Rf=0.32) to give rac-(2R,4S)-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]-4-oxidanyl-1-[rac-(2R)-2-[2-[2-[2-[2-[2-[2-[[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanoylamino]-3,3-dimethyl-butanoyl]pyrrolidine-2-carboxamide (16 mg, 0.01 mmol, 8% yield) as a yellow solid.

[Example 24]
Synthesis of compound 160570

化合物160491: 2-[4-[6-(ジメチルアミノ)-2-フルオラニル-ピリジン-3-イル]フェニル]イミダゾ[1,2-a]ピリジン-6-オール(0.43g、1.24mmol)の乾燥DMF(4mL)中溶液にNaH(0.10g、2.48mmol)を0℃で添加し、室温で1時間撹拌した。乾燥DMF(4mL)中の2-[2-(4-メチルフェニル)スルホニルオキシエトキシ]エチル4-メチルベンゼンスルホネート(1.54g、3.72mmol)を反応混合物に添加し、同一の温度で14時間撹拌した。混合物を0℃に冷却し、水(30mL)でクエンチし、DCM(30mL)で抽出し、これを添加した。有機層を水(30mL)及びブライン(30mL)で洗浄し、無水Na₂SO₄で乾燥させ、濃縮し、カラムクロマトグラフィー(EtOAc:DCM=1:5、Rf=0.33)によって精製して、2-[2-[2-[4-[6-(ジメチルアミノ)-2-フルオラニル-ピリジン-3-イル]フェニル]イミダゾ[1,2-a]ピリジン-6-イル]オキシエトキシ]エチル4-メチルベンゼンスルホネート(234mg、0.40mmol、収率32%)を橙色の固体として得た。

Compound 160491: To a solution of 2-[4-[6-(dimethylamino)-2-fluoranyl-pyridin-3-yl]phenyl]imidazo[1,2-a]pyridin-6-ol (0.43 g, 1.24 mmol) in dry DMF (4 mL) was added NaH (0.10 g, 2.48 mmol) at 0° C. and stirred at room temperature for 1 h. 2-[2-(4-methylphenyl)sulfonyloxyethoxy]ethyl 4-methylbenzenesulfonate (1.54 g, 3.72 mmol) in dry DMF (4 mL) was added to the reaction mixture and stirred at the same temperature for 14 h. The mixture was cooled to 0° C., quenched with water (30 mL), extracted with DCM (30 mL), which was added. The organic layer was washed with water (30 mL) and brine (30 mL), dried over _{anhydrous Na2SO4} , concentrated and purified by column chromatography (EtOAc:DCM=1:5, Rf=0.33) to give 2-[2-[2-[4-[6-(dimethylamino)-2-fluoranyl-pyridin-3-yl]phenyl]imidazo[1,2-a]pyridin-6-yl]oxyethoxy]ethyl 4-methylbenzenesulfonate (234 mg, 0.40 mmol, 32% yield) as an orange solid.

Compound 160508: A mixture of 2-[2-[[2-[4-[6-(dimethylamino)-2-fluoranyl-pyridin-3-yl]phenyl]-3,8a-dihydroimidazo[1,2-a]pyridin-6-yl]oxy]ethoxy]ethyl 4-methylbenzenesulfonate (232 mg, 0.39 mmol) and NaI (70 mg, 0.47 mmol) in ACN (2 mL) was heated at 80° C. for 14 h. Water was added to the mixture and it was extracted with DCM. The organic layer was washed with water (20 mL) and _brine (20 mL), dried over _Na2SO4 , concentrated, and purified by chromatography (EtOAc:DCM=1:10, Rf=0.20) to give 6-fluoranyl-5-[4-[6-[2-(2-iodanylethoxy)ethoxy]-3,8a-dihydroimidazo[1,2-a]pyridin-2-yl]phenyl]-N,N-dimethyl-pyridin-2-amine (204 mg, 0.37 mmol, 95% yield) as a pale yellow solid.

Compound 160570: A mixture of 2-[2,6-bis(oxidanylidene)piperidin-3-yl]-5-oxidanyl-isoindole-1,3-dione (101 mg, 0.37 mmol), _Cs2CO3 ( ₁₈₀ mg, 0.55 mmol) and 6-fluoranyl-5-[4-[6-[2-(2-iodanylethoxy)ethoxy]-3,8a-dihydroimidazo[1,2-a]pyridin-2-yl]phenyl]-N,N-dimethyl-pyridin-2-amine (101 mg, 0.18 mmol) in DMF (3 mL) was heated at 50° C. for 4 h and then stirred at room temperature for 3 days. The mixture was triturated with water and the resulting precipitate was collected and purified by column chromatography (EtOAc:DCM=1:4, Rf=0.05) to give 2-[1-[2-[2-[2-[4-[6-(dimethylamino)-2-fluoranyl-pyridin-3-yl]phenyl]imidazo[1,2-a]pyridin-6-yl]oxyethoxy]ethyl]-2,6-bis(oxidanylidene)piperidin-3-yl]-5-oxidanyl-isoindole-1,3-dione (15 mg, 0.02 mmol, 11% yield) as a brown solid.

[Example 25]
Synthesis of compound 160703

化合物160686: 2-[2,6-ビス(オキシダニリデン)ピペリジン-3-イル]-5-オキシダニル-イソインドール-1,3-ジオン(68mg、0.25mmol)、Cs₂CO₃(121mg、0.37mmol)及びtert-ブチルN-[5-[4-[6-(ジメチルアミノ)-1,3-ベンゾチアゾール-2-イル]フェニル]ピリジン-2-イル]-N-[2-(2-ヨーダニルエトキシ)エチル]カルバメート(80mg、0.12mmol)のDMF(5mL)中混合物を50℃で3時間加熱した。混合物をDCMで希釈し、水で抽出し、MgSO₄で脱水し、濃縮し、NHシリカゲルでのカラムクロマトグラフィー(MeOH:DCM=1:20、Rf=0.2)によって精製して、tert-ブチルN-[2-[2-[2-[2,6-ビス(オキシダニリデン)ピペリジン-3-イル]-1,3-ビス(オキシダニリデン)イソインドール-5-イル]オキシエトキシ]エチル]-N-[5-[4-[6-(ジメチルアミノ)-1,3-ベンゾチアゾール-2-イル]フェニル]ピリジン-2-イル]カルバメート(25mg、0.03mmol、収率25%)を黄色の固体として得た。

Compound 160686: A mixture of 2-[2,6-bis(oxidanylidene)piperidin-3-yl]-5-oxidanyl-isoindole-1,3-dione (68 mg, 0.25 mmol), _Cs2CO3 ( ₁₂₁ mg, 0.37 mmol) and tert-butyl N-[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]-N-[2-(2-iodanylethoxy)ethyl]carbamate (80 mg, 0.12 mmol) in DMF (5 mL) was heated at 50° C. for 3 h. The mixture was diluted with DCM, extracted with water, dried over _MgSO4 , concentrated, and purified by column chromatography on NH silica gel (MeOH:DCM=1:20, Rf=0.2) to give tert-butyl N-[2-[2-[2-[2,6-bis(oxidanylidene)piperidin-3-yl]-1,3-bis(oxidanylidene)isoindol-5-yl]oxyethoxy]ethyl]-N-[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]carbamate (25 mg, 0.03 mmol, 25% yield) as a yellow solid.

Compound 160703: To a solution of tert-butyl N-[2-[2-[2-[2,6-bis(oxidanylidene)piperidin-3-yl]-1,3-bis(oxidanylidene)isoindol-5-yl]oxyethoxy]ethyl]-N-[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]carbamate (42 mg, 0.05 mmol) in DCM (5 mL), TFA (0.04 mL, 0.53 mmol) was added at 0° C. and stirred at room temperature for 23 hours. The mixture was neutralized to pH 8 with saturated NaHCO ₃ solution and extracted with DCM. The organic layer was dried _{over Na2SO4} and concentrated to dryness to give 2-[1-[2-[2-[[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]amino]ethoxy]ethyl]-2,6-bis(oxidanylidene)piperidin-3-yl]-5-oxidanyl-isoindole-1,3-dione (34 mg, 0.05 mmol, 88% yield) as a yellow solid.

[Example 26]
Synthesis of compound 161262

化合物161176: tert-ブチル2-[4-[6-[(2-メチルプロパン-2-イル)オキシカルボニルアミノ]ピリジン-3-イル]フェニル]ピロロ[2,3-c]ピリジン-1-カルボキシレート(250mg、0.51mmol)のDMF(5mL)中溶液を0℃に冷却し、NaH(37mg、0.92mmol)を添加し、同一の温度で30分間撹拌した。ジメチル4-[2-[2-(4-メチルフェニル)スルホニルオキシエトキシ]エトキシ]ベンゼン-1,2-ジカルボキシレート(302mg、0.67mmol)を反応混合物に添加し、室温で20時間撹拌し、50℃に20時間加熱した。混合物を水でクエンチし、DCMで抽出した。有機層をブラインで洗浄し、MgSO₄で脱水し、濃縮し、シリカゲルでのカラムクロマトグラフィー(EtOAc:DCM=1:2.3、Rf=0.375)によって精製して、ジメチル4-[2-[2-[(2-メチルプロパン-2-イル)オキシカルボニル-[5-[4-[1-[(2-メチルプロパン-2-イル)オキシカルボニル]ピロロ[2,3-c]ピリジン-2-イル]フェニル]ピリジン-2-イル]アミノ]エトキシ]エトキシ]ベンゼン-1,2-ジカルボキシレート(183mg、0.24mmol、収率46%)を黄色の油状物として得た。

Compound 161176: A solution of tert-butyl 2-[4-[6-[(2-methylpropan-2-yl)oxycarbonylamino]pyridin-3-yl]phenyl]pyrrolo[2,3-c]pyridine-1-carboxylate (250 mg, 0.51 mmol) in DMF (5 mL) was cooled to 0° C., NaH (37 mg, 0.92 mmol) was added, and stirred at the same temperature for 30 min. Dimethyl 4-[2-[2-(4-methylphenyl)sulfonyloxyethoxy]ethoxy]benzene-1,2-dicarboxylate (302 mg, 0.67 mmol) was added to the reaction mixture, stirred at room temperature for 20 h, and heated to 50° C. for 20 h. The mixture was quenched with water and extracted with DCM. The organic layer was washed with brine, dried over _MgSO4 , concentrated and purified by column chromatography on silica gel (EtOAc:DCM=1:2.3, Rf=0.375) to give dimethyl 4-[2-[2-[(2-methylpropan-2-yl)oxycarbonyl-[5-[4-[1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolo[2,3-c]pyridin-2-yl]phenyl]pyridin-2-yl]amino]ethoxy]ethoxy]benzene-1,2-dicarboxylate (183 mg, 0.24 mmol, 46% yield) as a yellow oil.

Compound 161217: To a solution of dimethyl 4-[2-[2-[(2-methylpropan-2-yl)oxycarbonyl-[5-[4-[1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolo[2,3-c]pyridin-2-yl]phenyl]pyridin-2-yl]amino]ethoxy]ethoxy]benzene-1,2-dicarboxylate (273 mg, 0.36 mmol) in EtOH (3 mL), NaOH (228 mg, 5.70 mmol) in water (3 mL) was added and stirred at room temperature for 4 days. The reaction was neutralized to pH 1 with 1N HCl solution. The resulting precipitate was collected, washed with water (10 mL), and dried under reduced pressure to give 4-[2-[2-[[5-[4-[1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolo[2,3-c]pyridin-2-yl]phenyl]pyridin-2-yl]amino]ethoxy]ethoxy]phthalic acid (201 mg, 0.31 mmol, 88% yield) as a white solid.

Compound 161230: A mixture of 4-[2-[2-[[5-[4-[1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolo[2,3-c]pyridin-2-yl]phenyl]pyridin-2-yl]amino]ethoxy]ethoxy]phthalic acid (201 mg, 0.31 mmol) and 3-azanylpiperidine-2,6-dione hydrochloride (78 mg, 0.47 mmol) in pyridine (3 mL) was heated at 120 °C for 19 h. The solvent was removed under reduced pressure and the resulting residue was triturated with water. The precipitate was collected and purified by column chromatography on NH silica gel (MeOH:DCM=3:100, Rf=0.25) to give tert-butyl 2-[4-[6-[2-[2-[2-[2,6-bis(oxydanylidene)piperidin-3-yl]-1,3-bis(oxydanylidene)isoindol-5-yl]oxyethoxy]ethylamino]pyridin-3-yl]phenyl]pyrrolo[2,3-c]pyridine-1-carboxylate (47 mg, 0.06 mmol, 20% yield) as a yellow solid.

Compound 161262: tert-Butyl 2-[4-[6-[2-[2-[2-[2,6-bis(oxydanylidene)piperidin-3-yl]-1,3-bis(oxydanylidene)isoindol-5-yl]oxyethoxy]ethylamino]pyridin-3-yl]phenyl]pyrrolo[2,3-c]pyridine-1-carboxylate (47 mg, 0.06 mmol) in DCM (3 mL) was added with TFA (0.07 mL, 0.96 mmol) and stirred at room temperature for 23 hours. The mixture was neutralized to pH 8 with saturated NaHCO ₃ solution. The resulting precipitate was collected, washed with water, and dried under reduced pressure to give 2-[2,6-bis(oxidanylidene)piperidin-3-yl]-5-[2-[2-[[5-[4-(1H-pyrrolo[2,3-c]pyridin-2-yl)phenyl]pyridin-2-yl]amino]ethoxy]ethoxy]isoindole-1,3-dione (36 mg, 0.05 mmol, 82% yield) as a yellow solid.

[Example 27]
Synthesis of compound 164625

化合物164581: tert-ブチル3-[2-(2-ヨーダニルエトキシ)エトキシ]プロパノエート(500mg、1.45mmol)、K₂CO₃(602mg、4.36mmol)及びメチル5-アザニル-5-オキシダニリデン-4-(6-オキシダニル-3-オキシダニリデン-1H-イソインドール-2-イル)ペンタノエート(467mg、1.60mmol)のDMF(15mL)中混合物を80℃で7時間加熱した。混合物をEtOAcで希釈し、ブラインで抽出し、MgSO₄で脱水し、濃縮し、カラムクロマトグラフィー(MeOH:DCM=1:20、Rf=0.48)によって精製して、tert-ブチル3-[2-[2-[[2-[2,6-ビス(オキシダニリデン)ピペリジン-3-イル]-1-オキシダニリデン-3H-イソインドール-5-イル]オキシ]エトキシ]エトキシ]プロパノエート(387mg、0.81mmol、収率56%)を白色の固体として得た。

Compound 164581: A mixture of tert-butyl 3-[2-(2-iodanylethoxy)ethoxy]propanoate (500 mg, 1.45 _mmol ), _K2CO3 (602 mg, 4.36 mmol) and methyl 5-azanyl-5-oxidanylidene-4-(6-oxidanyl-3-oxidanylidene-1H-isoindol-2-yl)pentanoate (467 mg, 1.60 mmol) in DMF (15 mL) was heated at 80° C. for 7 h. The mixture was diluted with EtOAc, extracted with brine, dried over _MgSO4 , concentrated and purified by column chromatography (MeOH:DCM=1:20, Rf=0.48) to give tert-butyl 3-[2-[2-[[2-[2,6-bis(oxidanylidene)piperidin-3-yl]-1-oxidanylidene-3H-isoindol-5-yl]oxy]ethoxy]ethoxy]propanoate (387 mg, 0.81 mmol, 56% yield) as a white solid.

Compound 164617: To a solution of tert-butyl 3-[2-[2-[[2-[2,6-bis(oxidanylidene)piperidin-3-yl]-1-oxidanylidene-3H-isoindol-5-yl]oxy]ethoxy]ethoxy]propanoate (387 mg, 0.81 mmol) in DCM (10 mL), TFA (0.62 mL, 8.12 mmol) was added and stirred at room temperature for 15 h. The mixture was concentrated to dryness to give the TFA salt of 3-[2-[2-[[2-[2,6-bis(oxidanylidene)piperidin-3-yl]-1-oxidanylidene-3H-isoindol-5-yl]oxy]ethoxy]ethoxy]propanoic acid (494 mg, 1.18 mmol) as a white oil.

Compound 164625: A mixture of 3-[2-[2-[[2-[2,6-bis(oxidanylidene)piperidin-3-yl]-1-oxidanylidene-3H-isoindol-5-yl]oxy]ethoxy]ethoxy]propanoic acid (346 mg, 0.82 mmol), TBTU (352 mg, 1.10 mmol) and 2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-amine (190 mg, 0.55 mmol) in pyridine (3 mL) was stirred at room temperature for 17 hours. Water was added to the mixture, and the resulting precipitate was collected by filtration and purified by column chromatography (MeOH:DCM=1:19, Rf=0.3) to give 3-[2-[2-[[2-[2,6-bis(oxydanylidene)piperidin-3-yl]-1-oxydanylidene-3H-isoindol-5-yl]oxy]ethoxy]ethoxy]-N-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]propanamide (285 mg, 0.36 mmol, 66% yield) as a yellow solid.

[Example 28]
Synthesis of compound 164657

化合物164263: tert-ブチルN-(2-ブロマニル-1,3-ベンゾチアゾール-6-イル)カルバメート(1100mg、3.34mmol)、N,N-ジメチル-5-[4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)-3-(トリフルオロメチル)フェニル]ピリジン-2-アミン(1704mg、4.34mmol)、Pd(dppf)Cl₂(247mg、0.33mmol)及び2M Na₂CO₃(水)溶液(5mL、10.02mmol)のジオキサン(35mL)中混合物を80℃で16時間、アルゴン下で加熱した。混合物はセライトパッドを通して濾過し、残渣をEtOAc(100mL)及び水(50mL)に溶解した。有機層を水(50mL)、ブライン(50mL)で洗浄し、Na₂SO₄で脱水し、濃縮乾固させた。残渣をカラムクロマトグラフィー(EtOAc:Hex=1:4、Rf=0.15)によって精製して、tert-ブチルN-[2-[4-[6-(ジメチルアミノ)ピリジン-3-イル]-2-(トリフルオロメチル)フェニル]-1,3-ベンゾチアゾール-6-イル]カルバメート(1.06g、2.05mmol、収率61%)を黄色の油状物として得た。

Compound 164263: A mixture of tert-butyl N-(2-bromanyl-1,3-benzothiazol-6-yl)carbamate (1100 mg, 3.34 mmol), N,N-dimethyl-5-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)phenyl]pyridin-2-amine (1704 mg, 4.34 mmol), Pd(dppf) _Cl2 ( ₂₄₇ mg, 0.33 mmol) and 2M _Na2CO3 (aq) solution (5 mL, 10.02 mmol) in dioxane (35 mL) was heated at 80° C. for 16 h under argon. The mixture was filtered through a Celite pad and the residue was dissolved in EtOAc (100 mL) and water (50 mL). The organic layer was washed with water (50 mL), brine (50 mL), dried over _Na2SO4 , and concentrated to dryness. The residue was purified by column chromatography (EtOAc:Hex=1: ₄ , Rf=0.15) to give tert-butyl N-[2-[4-[6-(dimethylamino)pyridin-3-yl]-2-(trifluoromethyl)phenyl]-1,3-benzothiazol-6-yl]carbamate (1.06 g, 2.05 mmol, 61% yield) as a yellow oil.

Compound 164346: To a solution of tert-butyl N-[2-[4-[6-(dimethylamino)pyridin-3-yl]-2-(trifluoromethyl)phenyl]-1,3-benzothiazol-6-yl]carbamate (1056 mg, 2.05 mmol) in DMF (20 mL) was added NaH (148 mg, 6.16 mmol) at 0° C. and stirred at 25° C. for 1 h. 2-[2-(4-methylphenyl)sulfonyloxyethoxy]ethyl 4-methylbenzenesulfonate (2.55 g, 6.16 mmol) in DMF (20 mL) was added to the reaction mixture and stirred at room temperature for 14 h. The mixture was quenched with water at 0° C. The residue was dissolved in EtOAc (50 mL) and water (50 mL). The organic layer was washed with water (50 mL), brine (50 mL), dried over Na ₂ SO ₄ , and concentrated to dryness. The residue was purified by column chromatography (EtOAc:Hex=1:1, Rf=0.4) to give 2-[2-[[2-[4-[6-(dimethylamino)pyridin-3-yl]-2-(trifluoromethyl)phenyl]-1,3-benzothiazol-6-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethyl 4-methylbenzenesulfonate (955 mg, 1.26 mmol, 61% yield) as a yellow oil.

Compound 164398: A mixture of 2-[2-[[2-[4-[6-(dimethylamino)pyridin-3-yl]-2-(trifluoromethyl)phenyl]-1,3-benzothiazol-6-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethyl 4-methylbenzenesulfonate (955 mg, 1.26 mmol), NaI (378 mg, 2.52 mmol) in MeCN (20 mL) was heated at 80° C. for 17 h. The residue was dissolved in EtOAc (50 mL) and water (50 mL). The organic layer was washed with water (50 mL), brine (50 mL), dried over Na ₂ SO ₄ , and concentrated. The residue was purified by column chromatography (EtOAc:Hex=1:1, Rf=0.7) to give tert-butyl N-[2-[4-[6-(dimethylamino)pyridin-3-yl]-2-(trifluoromethyl)phenyl]-1,3-benzothiazol-6-yl]-N-[2-(2-iodanylethoxy)ethyl]carbamate (805 mg, 1.13 mmol, 90% yield) as a yellow oil.

Compound 164350: A mixture of tert-butyl N-[2-[4-[6-(dimethylamino)pyridin-3-yl]-2-(trifluoromethyl)phenyl]-1,3-benzothiazol-6-yl]-N-[2-(2-iodanylethoxy)ethyl]carbamate (110 mg, 0.15 mmol), _K2CO3 ( ₆₄ mg, 0.46 mmol) and methyl 5-azanyl-5-oxidanylidene-4-(6-oxidanylidene-3-oxidanylidene-1H-isoindol-2-yl)pentanoate (50 mg, 0.17 mmol) in DMF (2.5 mL) was heated at 80° C. for 8 h. The mixture was added with water, extracted with DCM, dried over _MgSO4 and concentrated to dryness. The residue was purified by column chromatography (MeOH:DCM=1:20, Rf=0.4) to give tert-butyl N-[2-[2-[[2-[2,6-bis(oxidanylidene)piperidin-3-yl]-1-oxidanylidene-3H-isoindol-5-yl]oxy]ethoxy]ethyl]-N-[2-[4-[6-(dimethylamino)pyridin-3-yl]-2-(trifluoromethyl)phenyl]-1,3-benzothiazol-6-yl]carbamate (110 mg, 0.13 mmol, 84% yield) as a yellow solid.

Compound 164657: To a solution of tert-butyl N-[2-[2-[[2-[2,6-bis(oxydanylidene)piperidin-3-yl]-1-oxydanylidene-3H-isoindol-5-yl]oxy]ethoxy]ethyl]-N-[2-[4-[6-(dimethylamino)pyridin-3-yl]-2-(trifluoromethyl)phenyl]-1,3-benzothiazol-6-yl]carbamate (550 mg, 0.65 mmol) in DCM (10 mL), TFA (0.75 mL, 9.76 mmol) was added at 25° C. and stirred for 15 hours. The mixture was poured into ice water and neutralized to pH 8 with saturated NaHCO ₃ solution. The residue was dissolved in DCM (20 mL) and water (10 mL). The organic layer was washed with water (10 mL), brine ( ₁₀ mL), dried over _Na2SO4 , and concentrated to dryness. The residue was purified by column chromatography (DCM:MeOH=10:1, Rf=0.58) to give 3-[6-[2-[2-[[2-[4-[6-(dimethylamino)pyridin-3-yl]-2-(trifluoromethyl)phenyl]-1,3-benzothiazol-6-yl]amino]ethoxy]ethoxy]-3-oxidanylidene-1H-isoindol-2-yl]piperidine-2,6-dione (254 mg, 0.34 mmol, 52% yield) as a yellow solid.

[Example 29]
Synthesis of compound 162640

化合物162534: tert-ブチルN-[4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)ピリジン-2-イル]カルバメート(1.52g、4.75mmol)、2-(4-ブロモフェニル)-6-メトキシ-イミダゾ[1,2-a]ピリジン(1.2g、3.96mmol)、及びトリフェニルホスフィン(34.6mg、0.13mmol)のEtOH(4mL)及びトルエン(2.8mL)中溶液をアルゴンでパージし、次いでK₂CO₃溶液(1.75M、7.92mL、13.85mmol)を滴加した。混合物にPd(OAc)₂(87mg、0.40mmol)をアルゴン下で添加し、90℃で4時間加熱した。混合物を、セライトパッドを通して濾過し、飽和NaHCO₃溶液に注ぎ入れ、EtOAcで抽出した。有機層をMgSO₄で脱水し、濃縮し、カラムクロマトグラフィー(EtOAc:DCM=1:4、Rf=0.3)によって精製して、tert-ブチルN-[4-[4-(6-メトキシイミダゾ[1,2-a]ピリジン-2-イル)フェニル]ピリジン-2-イル]カルバメート(987mg、2.37mmol、収率60%)を淡褐色の固体として得た。

Compound 162534: A solution of tert-butyl N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]carbamate (1.52 g, 4.75 mmol), 2-(4-bromophenyl)-6-methoxy-imidazo[1,2-a]pyridine (1.2 g, 3.96 mmol), and triphenylphosphine (34.6 mg, 0.13 mmol) in EtOH (4 mL) and toluene (2.8 mL) was purged with argon, and then _K2CO3 solution (1.75 M, 7.92 mL, 13.85 mmol) was added dropwise. Pd(OAc) ₂ (87 mg, 0.40 mmol) was added to the mixture under argon and heated at 90°C _for 4 hours. The mixture was filtered through a Celite pad, poured into saturated _NaHCO3 solution, and extracted with EtOAc. The organic layer was dried over _MgSO4 , concentrated, and purified by column chromatography (EtOAc:DCM=1:4, Rf=0.3) to give tert-butyl N-[4-[4-(6-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl]pyridin-2-yl]carbamate (987 mg, 2.37 mmol, 60% yield) as a light brown solid.

Compound 162547: To a solution of 2-[2-(4-methylphenyl)sulfonyloxyethoxy]ethyl 4-methylbenzenesulfonate (2.86 g, 6.90 mmol) in DMF (10 mL) was added NaH (368 mg, 9.20 mmol) at 0° C. and stirred at room temperature for 1 h. To the mixture was added 2-[2-(4-methylphenyl)sulfonyloxyethoxy]ethyl 4-methylbenzenesulfonate (2.86 g, 6.90 mmol) in DMF (10 mL) and stirred at room temperature for 19 h. The mixture was cooled to 0° C. and quenched by adding water and diluted with DCM. The resulting mixture was washed with water and _brine , dried over _Na2SO4 , concentrated and purified by column chromatography (EtOAc:DCM=4:1, Rf=0.4) to give 2-[2-[[4-[4-(6-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl]pyridin-2-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethyl 4-methylbenzenesulfonate (924 mg, 1.40 mmol, 61% yield) as an orange oil.

Compound ₁₆₂₅₆₈ : A mixture of 2-[2-[[4-[4-(6-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl]pyridin-2-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethyl 4-methylbenzenesulfonate (924 mg, 1.40 mmol) and NaI (421 mg, 2.81 mmol) in CH3CN (20 mL) was heated at 80°C for 17 h. The mixture was diluted with _{DCM, washed with water (50 mL) and brine (50 mL), dried over Na2SO4 ,} concentrated and purified by column chromatography (MeOH:DCM=1:100, Rf=0.19) to give tert-butyl N-[2-(2-iodanylethoxy)ethyl]-N-[4-[4-(6-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl]pyridin-2-yl]carbamate (585 mg, 0.95 mmol, 68% yield) as an orange solid.

Compound 162599: A solution of tert-butyl N-[2-(2-iodanylethoxy)ethyl]-N-[4-[4-(6-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl]pyridin-2-yl]carbamate (250 mg, 0.41 mmol), 3-(6-oxidanyl-3-oxidanylidene-1H-isoindol-2-yl)piperidine-2,6-dione (212 mg, 0.81 mmol) and _K2CO3 ( ₁₆₉ mg, 1.22 mmol) in DMF (4 mL) was heated at 50° C. for 3 h. The mixture was quenched with water and the resulting solid was collected by filtration. The solid was washed with water, and the residue was purified by NH gel column chromatography (MeOH:DCM=3:100, Rf=0.33) to give tert-butyl N-[2-[2-[[2-[2,6-bis(oxydanylidene)piperidin-3-yl]-1-oxydanylidene-3H-isoindol-5-yl]oxy]ethoxy]ethyl]-N-[4-[4-(6-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl]pyridin-2-yl]carbamate (76 mg, 0.10 mmol, 25% yield) as a white solid.

Compound 162640: tert-Butyl N-[2-[2-[[2-[2,6-bis(oxydanylidene)piperidin-3-yl]-1-oxydanylidene-3H-isoindol-5-yl]oxy]ethoxy]ethyl]-N-[4-[4-(6-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl]pyridin-2-yl]carbamate (76 mg, 0.10 mmol) in DCM (2 mL) was added with TFA (0.12 mL, 1.53 mmol) and stirred for 38 hours. The mixture was poured into ice water and neutralized to pH 8 with saturated NaHCO ₃ solution. The residue was dissolved in DCM (20 mL) and water (10 mL). The organic layer was washed with water (10 mL), brine ( ₁₀ mL), dried over _Na2SO4 , concentrated and purified by column chromatography (DCM:MeOH=100:3, Rf=0.35) to give 3-[6-[2-[2-[[4-[4-(6-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl]pyridin-2-yl]amino]ethoxy]ethoxy]-3-oxidanylidene-1H-isoindol-2-yl]piperidine-2,6-dione (22 mg, 0.03 mmol, 33% yield) as a light brown solid.

[Example 30]
Synthesis of compound 162843

化合物162723: 2-[2-(4-メチルフェニル)スルホニルオキシエトキシ]エチル4-メチルベンゼンスルホネート(4.72g、11.38mmol)のDMF(30mL)中溶液に、NaH(455mg、11.38mmol)を0℃で添加し、室温で1時間撹拌した。DMF(30mL)中の2-[2-(4-メチルフェニル)スルホニルオキシエトキシ]エチル4-メチルベンゼンスルホネート(4.72g、11.38mmol)を反応混合物に添加し、室温でさらに16時間撹拌した。混合物を0℃に冷却し、水でクエンチした。混合物をDCMで希釈し、水及びブラインで洗浄し、Na₂SO₄で脱水し、濃縮し、カラムクロマトグラフィー(EtOAc:Hex=1:1、Rf=0.23)によって精製して、2-[2-[[5-[4-(6-メトキシイミダゾ[1,2-a]ピリジン-2-イル)フェニル]ピリジン-2-イル]-[(2-メチルプロパン-2-イル)オキシカルボニル]アミノ]エトキシ]エチル4-メチルベンゼンスルホネート(1.3g、1.97mmol、収率69%)を橙色の固体として得た。

Compound 162723: To a solution of 2-[2-(4-methylphenyl)sulfonyloxyethoxy]ethyl 4-methylbenzenesulfonate (4.72 g, 11.38 mmol) in DMF (30 mL), NaH (455 mg, 11.38 mmol) was added at 0° C. and stirred at room temperature for 1 h. 2-[2-(4-methylphenyl)sulfonyloxyethoxy]ethyl 4-methylbenzenesulfonate (4.72 g, 11.38 mmol) in DMF (30 mL) was added to the reaction mixture and stirred at room temperature for an additional 16 h. The mixture was cooled to 0° C. and quenched with water. The mixture was diluted with DCM, washed with water and _brine , dried over _Na2SO4 , concentrated and purified by column chromatography (EtOAc:Hex=1:1, Rf=0.23) to give 2-[2-[[5-[4-(6-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl]pyridin-2-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethyl 4-methylbenzenesulfonate (1.3 g, 1.97 mmol, 69% yield) as an orange solid.

Compound 162762: A mixture of 2-[2-[[5-[4-(6-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl]pyridin-2-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethyl 4-methylbenzenesulfonate (1.3 g, 1.97 mmol) and NaI (592 mg, 3.95 mmol) in ACN (10 mL) was heated at 80° C. for 15 h. Water was added to the mixture and it was extracted with DCM. The organic layer was washed with water (50 mL), brine ( ₅₀ mL), dried over _Na2SO4 , concentrated to dryness and purified by chromatography (MeOH:DCM=1:100, Rf=0.19) to give tert-butyl N-[2-(2-iodanylethoxy)ethyl]-N-[5-[4-(6-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl]pyridin-2-yl]carbamate (920 mg, 1.50 mmol, 76% yield) as a yellow solid.

Compound 162798: A mixture of tert-butyl N-[2-(2-iodanylethoxy)ethyl]-N-[5-[4-(6-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl]pyridin-2-yl]carbamate (200 mg, 0.33 mmol), 3-(6-oxidanyl-3-oxidanylidene-1H-isoindol-2-yl)piperidine-2,6-dione (169 mg, 0.65 mmol) and _Na2CO3 ( ₁₀₃ mg, 0.98 mmol) in DMF (4 mL) was heated at 50° C. for 37 h. Water was added to the mixture and the resulting precipitate was collected by filtration, washed with water and purified by column chromatography on NH gel (MeOH:DCM=1:100, Rf=0.21) to give tert-butyl N-[2-[2-[[2-[2,6-bis(oxidanylidene)piperidin-3-yl]-1-oxidanylidene-3H-isoindol-5-yl]oxy]ethoxy]ethyl]-N-[5-[4-(6-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl]pyridin-2-yl]carbamate (68 mg, 0.09 mmol, 28% yield) as a yellow solid.

Compound 162843: To a solution of tert-butyl N-[2-[2-[[2-[2,6-bis(oxydanylidene)piperidin-3-yl]-1-oxydanylidene-3H-isoindol-5-yl]oxy]ethoxy]ethyl]-N-[5-[4-(6-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl]pyridin-2-yl]carbamate (68 mg, 0.09 mmol) in DCM (2 mL), TFA (0.07 mL, 0.9100 mmol) was added and stirred at room temperature for 48 hours. The mixture was diluted with DCM (3 mL) and neutralized to pH 8 with saturated NaHCO ₃ (aq) solution. The precipitate was collected and washed with DCM to give 3-[6-[2-[2-[[5-[4-(6-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl]pyridin-2-yl]amino]ethoxy]ethoxy]-3-oxidanylidene-1H-isoindol-2-yl]piperidine-2,6-dione (38 mg, 0.05 mmol, 59% yield) as a yellow solid.

[Example 31]
Synthesis of compound 165559

化合物165511:2-[2-(4-メチルフェニル)スルホニルオキシエトキシ]エチル4-メチルベンゼンスルホネート(2567mg、6.19mmol)のDMF(10mL)中溶液を0^oCに冷却し、NaH(248mg、6.19mmol)を添加し、次いで室温で1時間撹拌した。2-[2-(4-メチルフェニル)スルホニルオキシエトキシ]エチル4-メチルベンゼンスルホネート(2567mg、6.19mmol)を反応混合物に添加し、室温で17時間撹拌した。反応を0℃に冷却し、水を添加することによりクエンチした。混合物をDCMで希釈し、水及びブラインで洗浄し、Na₂SO₄で脱水し、濃縮し、カラムクロマトグラフィー(DCM:EtOAc=10:1、Rf=0.3)によって精製して、2-[2-[[4-[4-(6-フルオラニル-1,3-ベンゾチアゾール-2-イル)フェニル]ピリジン-2-イル]-[(2-メチルプロパン-2-イル)オキシカルボニル]アミノ]エトキシ]エチル4-メチルベンゼンスルホネート(455mg、0.68mmol、収率33%)を白色の固体として得た。

Compound 165511: A solution of 2-[2-(4-methylphenyl)sulfonyloxyethoxy]ethyl 4-methylbenzenesulfonate (2567 mg, 6.19 mmol) in DMF (10 mL) was cooled to 0 ^° C. and NaH (248 mg, 6.19 mmol) was added and then stirred at room temperature for 1 h. 2-[2-(4-methylphenyl)sulfonyloxyethoxy]ethyl 4-methylbenzenesulfonate (2567 mg, 6.19 mmol) was added to the reaction mixture and stirred at room temperature for 17 h. The reaction was cooled to 0° C. and quenched by adding water. The mixture was diluted with DCM, washed with water and _brine , dried over _Na2SO4 , concentrated and purified by column chromatography (DCM:EtOAc=10:1, Rf=0.3) to give 2-[2-[[4-[4-(6-fluoranyl-1,3-benzothiazol-2-yl)phenyl]pyridin-2-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethyl 4-methylbenzenesulfonate (455 mg, 0.68 mmol, 33% yield) as a white solid.

Compound 165547: A mixture of methyl 5-azanyl-5-oxidanylidene-4-(6-oxidanyl-3-oxidanylidene-1H-isoindol-2-yl)pentanoate (220 mg, 0.75 mmol), _K2CO3 (284 mg, 2.06 mmol), KI (11 mg, 0.07 mmol) and 2-[2-[[4-[4-(6 _- fluoranyl-1,3-benzothiazol-2-yl)phenyl]pyridin-2-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethyl 4-methylbenzenesulfonate (455 mg, 0.69 mmol) in DMF (6 mL) was heated at 80° C. for 7 h. The mixture was diluted with _EtOAc (20 mL), extracted with water (10 mL) and brine (10 mL), dried over _Na2SO4 , concentrated and purified by column chromatography (MeOH:DCM=1:20, Rf=0.4) to give tert-butyl N-[2-[2-[[2-[2,6-bis(oxidanylidene)piperidin-3-yl]-1-oxidanylidene-3H-isoindol-5-yl]oxy]ethoxy]ethyl]-N-[4-[4-(6-fluoranyl-1,3-benzothiazol-2-yl)phenyl]pyridin-2-yl]carbamate (245 mg, 0.33 mmol, 48% yield) as a white solid.

Compound 165559: tert-Butyl N-[2-[2-[[2-[2,6-bis(oxydanylidene)piperidin-3-yl]-1-oxydanylidene-3H-isoindol-5-yl]oxy]ethoxy]ethyl]-N-[4-[4-(6-fluoranyl-1,3-benzothiazol-2-yl)phenyl]pyridin-2-yl]carbamate (245 mg, 0.33 mmol) in DCM (5 mL) was added with TFA (0.38 mL, 4.89 mmol) and stirred at room temperature for 20 hours. The mixture was diluted with DCM (20 mL) and neutralized to pH 8 with saturated NaHCO ₃ solution. The mixture was extracted with water, dried over MgSO4, concentrated and purified by column chromatography (DCM:MeOH=20:1, Rf=0.3) to give 3-[6-[2-[2-[[4-[4-(6-fluoranyl-1,3-benzothiazol-2-yl)phenyl]pyridin-2-yl]amino]ethoxy]ethoxy]-3-oxidanylidene-1H-isoindol-2-yl]piperidine-2,6-dione (160 mg, 0.24 mmol, 75% yield) as a white solid.

[Example 32]
Synthesis of compound 163685

化合物162862: 2-[4-[6-(ジメチルアミノ)ピリジン-3-イル]-2-(トリフルオロメチル)フェニル]-1,3-ベンゾチアゾール-6-オール(516mg、1.24mmol)の乾燥DMF(12mL)中溶液にNaH(149mg、3.72mmol)を0℃で添加し、室温で1時間撹拌した。乾燥DMF(12mL)中2-[2-(4-メチルフェニル)スルホニルオキシエトキシ]エチル4-メチルベンゼンスルホネート(1543mg、3.72mmol)を反応混合物に添加し、同一の温度で18時間撹拌した。混合物を水(50mL)に注ぎ入れ、DCM(50mL)で抽出した。有機層を水(50mL)及びブライン(50mL)で洗浄し、無水Na₂SO₄で乾燥させ、濃縮し、カラムクロマトグラフィー(Rf=0.51、EtOAc:DCM=1:9)によって精製して、2-[2-[[2-[4-[6-(ジメチルアミノ)ピリジン-3-イル]-2-(トリフルオロメチル)フェニル]-1,3-ベンゾチアゾール-6-イル]オキシ]エトキシ]エチル4-メチルベンゼンスルホネート(627mg、0.95mmol、収率77%)を淡黄色の固体として得た。

Compound 162862: To a solution of 2-[4-[6-(dimethylamino)pyridin-3-yl]-2-(trifluoromethyl)phenyl]-1,3-benzothiazol-6-ol (516 mg, 1.24 mmol) in dry DMF (12 mL) was added NaH (149 mg, 3.72 mmol) at 0° C. and stirred at room temperature for 1 h. 2-[2-(4-methylphenyl)sulfonyloxyethoxy]ethyl 4-methylbenzenesulfonate (1543 mg, 3.72 mmol) in dry DMF (12 mL) was added to the reaction mixture and stirred at the same temperature for 18 h. The mixture was poured into water (50 mL) and extracted with DCM (50 mL). The organic layer was washed with water (50 mL) and brine (50 mL), dried over _{anhydrous Na2SO4} , concentrated and purified by column chromatography (Rf=0.51, EtOAc:DCM=1:9) to give 2-[2-[[2-[4-[6-(dimethylamino)pyridin-3-yl]-2-(trifluoromethyl)phenyl]-1,3-benzothiazol-6-yl]oxy]ethoxy]ethyl 4-methylbenzenesulfonate (627 mg, 0.95 mmol, 77% yield) as a pale yellow solid.

Compound 162891: A mixture of 2-[2-[[2-[4-[6-(dimethylamino)pyridin-3-yl]-2-(trifluoromethyl)phenyl]-1,3-benzothiazol-6-yl]oxy]ethoxy]ethyl 4-methylbenzenesulfonate (627 mg, 0.95 mmol) and NaI (286 mg, 1.91 mmol) in ACN (10 mL) was heated at 80° C. for 17 h. Water (20 mL) was added to the mixture and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO ₄ , and concentrated to dryness to give 5-[4-[6-[2-(2-iodanylethoxy)ethoxy]-1,3-benzothiazol-2-yl]-3-(trifluoromethyl)phenyl]-N,N-dimethyl-pyridin-2-amine (540 mg, 0.88 mmol, 92% yield) as a yellow solid.

Compound 163685: A mixture of 5-[4-[6-[2-(2-iodanylethoxy)ethoxy]-1,3-benzothiazol-2-yl]-3-(trifluoromethyl)phenyl]-N,N-dimethyl-pyridin-2-amine (100 mg, 0.16 mmol), 3-(7-oxidanyl-3-oxidanylidene-1H-isoindol-2-yl)piperidine-2,6-dione (85 mg, 0.33 mmol) and _K2CO3 ( ₆₈ mg, 0.49 mmol) in DMF (5 mL) was heated at 50° C. for 18 hours. Water was added to the mixture and it was extracted with DCM. The organic layer was washed with brine, dried over _MgSO4 , concentrated and purified by column chromatography (MeOH:DCM=1:20, Rf=0.45) to give 3-[7-[2-[2-[[2-[4-[6-(dimethylamino)pyridin-3-yl]-2-(trifluoromethyl)phenyl]-1,3-benzothiazol-6-yl]oxy]ethoxy]ethoxy]-3-oxidanylidene-1H-isoindol-2-yl]piperidine-2,6-dione (33 mg, 0.04 mmol, 25% yield) as a yellow solid.

[Example 33]
Synthesis of compound 163863

化合物163863: 2-[4-[6-(ジメチルアミノ)ピリジン-3-イル]フェニル]-1,3-ベンゾチアゾール-6-オール(166mg、0.48mmol)、3-[2-[[2-[2,6-ビス(オキシダニリデン)ピペリジン-3-イル]-1-オキシダニリデン-3H-イソインドール-5-イル]オキシ]エトキシ]プロパン酸(90mg、0.24mmol)、DMAP(3mg、0.02mmol)及びDCC(52mg、0.25mmol)のピリジン(2mL)中混合物を室温で15時間撹拌した。溶媒を減圧により除去した。残渣をDCM(10mL)に再溶解し、水(5mL)及びブライン(5mL)で洗浄し、MgSO4で脱水し、濃縮し、カラムクロマトグラフィー(MeOH:DCM=5:100、Rf=0.14)によって精製して、[2-[4-[6-(ジメチルアミノ)ピリジン-3-イル]フェニル]-1,3-ベンゾチアゾール-6-イル]3-[2-[[2-[2,6-ビス(オキシダニリデン)ピペリジン-3-イル]-1-オキシダニリデン-3H-イソインドール-5-イル]オキシ]エトキシ]プロパノエート(14mg、0.02mmol、収率8%)を黄色の固体として得た。

Compound 163863: A mixture of 2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-ol (166 mg, 0.48 mmol), 3-[2-[[2-[2,6-bis(oxydanylidene)piperidin-3-yl]-1-oxydanylidene-3H-isoindol-5-yl]oxy]ethoxy]propanoic acid (90 mg, 0.24 mmol), DMAP (3 mg, 0.02 mmol) and DCC (52 mg, 0.25 mmol) in pyridine (2 mL) was stirred at room temperature for 15 hours. The solvent was removed by reduced pressure. The residue was redissolved in DCM (10 mL), washed with water (5 mL) and brine (5 mL), dried over MgSO4, concentrated and purified by column chromatography (MeOH:DCM=5:100, Rf=0.14) to give [2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]3-[2-[[2-[2,6-bis(oxidanylidene)piperidin-3-yl]-1-oxidanylidene-3H-isoindol-5-yl]oxy]ethoxy]propanoate (14 mg, 0.02 mmol, 8% yield) as a yellow solid.

[Example 34]
Synthesis of compound 164484

化合物164431: 乾燥DMF(10mL)中のtert-ブチルN-[4-[4-(6-メトキシイミダゾ[1,2-a]ピリジン-2-イル)フェニル]ピリジン-2-イル]カルバメート(400mg、0.96mmol)の溶液を、0℃に冷却し、NaH(115mg、2.88mmol)を添加した。得られた混合物を室温で1時間撹拌した。乾燥DMF(10mL)中の2-[2-[2-(4-メチルフェニル)スルホニルオキシエトキシ]エトキシ]エチル4-メチルベンゼンスルホネート(1321mg、2.88mmol)を反応混合物に添加し、同一の温度で17時間撹拌した。混合物を水(30mL)でクエンチし、DCM(30mL)で抽出した。有機層をブライン(30mL)で洗浄し、無水Na₂SO₄で乾燥させ、濃縮し、カラムクロマトグラフィー(EtOAc:DCM=1:4、Rf=0.4)によって精製して、2-[2-[2-[[4-[4-(6-メトキシイミダゾ[1,2-a]ピリジン-2-イル)フェニル]ピリジン-2-イル]-[(2-メチルプロパン-2-イル)オキシカルボニル]アミノ]エトキシ]エトキシ]エチル4-メチルベンゼンスルホネート(350mg、0.50mmol、収率52%)を黄色の固体として得た。

Compound 164431: A solution of tert-butyl N-[4-[4-(6-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl]pyridin-2-yl]carbamate (400 mg, 0.96 mmol) in dry DMF (10 mL) was cooled to 0° C. and NaH (115 mg, 2.88 mmol) was added. The resulting mixture was stirred at room temperature for 1 h. 2-[2-[2-(4-methylphenyl)sulfonyloxyethoxy]ethoxy]ethyl 4-methylbenzenesulfonate (1321 mg, 2.88 mmol) in dry DMF (10 mL) was added to the reaction mixture and stirred at the same temperature for 17 h. The mixture was quenched with water (30 mL) and extracted with DCM (30 mL). The organic layer was washed with brine (30 mL), dried over anhydrous _Na2SO4 , concentrated and purified by column chromatography (EtOAc:DCM=1: ₄ , Rf=0.4) to give 2-[2-[2-[[4-[4-(6-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl]pyridin-2-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethoxy]ethyl 4-methylbenzenesulfonate (350 mg, 0.50 mmol, 52% yield) as a yellow solid.

Compound 164438: A mixture of 2-[2-[2-[[4-[4-(6-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl]pyridin-2-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethoxy]ethyl 4-methylbenzenesulfonate (350 mg, 0.50 mmol) and NaI (149 mg, 1.00 mmol) in ACN (10 mL) was heated at 80 °C for 6 h. Water was added to the mixture and it was extracted with DCM. The organic layer was washed with water (50 mL) and brine (50 mL), dried over Na2SO4, and concentrated to dryness to give tert-butyl N-[2-[2-(2-iodanylethoxy)ethoxy]ethyl]-N-[4-[4-(6-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl]pyridin-2-yl]carbamate (317 mg, 0.48 mmol, 97% yield) as a yellow solid.

Compound 164465: A mixture of tert-butyl N-[2-[2-(2-iodanylethoxy)ethoxy]ethyl]-N-[4-[4-(6-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl]pyridin-2-yl]carbamate (100 mg, 0.15 mmol), _K2CO3 (63 mg, 0.46 mmol) and methyl 5-azanyl- ₅ -oxidanylidene-4-(6-oxidanylidene-3-oxidanylidene-1H-isoindol-2-yl)pentanoate (49 mg, 0.17 mmol) in DMF (5 mL) was heated at 80° C. for 6 h. Water was added to the mixture and it was extracted with DCM. The organic layer was dried over _MgSO4 , concentrated and purified by column chromatography (MeOH:DCM=3:100, Rf=0.3) to give tert-butyl N-[2-[2-[2-[[2-[2,6-bis(oxidanylidene)piperidin-3-yl]-1-oxidanylidene-3H-isoindol-5-yl]oxy]ethoxy]ethoxy]ethyl]-N-[4-[4-(6-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl]pyridin-2-yl]carbamate (63 mg, 0.08 mmol, 52% yield) as a white solid.

Compound 164484: tert-Butyl N-[2-[2-[2-[[2-[2,6-bis(oxydanylidene)piperidin-3-yl]-1-oxydanylidene-3H-isoindol-5-yl]oxy]ethoxy]ethoxy]ethyl]-N-[4-[4-(6-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl]pyridin-2-yl]carbamate (63 mg, 0.08 mmol) in DCM (5 mL) was added with TFA (0.09 mL, 1.19 mmol) and stirred at room temperature for 14 hours. The mixture was poured into ice water and neutralized to pH 8 with saturated NaHCO ₃ solution. The mixture was diluted with DCM (20 mL), extracted with water (10 mL) and brine (10 mL), dried over Na2SO4 and concentrated to dryness to give 3-[6-[2-[2-[2-[[4-[4-(6-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl]pyridin-2-yl]amino]ethoxy]ethoxy]ethoxy]-3-oxidanylidene-1H-isoindol-2-yl]piperidine-2,6-dione (52 mg, 0.07 mmol, 89% yield) as a light brown solid.

[Example 35]
Synthesis of compound 165013

化合物164953: tert-ブチルN-メチル-N-[5-[4-[6-[(2-メチルプロパン-2-イル)オキシカルボニルアミノ]-1,3-ベンゾチアゾール-2-イル]-3-(トリフルオロメチル)フェニル]ピリジン-2-イル]カルバメート(200mg、0.33mmol)の乾燥DMF(5mL)中溶液にNaH(40mg、1.00mmol)を0℃で添加し、室温で1時間撹拌した。乾燥DMF(5mL)中の2-[2-(4-メチルフェニル)スルホニルオキシエトキシ]エチル4-メチルベンゼンスルホネート(414mg、1.00mmol)を反応混合物に添加し、同一の温度で14時間撹拌した。混合物を水(30mL)でクエンチし、DCM(30mL)で抽出した。有機層を水(30mL)及びブライン(30mL)で洗浄し、無水Na₂SO₄で乾燥させ、濃縮し、カラムクロマトグラフィー(EtOAc:DCM=1:9、Rf=0.4)によって精製して、2-[2-[[2-[4-[6-[メチル-[(2-メチルプロパン-2-イル)オキシカルボニル]アミノ]ピリジン-3-イル]-2-(トリフルオロメチル)フェニル]-1,3-ベンゾチアゾール-6-イル]-[(2-メチルプロパン-2-イル)オキシカルボニル]アミノ]エトキシ]エチル4-メチルベンゼンスルホネート(130mg、0.15mmol、収率46%)を黄色の固体として得た。

Compound 164953: To a solution of tert-butyl N-methyl-N-[5-[4-[6-[(2-methylpropan-2-yl)oxycarbonylamino]-1,3-benzothiazol-2-yl]-3-(trifluoromethyl)phenyl]pyridin-2-yl]carbamate (200 mg, 0.33 mmol) in dry DMF (5 mL) was added NaH (40 mg, 1.00 mmol) at 0° C. and stirred at room temperature for 1 h. 2-[2-(4-methylphenyl)sulfonyloxyethoxy]ethyl 4-methylbenzenesulfonate (414 mg, 1.00 mmol) in dry DMF (5 mL) was added to the reaction mixture and stirred at the same temperature for 14 h. The mixture was quenched with water (30 mL) and extracted with DCM (30 mL). The organic layer was washed with water (30 mL) and brine (30 mL), dried over _{anhydrous Na2SO4} , concentrated and purified by column chromatography (EtOAc:DCM=1:9, Rf=0.4) to give 2-[2-[[2-[4-[6-[methyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]pyridin-3-yl]-2-(trifluoromethyl)phenyl]-1,3-benzothiazol-6-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethyl 4-methylbenzenesulfonate (130 mg, 0.15 mmol, 46% yield) as a yellow solid.

Compound 164984: A mixture of methyl 5-azanyl-5-oxidanylidene-4-(6-oxidanyl-3 _- oxidanylidene-1H-isoindol-2-yl)pentanoate (50 mg, 0.17 mmol), _K2CO3 (64 mg, 0.46 mmol), KI (2.56 mg, 0.02 mmol) and 2-[2-[[2-[4-[6-[methyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]pyridin-3-yl]-2-(trifluoromethyl)phenyl]-1,3-benzothiazol-6-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethyl 4-methylbenzenesulfonate (130 mg, 0.15 mmol) in DMF (5 mL) was heated at 80° C. for 6 h. The mixture was diluted with DCM (5 mL), cooled to 0° C., and water (5 mL) was added dropwise. The mixture was extracted with water (10 mL) and brine (10 mL), dried over Na ₂ SO ₄ , concentrated, and purified by column chromatography (MeOH:DCM=3:100, Rf=0.3) to give tert-butyl N-[2-[2-[[2-[2,6-bis(oxydanylidene)piperidin-3-yl]-1-oxydanylidene-3H-isoindol-5-yl]oxy]ethoxy]ethyl]-N-[2-[4-[6-[methyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]pyridin-3-yl]-2-(trifluoromethyl)phenyl]-1,3-benzothiazol-6-yl]carbamate (79 mg, 0.08 mmol, 55% yield) as a colorless oil.

Compound 165013: To a solution of tert-butyl N-[2-[2-[[2-[2,6-bis(oxydanylidene)piperidin-3-yl]-1-oxydanylidene-3H-isoindol-5-yl]oxy]ethoxy]ethyl]-N-[2-[4-[6-[methyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]pyridin-3-yl]-2-(trifluoromethyl)phenyl]-1,3-benzothiazol-6-yl]carbamate (79 mg, 0.08 mmol) in DCM (3 mL), TFA (0.1 mL, 1.27 mmol) was added and stirred at room temperature for 14 hours. The mixture was poured into ice water and neutralized to pH 8 with saturated NaHCO ₃ solution. The mixture was diluted with DCM (20 mL) and extracted with water (10 mL) and brine (10 mL). The organic layer was collected, dried _{over Na2SO4} , concentrated and purified by column chromatography on silica gel (MeOH:DCM=3:100, Rf=0.2) to give 3-[6-[2-[2-[[2-[4-[6-(methylamino)pyridin-3-yl]-2-(trifluoromethyl)phenyl]-1,3-benzothiazol-6-yl]amino]ethoxy]ethoxy]-3-oxidanylidene-1H-isoindol-2-yl]piperidine-2,6-dione (29 mg, 0.04 mmol, 45% yield) as a yellow solid.

[Example 36]
Synthesis of compound 166288

化合物166191: tert-ブチルN-[2-[4-[6-(ジメチルアミノ)ピリジン-3-イル]-2-(トリフルオロメチル)フェニル]-1,3-ベンゾチアゾール-6-イル]カルバメート(447mg、0.87mmol)のDMF(8mL)中溶液にNaH(63mg、2.61mmol)を0℃で添加し、室温で1時間撹拌し、次いでDMF(8mL)中の5-(4-メチルフェニル)スルホニルオキシペンチル4-メチルベンゼンスルホネート(1075mg、2.61mmol)を添加した。得られた混合物を室温でさらに16時間撹拌し、0℃に冷却し、水を添加することによりクエンチした。残渣をDCM(50mL)及び水(50mL)に溶解した。有機層を水(50mL)、ブライン(50mL)で洗浄し、Na₂SO₄で脱水し、シリカゲルでのカラムクロマトグラフィー(DCM:EtOAc=9:1、Rf=0.52)によって精製して、5-[[2-[4-[6-(ジメチルアミノ)ピリジン-3-イル]-2-(トリフルオロメチル)フェニル]-1,3-ベンゾチアゾール-6-イル]-[(2-メチルプロパン-2-イル)オキシカルボニル]アミノ]ペンチル4-メチルベンゼンスルホネート(515mg、0.68mmol、収率79%)を黄色の固体として得た。

Compound 166191: To a solution of tert-butyl N-[2-[4-[6-(dimethylamino)pyridin-3-yl]-2-(trifluoromethyl)phenyl]-1,3-benzothiazol-6-yl]carbamate (447 mg, 0.87 mmol) in DMF (8 mL) was added NaH (63 mg, 2.61 mmol) at 0° C. and stirred at room temperature for 1 h, followed by addition of 5-(4-methylphenyl)sulfonyloxypentyl 4-methylbenzenesulfonate (1075 mg, 2.61 mmol) in DMF (8 mL). The resulting mixture was stirred at room temperature for an additional 16 h, cooled to 0° C., and quenched by adding water. The residue was dissolved in DCM (50 mL) and water (50 mL). The organic layer was washed with water (50 mL), brine ( ₅₀ mL), dried over _Na2SO4 , and purified by column chromatography on silica gel (DCM:EtOAc=9:1, Rf=0.52) to give 5-[[2-[4-[6-(dimethylamino)pyridin-3-yl]-2-(trifluoromethyl)phenyl]-1,3-benzothiazol-6-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]pentyl 4-methylbenzenesulfonate (515 mg, 0.68 mmol, 79% yield) as a yellow solid.

Compound 166226: A mixture of 5-[[2-[4-[6-(dimethylamino)pyridin-3-yl]-2-(trifluoromethyl)phenyl]-1,3-benzothiazol-6-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]pentyl 4-methylbenzenesulfonate (514 mg, 0.68 mmol), _K2CO3 (282 mg, 2.04 mmol), KI (11 mg, 0.07 mmol) and methyl 5-azanyl- ₅ -oxidanylidene-4-(6-oxidanyl-3-oxidanylidene-1H-isoindol-2-yl)pentanoate (219 mg, 0.75 mmol) in DMF (8 mL) was stirred at room temperature for 22 h and then heated to 80° C. for 6 h. The mixture was diluted with DCM (5 mL), cooled to 0° C. and water (5 mL) was added dropwise. The mixture was washed with water ( ₁₀ mL) and brine (10 mL), dried over _Na2SO4 , concentrated, and purified by column chromatography on silica gel (MeOH:DCM=1:20, Rf=0.55) to give tert-butyl N-[5-[[2-[2,6-bis(oxidanylidene)piperidin-3-yl]-1-oxidanylidene-3H-isoindol-5-yl]oxy]pentyl]-N-[2-[4-[6-(dimethylamino)pyridin-3-yl]-2-(trifluoromethyl)phenyl]-1,3-benzothiazol-6-yl]carbamate (205 mg, 0.24 mmol, 36% yield) as a yellow solid.

Compound 166288: To a solution of tert-butyl N-[5-[[2-[2,6-bis(oxydanylidene)piperidin-3-yl]-1-oxydanylidene-3H-isoindol-5-yl]oxy]pentyl]-N-[2-[4-[6-(dimethylamino)pyridin-3-yl]-2-(trifluoromethyl)phenyl]-1,3-benzothiazol-6-yl]carbamate (205 mg, 0.24 mmol) in DCM (3 mL), TFA (0.28 mL, 3.65 mmol) was added and stirred at room temperature for 16 hours. The mixture was poured into ice water and neutralized to pH 8 with saturated NaHCO3 solution. The residue was dissolved in DCM (20 mL) and water (10 mL). The organic layer was washed with water (10 mL) and brine ( ₁₀ mL), dried over _Na2SO4 , and concentrated to dryness to give 3-[6-[5-[[2-[4-[6-(dimethylamino)pyridin-3-yl]-2-(trifluoromethyl)phenyl]-1,3-benzothiazol-6-yl]amino]pentoxy]-3-oxidanylidene-1H-isoindol-2-yl]piperidine-2,6-dione (132 mg, 0.17 mmol, 71% yield) as a yellow solid.

[Example 37]
Synthesis of compound 166399

化合物166196: tert-ブチルN-[2-[4-[6-(ジメチルアミノ)ピリジン-3-イル]-2-(トリフルオロメチル)フェニル]-1,3-ベンゾチアゾール-6-イル]カルバメート(300mg、0.58mmol)のDMF(5mL)中溶液を0℃に冷却し、NaH(56mg、2.33mmol)を添加した。混合物を室温で1時間撹拌し、DMF(5mL)中の2-アジドエチル4-メチルベンゼンスルホネート(281mg、1.17mmol)を添加し、50℃で20時間加熱した。混合物を0℃に冷却し、水(5mL)を添加した。得られた沈殿物を濾取し、水で洗浄し、減圧で乾燥させた。残渣をシリカゲルでのカラムクロマトグラフィー(EtOAc:DCM=1:20、Rf=0.6)によって精製して、tert-ブチルN-(2-アジドエチル)-N-[2-[4-[6-(ジメチルアミノ)ピリジン-3-イル]-2-(トリフルオロメチル)フェニル]-1,3-ベンゾチアゾール-6-イル]カルバメート(320mg、0.55mmol、収率94%)を黄色の固体として得た。

Compound 166196: A solution of tert-butyl N-[2-[4-[6-(dimethylamino)pyridin-3-yl]-2-(trifluoromethyl)phenyl]-1,3-benzothiazol-6-yl]carbamate (300 mg, 0.58 mmol) in DMF (5 mL) was cooled to 0° C. and NaH (56 mg, 2.33 mmol) was added. The mixture was stirred at room temperature for 1 h, 2-azidoethyl 4-methylbenzenesulfonate (281 mg, 1.17 mmol) in DMF (5 mL) was added and heated at 50° C. for 20 h. The mixture was cooled to 0° C. and water (5 mL) was added. The resulting precipitate was collected by filtration, washed with water and dried under reduced pressure. The residue was purified by column chromatography on silica gel (EtOAc:DCM=1:20, Rf=0.6) to give tert-butyl N-(2-azidoethyl)-N-[2-[4-[6-(dimethylamino)pyridin-3-yl]-2-(trifluoromethyl)phenyl]-1,3-benzothiazol-6-yl]carbamate (320 mg, 0.55 mmol, 94% yield) as a yellow solid.

Compound 166264: To a solution of tert-butyl N-(2-azidoethyl)-N-[2-[4-[6-(dimethylamino)pyridin-3-yl]-2-(trifluoromethyl)phenyl]-1,3-benzothiazol-6-yl]carbamate (341 mg, 0.58 mmol) in THF (5 mL)/EtOH (5 mL) was added Pd(OH) ₂ (1701 mg, 1.61 mmol) and stirred under ₁ atm of H2 for 4 h. The mixture was filtered through a pad of Celite and the filtrate was concentrated to dryness. The residue was purified by column chromatography (DCM: EtOAc = 20: 1, Rf = 0.15) to give tert-butyl N- (2-azanylethyl) -N- [2- [4- [6- (dimethylamino) pyridin-3-yl] -2- (trifluoromethyl) phenyl] -1, 3-benzothiazol-6-yl] carbamate (226 mg, 0.41 mmol, yield 69%) as a pale yellow solid.

Compound 166306: tert-Butyl N-(2-azanylethyl)-N-[2-[4-[6-(dimethylamino)pyridin-3-yl]-2-(trifluoromethyl)phenyl]-1,3-benzothiazol-6-yl]carbamate (326 mg, 0.59 mmol), 2-[[2-[2,6-bis(oxydanylidene)piperidin-3-yl]-1-oxydanylidene-3H-isoindol-5-yl]oxy]ethanoic acid (372 mg, 1.17 mmol), EDC (280 mg, 1.46 mmol) and HOBt (198 mg, 1.46 mmol) in pyridine (6 mL) were stirred at room temperature for 16 hours. The solvent was removed under reduced pressure and the resulting residue was redissolved in EtOAc (100 mL) and washed with water (50 mL) and brine (50 mL). The organic layer was dried _{over Na2SO4} , concentrated and purified by column chromatography on silica gel (MeOH:DCM=1:20, Rf=0.3) to give tert-butyl N-[2-[2-[[2-[2,6-bis(oxidanylidene)piperidin-3-yl]-1-oxidanylidene-3H-isoindol-5-yl]oxy]ethanoylamino]ethyl]-N-[2-[4-[6-(dimethylamino)pyridin-3-yl]-2-(trifluoromethyl)phenyl]-1,3-benzothiazol-6-yl]carbamate (277 mg, 0.32 mmol, 55% yield) as a yellow solid.

Compound 166399: tert-Butyl N-[2-[2-[[2-[2,6-bis(oxydanylidene)piperidin-3-yl]-1-oxydanylidene-3H-isoindol-5-yl]oxy]ethanoylamino]ethyl]-N-[2-[4-[6-(dimethylamino)pyridin-3-yl]-2-(trifluoromethyl)phenyl]-1,3-benzothiazol-6-yl]carbamate (277 mg, 0.32 mmol) in DCM (3 mL) was added to TFA (0.37 mL, 4.85 mmol) and stirred at room temperature for 23 hours. The mixture was poured into ice water and neutralized to pH 8 with saturated NaHCO3 solution. The residue was dissolved in DCM (20 mL) and water (10 mL). The organic layer was washed with water (10 mL) and brine ( ₁₀ mL), dried over _Na2SO4 , and concentrated to give 2-[[2-[2,6-bis(oxidanylidene)piperidin-3-yl]-1-oxidanylidene-3H-isoindol-5-yl]oxy]-N-[2-[[2-[4-[6-(dimethylamino)pyridin-3-yl]-2-(trifluoromethyl)phenyl]-1,3-benzothiazol-6-yl]amino]ethyl]ethanamide (239 mg, 0.30 mmol, 93% yield) as a yellow solid.

[Example 38]
Alpha-synuclein competitive binding assay
(A) Expression and purification of recombinant wild-type human α-synuclein: 0.5 mM IPTG was used to induce the production of wild-type human α-synuclein by bacteria transformed with a full-length α-synuclein expression plasmid. After shaking for 20 h at 16°C, the cell pellet was resuspended in lysis buffer (10 mM Tris, 1 mM EGTA, 0.75 mM NaCl, 1 mM PMSF, pH 7.5) and lysed by sonication, followed by centrifugation (6000g, 30 min, 4°C). The supernatant was then boiled at 95°C for 15 min with manual swirling every 5 min, followed by centrifugation (6000g, 30 min, 4°C). The supernatant was dialyzed against (10 mM Tris, 1 mM EGTA, 50 mM NaCl, pH 7.5) buffer and concentrated in a concentrator. The collected sample was loaded onto a Superdex200 column, and the flow-through was then loaded onto a Q-HP column. The collected fractions containing the α-synuclein eluate were pooled, concentrated and stored at -80°C.

(B) Preparation of aggregated α-synuclein: 5 mg/mL α-synuclein in PBS buffer (pH 7.4) was incubated in a tube with shaking at 37°C for 5–10 days.

(C) In vitro fluorometric alpha-synuclein binding assay: 2 μM alpha-synuclein was incubated with serially diluted compounds (three-fold serial dilutions, 10 μM to 0.001 μM) in a 96-well plate for 1 h at 37° C. Fluorescence intensity was read on a microplate spectrometer. The Kd value of the compound was calculated using the following equation: Y=B _max ×X/(Kd+X), where X is the concentration of the compound; Y is the fluorescence signal of (compound+alpha-synuclein)-(compound+DMSO); B _max is the maximum signal.

(D) PBB5 competition assay: 2 μM alpha-synuclein was incubated with 0.26 μM 2-(4-(2-(methylamino)pyridin-5-yl)-1,3-butadien-1-yl)benzothiazol-6-ol (PBB5) and serially diluted compounds (three-fold serial dilutions, 10 μM to 0.001 μM) in a 96-well plate for 1 h at 37° C. The fluorescence intensity of PBB5 (excitation/emission=530/690 nm) was read on a microplate spectrometer. The percentage of competition was calculated using the following equation: (Max-wells with compound alone)/(Max-Min)×100%, where Max=signal of (alpha-synuclein+PBB5)−signal of (buffer+PBB5); and Min=signal of (buffer+PBB5)−signal of (buffer+PBB5). The _IC50 value for each compound was calculated using GraphPad Prism software using the "4-parameter logistic or sigmoidal dose-response model":
Y=Bottom+(Top-Bottom)/(1+(IC50/X)^HillSlope)

[Example 39]
In vitro assay to disassemble α-synuclein aggregates
ReNcell VM α-synuclein aggregation assays were performed at Charles River Laboratories (CRL). ReNcell VM is an immortalized human neural progenitor cell line derived from the ventral midbrain region of the brain. ReNcell VM cells were selected as an in vitro cell model for α-synuclein aggregation assays based on their growth characteristics, differentiation potential into terminally differentiated neurons, and amenability to adenoviral transduction. Aggregated human wild-type α-synuclein was overexpressed through adenoviral delivery. Aggregated α-synuclein was detected using the aggregation-selective anti-α-synuclein antibody MJFR14 using immunocytochemistry, and total α-synuclein levels were detected using Syn205 (an α/β-synuclein specific antibody).

The ReNcell VM α-synuclein aggregation assay was applied to screen compounds to identify those capable of degrading α-synuclein aggregates. Specifically, adenovirally transduced ReNcell VM cells were treated with test compounds (serial dilutions) for 24 hours, followed by fixation and then processing for ReNcell immunocytochemistry by staining with Syn205 and MJFR14. Immunoreactivity for aggregated (MJFR14) and total α-synuclein (Syn205) was quantified using high content-based segmentation of immunoreactive regions in immunocytochemistry images (performed on an IN Cell 2200 (GE Healthcare)), followed by quantification of immunofluorescence intensity (performed by an algorithm developed by CRL using the IN Cell Developer Toolbox software).

A set of over 100 compounds was tested for inhibition of MJFR14 immunoreactivity. Figure 1 shows the quantification based on the high content of aggregated α-synuclein species combined with the determination of nuclear counts (% remaining cells) in differentiated ReNcell VM cells. The results showed that 24 h treatment with test compounds 166362, 170357, 162640 and 180948, respectively, induced a concentration-dependent inhibition of MJFR14 immunoreactivity indicative of reduced α-synuclein aggregation. Each panel of the graph presents data normalized to percentage effect (PE) and remaining cells (%).

Percentage effect (PE): Inhibition compared to blank (0.1% DMSO).

PE=100-(compound signal/average blank signal)×100

Compound-induced cytotoxicity (% remaining cells)

% remaining cells = (compound nuclei count/average blank nuclei count) x 100

Figures 2A-2D show representative immunocytochemistry images of cells treated with vehicle (0.1% DMSO) and test compounds 132168, 166362, and 170357 and immunostained with MJFR14 illustrating the reduction of α-synuclein expression after treatment with compounds 132168 and 166362. The results demonstrated that 6 days of treatment with compounds 132168 and 166362, respectively, induced a clear inhibition of MJFR14 immunoreactivity indicating that compounds 132168 and 166362 efficiently reduced α-synuclein aggregation.

Some embodiments of the compounds were evaluated in the ReNcell VM α-synuclein aggregation assay. Results are summarized in Table 3.

[Example 40]
In vivo assay to disassemble α-synuclein aggregates
Three-month-old male transgenic line 61 mice were used in the study. Mice were treated once with intravenous injection of compound 132168 (25 mpk). Plasma and brain samples were collected 0.25, 0.5, 1, 2, 4, 8 and 24 hours after treatment. Blood samples were collected by cardiac puncture into MiniCollect® 0.5mL K2EDTA (potassium ethylenediaminetetraacetate) tubes. Blood samples were centrifuged at 3000×g for 10 minutes at room temperature (22° C.). Plasma was transferred to pre-labeled 1.5ml LoBind Eppendorf tubes (two aliquots, approximately 75 μl each), frozen on dry ice, and stored at −80° C. until analysis. Brain samples were perfused with 0.9% saline before collection. Brains were weighed, cut into two halves on a cold surface, weighed, and flash frozen. Half the brain was used for WES System analysis of human α-synuclein in the soluble and insoluble fractions. Treatment with compound 132168 reduced the insoluble α-synuclein fraction by 30% compared to the DMSO vehicle control, reflecting a reduction in insoluble α-synuclein aggregates. The results are shown in Figure 3.

[Example 41]
In Vivo Pharmacokinetic Studies To determine whether compounds of the present disclosure can cross the blood-brain barrier (BBB), example compound 132168 was administered to mice (10 and 25 mg/kg, intravenously) in a pharmacokinetic study.

Animal Care: Mice were housed in an animal room environment with 15 air changes/hour, 12 hours of light/day, 20°C-24°C temperature, and 40%-70% humidity. The test room was disinfected and cleaned before the start of the study, and the operating area was cleaned after each dosing or sampling during the study. All animals had free access to food and water during the study. Animals were provided with a Certified Rodent Diet and water ad libitum. Nutritional composition and contaminant levels of the food and impurities and contaminants of the water were monitored by a third party. The health status of the animals was assessed according to accepted animal care procedures and deemed suitable for experimental use.

Sample collection and processing: Approximately 110 μL of whole blood was collected from all animals by face or cardiac puncture under isoflurane anesthesia at 0.25, 0.5, 1, 2, 4, 8, and 24 hours after dosing and placed into tubes containing potassium ethylenediaminetetraacetate ( _K2EDTA ). Brain samples were collected at 0.25, 0.5, 1, 2, 4, 8, and 24 hours after dosing. Perfusion with pre-chilled saline was performed by cardiac puncture before collecting the brains. Plasma samples were obtained by centrifuging the blood samples at 2000g for 5 minutes at 4°C and transferring the supernatant to a new tube. All plasma and brain samples were stored at approximately -70°C until analysis.

Bioanalytical method development: Compound concentrations in plasma and brain samples were determined using a method based on liquid chromatography with tandem mass spectrometry (LC-MS/MS).
Results: The PK parameters are summarized in Table 4. Compound 132168 was able to penetrate the BBB in a short time.

One particular embodiment is as follows:

Embodiment 1. A method of treating a synucleinopathy in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula A
EBM-L-SBM (Formula A)
[Wherein,
EBM is an E3 ubiquitin ligase binding moiety
L is a linker covalently linking the EBM and TBM;
SBM has the formula:

のα-シヌクレインタンパク質結合部分であり、

is the alpha-synuclein protein-binding portion of

はLに共有結合し、
(i)

is covalently bonded to L,
(i)

は、O、S及びNから選択される少なくとも1個の環ヘテロ原子を含有する置換若しくは非置換二環式縮合芳香族環であり、

is a substituted or unsubstituted bicyclic fused aromatic ring containing at least one ring heteroatom selected from O, S and N;

は、O、S及びNから選択される0～2個の環ヘテロ原子を含有する置換若しくは非置換単環式芳香族環であり、

is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S and N;

は、O、S及びNから選択される0～2個の環ヘテロ原子を含有する置換若しくは非置換単環式芳香族環であり、又は
(ii)

is a substituted or unsubstituted monocyclic aromatic ring containing 0-2 ring heteroatoms selected from O, S and N; or
(ii)

は、O、S及びNから選択される0～2個の環ヘテロ原子を含有する置換若しくは非置換単環式芳香族環であり、

is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S and N;

は、O、S及びNから選択される0～2個の環ヘテロ原子を含有する置換若しくは非置換単環式芳香族環であり、

is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S and N;

は、O、S及びNから選択される少なくとも1個の環ヘテロ原子を含有する置換若しくは非置換二環式縮合芳香族環である]の化合物又はその薬学的に許容される塩、鏡像異性体、非鏡像異性体、互変異性体、ラセミ化合物、溶媒和物、代謝前駆体、プロドラッグを投与することを含む、方法。

is a substituted or unsubstituted bicyclic fused aromatic ring containing at least one ring heteroatom selected from O, S and N, or a pharma- ceutically acceptable salt, enantiomer, non-enantiomer, tautomer, racemate, solvate, metabolic precursor, or prodrug thereof.

Embodiment 2. A method of reducing alpha-synuclein aggregation in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula A
EBM-L-SBM (Formula A)
[Wherein,
EBM is an E3 ubiquitin ligase binding moiety
L is a linker covalently linking the EBM and TBM;
SBM has the formula:

のα-シヌクレインタンパク質結合部分であり、

is the alpha-synuclein protein-binding portion of

はLに共有結合し、
(i)

is covalently bonded to L,
(i)

は、O、S及びNから選択される少なくとも1個の環ヘテロ原子を含有する置換若しくは非置換二環式縮合芳香族環であり、

is a substituted or unsubstituted bicyclic fused aromatic ring containing at least one ring heteroatom selected from O, S and N;

は、O、S及びNから選択される0～2個の環ヘテロ原子を含有する置換若しくは非置換単環式芳香族環であり、

is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S and N;

は、O、S及びNから選択される0～2個の環ヘテロ原子を含有する置換若しくは非置換単環式芳香族環であり、又は
(ii)

is a substituted or unsubstituted monocyclic aromatic ring containing 0-2 ring heteroatoms selected from O, S and N; or
(ii)

は、O、S及びNから選択される0～2個の環ヘテロ原子を含有する置換若しくは非置換単環式芳香族環であり、

is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S and N;

は、O、S及びNから選択される0～2個の環ヘテロ原子を含有する置換若しくは非置換単環式芳香族環であり、

is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S and N;

は、O、S及びNから選択される少なくとも1個の環ヘテロ原子を含有する置換若しくは非置換二環式縮合芳香族環である]の化合物又はその薬学的に許容される塩、鏡像異性体、非鏡像異性体、互変異性体、ラセミ化合物、溶媒和物、代謝前駆体、プロドラッグを投与することを含む、方法。

is a substituted or unsubstituted bicyclic fused aromatic ring containing at least one ring heteroatom selected from O, S and N, or a pharma- ceutically acceptable salt, enantiomer, non-enantiomer, tautomer, racemate, solvate, metabolic precursor, or prodrug thereof.

Embodiment 3. A method of reducing Lewy bodies in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula A.
EBM-L-SBM (Formula A)
[Wherein,
EBM is an E3 ubiquitin ligase binding moiety
L is a linker covalently linking the EBM and TBM;
SBM has the formula:

のα-シヌクレインタンパク質結合部分であり、

is the alpha-synuclein protein-binding portion of

はLに共有結合し、
(i)

is covalently bonded to L,
(i)

は、O、S及びNから選択される少なくとも1個の環ヘテロ原子を含有する置換若しくは非置換二環式縮合芳香族環であり、

is a substituted or unsubstituted bicyclic fused aromatic ring containing at least one ring heteroatom selected from O, S and N;

は、O、S及びNから選択される0～2個の環ヘテロ原子を含有する置換若しくは非置換単環式芳香族環であり、

is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S and N;

は、O、S及びNから選択される0～2個の環ヘテロ原子を含有する置換若しくは非置換単環式芳香族環であり、又は
(ii)

is a substituted or unsubstituted monocyclic aromatic ring containing 0-2 ring heteroatoms selected from O, S and N; or
(ii)

は、O、S及びNから選択される0～2個の環ヘテロ原子を含有する置換若しくは非置換単環式芳香族環であり、

is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S and N;

は、O、S及びNから選択される0～2個の環ヘテロ原子を含有する置換若しくは非置換単環式芳香族環であり、

is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S and N;

は、O、S及びNから選択される少なくとも1個の環ヘテロ原子を含有する置換若しくは非置換二環式縮合芳香族環である]の化合物又はその薬学的に許容される塩、鏡像異性体、非鏡像異性体、互変異性体、ラセミ化合物、溶媒和物、代謝前駆体、プロドラッグを投与することを含む、方法。

is a substituted or unsubstituted bicyclic fused aromatic ring containing at least one ring heteroatom selected from O, S and N, or a pharma- ceutically acceptable salt, enantiomer, non-enantiomer, tautomer, racemate, solvate, metabolic precursor, or prodrug thereof.

Embodiment 4. In the manufacture of a medicament for treating a synucleinopathy, a compound of formula A:
EBM-L-SBM (Formula A)
[Wherein,
EBM is an E3 ubiquitin ligase binding moiety
L is a linker covalently linking the EBM and TBM;
SBM has the formula:

のα-シヌクレインタンパク質結合部分であり、

is the alpha-synuclein protein-binding portion of

はLに共有結合し、
(i)

is covalently bonded to L,
(i)

は、O、S及びNから選択される少なくとも1個の環ヘテロ原子を含有する置換若しくは非置換二環式縮合芳香族環であり、

is a substituted or unsubstituted bicyclic fused aromatic ring containing at least one ring heteroatom selected from O, S and N;

は、O、S及びNから選択される0～2個の環ヘテロ原子を含有する置換若しくは非置換単環式芳香族環であり、

is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S and N;

は、O、S及びNから選択される0～2個の環ヘテロ原子を含有する置換若しくは非置換単環式芳香族環であり、又は
(ii)

is a substituted or unsubstituted monocyclic aromatic ring containing 0-2 ring heteroatoms selected from O, S and N; or
(ii)

は、O、S及びNから選択される0～2個の環ヘテロ原子を含有する置換若しくは非置換単環式芳香族環であり、

is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S and N;

は、O、S及びNから選択される0～2個の環ヘテロ原子を含有する置換若しくは非置換単環式芳香族環であり、

is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S and N;

は、O、S及びNから選択される少なくとも1個の環ヘテロ原子を含有する置換若しくは非置換二環式縮合芳香族環である]の化合物又はその薬学的に許容される塩、鏡像異性体、非鏡像異性体、互変異性体、ラセミ化合物、溶媒和物、代謝前駆体若しくはプロドラッグの使用。

is a substituted or unsubstituted bicyclic fused aromatic ring containing at least one ring heteroatom selected from O, S and N, or a pharma- ceutically acceptable salt, enantiomer, non-enantiomer, tautomer, racemate, solvate, metabolic precursor or prodrug thereof.

Embodiment 5. In the manufacture of a medicament for reducing alpha-synuclein aggregation, a compound of formula A:
EBM-L-SBM (Formula A)
[Wherein,
EBM is an E3 ubiquitin ligase binding moiety
L is a linker covalently linking the EBM and TBM;
SBM has the formula:

のα-シヌクレインタンパク質結合部分であり、

is the alpha-synuclein protein-binding portion of

はLに共有結合し、
(i)

is covalently bonded to L,
(i)

は、O、S及びNから選択される少なくとも1個の環ヘテロ原子を含有する置換若しくは非置換二環式縮合芳香族環であり、

is a substituted or unsubstituted bicyclic fused aromatic ring containing at least one ring heteroatom selected from O, S and N;

は、O、S及びNから選択される0～2個の環ヘテロ原子を含有する置換若しくは非置換単環式芳香族環であり、

is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S and N;

は、O、S及びNから選択される0～2個の環ヘテロ原子を含有する置換若しくは非置換単環式芳香族環であり、又は
(ii)

is a substituted or unsubstituted monocyclic aromatic ring containing 0-2 ring heteroatoms selected from O, S and N; or
(ii)

は、O、S及びNから選択される0～2個の環ヘテロ原子を含有する置換若しくは非置換単環式芳香族環であり、

is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S and N;

は、O、S及びNから選択される0～2個の環ヘテロ原子を含有する置換若しくは非置換単環式芳香族環であり、

is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S and N;

は、O、S及びNから選択される少なくとも1個の環ヘテロ原子を含有する置換若しくは非置換二環式縮合芳香族環である]の化合物又はその薬学的に許容される塩、鏡像異性体、非鏡像異性体、互変異性体、ラセミ化合物、溶媒和物、代謝前駆体若しくはプロドラッグの使用。

is a substituted or unsubstituted bicyclic fused aromatic ring containing at least one ring heteroatom selected from O, S and N, or a pharma- ceutically acceptable salt, enantiomer, non-enantiomer, tautomer, racemate, solvate, metabolic precursor or prodrug thereof.

Embodiment 6. In the manufacture of a medicament for reducing Lewy bodies, a compound of formula A:
EBM-L-SBM (Formula A)
[Wherein,
EBM is an E3 ubiquitin ligase binding moiety
L is a linker covalently linking the EBM and TBM;
SBM has the formula:

のα-シヌクレインタンパク質結合部分であり、

is the alpha-synuclein protein-binding portion of

はLに共有結合し、
(i)

is covalently bonded to L,
(i)

は、O、S及びNから選択される少なくとも1個の環ヘテロ原子を含有する置換若しくは非置換二環式縮合芳香族環であり、

is a substituted or unsubstituted bicyclic fused aromatic ring containing at least one ring heteroatom selected from O, S and N;

は、O、S及びNから選択される0～2個の環ヘテロ原子を含有する置換若しくは非置換単環式芳香族環であり、

is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S and N;

は、O、S及びNから選択される0～2個の環ヘテロ原子を含有する置換若しくは非置換単環式芳香族環であり、又は
(ii)

is a substituted or unsubstituted monocyclic aromatic ring containing 0-2 ring heteroatoms selected from O, S and N; or
(ii)

は、O、S及びNから選択される0～2個の環ヘテロ原子を含有する置換若しくは非置換単環式芳香族環であり、

is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S and N;

は、O、S及びNから選択される0～2個の環ヘテロ原子を含有する置換若しくは非置換単環式芳香族環であり、

is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S and N;

は、O、S及びNから選択される少なくとも1個の環ヘテロ原子を含有する置換若しくは非置換二環式縮合芳香族環である]の化合物又はその薬学的に許容される塩、鏡像異性体、非鏡像異性体、互変異性体、ラセミ化合物、溶媒和物、代謝前駆体若しくはプロドラッグの使用。

is a substituted or unsubstituted bicyclic fused aromatic ring containing at least one ring heteroatom selected from O, S and N, or a pharma- ceutically acceptable salt, enantiomer, non-enantiomer, tautomer, racemate, solvate, metabolic precursor or prodrug thereof.

Embodiment 7. The method of embodiment 1 or the use of embodiment 4, wherein the synucleinopathy is Parkinson's disease (PD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA), or a combination of two or more thereof.

Embodiment 8. The method or use of any one of embodiments 1 to 7, wherein the substituted or unsubstituted bicyclic fused aromatic ring is a substituted or unsubstituted bicyclic 5-6 system.

Embodiment 9. SBM is of formula B or formula C

のSBMであり、
ZはC又はNであり、UはO、S又はCHであり、VはN又はNHであり、
KはCH又はNであり、QはCH又はNであり、ここでK及びQが同時にNであることはなく、
各出現のR'''はH、OH、NH₂、C_1～6アルキル、C_1～6アルキルアミノ、C_1～6アルコキシ及びハロゲンからなる群から独立して選択され、kは0、1、2又は3であり、
各出現のR'はH、ハロゲン、OH、C_1～6アルキル、C_1～6ハロアルキル及びC_1～6アルコキシからなる群から独立して選択され、mは0、1、2、3又は4であり、
各出現のR''はH、ハロ、OH、NH₂、C_1～6アルキル、C_1～6アルコキシ、C_1～6ハロアルキル、C_1～6アルキルアミノ、C_3～6シクロアルキルアミノ、C_3～6シクロアルキル及びC_3～6ヘテロシクロアルキルからなる群から独立して選択され、nは0、1又は2であり、
JはCR⁶又はNであり、XはCR⁶又はNであり、YはCR⁶又はNであり、ここでJ、X及びYのうちの少なくとも1つがNであるが、J及びYが同時にNであることはなく、X及びYが同時にNであることはなく、
R⁶はH、NH₂、C_1～6アルキル及びC_1～6アルコキシからなる群から独立して選択され、NH₂、C_1～6アルキル又はC_1～6アルコキシは、C_1～3アルキル、C_3～6シクロアルキル及び/又はハロのうちの1～3つで場合により置換されており、
式Bにおいて、VはNであり、ここでZ及びUは同時にヘテロ原子であることはなく、
式Cにおいて、VはN又はNHであり、TはCH又はNであり、ここでU、Z、V及びTのうちの2つまでがヘテロ原子を含有する、実施形態1～8のいずれかの1つの方法又は使用。

SBM of
Z is C or N, U is O, S or CH, V is N or NH;
K is CH or N and Q is CH or N, where K and Q are not both N;
each occurrence of R''' is independently selected from the group consisting of H, OH, _NH2 , _C1-6 alkyl, _C1-6 alkylamino, _C1-6 alkoxy, and halogen; k is 0, 1, 2, or 3;
each occurrence of R' is independently selected from the group consisting of H, halogen, OH, _C1-6 alkyl, _C1-6 haloalkyl, and _C1-6 alkoxy; and m is 0, 1, 2, 3, or 4;
each occurrence of R'' is independently selected from the group consisting of H, halo, OH, NH2, _C1-6 alkyl, _C1-6 alkoxy _{, C1-6} haloalkyl, _C1-6 alkylamino, _C3-6 cycloalkylamino, _C3-6 cycloalkyl, and _C3-6 heterocycloalkyl; n is 0, 1, or 2;
J is ^CR6 or N, X is ^CR6 or N, and Y is ^CR6 or N, where at least one of J, X, and Y is N, but J and Y are not both N, and X and Y are not both N;
R ⁶ is independently selected from the group consisting of H, NH ₂ , C _1-6 alkyl, and C _1-6 alkoxy, wherein NH ₂ , C _1-6 alkyl, or C _1-6 alkoxy is optionally substituted with one to three of C _1-3 alkyl, C _3-6 cycloalkyl, and/or halo;
In formula B, V is N, where Z and U are not both heteroatoms;
The method or use of any one of embodiments 1 to 8, wherein in formula C, V is N or NH and T is CH or N, where up to two of U, Z, V and T contain a heteroatom.

Embodiment 10.EBM is

であり、
R^3'はH又はC_1～6アルキルであり、
各出現のR^2'はH、OH、C_1～6アルキル、C_1～6アルコキシ、C_1～6アルキルアミノ及びNH₂からなる群から独立して選択され、
m6は0、1、2、3又は4であり、
Y₁はCH₂又は

and
R ^3' is H or C _1-6 alkyl;
each occurrence of R2 ^' is independently selected from the group consisting of H, OH, _C1-6 alkyl, _C1-6 alkoxy, _C1-6 alkylamino, and _NH2 ;
m6 is 0, 1, 2, 3 or 4;
_Y1 is _CH2 or

である、実施形態1～9のいずれかの1つの方法又は使用。

The method or use of any one of embodiments 1 to 9, wherein

Embodiment 11. The compound is represented by formula I to formula VI

[式中、
L₁は結合、-C(=O)-、-NR-、-O-又は-S-であり、Rが水素、場合により置換されているアシル、場合により置換されているアルキル又は窒素保護基であり、
L₂は置換又は非置換C_1～50炭化水素鎖であり、場合により炭化水素鎖の1個以上の鎖原子が-C(=O)-、-O-、-NR^a1-、-S-又は環状部分で独立して置き換えられており、R^a1が独立して水素、置換又は非置換C_1～6アルキル又は窒素保護基であり、
ZはC又はNであり、UはO、S又はCHであり、
KはCH又はNであり、QはCH又はNであり、ここでK及びQが同時にNであることはなく、
各出現のR'''はH、OH、NH₂、C_1～6アルキル、C_1～6アルキルアミノ、C_1～6アルコキシ及びハロゲンからなる群から独立して選択され、kは0、1、2又は3であり、
各出現のR'はH、ハロゲン、OH、C_1～6アルキル、C_1～6ハロアルキル及びC_1～6アルコキシからなる群から独立して選択され、mは0、1、2、3又は4であり、
各出現のR''はH、ハロ、OH、NH₂、C_1～6アルキル、C_1～6アルコキシ、C_1～6ハロアルキル、C_1～6アルキルアミノ、C_3～6シクロアルキルアミノ、C_3～6シクロアルキル及びC_3～6ヘテロシクロアルキルからなる群から独立して選択され、nは0、1又は2であり、
JはCR⁶又はNであり、XはCR⁶又はNであり、YはCR⁶又はNであり、ここでJ、X及びYのうちの少なくとも1つがNであるが、J及びYが同時にNであることはなく、X及びYが同時にNであることはなく、
R⁶はH、NH₂、C_1～6アルキル及びC_1～6アルコキシからなる群から独立して選択され、NH₂、C_1～6アルキル又はC_1～6アルコキシが、C_1～3アルキル、C_3～6シクロアルキル及び/又はハロのうちの1～3つで場合により置換されており、
式Iにおいて、L₃は結合、-NR-、-O-又は-S-であり、Rが水素、場合により置換されているアシル、場合により置換されているアルキル又は窒素保護基であり、R^3'はH又はC_1～6アルキルであり、Y₁はCH₂又は

であり、VはNであり、ここでZ及びUが同時にヘテロ原子であることはなく、
式IIにおいて、各出現のR^2'はH、OH、C_1～6アルキル、C_1～6アルコキシ、C_1～6アルキルアミノ及びNH₂からなる群から独立して選択され、m6は0、1、2、3又は4であり、Y₁はCH₂又は

であり、VはNであり、ここでZ及びUが同時にヘテロ原子であることはなく、
式IIIにおいて、VはNであり、ここでZ及びUが同時にヘテロ原子であることはなく、
式IVにおいて、L₃は結合、-NR-、-O-又は-S-であり、Rが水素、場合により置換されているアシル、場合により置換されているアルキル又は窒素保護基であり、R^3'はH又はC_1～6アルキルであり、Y₁はCH₂又は

であり、VはN又はNHであり、TはCH又はNであり、ここでU、Z、V及びTのうちの2つまでがヘテロ原子を含有し、
式Vにおいて、各出現のR^2'が、H、OH、C_1～6アルキル、C_1～6アルコキシ、C_1～6アルキルアミノ及びNH₂からなる群から独立して選択され、m6は0、1、2、3又は4であり、Y₁はCH₂又は

であり、VはN又はNHであり、TはCH又はNであり、ここでU、Z、V及びTのうちの2つまでがヘテロ原子を含有し、
式VIにおいて、VはNであり、TはCH又はNであり、ここでU、Z、V及びTのうちの2つまでがヘテロ原子を含有する]のいずれか1つの化合物又はその薬学的に許容される塩、鏡像異性体、非鏡像異性体、互変異性体、ラセミ化合物、溶媒和物、代謝前駆体若しくはプロドラッグである、実施形態1～10のいずれかの1つの方法又は使用。

[Wherein,
_L1 is a bond, -C(=O)-, -NR-, -O- or -S-, and R is hydrogen, optionally substituted acyl, optionally substituted alkyl or a nitrogen protecting group;
_L2 is a substituted or unsubstituted _C1-50 hydrocarbon chain, optionally wherein one or more chain atoms of the hydrocarbon chain are independently replaced with -C(=O)-, -O-, -NR ^a1 -, -S-, or a cyclic moiety, and R ^a1 is independently hydrogen, substituted or unsubstituted _C1-6 alkyl, or a nitrogen protecting group;
Z is C or N and U is O, S or CH;
K is CH or N and Q is CH or N, where K and Q are not both N;
each occurrence of R''' is independently selected from the group consisting of H, OH, _NH2 , _C1-6 alkyl, _C1-6 alkylamino, _C1-6 alkoxy, and halogen; k is 0, 1, 2, or 3;
each occurrence of R' is independently selected from the group consisting of H, halogen, OH, _C1-6 alkyl, _C1-6 haloalkyl, and _C1-6 alkoxy; and m is 0, 1, 2, 3, or 4;
each occurrence of R'' is independently selected from the group consisting of H, halo, OH, NH2, _C1-6 alkyl, _C1-6 alkoxy _{, C1-6} haloalkyl, _C1-6 alkylamino, _C3-6 cycloalkylamino, _C3-6 cycloalkyl, and _C3-6 heterocycloalkyl; n is 0, 1, or 2;
J is ^CR6 or N, X is ^CR6 or N, and Y is ^CR6 or N, where at least one of J, X, and Y is N, but J and Y are not both N, and X and Y are not both N;
R ⁶ is independently selected from the group consisting of H, NH ₂ , C _1-6 alkyl, and C _1-6 alkoxy, wherein NH ₂ , C _1-6 alkyl, or C _1-6 alkoxy is optionally substituted with one to three of C _1-3 alkyl, C _3-6 cycloalkyl, and/or halo;
In formula I, _L3 is a bond, -NR-, -O- or -S-; R is hydrogen, optionally substituted acyl, optionally substituted alkyl or a nitrogen protecting group; R3 ^' is H or _C1-6 alkyl; _Y1 is _CH2 or

and V is N, where Z and U are not both heteroatoms;
In formula II, R2 ^' at each occurrence is independently selected from the group consisting of H, OH, _C1-6 alkyl, _C1-6 alkoxy, _C1-6 alkylamino, and _NH2 ; m6 is 0, 1, 2, 3, or 4; _Y1 is _CH2 or

and V is N, where Z and U are not both heteroatoms;
In formula III, V is N, where Z and U are not both heteroatoms;
In formula IV, _L3 is a bond, -NR-, -O- or -S-; R is hydrogen, optionally substituted acyl, optionally substituted alkyl or a nitrogen protecting group; R3 ^' is H or _C1-6 alkyl; _Y1 is _CH2 or

wherein V is N or NH and T is CH or N, where up to two of U, Z, V and T contain a heteroatom;
In formula V, each occurrence of R2 ^' is independently selected from the group consisting of H, OH, _C1-6 alkyl, _{C1-6 alkoxy, C1-6 alkylamino} , and NH2; m6 is 0, 1, 2, 3, or ₄ ; and _Y1 is _CH2 or

wherein V is N or NH and T is CH or N, where up to two of U, Z, V and T contain a heteroatom;
or a pharma- ceutically acceptable salt, enantiomer, non-enantiomer, tautomer, racemate, solvate, metabolic precursor or prodrug thereof.

Embodiment 12. _L2 is an optionally substituted _C1-45 hydrocarbon chain, optionally wherein one or more chain atoms of the hydrocarbon chain are independently replaced with -C(=O)-, -O-, -NR ^a1 -, -S-, or a cyclic moiety, and R ^a1 is independently hydrogen, substituted or unsubstituted _C1-6 alkyl, or a nitrogen protecting group;
Preferably, _L2 is a substituted or unsubstituted _C5-40 hydrocarbon chain;
Preferably, _L2 is a substituted or unsubstituted _C1-30 , _C1-24 or _C1-20 hydrocarbon chain, optionally wherein one or more chain atoms of the hydrocarbon chain are independently replaced with -C(=O)-, -O-, ^-NRa1- , -S- or a cyclic moiety, and ^Ra1 is independently hydrogen, substituted or unsubstituted _C1-6 alkyl or a nitrogen protecting group;
The method or use of embodiment 11, preferably wherein L ₂ is an unsubstituted C _1-26 , C _5-26 , C _5-20 , C _5-15 , C _15-20 or C _20-25 hydrocarbon chain, wherein one or more chain atoms of the hydrocarbon chain are independently replaced with -C(=O)-, -O- or -NR ^a1 -, and R ^a1 is independently hydrogen, substituted or unsubstituted C _1-6 alkyl or a nitrogen protecting group.

Embodiment 13. _L2 is an optionally substituted _C1-30 hydrocarbon chain, in which one or more chain atoms of the hydrocarbon chain are independently replaced with -O- or -NR ^a1 -, and R ^a1 is independently hydrogen, substituted or unsubstituted _C1-6 alkyl or a nitrogen protecting group;
The method or use of embodiment 11, wherein preferably at least one chain atom of the hydrocarbon chain of _L2 is independently replaced with -C(=O)-, -O-, -S-, -NR ^a1 -, -N= or =N-, and R ^a1 is independently hydrogen, substituted or unsubstituted C _1-6 alkyl or a nitrogen protecting group, preferably replaced with -O-.

Embodiment 14. _L2 is selected from the group consisting of substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted heteroalkylene, and combinations thereof;
The method or use of embodiment 11, wherein _L2 is selected from the group consisting of substituted and unsubstituted alkylene, substituted and unsubstituted alkenylene, substituted and unsubstituted alkynylene, substituted and unsubstituted heteroalkylene, substituted and unsubstituted heteroalkenylene, substituted and unsubstituted heteroalkynylene, substituted and unsubstituted heterocyclylene, substituted and unsubstituted carbocyclylene, substituted and unsubstituted arylene, substituted and unsubstituted heteroarylene, and combinations thereof.

Embodiment 15. Carbocyclylene or heterocyclylene

である、実施形態14の方法又は使用。

15. The method or use of embodiment 14, wherein

Embodiment 16. The method or use of embodiment 14, wherein _L2 comprises at least one example selected from the group consisting of substituted or unsubstituted _C1-6 alkylene, substituted or unsubstituted _C2-6 alkenylene, substituted or unsubstituted _C2-6 alkynylene, substituted or unsubstituted hetero _C1-6 alkylene, substituted or unsubstituted hetero _C2-6 alkenylene, substituted or unsubstituted hetero _C2-6 alkynylene, substituted or unsubstituted _C3-6 carbocyclylene, substituted or unsubstituted 3-6 membered heterocyclylene, substituted or unsubstituted phenylene and substituted or unsubstituted 5-6 membered heteroarylene.

Embodiment 17. _L2 is substituted or unsubstituted methylene, ethylene, n-propylene, n-butylene, n-pentylene, n-hexylene, -( _CH2 ) ₂ -O( _CH2 ) _2- , -OCH2-, -CH2O- _, -O( _CH2 ) _2- , -( _CH2 ) _{2O-, -O(CH2)3- , - ( CH2} ) _{3O-, -O(CH2)4-, -(CH2)4O- , -O ( CH2 ) 5-} , -( _CH2 )5O-, _{-O(CH2)6- , -O} ( _CH2 ) ₆ 15. The method or use of embodiment 14, comprising at least one example selected from the group consisting of: -O-, -C(=O)O-, -OC(=O)-, -NH-C(=O)- and -C(=O)NH-.

Embodiment 18. At least one chain atom of the hydrocarbon chain of _L2 is independently replaced with a 6-membered heterocyclyl group having 1 to 3 ring heteroatoms selected from the group consisting of nitrogen and oxygen;
Preferably, at least one chain atom of the hydrocarbon chain of _L2 is independently replaced with piperidine, piperazine or morpholine;
The method or use of embodiment 14, wherein preferably at least one chain atom of the hydrocarbon chain of _L2 is independently replaced with an optionally substituted phenyl group.

Embodiment 19. The method or use of embodiment 14, wherein L ₂ is an unsubstituted hydrocarbon chain, optionally one or more chain atoms of the hydrocarbon chain are independently replaced with -NR ^a1 -, and each instance of R ^a1 is independently hydrogen, substituted or unsubstituted C _1-6 alkyl or a nitrogen protecting group, or optionally two instances of R ^a1 together with intervening atoms form a substituted or unsubstituted heterocyclic ring or a substituted or unsubstituted heteroaryl ring.

Embodiment 20. The method or use of embodiment 19, wherein at least one instance of R ^a1 is hydrogen, substituted or unsubstituted C _1-6 alkyl (e.g., substituted or unsubstituted methyl or ethyl), or a nitrogen protecting group (e.g., benzyl, t-butyl carbonate, benzyl carbamate, 9-fluorenylmethyl carbonate, trifluoroacetyl, triphenylmethyl, acetyl, or p-toluenesulfonamide).

であり、gは1、2、3、4、5又は6である、実施形態11の方法又は使用。 In embodiment _21.L2

and g is 1, 2, 3, 4, 5 or 6.

、-NHC(=O)-又は-NH-を含む、実施形態11の方法又は使用。 Embodiment 22. _L2 is the moiety -O-,

12. The method or use of embodiment 11, comprising -NHC(=O)- or -NH-.

からなる群から選択され、各gが独立して1、2、3、4、5又は6であり、fは1、2、3、4、5又は6であり、hは1、2、3、4、5又は6である、実施形態11の方法又は使用。 In the embodiment _23.L2

and each g is independently 1, 2, 3, 4, 5 or 6; f is 1, 2, 3, 4, 5 or 6; and h is 1, 2, 3, 4, 5 or 6.

Embodiment 24. The compound of formula I is of formula I-1

の化合物又はその薬学的に許容される塩、鏡像異性体、非鏡像異性体、互変異性体、ラセミ化合物、溶媒和物、代謝前駆体若しくはプロドラッグである、実施形態11の方法又は使用。

or a pharma- ceutically acceptable salt, enantiomer, non-enantiomer, tautomer, racemate, solvate, metabolic precursor or prodrug thereof.

の化合物又はその薬学的に許容される塩、鏡像異性体、非鏡像異性体、互変異性体、ラセミ化合物、溶媒和物、代謝前駆体若しくはプロドラッグである、実施形態11の方法又は使用。 Embodiment 25. The compound of formula II is represented by formula II-1

or a pharma- ceutically acceptable salt, enantiomer, non-enantiomer, tautomer, racemate, solvate, metabolic precursor or prodrug thereof.

の化合物又はその薬学的に許容される塩、鏡像異性体、非鏡像異性体、互変異性体、ラセミ化合物、溶媒和物、代謝前駆体若しくはプロドラッグである、実施形態11の方法又は使用。 Embodiment 26. The compound of formula III is represented by formula III-1

or a pharma- ceutically acceptable salt, enantiomer, non-enantiomer, tautomer, racemate, solvate, metabolic precursor or prodrug thereof.

の化合物又はその薬学的に許容される塩、鏡像異性体、非鏡像異性体、互変異性体、ラセミ化合物、溶媒和物、代謝前駆体若しくはプロドラッグである、実施形態11の方法又は使用。 Embodiment 27. The compound of formula IV is represented by formula IV-1

or a pharma- ceutically acceptable salt, enantiomer, non-enantiomer, tautomer, racemate, solvate, metabolic precursor or prodrug thereof.

の化合物又はその薬学的に許容される塩、鏡像異性体、非鏡像異性体、互変異性体、ラセミ化合物、溶媒和物、代謝前駆体若しくはプロドラッグである、実施形態11の方法又は使用。 Embodiment 28. The compound of formula V is represented by formula V-1

or a pharma- ceutically acceptable salt, enantiomer, non-enantiomer, tautomer, racemate, solvate, metabolic precursor or prodrug thereof.

の化合物又はその薬学的に許容される塩、鏡像異性体、非鏡像異性体、互変異性体、ラセミ化合物、溶媒和物、代謝前駆体若しくはプロドラッグである、実施形態11の方法又は使用。 Embodiment 29. The compound of formula VI is represented by formula VI-1

or a pharma- ceutically acceptable salt, enantiomer, non-enantiomer, tautomer, racemate, solvate, metabolic precursor or prodrug thereof.

Embodiment 30. The compound of formula I-1 is of formula 1, 5, 6, 8, 10 or 13

[式中、
各Aは独立してO、NH、

[Wherein,
Each A is independently O, NH,

であり、
m2は1、2、3、4、5、6又は7であり
m3は1、2、3、4、5又は6であり、
m4は0、1、2又は3であり、
m5は0、1、2又は3であり、
R^1'はO、NH、

and
m2 is 1, 2, 3, 4, 5, 6, or 7
m3 is 1, 2, 3, 4, 5 or 6;
m4 is 0, 1, 2 or 3;
m5 is 0, 1, 2 or 3;
R ^1' is O, NH,

である]の化合物又はその薬学的に許容される塩、鏡像異性体、非鏡像異性体、互変異性体、ラセミ化合物、溶媒和物、代謝前駆体若しくはプロドラッグである、実施形態24の方法又は使用。

or a pharma- ceutically acceptable salt, enantiomer, non-enantiomer, tautomer, racemate, solvate, metabolic precursor or prodrug thereof.

Embodiment 31. The compound is of formula 1 or a pharma- ceutically acceptable salt, enantiomer, non-enantiomer, tautomer, racemate, solvate, metabolic precursor or prodrug thereof, wherein R' is H, _C1-3 haloalkyl or _C1-3 alkoxy, and/or R'' is H, halo, OH, _NH2 , _C1-3 alkoxy, _C1-3 alkylamino, _C3-5 cycloalkyl, _C3-5 cycloalkylamino and _C3-5 heterocycloalkyl, and/or R''' is H, OH or halogen, and/or R1 ^' is O, NH,

であり、並びに/又は、AがO、NH、

and/or A is O, NH,

であり、並びに/又は、m2が2、3、4若しくは6であり、並びに/又は、R^3'がH若しくはC_1～3アルキルである、実施形態30の方法又は使用。

and/or m2 is 2, 3, 4 or 6; and/or R ^3' is H or C _1-3 alkyl.

Embodiment 32. The compound is a compound of formula 5, or a pharma- ceutically acceptable salt, enantiomer, non-enantiomer, tautomer, racemate, solvate, metabolic precursor, or prodrug thereof,
R ^3' is H or C _1-3 alkyl, and/or each A is independently O, NH,

であり、及び/又は、m4が0、1、2若しくは3であり、及び/又は、m5が0、1、2若しくは3であり、及び/又は、m3が1、2、3、4、5若しくは6であり、及び/又は、R^1'がO、NH若しくは

and/or m4 is 0, 1, 2 or 3, and/or m5 is 0, 1, 2 or 3, and/or m3 is 1, 2, 3, 4, 5 or 6, and/or R ^1′ is O, NH or

であり、及び/又は、R'''がH、OH、C_1～3アルキル、C_1～3アルコキシ若しくはハロゲンであり、及び/又は、R'がH、ハロゲン、OH、C_1～3アルキル、C_1～3ハロアルキル若しくはC_1～3アルコキシであり、及び/又は、mが0、1、2若しくは3であり、及び/又は、R''がH、ハロ、OH、NH₂、C_1～3アルキル、C_1～3アルコキシ、C_1～3ハロアルキル、C_1～3アルキルアミノ、C_3～5シクロアルキル、C_3～5シクロアルキルアミノ若しくはC_3～5ヘテロシクロアルキルである、実施形態30の方法又は使用。

and/or R''' is H, OH, _{C1-3 alkyl, C1-3 alkoxy or halogen, and/or R' is H, halogen, OH, C1-3 alkyl, C1-3 haloalkyl or C1-3 alkoxy , and} /or m is 0, 1, 2 or 3, and/or R'' is H, halo, OH, _NH2 , _C1-3 alkyl, _{C1-3 alkoxy, C1-3 haloalkyl} , _C1-3 alkylamino, _C3-5 cycloalkyl, _C3-5 cycloalkylamino or _C3-5 heterocycloalkyl.

Embodiment 33. The compound is of formula 6 or a pharma- ceutically acceptable salt, enantiomer, non-enantiomer, tautomer, racemate, solvate, metabolic precursor, or prodrug thereof, and R3 ^' is H or _C1-3 alkyl, and/or A is O, NH, or

であり、及び/又は、m2は1、2、3、4、5、6若しくは7であり、及び/又は、R^1'はO、NH若しくは

and/or m2 is 1, 2, 3, 4, 5, 6 or 7, and/or R ^1′ is O, NH or

であり、及び/又は、R'''がH、OH、C_1～3アルキル、C_1～3アルコキシ若しくはハロゲンであり、及び/又は、R'がH、ハロゲン、OH、C_1～3アルキル、C_1～3ハロアルキル若しくはC_1～3アルコキシであり、及び/又は、mが0、1、2若しくは3であり、及び/又は、R''がH、ハロ、OH、NH₂、C_1～3アルキル、C_1～3アルコキシ、C_1～3ハロアルキル、C_1～3アルキルアミノ、C_3～5シクロアルキル、C_3～5シクロアルキルアミノ若しくはC_3～5ヘテロシクロアルキルであり、及び/又は、nが0若しくは1である、実施形態30の方法又は使用。

and/or R''' is H, OH, _{C1-3 alkyl, C1-3 alkoxy or halogen, and/or R' is H, halogen, OH, C1-3 alkyl, C1-3 haloalkyl or C1-3 alkoxy , and} /or m is 0, 1, 2 or 3, and/or R'' is H, halo, OH, NH2, _C1-3 alkyl, _C1-3 alkoxy, _C1-3 haloalkyl, _C1-3 alkylamino, _C3-5 cycloalkyl, _C3-5 cycloalkylamino or _C3-5 heterocycloalkyl, and/or n is 0 _or 1.

Embodiment 34. The compound is a compound of formula 8 or a pharma- ceutically acceptable salt, enantiomer, non-enantiomer, tautomer, racemate, solvate, metabolic precursor, or prodrug thereof, and R3 ^' is H or _C1-3 alkyl, and/or A is O, NH,

であり、及び/又は、m2が1、2、3若しくは4であり、及び/又は、R^1'がO、NH、

and/or m2 is 1, 2, 3 or 4, and/or R ^1′ is O, NH,

であり、及び/又は、R'''がH、OH、C_1～3アルキル、C_1～3アルコキシ若しくはハロゲンであり、及び/又は、kが0若しくは1であり、及び/又は、R'がH、ハロゲン、OH、C_1～3アルキル、C_1～3ハロアルキル若しくはC_1～3アルコキシであり、及び/又は、mが0、1若しくは2であり、及び/又は、R''がH、ハロ、OH、NH₂、C_1～3アルキル、C_1～3アルコキシ、C_1～3ハロアルキル、C_1～3アルキルアミノ、C_3～5シクロアルキル、C_3～5シクロアルキルアミノ若しくはC_3～5ヘテロシクロアルキルであり、及び/又は、nが0、1若しくは2である、実施形態30の方法又は使用。

and/or R''' is H, OH, _{C1-3 alkyl, C1-3} alkoxy or halogen, and/or k is 0 or 1, and/or R' is H, halogen, OH, _C1-3 alkyl, _C1-3 haloalkyl or _C1-3 alkoxy, and/or m is 0, 1 or 2, and/or R'' is H, halo, OH, _NH2 , _C1-3 alkyl, _C1-3 alkoxy, _C1-3 haloalkyl, _C1-3 alkylamino, _C3-5 cycloalkyl, _C3-5 cycloalkylamino or _C3-5 heterocycloalkyl, and/or n is 0, 1 _or 2.

Embodiment 35. The compound is of formula 10 or a pharma- ceutically acceptable salt, enantiomer, non-enantiomer, tautomer, racemate, solvate, metabolic precursor, or prodrug thereof, and R3 ^' is H or _C1-3 alkyl, and/or each A is independently O, NH,

であり、及び/又は、m5が0若しくは1であり、及び/又は、m4が0若しくは1であり、及び/又は、m3が1、2、3、4若しくは5であり、及び/又は、R^1'がO、NH、

and/or m5 is 0 or 1, and/or m4 is 0 or 1, and/or m3 is 1, 2, 3, 4 or 5, and/or R ^1′ is O, NH,

であり、及び/又は、R'''がH、OH、C_1～3アルキル、C_1～3アルコキシ若しくはハロゲンであり、及び/又は、kが0若しくは1であり、及び/又は、R'がH、ハロゲン、OH、C_1～3アルキル、C_1～3ハロアルキル若しくはC_1～3アルコキシであり、及び/又は、mが0若しくは1であり、及び/又は、R''がH、ハロ、OH、NH₂、C_1～3アルキル、C_1～3アルコキシ、C_1～3ハロアルキル、C_1～3アルキルアミノ、C_3～5シクロアルキル、C_3～5シクロアルキルアミノ若しくはC_3～5ヘテロシクロアルキルであり、及び/又は、nが0若しくは1である、実施形態30の方法又は使用。

and/or R''' is H, OH, _{C1-3 alkyl, C1-3} alkoxy or halogen, and/or k is 0 or 1, and/or R' is H, halogen, OH, _C1-3 alkyl, _C1-3 haloalkyl or _C1-3 alkoxy, and/or m is 0 or 1, and/or R'' is H, halo, OH, _NH2 , _C1-3 alkyl, _C1-3 alkoxy, _C1-3 haloalkyl, _C1-3 alkylamino, _C3-5 cycloalkyl _{, C3-5} cycloalkylamino or _C3-5 heterocycloalkyl, and/or n is 0 or 1.

Embodiment 36. The compound is of formula 13 or a pharma- ceutically acceptable salt, enantiomer, non-enantiomer, tautomer, racemate, solvate, metabolic precursor, or prodrug thereof, and R3 ^' is H or _C1-3 alkyl, and/or A is O, NH,

であり、及び/又は、m2が1、2、3若しくは4であり、及び/又は、R^1'がO、NH、

and/or m2 is 1, 2, 3 or 4, and/or R ^1′ is O, NH,

であり、及び/又は、R'''がH、OH、C_1～3アルキル、C_1～3アルコキシ若しくはハロゲンであり、及び/又は、R'がH、ハロゲン、OH、C_1～3アルキル、C_1～3ハロアルキル若しくはC_1～3アルコキシであり、及び/又は、mが0、1、2若しくは3であり、及び/又は、R''がH、ハロ、OH、NH₂、C_1～3アルキル、C_1～3アルコキシ、C_1～3ハロアルキル、C_1～3アルキルアミノ、C_3～5シクロアルキル、C_3～5シクロアルキルアミノ若しくはC_3～5ヘテロシクロアルキルである、実施形態30の方法又は使用。

and/or R''' is H, OH, _{C1-3 alkyl, C1-3 alkoxy or halogen, and/or R' is H, halogen, OH, C1-3 alkyl, C1-3 haloalkyl or C1-3 alkoxy , and} /or m is 0, 1, 2 or 3, and/or R'' is H, halo, OH, _NH2 , _C1-3 alkyl, _{C1-3 alkoxy, C1-3 haloalkyl} , _C1-3 alkylamino, _C3-5 cycloalkyl, _C3-5 cycloalkylamino or _C3-5 heterocycloalkyl.

Embodiment 37. The compound of formula 1 is represented by formula 1-1

の化合物又はその薬学的に許容される塩、鏡像異性体、非鏡像異性体、互変異性体、ラセミ化合物、溶媒和物、代謝前駆体若しくはプロドラッグである、実施形態30の方法又は使用。

or a pharma- ceutically acceptable salt, enantiomer, non-enantiomer, tautomer, racemate, solvate, metabolic precursor or prodrug thereof.

Embodiment 38. The compound of formula 5 is represented by formula 5-1

の化合物又はその薬学的に許容される塩、鏡像異性体、非鏡像異性体、互変異性体、ラセミ化合物、溶媒和物、代謝前駆体若しくはプロドラッグである、実施形態30の方法又は使用。

or a pharma- ceutically acceptable salt, enantiomer, non-enantiomer, tautomer, racemate, solvate, metabolic precursor or prodrug thereof.

Embodiment 39. The compound of formula 6 is represented by formula 6-1

の化合物又はその薬学的に許容される塩、鏡像異性体、非鏡像異性体、互変異性体、ラセミ化合物、溶媒和物、代謝前駆体若しくはプロドラッグである実施形態30の方法又は使用。

or a pharma- ceutically acceptable salt, enantiomer, non-enantiomer, tautomer, racemate, solvate, metabolic precursor or prodrug thereof.

Embodiment 40. R ^3′ is H or C _1-3 alkyl and A is O, NH,

であり、m2が1、2、3、4、5、6及び7であり、R^1'がO、NH、

m2 is 1, 2, 3, 4, 5, 6, or 7; R ^1′ is O, NH,

であり、R'がH、C_1～3ハロアルキル又はC_1～3アルコキシであり、R''がH、F、Cl、OH、NH₂、C_1～3アルコキシ、メチルアミノ、ジメチルアミノ、ジエチルアミノ又はシクロプロピルアミノである、実施形態37の方法又は使用。

38. The method or use of embodiment 37, wherein R' is H, _C1-3 haloalkyl or _C1-3 alkoxy and R'' is H, F, Cl, OH, _NH2 , _C1-3 alkoxy, methylamino, dimethylamino, diethylamino or cyclopropylamino.

Embodiment 41. R ^3′ is H or C _1-3 alkyl and A is O, NH,

であり、m5が0又は1であり、m4が0、1、2、3又は4であり、m3が1、2、3、4、5又は6であり、R^1'がO、NH、

m5 is 0 or 1, m4 is 0, 1, 2, 3 or 4, m3 is 1, 2, 3, 4, 5 or 6, and R ^1′ is O, NH,

であり、R'''がH、OH、C_1～3アルキル、C_1～3アルコキシ又はハロゲンであり、R'がH、ハロゲン、OH、C_1～3アルキル、C_1～3ハロアルキル又はC_1～3アルコキシであり、R''がH、ハロ、OH、NH₂、C_1～3アルキル、C_1～3アルコキシ、C_1～3ハロアルキル、C_1～3アルキルアミノ、C_3～5シクロアルキル、C_3～5シクロアルキルアミノ及びC_3～5ヘテロシクロアルキルである、実施形態38の方法又は使用。

and R''' is H, OH, _C1-3 alkyl, _{C1-3 alkoxy or halogen, R' is H, halogen, OH, C1-3} alkyl, _C1-3 haloalkyl or _{C1-3 alkoxy, and R'' is H, halo, OH, NH2, C1-3 alkyl, C1-3 alkoxy , C1-3 haloalkyl , C1-3 alkylamino, C3-5 cycloalkyl, C3-5 cycloalkylamino and C3-5 heterocycloalkyl} .

Embodiment 42. R ^3′ is H or C _1-3 alkyl and A is O, NH,

であり、m2が1、2、3、4、5、6又は7であり、R^1'がO、NH、

m2 is 1, 2, 3, 4, 5, 6 or 7; R ^1′ is O, NH,

であり、R'''がH、OH、C_1～3アルキル、C_1～3アルコキシ若しくはハロゲンであり、R'がH、ハロゲン、OH、C_1～3アルキル、C_1～3ハロアルキル又はC_1～3アルコキシであり、mが0、1、2又は3であり、R''がH、ハロ、OH、NH₂、C_1～3アルキル、C_1～3アルコキシ、C_1～3ハロアルキル、C_1～3アルキルアミノ、C_3～5シクロアルキル、C_3～5シクロアルキルアミノ又はC_3～5ヘテロシクロアルキルである、実施形態39の方法又は使用。

40. The method or use of embodiment 39, wherein R''' is H, OH, _C1-3 alkyl, C1-3 alkoxy or halogen, R' is H, halogen, OH, _C1-3 alkyl, _C1-3 haloalkyl or _C1-3 alkoxy, m is 0, ₁ , ₂ or 3, and R'' is H, halo, OH, NH2, _C1-3 alkyl, _C1-3 alkoxy, _C1-3 haloalkyl, _C1-3 alkylamino, _C3-5 cycloalkyl, _C3-5 cycloalkylamino or _C3-5 heterocycloalkyl.

Embodiment 43. The method or use of embodiment 30, wherein the compound is a compound of formula 1, 5, 6, 8, 10 or 13 or a pharma- ceutically acceptable salt, enantiomer, non-enantiomer, tautomer, racemate, solvate, metabolic precursor or prodrug thereof, and K is CH and Q is N, or K is N and Q is CH, or both K and Q are CH.

Embodiment 44. The compound has the formula 3

の化合物又はその薬学的に許容される塩、鏡像異性体、非鏡像異性体、互変異性体、ラセミ化合物、溶媒和物、代謝前駆体若しくはプロドラッグであり、
R^1'がO、NH、

or a pharma- ceutically acceptable salt, enantiomer, non-enantiomer, tautomer, racemate, solvate, metabolic precursor, or prodrug thereof,
R ^1' is O, NH,

である、実施形態25の方法又は使用。

26. The method or use of embodiment 25,

Embodiment 45. The method or use of embodiment 44, wherein ^R2' is H, OH, _C1-3 alkyl, _C1-3 alkoxy, _C1-3 alkylamino or _NH2 , and/or m6 is 0, 1, 2 or 3, and/or R1 ^' is O or NH, and/or R' is H, halogen, OH, _C1-3 alkyl, _C1-3 haloalkyl or _C1-3 alkoxy, and/or R'' is H, halo, _{OH, NH2, C1-3 alkoxy, C3-5 cycloalkyl, C3-5 cycloalkylamino or C1-3 alkylamino, and/or R''' is H, OH, C1-3 alkyl , C1-3 alkoxy or halogen} .

Embodiment 46. Z is C and U is O or S, or Z is N and U is CH;
and/or the method or use of embodiment 44, wherein K is CH and Q is N, or K is N and Q is CH, or both K and Q are CH.

Embodiment 47. The compound has the formula 3-1

の化合物又はその薬学的に許容される塩、鏡像異性体、非鏡像異性体、互変異性体、ラセミ化合物、溶媒和物、代謝前駆体若しくはプロドラッグである、実施形態44の方法又は使用。

or a pharma- ceutically acceptable salt, enantiomer, non-enantiomer, tautomer, racemate, solvate, metabolic precursor or prodrug thereof.

Embodiment 48. ^R2' is H, OH, _C1-3 alkyl, C1-3 alkoxy, _C1-3 alkylamino or _NH2 , m6 is 0, _1, 2 or 3, and R1 ^' is O, NH,

であり、R''がH、ハロ、OH、NH₂、C_1～3アルコキシ、C_1～3ハロアルキル、C_3～5シクロアルキル、C_3～5シクロアルキルアミノ又はC_1～3アルキルアミノである、実施形態47の方法又は使用。

and R'' is H, halo, OH, NH2, _C1-3 alkoxy, _C1-3 haloalkyl _{, C3-5} cycloalkyl, _C3-5 cycloalkylamino or _C1-3 alkylamino.

Embodiment 49. The compound has the formula 15

の化合物又はその薬学的に許容される塩、鏡像異性体、非鏡像異性体、互変異性体、ラセミ化合物、溶媒和物、代謝前駆体若しくはプロドラッグであり、
m2が1、2、3、4、5、6又は7であり、R^1'がO、NH、

or a pharma- ceutically acceptable salt, enantiomer, non-enantiomer, tautomer, racemate, solvate, metabolic precursor, or prodrug thereof,
m2 is 1, 2, 3, 4, 5, 6 or 7; R ^1′ is O, NH,

である、実施形態26の方法又は使用。

27. The method or use of embodiment 26, wherein

In embodiment 50, m2 is 1, 2, 3, 4, 5, 6 or 7, and/or R ^1′ is O, NH,

であり、及び/又は、R'''がH、OH、C_1～3アルキル、C_1～3アルコキシ若しくはハロゲンであり、及び/又は、R'がH、ハロゲン、OH、C_1～3アルキル、C_1～3ハロアルキル若しくはC_1～3アルコキシであり、mが0、1、2若しくは3であり、及び/又は、R''がH、ハロ、OH、NH₂、C_1～3アルコキシ、C_3～5シクロアルキル、C_3～5シクロアルキルアミノ若しくはC_1～3アルキルアミノである、実施形態49の方法又は使用。

and/or R''' is H, OH, _{C1-3 alkyl, C1-3 alkoxy or halogen; and/or R' is H, halogen, OH, C1-3 alkyl} , _C1-3 haloalkyl or _C1-3 alkoxy, m is 0, 1, ₂ or 3; and/or R'' is H, halo, OH, _NH2 , _C1-3 alkoxy, _C3-5 cycloalkyl, _C3-5 cycloalkylamino or _C1-3 alkylamino.

Embodiment 51. The compound is of formula 2, 7, 9, 11, 12 or 14.

の化合物又はその薬学的に許容される塩、鏡像異性体、非鏡像異性体、互変異性体、ラセミ化合物、溶媒和物、代謝前駆体若しくはプロドラッグであり、
各Aが独立してO、NH、

or a pharma- ceutically acceptable salt, enantiomer, non-enantiomer, tautomer, racemate, solvate, metabolic precursor, or prodrug thereof,
Each A is independently O, NH,

であり
m2が2、3、4、5又は6であり、
m3が1、2、3、4、5又は6であり、
m4が0、1、2、3又は4であり、
m5が0、1、2又は3であり、
R^1'がO、NH、

and
m2 is 2, 3, 4, 5 or 6;
m3 is 1, 2, 3, 4, 5 or 6;
m4 is 0, 1, 2, 3 or 4;
m5 is 0, 1, 2 or 3;
R ^1' is O, NH,

である、実施形態27の方法又は使用。

28. The method or use of embodiment 27,

Embodiment 52. The compound is a compound of formula 2 or a pharma- ceutically acceptable salt, enantiomer, non-enantiomer, tautomer, racemate, solvate, metabolic precursor, or prodrug thereof, and R3 ^' is H or _C1-3 alkyl, and/or A is O, NH,

であり、及び/又は、m2が2、3、4、5若しくは6であり、及び/又は、R^1'がO、NH、

and/or m2 is 2, 3, 4, 5 or 6, and/or R ^1′ is O, NH,

であり、及び/又は、R''がH、ハロ、OH、NH₂、C_1～3アルキル、C_1～3アルコキシ、C_1～3ハロアルキル、C_1～3アルキルアミノ、C_3～5シクロアルキル、C_3～5シクロアルキルアミノ若しくはC_3～5ヘテロシクロアルキルであり、及び/又は、R'がH、ハロゲン、OH、C_1～3アルキル、C_1～3ハロアルキル若しくはC_1～3アルコキシであり、及び/又は、mが0、1、2若しくは3であり、及び/又は、R'''がH、OH、NH₂、C_1～3アルキル、C_1～3アルキルアミノ、C_1～3アルコキシ若しくはハロゲンである、実施形態51の方法又は使用。

and/or R″ is H, halo, OH, NH2, _C1-3 alkyl, _C1-3 alkoxy, _C1-3 haloalkyl, _C1-3 alkylamino, _C3-5 cycloalkyl, _C3-5 cycloalkylamino or _C3-5 heterocycloalkyl; and/or R′ is H, halogen, OH, _C1-3 alkyl, _C1-3 haloalkyl or _C1-3 alkoxy; and/or m is 0, 1 _{, 2 or 3; and/or R′″ is H, OH, NH2, C1-3 alkyl, C1-3 alkylamino , C1-3 alkoxy} or halogen.

Embodiment 53. The compound is of formula 7 or a pharma- ceutically acceptable salt, enantiomer, non-enantiomer, tautomer, racemate, solvate, metabolic precursor, or prodrug thereof, and R3 ^' is H or _C1-3 alkyl, and/or A is O, NH,

であり、及び/又は、m2が2、3、4、5若しくは6であり、及び/又は、R^1'がO、NH、

and/or m2 is 2, 3, 4, 5 or 6, and/or R ^1′ is O, NH,

であり、及び/又は、R''がH、ハロ、OH、NH₂、C_1～3アルキル、C_1～3アルコキシ、C_1～3ハロアルキル、C_1～3アルキルアミノ、C_3～5シクロアルキル、C_3～5シクロアルキルアミノ若しくはC_3～5ヘテロシクロアルキルであり、及び/又は、R'がH、ハロゲン、OH、C_1～3アルキル、C_1～3ハロアルキル若しくはC_1～3アルコキシであり、及び/又は、mが0、1、2若しくは3である、実施形態51の方法又は使用。

and/or R″ is H, halo, OH, NH2, _C1-3 alkyl, _C1-3 alkoxy, _C1-3 haloalkyl, _C1-3 alkylamino, _C3-5 cycloalkyl, _C3-5 cycloalkylamino or _C3-5 heterocycloalkyl; and/or R′ is H, halogen, OH, _C1-3 alkyl, _C1-3 haloalkyl or _C1-3 alkoxy; and/or m is 0, 1, ₂ or 3.

Embodiment 54. The compound is of formula 9 or a pharma- ceutically acceptable salt, enantiomer, non-enantiomer, tautomer, racemate, solvate, metabolic precursor, or prodrug thereof, and R3 ^' is H or _C1-3 alkyl, and/or A is O, NH,

であり、及び/又は、m2が2、3、4、5若しくは6であり、及び/又は、R^1'がO、NH、

and/or m2 is 2, 3, 4, 5 or 6, and/or R ^1′ is O, NH,

であり、及び/又は、R''がH、ハロ、OH、NH₂、C_1～3アルキル、C_1～3アルコキシ、C_1～3ハロアルキル、C_1～3アルキルアミノ、C_3～5シクロアルキル、C_3～5シクロアルキルアミノ若しくはC_3～5ヘテロシクロアルキルであり、及び/又は、R'がH、ハロゲン、OH、C_1～3アルキル、C_1～3ハロアルキル若しくはC_1～3アルコキシであり、及び/又は、mが0、1、2若しくは3であり、及び/又は、R'''がH、OH、NH₂、C_1～3アルキル、C_1～3アルキルアミノ、C_1～3アルコキシ若しくはハロゲンである、実施形態51の方法又は使用。

and/or R″ is H, halo, OH, NH2, _C1-3 alkyl, _C1-3 alkoxy, _C1-3 haloalkyl, _C1-3 alkylamino, _C3-5 cycloalkyl, _C3-5 cycloalkylamino or _C3-5 heterocycloalkyl; and/or R′ is H, halogen, OH, _C1-3 alkyl, _C1-3 haloalkyl or _C1-3 alkoxy; and/or m is 0, 1 _{, 2 or 3; and/or R′″ is H, OH, NH2, C1-3 alkyl, C1-3 alkylamino , C1-3 alkoxy} or halogen.

Embodiment 55. The compound is of formula 11 or a pharma- ceutically acceptable salt, enantiomer, non-enantiomer, tautomer, racemate, solvate, metabolic precursor, or prodrug thereof, and R3 ^' is H or _C1-3 alkyl, and/or A is O, NH,

であり、及び/又は、m2が2、3、4、5若しくは6であり、及び/又は、R^1'がO、NH、

and/or m2 is 2, 3, 4, 5 or 6, and/or R ^1′ is O, NH,

であり、及び/又は、R''がH、ハロ、OH、NH₂、C_1～3アルキル、C_1～3アルコキシ、C_1～3ハロアルキル、C_1～3アルキルアミノ、C_3～5シクロアルキル、C_3～5シクロアルキルアミノ若しくはC_3～5ヘテロシクロアルキルであり、及び/又は、R'がH、ハロゲン、OH、C_1～3アルキル、C_1～3ハロアルキル若しくはC_1～3アルコキシであり、及び/又は、mが0、1、2若しくは3であり、及び/又は、R'''がH、OH、NH₂、C_1～3アルキル、C_1～3アルキルアミノ、C_1～3アルコキシ若しくはハロゲンである、実施形態51の方法又は使用。

and/or R″ is H, halo, OH, NH2, _C1-3 alkyl, _C1-3 alkoxy, _C1-3 haloalkyl, _C1-3 alkylamino, _C3-5 cycloalkyl, _C3-5 cycloalkylamino or _C3-5 heterocycloalkyl; and/or R′ is H, halogen, OH, _C1-3 alkyl, _C1-3 haloalkyl or _C1-3 alkoxy; and/or m is 0, 1 _{, 2 or 3; and/or R′″ is H, OH, NH2, C1-3 alkyl, C1-3 alkylamino , C1-3 alkoxy} or halogen.

Embodiment 56. The compound is of formula 12 or a pharma- ceutically acceptable salt, enantiomer, non-enantiomer, tautomer, racemate, solvate, metabolic precursor, or prodrug thereof, wherein R3 ^' is H or _C1-3 alkyl, and each A is independently O, NH,

であり、m3が1、2、3、4、5又は6であり、m4が0又は1、2又は3であり、m5が0又は1、2又は3であり、R^1'がO、NH、

m3 is 1, 2, 3, 4, 5 or 6, m4 is 0 or 1, 2 or 3, m5 is 0 or 1, 2 or 3, and R ^1′ is O, NH,

であり、R''がH、ハロ、OH、NH₂、C_1～3アルキル、C_1～3アルコキシ、C_1～3ハロアルキル、C_1～3アルキルアミノ、C_3～5シクロアルキル、C_3～5シクロアルキルアミノ又はC_3～5ヘテロシクロアルキルであり、R'がH、ハロゲン、OH、C_1～3アルキル、C_1～3ハロアルキル又はC_1～3アルコキシであり、mが0、1、2又は3であり、R'''がH、OH、NH₂、C_1～3アルキル、C_1～3アルキルアミノ、C_1～3アルコキシ又はハロゲンである、実施形態51の方法又は使用。

and R″ is H, halo, OH, NH2, _C1-3 alkyl, _C1-3 alkoxy, _{C1-3 haloalkyl, C1-3 alkylamino, C3-5 cycloalkyl, C3-5 cycloalkylamino or C3-5 heterocycloalkyl; R′ is H, halogen, OH, C1-3 alkyl , C1-3 haloalkyl or C1-3 alkoxy} ; m is 0, 1, 2 or ₃ ; and R′″ is H, OH, _NH2 , _C1-3 alkyl, _C1-3 alkylamino, _C1-3 alkoxy or halogen.

Embodiment 57. The compound is of formula 14 or a pharma- ceutically acceptable salt, enantiomer, non-enantiomer, tautomer, racemate, solvate, metabolic precursor, or prodrug thereof, and R3 ^' is H or _C1-3 alkyl, and/or each A is independently O, NH,

であり、及び/又は、m3が1、2、3、4、5若しくは6であり、及び/又は、m4が0、1、2、3若しくは4であり、及び/又は、m5が0若しくは1、2若しくは3であり、及び/又は、R^1'がO、NH、

and/or m3 is 1, 2, 3, 4, 5 or 6, and/or m4 is 0, 1, 2, 3 or 4, and/or m5 is 0, 1, 2 or 3, and/or R ^{1 '} is O, NH,

であり、及び/又は、R''がH、ハロ、OH、NH₂、C_1～3アルキル、C_1～3アルコキシ、C_1～3ハロアルキル、C_1～3アルキルアミノ、C_3～5シクロアルキル、C_3～5シクロアルキルアミノ若しくはC_3～5ヘテロシクロアルキルであり、及び/又は、R'がH、ハロゲン、OH、C_1～3アルキル、C_1～3ハロアルキル若しくはC_1～3アルコキシであり、mが0、1、2若しくは3であり、及び/又は、R'''がH、OH、NH₂、C_1～3アルキル、C_1～3アルキルアミノ、C_1～3アルコキシ若しくはハロゲンである、実施形態51の方法又は使用。

and/or R″ is H, halo, OH, NH2, _C1-3 alkyl, _C1-3 alkoxy, _C1-3 haloalkyl, _C1-3 alkylamino, _C3-5 cycloalkyl, _C3-5 cycloalkylamino or _C3-5 heterocycloalkyl; and/or R′ is H, halogen, OH, _C1-3 alkyl, _C1-3 haloalkyl or _C1-3 alkoxy; m is 0, 1 _{, 2 or 3; and/or R′″ is H, OH, NH2, C1-3 alkyl, C1-3 alkylamino , C1-3 alkoxy} or halogen.

Embodiment 58. The compound has the formula 4

の化合物又はその薬学的に許容される塩、鏡像異性体、非鏡像異性体、互変異性体、ラセミ化合物、溶媒和物、代謝前駆体若しくはプロドラッグであり、
R^1'がO、NH、

or a pharma- ceutically acceptable salt, enantiomer, non-enantiomer, tautomer, racemate, solvate, metabolic precursor, or prodrug thereof,
R ^1' is O, NH,

である、実施形態28の方法又は使用。

29. The method or use of embodiment 28, wherein

Embodiment 59. ^R2' is H, OH, _C1-3 alkyl, _{C1-3 alkoxy, C1-3 alkylamino} or _NH2 , and/or m6 is 0, 1, 2 or 3, and/or R1 ^' is O, NH,

であり、及び/又は、R'がH、ハロゲン、OH、C_1～3アルキル、C_1～3ハロアルキル若しくはC_1～3アルコキシであり、R''がH、ハロ、OH、NH₂、C_1～3アルコキシ、C_3～5シクロアルキル、C_3～5シクロアルキルアミノ若しくはC_1～3アルキルアミノであり、及び/又は、R'''がH、OH、NH₂、C_1～3アルキル、C_1～3アルキルアミノ、C_1～3アルコキシ若しくはハロゲンである、実施形態58の方法又は使用。

and/or R' is H, halogen, OH, _C1-3 alkyl, _{C1-3 haloalkyl or C1-3 alkoxy} ; R'' is H, halo, OH, _NH2 , _C1-3 alkoxy, _C3-5 cycloalkyl, _C3-5 cycloalkylamino _or C1-3 alkylamino; and/or R''' is H, OH, _NH2 , _C1-3 alkyl, _C1-3 alkylamino, _C1-3 alkoxy or halogen.

Embodiment 60. The compound has the formula 4-1

の化合物又はその薬学的に許容される塩、鏡像異性体、非鏡像異性体、互変異性体、ラセミ化合物、溶媒和物、代謝前駆体若しくはプロドラッグである、実施形態58の方法又は使用。

or a pharma- ceutically acceptable salt, enantiomer, non-enantiomer, tautomer, racemate, solvate, metabolic precursor, or prodrug thereof.

Embodiment 61. The compound is of formula 16 or 17

の化合物又はその薬学的に許容される塩、鏡像異性体、非鏡像異性体、互変異性体、ラセミ化合物、溶媒和物、代謝前駆体若しくはプロドラッグであり、
m2が1、2、3、4、5、6又は7であり、R^1'がO、NH、

or a pharma- ceutically acceptable salt, enantiomer, non-enantiomer, tautomer, racemate, solvate, metabolic precursor, or prodrug thereof,
m2 is 1, 2, 3, 4, 5, 6 or 7; R ^1′ is O, NH,

である、実施形態29の方法又は使用。

30. The method or use of embodiment 29, wherein

Embodiment 62. The method or use of embodiment 61, wherein the compound is a compound of formula 16 or a pharma- ceutically acceptable salt, enantiomer, non-enantiomer, tautomer, racemate, solvate, metabolic precursor or prodrug thereof, and Z is C, U is O or S, and T is CH, or Z is N, U is CH, T is CH, Z is C, T is N, and U is CH.

Embodiment 63. The method or use of embodiment 61, wherein the compound is a compound of formula 17 or a pharma- ceutically acceptable salt, enantiomer, non-enantiomer, tautomer, racemate, solvate, metabolic precursor or prodrug thereof, and Z is C, U is O or S, and T is CH, or Z is N, U is CH, T is CH, Z is C, T is N, and U is CH.

Embodiment 64. The method or use of any one of embodiments 1 to 7, wherein the compound is selected from the compounds listed in Table 2 or a pharma- ceutically acceptable salt, enantiomer, non-enantiomer, tautomer, racemate, solvate, metabolic precursor, or prodrug thereof.

Embodiment 65. Formula A for treating synucleinopathy:
EBM-L-SBM (Formula A)
[Wherein,
EBM is an E3 ubiquitin ligase binding moiety
L is a linker covalently linking the EBM and TBM;
SBM has the formula:

のα-シヌクレインタンパク質結合部分
又はその薬学的に許容される塩、鏡像異性体、非鏡像異性体、互変異性体、ラセミ化合物、溶媒和物、代謝前駆体、プロドラッグであり、

or a pharma- ceutically acceptable salt, enantiomer, non-enantiomer, tautomer, racemate, solvate, metabolic precursor, or prodrug thereof;

はLに共有結合し、
(i)

is covalently bonded to L,
(i)

は、O、S及びNから選択される少なくとも1個の環ヘテロ原子を含有する置換若しくは非置換二環式縮合芳香族環であり、

is a substituted or unsubstituted bicyclic fused aromatic ring containing at least one ring heteroatom selected from O, S and N;

は、O、S及びNから選択される0～2個の環ヘテロ原子を含有する置換若しくは非置換単環式芳香族環であり、

is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S and N;

は、O、S及びNから選択される0～2個の環ヘテロ原子を含有する置換若しくは非置換単環式芳香族環であり、又は
(ii)

is a substituted or unsubstituted monocyclic aromatic ring containing 0-2 ring heteroatoms selected from O, S and N; or
(ii)

は、O、S及びNから選択される0～2個の環ヘテロ原子を含有する置換若しくは非置換単環式芳香族環であり、

is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S and N;

は、O、S及びNから選択される0～2個の環ヘテロ原子を含有する置換若しくは非置換単環式芳香族環であり、

is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S and N;

は、O、S及びNから選択される少なくとも1個の環ヘテロ原子を含有する置換若しくは非置換二環式縮合芳香族環である]の化合物又はその薬学的に許容される塩、鏡像異性体、非鏡像異性体、互変異性体、ラセミ化合物、溶媒和物、代謝前駆体若しくはプロドラッグ。

is a substituted or unsubstituted bicyclic fused aromatic ring containing at least one ring heteroatom selected from O, S and N, or a pharma- ceutically acceptable salt, enantiomer, non-enantiomer, tautomer, racemate, solvate, metabolic precursor or prodrug thereof.

Embodiment 66. Reducing α-synuclein aggregation Formula A:
EBM-L-SBM (Formula A)
[Wherein,
EBM is an E3 ubiquitin ligase binding moiety
L is a linker covalently linking the EBM and TBM;
SBM has the formula:

のα-シヌクレインタンパク質結合部分、
又はその薬学的に許容される塩、鏡像異性体、非鏡像異性体、互変異性体、ラセミ化合物、溶媒和物、代謝前駆体、プロドラッグであり、

the α-synuclein protein-binding portion of
or a pharma- ceutically acceptable salt, enantiomer, non-enantiomer, tautomer, racemate, solvate, metabolic precursor, or prodrug thereof;

はLに共有結合し、
(i)

is covalently bonded to L,
(i)

は、O、S及びNから選択される少なくとも1個の環ヘテロ原子を含有する置換若しくは非置換二環式縮合芳香族環であり、

is a substituted or unsubstituted bicyclic fused aromatic ring containing at least one ring heteroatom selected from O, S and N;

は、O、S及びNから選択される0～2個の環ヘテロ原子を含有する置換若しくは非置換単環式芳香族環であり、

is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S and N;

は、O、S及びNから選択される0～2個の環ヘテロ原子を含有する置換若しくは非置換単環式芳香族環であり、又は
(ii)

is a substituted or unsubstituted monocyclic aromatic ring containing 0-2 ring heteroatoms selected from O, S and N; or
(ii)

は、O、S及びNから選択される0～2個の環ヘテロ原子を含有する置換若しくは非置換単環式芳香族環であり、

is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S and N;

は、O、S及びNから選択される0～2個の環ヘテロ原子を含有する置換若しくは非置換単環式芳香族環であり、

is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S and N;

は、O、S及びNから選択される少なくとも1個の環ヘテロ原子を含有する置換若しくは非置換二環式縮合芳香族環である]の化合物又はその薬学的に許容される塩、鏡像異性体、非鏡像異性体、互変異性体、ラセミ化合物、溶媒和物、代謝前駆体若しくはプロドラッグ。

is a substituted or unsubstituted bicyclic fused aromatic ring containing at least one ring heteroatom selected from O, S and N, or a pharma- ceutically acceptable salt, enantiomer, non-enantiomer, tautomer, racemate, solvate, metabolic precursor or prodrug thereof.

Embodiment 67. Formula A for reducing Lewy bodies:
EBM-L-SBM (Formula A)
[Wherein,
EBM is an E3 ubiquitin ligase binding moiety
L is a linker covalently linking the EBM and TBM;
SBM has the formula:

のα-シヌクレインタンパク質結合部分、
又はその薬学的に許容される塩、鏡像異性体、非鏡像異性体、互変異性体、ラセミ化合物、溶媒和物、代謝前駆体、プロドラッグであり、

the α-synuclein protein-binding portion of
or a pharma- ceutically acceptable salt, enantiomer, non-enantiomer, tautomer, racemate, solvate, metabolic precursor, or prodrug thereof;

はLに共有結合し、
(i)

is covalently bonded to L,
(i)

は、O、S及びNから選択される少なくとも1個の環ヘテロ原子を含有する置換若しくは非置換二環式縮合芳香族環であり、

is a substituted or unsubstituted bicyclic fused aromatic ring containing at least one ring heteroatom selected from O, S and N;

は、O、S及びNから選択される0～2個の環ヘテロ原子を含有する置換若しくは非置換単環式芳香族環であり、

is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S and N;

は、O、S及びNから選択される0～2個の環ヘテロ原子を含有する置換若しくは非置換単環式芳香族環であり、又は
(ii)

is a substituted or unsubstituted monocyclic aromatic ring containing 0-2 ring heteroatoms selected from O, S and N; or
(ii)

は、O、S及びNから選択される0～2個の環ヘテロ原子を含有する置換若しくは非置換単環式芳香族環であり、

is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S and N;

は、O、S及びNから選択される0～2個の環ヘテロ原子を含有する置換若しくは非置換単環式芳香族環であり、

is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S and N;

は、O、S及びNから選択される少なくとも1個の環ヘテロ原子を含有する置換若しくは非置換二環式縮合芳香族環である]の化合物又はその薬学的に許容される塩、鏡像異性体、非鏡像異性体、互変異性体、ラセミ化合物、溶媒和物、代謝前駆体若しくはプロドラッグ。

is a substituted or unsubstituted bicyclic fused aromatic ring containing at least one ring heteroatom selected from O, S and N, or a pharma- ceutically acceptable salt, enantiomer, non-enantiomer, tautomer, racemate, solvate, metabolic precursor or prodrug thereof.

Claims (64)

A method of treating a synucleinopathy in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula A.
EBM-L-SBM (Formula A)
[Wherein,
EBM is an E3 ubiquitin ligase binding moiety
L is a linker covalently linking the EBM and TBM;
SBM has the formula:

is the alpha-synuclein protein-binding portion of

is covalently bonded to L,
(i)

is a substituted or unsubstituted bicyclic fused aromatic ring containing at least one ring heteroatom selected from O, S and N;

is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S and N;

is a substituted or unsubstituted monocyclic aromatic ring containing 0-2 ring heteroatoms selected from O, S and N; or
(ii)

is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S and N;

is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S and N;

is a substituted or unsubstituted bicyclic fused aromatic ring containing at least one ring heteroatom selected from O, S and N, or a pharma- ceutically acceptable salt, enantiomer, non-enantiomer, tautomer, racemate, solvate, metabolic precursor, or prodrug thereof. A method for reducing alpha-synuclein aggregation in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula A,
EBM-L-SBM (Formula A)
[Wherein,
EBM is an E3 ubiquitin ligase binding moiety
L is a linker covalently linking the EBM and TBM;
SBM has the formula:

is the alpha-synuclein protein-binding portion of

is covalently bonded to L,
(i)

is a substituted or unsubstituted bicyclic fused aromatic ring containing at least one ring heteroatom selected from O, S and N;

is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S and N;

is a substituted or unsubstituted monocyclic aromatic ring containing 0-2 ring heteroatoms selected from O, S and N; or
(ii)

is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S and N;

is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S and N;

is a substituted or unsubstituted bicyclic fused aromatic ring containing at least one ring heteroatom selected from O, S and N, or a pharma- ceutically acceptable salt, enantiomer, non-enantiomer, tautomer, racemate, solvate, metabolic precursor, or prodrug thereof. A method for reducing Lewy bodies in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula A
EBM-L-SBM (Formula A)
[Wherein,
EBM is an E3 ubiquitin ligase binding moiety
L is a linker covalently linking the EBM and TBM;
SBM has the formula:

is the alpha-synuclein protein-binding portion of

is covalently bonded to L,
(i)

is a substituted or unsubstituted bicyclic fused aromatic ring containing at least one ring heteroatom selected from O, S and N;

is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S and N;

is a substituted or unsubstituted monocyclic aromatic ring containing 0-2 ring heteroatoms selected from O, S and N; or
(ii)

is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S and N;

is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S and N;

is a substituted or unsubstituted bicyclic fused aromatic ring containing at least one ring heteroatom selected from O, S and N, or a pharma- ceutically acceptable salt, enantiomer, non-enantiomer, tautomer, racemate, solvate, metabolic precursor, or prodrug thereof. In the manufacture of a medicament for treating a synucleinopathy,
EBM-L-SBM (Formula A)
[Wherein,
EBM is an E3 ubiquitin ligase binding moiety
L is a linker covalently linking the EBM and TBM;
SBM has the formula:

is the alpha-synuclein protein-binding portion of

is covalently bonded to L,
(i)

is a substituted or unsubstituted bicyclic fused aromatic ring containing at least one ring heteroatom selected from O, S and N;

is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S and N;

is a substituted or unsubstituted monocyclic aromatic ring containing 0-2 ring heteroatoms selected from O, S and N; or
(ii)

is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S and N;

is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S and N;

is a substituted or unsubstituted bicyclic fused aromatic ring containing at least one ring heteroatom selected from O, S and N, or a pharma- ceutically acceptable salt, enantiomer, non-enantiomer, tautomer, racemate, solvate, metabolic precursor, or prodrug thereof. In the manufacture of a medicament for reducing α-synuclein aggregation,
EBM-L-SBM (Formula A)
[Wherein,
EBM is an E3 ubiquitin ligase binding moiety
L is a linker covalently linking the EBM and TBM;
SBM has the formula:

is the alpha-synuclein protein-binding portion of

is covalently bonded to L,
(i)

is a substituted or unsubstituted bicyclic fused aromatic ring containing at least one ring heteroatom selected from O, S and N;

is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S and N;

is a substituted or unsubstituted monocyclic aromatic ring containing 0-2 ring heteroatoms selected from O, S and N; or
(ii)

is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S and N;

is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S and N;

is a substituted or unsubstituted bicyclic fused aromatic ring containing at least one ring heteroatom selected from O, S and N, or a pharma- ceutically acceptable salt, enantiomer, non-enantiomer, tautomer, racemate, solvate, metabolic precursor, or prodrug thereof. In the manufacture of a medicament for reducing Lewy bodies,
EBM-L-SBM (Formula A)
[Wherein,
EBM is an E3 ubiquitin ligase binding moiety
L is a linker covalently linking the EBM and TBM;
SBM has the formula:

is the alpha-synuclein protein-binding portion of

is covalently bonded to L,
(i)

is a substituted or unsubstituted bicyclic fused aromatic ring containing at least one ring heteroatom selected from O, S and N;

is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S and N;

is a substituted or unsubstituted monocyclic aromatic ring containing 0-2 ring heteroatoms selected from O, S and N; or
(ii)

is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S and N;

is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S and N;

is a substituted or unsubstituted bicyclic fused aromatic ring containing at least one ring heteroatom selected from O, S and N, or a pharma- ceutically acceptable salt, enantiomer, non-enantiomer, tautomer, racemate, solvate, metabolic precursor, or prodrug thereof. The method according to claim 1 or the use according to claim 4, wherein the synucleinopathy is Parkinson's disease (PD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA), or a combination of two or more thereof. The method or use according to any one of claims 1 to 7, wherein the substituted or unsubstituted bicyclic fused aromatic ring is a substituted or unsubstituted bicyclic 5-6 system. the SBM being of formula B or formula C;

In the formula,
Z is C or N, U is O, S or CH, V is N or NH;
K is CH or N and Q is CH or N, where K and Q are not both N;
each occurrence of R''' is independently selected from the group consisting of H, OH, _NH2 , _C1-6 alkyl, _C1-6 alkylamino, _C1-6 alkoxy, and halogen; k is 0, 1, 2, or 3;
each occurrence of R' is independently selected from the group consisting of H, halogen, OH, _C1-6 alkyl, _C1-6 haloalkyl, and _C1-6 alkoxy; and m is 0, 1, 2, 3, or 4;
each occurrence of R'' is independently selected from the group consisting of H, halo, OH, NH2, _C1-6 alkyl, _C1-6 alkoxy _{, C1-6} haloalkyl, _C1-6 alkylamino, _C3-6 cycloalkylamino, _C3-6 cycloalkyl, and _C3-6 heterocycloalkyl; n is 0, 1, or 2;
J is ^CR6 or N, X is ^CR6 or N, and Y is ^CR6 or N, where at least one of J, X, and Y is N, but J and Y are not both N, and X and Y are not both N;
R ⁶ is independently selected from the group consisting of H, NH ₂ , C _1-6 alkyl, and C _1-6 alkoxy, wherein NH ₂ , C _1-6 alkyl, or C _1-6 alkoxy is optionally substituted with one to three of C _1-3 alkyl, C _3-6 cycloalkyl, and/or halo;
In formula B, V is N, where Z and U are not both heteroatoms;
9. The method or use according to any one of claims 1 to 8, wherein in formula C, V is N or NH and T is CH or N, and up to two of U, Z, V and T contain a heteroatom. EBM,

and
R ^3' is H or C _1-6 alkyl;
each occurrence of R2 ^' is independently selected from the group consisting of H, OH, _C1-6 alkyl, _C1-6 alkoxy, _C1-6 alkylamino, and _NH2 ;
m6 is 0, 1, 2, 3 or 4;
_Y1 is _CH2 or

10. The method or use according to any one of claims 1 to 9, wherein The compound is represented by Formula I to Formula VI

[Wherein,
_L1 is a bond, -C(=O)-, -NR-, -O- or -S-, and R is hydrogen, optionally substituted acyl, optionally substituted alkyl or a nitrogen protecting group.
_L2 is a substituted or unsubstituted _C1-50 hydrocarbon chain, optionally wherein one or more chain atoms of the hydrocarbon chain are independently replaced with -C(=O)-, -O-, -NR ^a1 -, -S-, or a cyclic moiety, and R ^a1 is independently hydrogen, substituted or unsubstituted _C1-6 alkyl, or a nitrogen protecting group;
Z is C or N and U is O, S or CH;
K is CH or N and Q is CH or N, where K and Q are not both N;
each occurrence of R''' is independently selected from the group consisting of H, OH, _NH2 , _C1-6 alkyl, _C1-6 alkylamino, _C1-6 alkoxy, and halogen; k is 0, 1, 2, or 3;
each occurrence of R' is independently selected from the group consisting of H, halogen, OH, _C1-6 alkyl, _C1-6 haloalkyl, and _C1-6 alkoxy; and m is 0, 1, 2, 3, or 4;
each occurrence of R'' is independently selected from the group consisting of H, halo, OH, NH2, _C1-6 alkyl, _C1-6 alkoxy _{, C1-6} haloalkyl, _C1-6 alkylamino, _C3-6 cycloalkylamino, _C3-6 cycloalkyl, and _C3-6 heterocycloalkyl; n is 0, 1, or 2;
J is ^CR6 or N, X is ^CR6 or N, and Y is ^CR6 or N, where at least one of J, X, and Y is N, but J and Y are not both N, and X and Y are not both N;
R ⁶ is independently selected from the group consisting of H, NH ₂ , C _1-6 alkyl, and C _1-6 alkoxy, wherein NH ₂ , C _1-6 alkyl, or C _1-6 alkoxy is optionally substituted with one to three of C _1-3 alkyl, C _3-6 cycloalkyl, and/or halo;
In formula I, _L3 is a bond, -NR-, -O- or -S-; R is hydrogen, optionally substituted acyl, optionally substituted alkyl or a nitrogen protecting group; R3 ^' is H or _C1-6 alkyl; _Y1 is _CH2 or

and V is N, where Z and U are not both heteroatoms;
In formula II, R2 ^' at each occurrence is independently selected from the group consisting of H, OH, _C1-6 alkyl, _C1-6 alkoxy, _C1-6 alkylamino, and _NH2 ; m6 is 0, 1, 2, 3, or 4; _Y1 is _CH2 or

and V is N, where Z and U are not both heteroatoms;
In formula III, V is N, where Z and U are not both heteroatoms;
In formula IV, _L3 is a bond, -NR-, -O- or -S-; R is hydrogen, optionally substituted acyl, optionally substituted alkyl or a nitrogen protecting group; R3 ^' is H or _C1-6 alkyl; _Y1 is _CH2 or

wherein V is N or NH and T is CH or N, where up to two of U, Z, V and T contain a heteroatom;
In formula V, each occurrence of R2 ^' is independently selected from the group consisting of H, OH, _C1-6 alkyl, _{C1-6 alkoxy, C1-6 alkylamino} , and NH2; m6 is 0, 1, 2, 3, or ₄ ; and _Y1 is _CH2 or

wherein V is N or NH and T is CH or N, where up to two of U, Z, V and T contain a heteroatom;
11. The method or use according to any one of claims 1 to 10, wherein the compound is any one of the compounds of formula VI, wherein V is N and T is CH or N, and up to two of U, Z, V and T contain a heteroatom; or a pharma- ceutically acceptable salt, enantiomer, non-enantiomer, tautomer, racemate, solvate, metabolic precursor or prodrug thereof. _L2 is an optionally substituted _C1-45 hydrocarbon chain, optionally wherein one or more chain atoms of the hydrocarbon chain are independently replaced with -C(=O)-, -O-, -NR ^a1 -, -S-, or a cyclic moiety, and R ^a1 is independently hydrogen, substituted or unsubstituted _C1-6 alkyl, or a nitrogen protecting group;
Preferably, _L2 is a substituted or unsubstituted _C5-40 hydrocarbon chain;
Preferably, _L2 is a substituted or unsubstituted _C1-30 , _C1-24 or _C1-20 hydrocarbon chain, optionally wherein one or more chain atoms of the hydrocarbon chain are independently replaced with -C(=O)-, -O-, ^-NRa1- , -S- or a cyclic moiety, and ^Ra1 is independently hydrogen, substituted or unsubstituted _C1-6 alkyl or a nitrogen protecting group;
The method or use according to claim 11, preferably wherein L ₂ is an unsubstituted C _1-26 , C _5-26 , C _5-20 , C _5-15 , C _15-20 or C _20-25 hydrocarbon chain in which one or more chain atoms of the hydrocarbon chain are independently replaced by -C(=O)-, -O- or -NR ^a1 -, and R ^a1 is independently hydrogen, substituted or unsubstituted C _1-6 alkyl or a nitrogen protecting group. _L2 is an optionally substituted _C1-30 hydrocarbon chain, in which one or more chain atoms of the hydrocarbon chain are independently replaced with -O- or -NR ^a1 -, and R ^a1 is independently hydrogen, substituted or unsubstituted _C1-6 alkyl or a nitrogen protecting group;
The method or use according to claim 11, wherein preferably at least one chain atom of the hydrocarbon chain of _L2 is independently replaced by -C(=O)-, -O-, -S-, -NR ^a1 -, -N= or =N-, and R ^a1 is independently hydrogen, substituted or unsubstituted C _1-6 alkyl or a nitrogen protecting group, preferably replaced by -O-. _L2 is selected from the group consisting of substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted heteroalkylene, and combinations thereof;
The method or use according to claim 11, wherein _L2 is selected from the group consisting of substituted and unsubstituted alkylene, substituted and unsubstituted alkenylene, substituted and unsubstituted alkynylene, substituted and unsubstituted heteroalkylene, substituted and unsubstituted heteroalkenylene, substituted and unsubstituted heteroalkynylene, substituted and unsubstituted heterocyclylene, substituted and unsubstituted carbocyclylene, substituted and unsubstituted arylene, substituted and unsubstituted heteroarylene and combinations thereof. Carbocyclylene or heterocyclylene

15. The method or use according to claim 14, wherein 15. The method or use of claim 14, wherein L ₂ comprises at least one example selected from the group consisting of substituted _or unsubstituted C _1-6 alkylene, substituted or unsubstituted C _2-6 alkenylene, substituted or unsubstituted C _2-6 alkynylene, substituted or unsubstituted hetero C _1-6 alkylene, substituted or unsubstituted hetero C _2-6 alkenylene, substituted or unsubstituted hetero C _{2-6 alkynylene, substituted or unsubstituted C 3-6} carbocyclylene, substituted or unsubstituted 3-6 membered heterocyclylene, substituted or unsubstituted phenylene and substituted or unsubstituted 5-6 membered heteroarylene. 15. The method or use of claim 14, wherein _L2 comprises at _least one _example selected from _the group consisting of substituted or unsubstituted methylene, ethylene, _n -propylene _{, n} -butylene, n-pentylene, n-hexylene, -( _CH2 ) _{2 -} O( _CH2 ) _{2- ,} -OCH2-, -CH2O-, -O( _CH2 ) _2- , -( _CH2 ) _2O- , -O(CH2) _3- , -( _CH2 )3O-, -O( _CH2 ) _4- , -( _CH2 ) _{4O-, -O(CH2)5- , -} (CH2 _{) 5O-} , -O(CH2)6-, -O(CH2)6O-, -C(=O)O-, -OC(=O)-, -NH-C(=O)- and -C(=O)NH-. at least one chain atom of the hydrocarbon chain of _L2 is independently replaced with a 6-membered heterocyclyl group having 1 to 3 ring heteroatoms selected from the group consisting of nitrogen and oxygen;
Preferably, at least one chain atom of the hydrocarbon chain of _L2 is independently replaced with piperidine, piperazine or morpholine;
15. The method or use of claim 14, wherein preferably at least one chain atom of the hydrocarbon chain of _L2 is independently replaced with an optionally substituted phenyl group. The method or use of claim 14, wherein _L2 is an unsubstituted hydrocarbon chain, optionally one or more chain atoms of the hydrocarbon chain are independently replaced with -NR ^a1 -, and each instance of R ^a1 is independently hydrogen, substituted or unsubstituted C _1-6 alkyl or a nitrogen protecting group, or optionally two instances of R ^a1 together with intervening atoms form a substituted or unsubstituted heterocyclic ring or a substituted or unsubstituted heteroaryl ring. 20. The method or use of claim 19, wherein at least one instance of R ^a1 is hydrogen, a substituted or unsubstituted C _1-6 alkyl (e.g., substituted or unsubstituted methyl or ethyl), or a nitrogen protecting group (e.g., benzyl, t-butyl carbonate, benzyl carbamate, 9-fluorenylmethyl carbonate, trifluoroacetyl, triphenylmethyl, acetyl, or p-toluenesulfonamide). _L2

and g is 1, 2, 3, 4, 5 or 6. _L2 is the moiety -O-,

12. The method or use of claim 11, comprising -NHC(=O)- or -NH-. _L2 ,

wherein each g is independently 1, 2, 3, 4, 5 or 6; f is 1, 2, 3, 4, 5 or 6; and h is 1, 2, 3, 4, 5 or 6. The compound of formula I is represented by formula I-1

or a pharma- ceutically acceptable salt, enantiomer, non-enantiomer, tautomer, racemate, solvate, metabolic precursor or prodrug thereof. The compound of formula II is represented by formula II-1

or a pharma- ceutically acceptable salt, enantiomer, non-enantiomer, tautomer, racemate, solvate, metabolic precursor or prodrug thereof. The compound of formula III is represented by formula III-1

or a pharma- ceutically acceptable salt, enantiomer, non-enantiomer, tautomer, racemate, solvate, metabolic precursor or prodrug thereof. The compound of formula IV is represented by formula IV-1

or a pharma- ceutically acceptable salt, enantiomer, non-enantiomer, tautomer, racemate, solvate, metabolic precursor or prodrug thereof. The compound of formula V is represented by formula V-1

or a pharma- ceutically acceptable salt, enantiomer, non-enantiomer, tautomer, racemate, solvate, metabolic precursor or prodrug thereof. The compound of formula VI is represented by formula VI-1

or a pharma- ceutically acceptable salt, enantiomer, non-enantiomer, tautomer, racemate, solvate, metabolic precursor or prodrug thereof. The compound of formula I-1 is represented by formula 1, 5, 6, 8, 10 or 13

or a pharma- ceutically acceptable salt, enantiomer, non-enantiomer, tautomer, racemate, solvate, metabolic precursor, or prodrug thereof,
Each A is independently O, NH,

and
m2 is 1, 2, 3, 4, 5, 6, or 7
m3 is 1, 2, 3, 4, 5 or 6;
m4 is 0, 1, 2 or 3;
m5 is 0, 1, 2 or 3;
R ^1' is O, NH,

25. The method or use of claim 24, wherein The compound is of formula 1 or a pharma- ceutically acceptable salt, enantiomer, non-enantiomer, tautomer, racemate, solvate, metabolic precursor or prodrug thereof, R' is H, _C1-3 haloalkyl or _C1-3 alkoxy, and/or R'' is H, halo, OH, _NH2 , _C1-3 alkoxy, C1-3 alkylamino _{, C3-5} cycloalkyl, _C3-5 cycloalkylamino and _C3-5 heterocycloalkyl, and/or R''' is H, OH or halogen, and/or R1 ^' is O, NH,

and/or A is O, NH,

and/or m2 is 2, 3, 4 or 6; and/or R ^3' is H or C _1-3 alkyl. The compound is of formula 5 or a pharma- ceutically acceptable salt, enantiomer, non-enantiomer, tautomer, racemate, solvate, metabolic precursor, or prodrug thereof, R3 ^' is H or _C1-3 alkyl, and/or each A is independently O, NH,

and/or m4 is 0, 1, 2 or 3, and/or m5 is 0, 1, 2 or 3, and/or m3 is 1, 2, 3, 4, 5 or 6, and/or R ^1′ is O, NH or

and/or R''' is H, OH, _{C1-3 alkyl, C1-3 alkoxy or halogen, and/or R' is H, halogen, OH, C1-3 alkyl, C1-3 haloalkyl or C1-3 alkoxy , and} /or m is 0, 1, 2 or 3, and/or R'' is H, halo, OH, _NH2 , _C1-3 alkyl, _{C1-3 alkoxy, C1-3 haloalkyl} , _C1-3 alkylamino, _C3-5 cycloalkyl, _C3-5 cycloalkylamino or _C3-5 heterocycloalkyl. the compound is of formula 6 or a pharma- ceutically acceptable salt, enantiomer, non-enantiomer, tautomer, racemate, solvate, metabolic precursor, or prodrug thereof, R ^3' is H or C _1-3 alkyl, and/or A is O, NH, or

and/or m2 is 1, 2, 3, 4, 5, 6 or 7, and/or R ^1′ is O, NH or

and/or R''' is H, OH, _{C1-3 alkyl, C1-3 alkoxy or halogen, and/or R' is H, halogen, OH, C1-3 alkyl, C1-3 haloalkyl or C1-3 alkoxy , and} /or m is 0, 1, 2 or 3, and/or R'' is H, halo, OH, _NH2 , _C1-3 alkyl, _C1-3 alkoxy, C1-3 haloalkyl, _C1-3 alkylamino, _C3-5 cycloalkyl, _C3-5 cycloalkylamino or _C3-5 heterocycloalkyl, and/or n is 0 _or 1. The compound is of formula 8 or a pharma- ceutically acceptable salt, enantiomer, non-enantiomer, tautomer, racemate, solvate, metabolic precursor or prodrug thereof, R3 ^' is H or _C1-3 alkyl, and/or A is O, NH,

and/or m2 is 1, 2, 3 or 4, and/or R ^1′ is O, NH,

and/or R''' is H, OH, _{C1-3 alkyl, C1-3} alkoxy or halogen, and/or k is 0 or 1, and/or R' is H, halogen, OH, _C1-3 alkyl, _C1-3 haloalkyl or _C1-3 alkoxy, and/or m is 0, 1 or 2, and/or R'' is H, halo, OH, _NH2 , _C1-3 alkyl, _C1-3 alkoxy, _C1-3 haloalkyl, _C1-3 alkylamino, _C3-5 cycloalkyl, _C3-5 cycloalkylamino or _C3-5 heterocycloalkyl, and/or n is 0, 1 _or 2. The compound is of formula 10, or a pharma- ceutically acceptable salt, enantiomer, non-enantiomer, tautomer, racemate, solvate, metabolic precursor, or prodrug thereof; R ^3' is H or C _1-3 alkyl; and/or each A is independently O, NH,

and/or m5 is 0 or 1, and/or m4 is 0 or 1, and/or m3 is 1, 2, 3, 4 or 5, and/or R ^1′ is O, NH,

and/or R''' is H, OH, _{C1-3 alkyl, C1-3} alkoxy or halogen, and/or k is 0 or 1, and/or R' is H, halogen, OH, _C1-3 alkyl, _C1-3 haloalkyl or _C1-3 alkoxy, and/or m is 0 or 1, and/or R'' is H, halo, OH, _NH2 , _C1-3 alkyl, _C1-3 alkoxy, _C1-3 haloalkyl, _C1-3 alkylamino, _C3-5 cycloalkyl, _C3-5 cycloalkylamino or _C3-5 heterocycloalkyl _, and/or n is 0 or 1. The compound is of formula 13 or a pharma- ceutically acceptable salt, enantiomer, non-enantiomer, tautomer, racemate, solvate, metabolic precursor or prodrug thereof, R3 ^' is H or _C1-3 alkyl, and/or A is O, NH,

and/or m2 is 1, 2, 3 or 4, and/or R ^1′ is O, NH,

and/or R''' is H, OH, _{C1-3 alkyl, C1-3 alkoxy or halogen, and/or R' is H, halogen, OH, C1-3 alkyl, C1-3 haloalkyl or C1-3 alkoxy , and} /or m is 0, 1, 2 or 3, and/or R'' is H, halo, OH, _NH2 , _C1-3 alkyl, _{C1-3 alkoxy, C1-3 haloalkyl} , _C1-3 alkylamino, _C3-5 cycloalkyl, _C3-5 cycloalkylamino or _C3-5 heterocycloalkyl. The compound of formula 1 is represented by formula 1-1

or a pharma- ceutically acceptable salt, enantiomer, non-enantiomer, tautomer, racemate, solvate, metabolic precursor or prodrug thereof. The compound of formula 5 is represented by formula 5-1

or a pharma- ceutically acceptable salt, enantiomer, non-enantiomer, tautomer, racemate, solvate, metabolic precursor or prodrug thereof. The compound of formula 6 is represented by formula 6-1

or a pharma- ceutically acceptable salt, enantiomer, non-enantiomer, tautomer, racemate, solvate, metabolic precursor or prodrug thereof. R ^3' is H or C _1-3 alkyl, A is O, NH,

m2 is 1, 2, 3, 4, 5, 6, or 7; R ^1′ is O, NH,

38. The method or use according to claim 37, wherein R' is H, _C1-3 haloalkyl or _C1-3 alkoxy and R'' is H, F, Cl, OH, _NH2 , _C1-3 alkoxy, methylamino, dimethylamino, diethylamino or cyclopropylamino. R ^3' is H or C _1-3 alkyl, A is O, NH,

m5 is 0 or 1, m4 is 0, 1, 2, 3 or 4, m3 is 1, 2, 3, 4, 5 or 6, and R ^1′ is O, NH,

39. The method or use according to claim 38, wherein R''' is H, OH, _C1-3 alkyl, _{C1-3 alkoxy or halogen, R' is H, halogen, OH, C1-3 alkyl} , _C1-3 haloalkyl or _C1-3 alkoxy and R'' is H, halo, OH, _NH2 , _C1-3 alkyl, _C1-3 alkoxy, _C1-3 haloalkyl, _C1-3 alkylamino, _C3-5 cycloalkyl, _C3-5 cycloalkylamino and _C3-5 heterocycloalkyl. R ^3' is H or C _1-3 alkyl, A is O, NH,

m2 is 1, 2, 3, 4, 5, 6 or 7; R ^1′ is O, NH,

40. The method or use of claim 39, wherein R''' is H, OH, _C1-3 alkyl, _{C1-3 alkoxy or halogen, R' is H, halogen, OH, C1-3} alkyl, _C1-3 haloalkyl or _C1-3 alkoxy, m is 0, 1 _{, 2 or 3 and R'' is H, halo, OH, NH2, C1-3 alkyl} , _C1-3 alkoxy, _C1-3 haloalkyl, _C1-3 alkylamino, _C3-5 cycloalkyl, _C3-5 cycloalkylamino or _C3-5 heterocycloalkyl. 31. The method or use of claim 30, wherein the compound is a compound of formula 1, 5, 6, 8, 10 or 13 or a pharma- ceutically acceptable salt, enantiomer, non-enantiomer, tautomer, racemate, solvate, metabolic precursor or prodrug thereof, and K is CH and Q is N, or K is N and Q is CH, or both K and Q are CH. The compound is of formula 3

or a pharma- ceutically acceptable salt, enantiomer, non-enantiomer, tautomer, racemate, solvate, metabolic precursor, or prodrug thereof, wherein R ^1′ is O, NH,

26. The method or use of claim 25, 45. The method or use according to claim 44, wherein R2 ^' is H, OH, _C1-3 alkyl, _C1-3 alkoxy, _C1-3 alkylamino or _NH2 , and/or m6 is 0, 1, 2 or 3, and/or ^R1' is O or NH, and/or R' is H, halogen, OH, _C1-3 alkyl, _C1-3 haloalkyl or _C1-3 alkoxy, and/or R'' is H, halo, OH, _NH2 , _C1-3 alkoxy, _C3-5 cycloalkyl, _C3-5 cycloalkylamino or _C1-3 alkylamino, and/or R''' is H, OH, _C1-3 alkyl, _C1-3 alkoxy or halogen. Z is C and U is O or S, or Z is N and U is CH;
45. The method or use of claim 44, wherein K is CH and Q is N, or K is N and Q is CH, or both K and Q are CH. The compound of formula 3-1

or a pharma- ceutically acceptable salt, enantiomer, non-enantiomer, tautomer, racemate, solvate, metabolic precursor or prodrug thereof. R2 ^' is H, OH, _C1-3 alkyl, _C1-3 alkoxy, _C1-3 alkylamino or _NH2 , m6 is 0, 1, 2 or 3, R1 ^' is O, NH,

48. The method or use of claim 47, wherein R'' is H, halo, OH, _NH2 , _C1-3 alkoxy, _C1-3 haloalkyl, _C3-5 cycloalkyl, _C3-5 cycloalkylamino or _C1-3 alkylamino. The compound is of formula 15

or a pharma- ceutically acceptable salt, enantiomer, non-enantiomer, tautomer, racemate, solvate, metabolic precursor, or prodrug thereof, wherein m2 is 1, 2, 3, 4, 5, 6, or 7; and R1 ^' is O, NH,

27. The method or use of claim 26, m2 is 1, 2, 3, 4, 5, 6 or 7, and/or R ^1′ is O, NH,

and/or R''' is H, OH, _{C1-3 alkyl, C1-3 alkoxy or halogen; and/or R' is H, halogen, OH, C1-3 alkyl} , _C1-3 haloalkyl or _C1-3 alkoxy, m is 0, 1, ₂ or 3; and/or R'' is H, halo, OH, _NH2 , _C1-3 alkoxy, _C3-5 cycloalkyl, _C3-5 cycloalkylamino or _C1-3 alkylamino. The compound is represented by formula 2, 7, 9, 11, 12 or 14

or a pharma- ceutically acceptable salt, enantiomer, non-enantiomer, tautomer, racemate, solvate, metabolic precursor, or prodrug thereof,
Each A is independently O, NH,

and
m2 is 2, 3, 4, 5 or 6;
m3 is 1, 2, 3, 4, 5 or 6;
m4 is 0, 1, 2, 3 or 4;
m5 is 0, 1, 2 or 3;
R ^1' is O, NH,

28. The method or use of claim 27, The compound is of formula 2 or a pharma- ceutically acceptable salt, enantiomer, non-enantiomer, tautomer, racemate, solvate, metabolic precursor or prodrug thereof, R3 ^' is H or _C1-3 alkyl, and/or A is O, NH,

and/or m2 is 2, 3, 4, 5 or 6, and/or R ^1′ is O, NH,

and/or R″ is H, halo, OH, NH2, _C1-3 alkyl, _C1-3 alkoxy, _C1-3 haloalkyl, _C1-3 alkylamino, _C3-5 cycloalkyl, _C3-5 cycloalkylamino or _C3-5 heterocycloalkyl; and/or R′ is H, halogen, OH, _C1-3 alkyl, _C1-3 haloalkyl or _C1-3 alkoxy; and/or m is 0, 1 _{, 2 or 3; and/or R′″ is H, OH, NH2, C1-3 alkyl, C1-3 alkylamino , C1-3 alkoxy} or halogen. The compound is of formula 7 or a pharma- ceutically acceptable salt, enantiomer, non-enantiomer, tautomer, racemate, solvate, metabolic precursor or prodrug thereof, R3 ^' is H or _C1-3 alkyl, and/or A is O, NH,

and/or m2 is 2, 3, 4, 5 or 6, and/or R ^1′ is O, NH,

and/or R″ is H, halo, OH, NH2, _C1-3 alkyl, _C1-3 alkoxy, _C1-3 haloalkyl, _C1-3 alkylamino, _C3-5 cycloalkyl, _C3-5 cycloalkylamino or _C3-5 heterocycloalkyl; and/or R′ is H, halogen, OH, _C1-3 alkyl, _C1-3 haloalkyl or _C1-3 alkoxy; and/or m is 0, 1, ₂ or 3. The compound is of formula 9 or a pharma- ceutically acceptable salt, enantiomer, non-enantiomer, tautomer, racemate, solvate, metabolic precursor or prodrug thereof, R3 ^' is H or _C1-3 alkyl, and/or A is O, NH,

and/or m2 is 2, 3, 4, 5 or 6, and/or R ^1′ is O, NH,

and/or R″ is H, halo, OH, NH2, _C1-3 alkyl, _C1-3 alkoxy, _C1-3 haloalkyl, _C1-3 alkylamino, _C3-5 cycloalkyl, _C3-5 cycloalkylamino or _C3-5 heterocycloalkyl; and/or R′ is H, halogen, OH, _C1-3 alkyl, _C1-3 haloalkyl or _C1-3 alkoxy; and/or m is 0, 1 _{, 2 or 3; and/or R′″ is H, OH, NH2, C1-3 alkyl, C1-3 alkylamino , C1-3 alkoxy} or halogen. The compound is of formula 11 or a pharma- ceutically acceptable salt, enantiomer, non-enantiomer, tautomer, racemate, solvate, metabolic precursor, or prodrug thereof, R3 ^' is H or _C1-3 alkyl, and/or A is O, NH,

and/or m2 is 2, 3, 4, 5 or 6, and/or R ^1′ is O, NH,

and/or R″ is H, halo, OH, NH2, _C1-3 alkyl, _C1-3 alkoxy, _C1-3 haloalkyl, _C1-3 alkylamino, _C3-5 cycloalkyl, _C3-5 cycloalkylamino or _C3-5 heterocycloalkyl; and/or R′ is H, halogen, OH, _C1-3 alkyl, _C1-3 haloalkyl or _C1-3 alkoxy; and/or m is 0, 1 _{, 2 or 3; and/or R′″ is H, OH, NH2, C1-3 alkyl, C1-3 alkylamino , C1-3 alkoxy} or halogen. The compound is of formula 12, or a pharma- ceutically acceptable salt, enantiomer, non-enantiomer, tautomer, racemate, solvate, metabolic precursor, or prodrug thereof, wherein R ^3' is H or C _1-3 alkyl, and each A is independently O, NH,

m3 is 1, 2, 3, 4, 5 or 6, m4 is 0 or 1, 2 or 3, m5 is 0 or 1, 2 or 3, and R ^1′ is O, NH,

52. The method or use of claim 51, wherein R'' is H, halo, OH, NH2, _C1-3 alkyl, _C1-3 alkoxy, _C1-3 haloalkyl, _C1-3 alkylamino, _C3-5 cycloalkyl, _C3-5 cycloalkylamino or _C3-5 heterocycloalkyl, R' is H, halogen, OH, _C1-3 alkyl, _C1-3 haloalkyl or _C1-3 alkoxy, m is 0, 1, ₂ or 3 and R''' is H, OH, _NH2 , _C1-3 alkyl, _C1-3 alkylamino, _C1-3 alkoxy or halogen. The compound is of formula 14, or a pharma- ceutically acceptable salt, enantiomer, non-enantiomer, tautomer, racemate, solvate, metabolic precursor, or prodrug thereof; R ^3' is H or C _1-3 alkyl; and/or each A is independently O, NH,

and/or m3 is 1, 2, 3, 4, 5 or 6, and/or m4 is 0, 1, 2, 3 or 4, and/or m5 is 0, 1, 2 or 3, and/or R ^{1 '} is O, NH,

and/or R″ is H, halo, OH, NH2, _C1-3 alkyl, _C1-3 alkoxy, _C1-3 haloalkyl, _C1-3 alkylamino, _C3-5 cycloalkyl, _C3-5 cycloalkylamino or _C3-5 heterocycloalkyl; and/or R′ is H, halogen, OH, _C1-3 alkyl, _C1-3 haloalkyl or _C1-3 alkoxy, m is 0, ₁ , 2 or 3; and/or R _′ ″ is H, OH, NH2, _C1-3 alkyl, _C1-3 alkylamino, _C1-3 alkoxy or halogen. The compound is of formula 4

or a pharma- ceutically acceptable salt, enantiomer, non-enantiomer, tautomer, racemate, solvate, metabolic precursor, or prodrug thereof, wherein R ^1′ is O, NH,

29. The method or use of claim 28, wherein R ^2' is H, OH, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 alkylamino or NH ₂ , and/or m6 is 0, 1, 2 or 3, and/or R ^1' is O, NH,

59. The method or use of claim 58, wherein: and/or R' is H, halogen, OH, _C1-3 alkyl, _{C1-3 haloalkyl or C1-3 alkoxy; R'' is H, halo, OH, NH2, C1-3 alkoxy , C3-5 cycloalkyl} , _C3-5 cycloalkylamino or _{C1-3 alkylamino; and/or R''' is H, OH, NH2, C1-3 alkyl, C1-3 alkylamino , C1-3 alkoxy} or halogen. The compound is represented by formula 4-1

or a pharma- ceutically acceptable salt, enantiomer, non-enantiomer, tautomer, racemate, solvate, metabolic precursor or prodrug thereof. The compound is represented by formula 16 or 17

or a pharma- ceutically acceptable salt, enantiomer, non-enantiomer, tautomer, racemate, solvate, metabolic precursor, or prodrug thereof, wherein m2 is 1, 2, 3, 4, 5, 6, or 7; and R1 ^' is O, NH,

30. The method or use of claim 29, wherein 62. The method or use of claim 61, wherein the compound is a compound of formula 16 or a pharma- ceutically acceptable salt, enantiomer, non-enantiomer, tautomer, racemate, solvate, metabolic precursor or prodrug thereof, and Z is C, U is O or S, and T is CH, or Z is N, U is CH, T is CH, Z is C, T is N and U is CH. 62. The method or use of claim 61, wherein the compound is a compound of formula 17 or a pharma- ceutically acceptable salt, enantiomer, non-enantiomer, tautomer, racemate, solvate, metabolic precursor, or prodrug thereof, and Z is C, U is O or S, and T is CH, or Z is N, U is CH, T is CH, Z is C, T is N, and U is CH. The method or use according to any one of claims 1 to 7, wherein the compound is selected from the compounds listed in Table 2, or a pharma- ceutically acceptable salt, enantiomer, non-enantiomer, tautomer, racemate, solvate, metabolic precursor or prodrug thereof.

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