CN110615779B - Process for preparing lenalidomide derivatives - Google Patents

Process for preparing lenalidomide derivatives Download PDF

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CN110615779B
CN110615779B CN201910529711.0A CN201910529711A CN110615779B CN 110615779 B CN110615779 B CN 110615779B CN 201910529711 A CN201910529711 A CN 201910529711A CN 110615779 B CN110615779 B CN 110615779B
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oxoisoindolin
dioxopiperidin
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杨小宝
姜标
孙宁
仇星
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ShanghaiTech University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
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    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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Abstract

The present disclosure relates to a process for preparing a compound of formula (I), the process comprising: the amino group of the compound of the formula (II) and the compound of the formula (III) are subjected to amino alkylation reaction in the presence of organic base to selectively obtain the compound of the formula (I). The disclosure also relates to compounds of formula (I).
Figure DDA0002099337970000011
R 1 -LIN formula (III).

Description

Process for preparing lenalidomide derivatives
Technical Field
The present disclosure relates to processes for preparing lenalidomide derivatives of formula (I) and said compounds of formula (I).
Figure BDA0002099337960000011
Background
Thalidomide and analogues pomalidomide and lenalidomide thereof are commonly used immunoregulation medicaments at present, and particularly have better curative effect on multiple myeloma 1 . The research finds that the medicines can pass through the pentanesImide structure and CUL4-RBX1-DDB 1-Cereblan (CRL 4) CRBN ) The combination of a substrate receptor Cereblin protein of the E3 ubiquitin ligase compound promotes the combination of a transcription factor IKZF1/3 and Cereblin, and induces the IKZF1/3 to have ubiquitination degradation 2 . In recent years, the characteristic that thalidomide and analogs thereof can be specifically combined with Cereblon E3 is utilized, and the fact that thalidomide and derivatives thereof can be used as E3 ligase to identify small molecular ligands is discovered, and the small molecular ligands are successfully introduced into the development of protein degradation Targeting drugs (PROTAD) 3 。
Figure BDA0002099337960000012
Ubiquitin-mediated protein degradation is the most main negative regulation mode of intracellular proteins, and ubiquitination degradation pathway participates in almost all vital activities such as regulation of cell cycle, proliferation, apoptosis, signal transmission and the like. Protein degradation targeted drug (PROTAD) technology platform utilizes ubiquitin-protease system to degrade pathogenic target proteins. Specifically, the proad molecule is composed of three parts: a small molecule inhibitor that binds to a target protein, a ligand that binds to E3 ligase, and a chemical chain linking the two (as shown in the PROTAD structural formula). Inside the cell, PROTAD can act by establishing a ternary complex with the target protein and E3 ligase, polyubiquitinating the target protein that would otherwise not be bound to E3, and then degrading by proteasome 4 。
Figure BDA0002099337960000021
In recent years, a plurality of CRBN E3-based protein degradation targeting small molecule compounds are designed and synthesized by connecting different target protein small molecule inhibitors with thalidomide or analogues thereof through a connecting group. Bradner 5 、Crews 6 Wang Shao Meng 7 The protein degradation targeting small molecule compound shown as the following structural formula is designed and synthesized, and the BET protein and the BCR-ABL fusion protein are successfully degraded.
Figure BDA0002099337960000022
Synthesizing the protein degradation targeting small molecule compound, a series of connector libraries based on CRBN ligand are firstly synthesized, one end of each connector library is provided with a carboxyl group, an amino group or a halogen functional group which can be combined with a small molecule inhibitor, and the other end of each connector library is reserved with a key glutarimide structural unit combined with CRBN.
Professor Bradner reported that a small molecule compound targeted for degradation of proteins of BAF complex factor BRD9, and compared the biological activities of small molecule compounds targeted for degradation of proteins with pomalidomide and lenalidomide acting as CRBN ligand moiety, found that lenalidomide-based small molecule compound B, as represented by the following formula (a), had better biological activity and similar results in comparison of the pharmacological effects of immunomodulatory drugs. Therefore, it is highly desirable to develop a method for synthesizing a library of lenalidomide-based linkers.
Figure BDA0002099337960000023
Figure BDA0002099337960000031
The pomalidomide-based linker library reported in the literature is mainly constructed by the aromatic nucleophilic substitution reaction and deprotection reaction of 4-fluoro substituted thalidomide and alkylamine 6 (scheme 1).
Figure BDA0002099337960000032
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On the basis, we firstly try to construct 4-fluoro substituted lenalidomide derivatives through ring-closing reaction, but the next nucleophilic aromatic substitution reaction for generating corresponding amino alkylation products cannot occur (scheme 2), and the development of a new synthetic method is very important and urgent.
Figure BDA0002099337960000033
Through literature research, the synthesis method of the corresponding amino alkylated compound in the literature has two general methods, namely reductive amination reaction 8 The second method is alkylation reaction 9 . Scheme 3 is not suitable for industrial production and scale-up due to the use of the expensive and dangerous reducing agent sodium cyanoborohydride and the reaction of the aldehyde substrate which is not readily available and unstable. The reductive amination reaction of lenalidomide with an aldehyde-substituted amine, building a lenalidomide-based linker, was reported by professor Bradner, but the reaction required complicated procedures, lacked versatility and had low overall yields (46%, scheme 3). Method II is Li in 2017 10 The corresponding aminoalkylated product 3a was prepared by alkylation of lenalidomide with alkyl bromide using an inorganic base, potassium carbonate, according to which we found that compound 3a' was the true product structure under the reaction conditions (scheme 4) and did not give the desired corresponding aminoalkylated product 3a.
Figure BDA0002099337960000041
Therefore, there is an urgent need to develop a novel method for synthesizing lenalidomide derivatives.
Disclosure of Invention
In order to obtain the desired correct aminoalkylation product, applicants have devised a novel process for the synthesis of lenalidomide derivatives which comprises reacting lenalidomide with a suitable alkylating agent under reaction conditions in which an organic base (such as, but not limited to, DIPEA or triethylamine) acts as an acid scavenger, to obtain the aminoalkylation product as a major product with high selectivity. The applicant further expands the condition to a series of alkylation reactions of alkylating agents with leaving groups and lenalidomide to obtain a high-selectivity amino alkylation main product, and applies the method to the technical development of protein degradation targeted drugs.
The above objects of the present disclosure are achieved by providing a process for preparing a lenalidomide derivative compound of formula (I),
Figure BDA0002099337960000042
wherein LIN represents-alkylene-U, wherein
The alkylene group is a linear or branched alkylene group optionally interrupted one or more times by one or more groups selected from: o, CONH, NHCO, NH, alkynylene, alkenylene, cycloalkylene, arylene, heterocyclylene, heteroarylene, or any combination thereof, wherein the linear or branched alkylene is optionally substituted with one or more substituents, and
the group U represents COOH, SO optionally protected by a protecting group 3 H or NH 2 (ii) a Or
The group U represents N 3 Alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, or any combination thereof; or
The group U represents hydrogen;
the method comprises the following steps: amino alkylation reaction is carried out on amino of the compound shown in the formula (II) and the compound shown in the formula (III) in the presence of organic base to selectively obtain the compound shown in the formula (I),
Figure BDA0002099337960000051
wherein R is 1 Represents a leaving group, and LIN represents-alkylene-U, wherein
The alkylene group is a linear or branched alkylene group optionally interrupted one or more times by one or more groups selected from: o, CONH, NHCO, NH, alkynylene, alkenylene, cycloalkylene, arylene, heterocyclylene, heteroarylene, or any combination thereof, wherein the linear or branched alkylene is optionally substituted with one or more substituents, and
the group U represents COOH, SO optionally protected by a protecting group 3 H or NH 2 (ii) a Or
The group U represents N 3 Alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, or any combination thereof; or
The group U represents hydrogen.
In another aspect, the present disclosure also provides a compound of formula (I),
Figure BDA0002099337960000052
wherein LIN represents-alkylene-U, wherein
The alkylene group is a linear or branched alkylene group optionally interrupted one or more times by one or more groups selected from: o, CONH, NHCO, NH, alkynylene, alkenylene, cycloalkylene, arylene, heterocyclylene, heteroarylene, or any combination thereof, wherein the linear or branched alkylene is optionally substituted with one or more substituents, and
the group U represents COOH, SO optionally protected by a protecting group 3 H or NH 2 (ii) a Or
The group U represents N 3 Alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, or any combination thereof; or
The group U represents hydrogen.
Detailed Description
Accordingly, the present disclosure provides a process for the preparation of lenalidomide derivatives of formula (I),
Figure BDA0002099337960000061
wherein LIN represents-alkylene-U, wherein
The alkylene group is a linear or branched alkylene group optionally interrupted one or more times by one or more groups selected from: o, CONH, NHCO, NH, alkynylene, alkenylene, cycloalkylene, arylene, heterocyclylene, heteroarylene, or any combination thereof, wherein the linear or branched alkylene is optionally substituted with one or more substituents, and
the group U represents COOH, SO optionally protected by a protecting group 3 H or NH 2 (ii) a Or
The group U represents N 3 Alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, or any combination thereof; or
The group U represents hydrogen;
the method comprises the following steps: amino alkylation reaction is carried out on amino of the compound shown in the formula (II) and the compound shown in the formula (III) in the presence of organic base to selectively obtain the compound shown in the formula (I),
Figure BDA0002099337960000062
wherein R is 1 Represents a leaving group, and LIN represents-alkylene-U, wherein
The alkylene group is a linear or branched alkylene group optionally interrupted one or more times by one or more groups selected from: o, CONH, NHCO, NH, alkynylene, alkenylene, cycloalkylene, arylene, heterocyclylene, heteroarylene, or any combination thereof, wherein the linear or branched alkylene is optionally substituted with one or more substituents, and
the group U represents COOH, SO optionally protected by a protecting group 3 H or NH 2 (ii) a Or
The group U represents N 3 Alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, or any combination thereof; or
The group U represents hydrogen.
In the present disclosure, the group in LIN of the compound of formula (III) may be protected as necessary using methods known in the art and appropriate protecting groups. In the case where the group U in LIN of the compound of formula (III) is protected by a protecting group (e.g. the group U represents COOH, SO protected by a protecting group) 3 H or NH 2 ) From compounds of formula (III) with compounds of formula (II)The protecting group of the group U in LIN, prepared by aminoalkylation of the amino group, of the corresponding compound of formula (I) may be retained or may be further deprotected by methods known in the art (as described hereinafter).
In an embodiment of the present disclosure, the organic base includes, but is not limited to, for example: triethylamine, dimethylamine, tri-tert-butylamine, N-dimethylaniline, DIPEA, N-diethylethylamine, DMAP, pyridine, quinoline, morpholine and NMM, and also one or more bases thereof.
In one embodiment of the present disclosure, the R group 1 Represents halogen, mesyloxy, trifluoromethanesulfonyloxy or p-toluenesulfonyloxy.
In an embodiment of the present disclosure, the LIN represents:
-C 1-30 alkylene-U, - (CH) 2 ) n1 -(O(CH 2 ) n2 ) m1 -U，-(CH 2 ) n1 -(O(CH 2 ) n2 ) m1 -(O(CH 2 ) n3 ) m2 -U，-(CR a1 R a2 ) n1 -(O(CR a3 R a4 ) n2 ) m1 -U，-(CR a5 R a6 ) n1 -(O(CR a7 R a8 ) n2 ) m1 -(O(CR a9 R a10 ) n3 ) m2 -U，-(CH 2 ) n1 -(CONH-(CH 2 ) n2 ) m1 -U，-(CH 2 ) n1 -(CONH-(CH 2 ) n2 ) m1 -(O(CH 2 ) n3 ) m2 -U，-(CH 2 ) n1 -(O(CH 2 ) n2 ) m1 -O-(CH 2 ) n3 -CONH-(CH 2 ) n4 -(O(CH 2 ) n5 ) m2 -O-(CH 2 ) n6 -U，-(CR a11 R a12 ) n1 -(O(CR a13 R a14 ) n2 ) m1 -O-(CR a15 R a16 ) n3 -CONH-(CR a17 R a18 ) n4 -(O(CR a19 R a20 ) n5 ) m2 -O-(CR a21 R a22 ) n6 -U，-(CR a23 R a24 ) n1 -CONH-(O(CR a25 R a26 ) n2 ) m1 -U，-(CH 2 ) n1 -(NHCO-(CH 2 ) n2 ) m1 -U，-(CH 2 ) n1 -(NHCO-(CH 2 ) n2 ) m1 -(O(CH 2 ) n3 ) m2 -U, a linear or branched-alkylene chain interrupted one or more times by one or more alkynylene, alkenylene, cycloalkylene, arylene, heterocyclylene or heteroarylene groups or any combination thereof-U, or- (CH) interrupted one or more times in its carbon chain by one or more arylene or heterocyclylene or heteroarylene groups or any combination thereof 2 ) n1 -(O(CH 2 ) n2 ) m1 -U；
Wherein R is a1 、R a2 、R a3 、R a4 、R a5 、R a6 、R a7 、R a8 、R a9 、R a10 、R a11 、R a12 、R a13 、R a14 、R a15 、R a16 、R a17 、R a18 、R a19 、R a20 、R a21 、R a22 、R a23 、R a24 、R a25 、R a26 Each independently represents H, straight-chain or branched C 1-10 Alkyl or C 3-10 Cycloalkyl, wherein R is when in the same said LIN a1 、R a2 、R a3 、R a4 Or R is a5 、R a6 、R a7 、R a8 、R a9 、R a10 Or R is a11 、R a12 、R a13 、R a14 、R a15 、R a16 、R a17 、R a18 、R a19 、R a20 、R a21 、R a22 Or R is a23 、R a24 、R a25 、R a26 Not H at the same time; and
n1, n2, n3, n4, n5, n6, m1, m2 each independently represent an integer 1,2,3, 4,5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20;
wherein the group U represents-COOH, -SO optionally protected by a protecting group 3 H or-NH 2 (ii) a Or the group U represents N 3 Alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, or any combination thereof; or the group U represents hydrogen.
In one embodiment of the present disclosure, the LIN is preferably-C 1-30 alkylene-U. In one embodiment of the present disclosure, the LIN is preferably-methylene-U or-C 2-30 alkylene-U, wherein said C 2-30 Alkylene being straight-chain or branched C 2-30 Alkylene (preferably C) 2 -C 29 Alkylene chain, C 2 -C 28 Alkylene chain, C 2 -C 27 Alkylene chain, C 2 -C 26 Alkylene chain, C 2 -C 25 Alkylene chain, C 2 -C 24 Alkylene chain, C 2 -C 23 Alkylene chain, C 2 -C 22 Alkylene chain, C 2 -C 21 Alkylene chain, C 2 -C 20 Alkylene chain, C 2 -C 19 Alkylene chain, C 2 -C 18 Alkylene chain, C 2 -C 17 Alkylene chain, C 2 -C 16 Alkylene chain, C 2 -C 15 Alkylene chain, C 2 -C 14 Alkylene chain, C 2 -C 13 Alkylene chain, C 2 -C 12 Alkylene chain, C 2 -C 11 Alkylene chain, C 2 -C 10 Alkylene chain, C 2 -C 9 Alkylene chain, C 2 -C 8 Alkylene chain, C 2 -C 7 Alkylene chain, C 2 -C 6 Alkylene chain, C 2 -C 5 Alkylene chain, C 2 -C 4 Alkylene chain, or C 2 -C 3 An alkylene chain) and the group U represents-COOH, -SO optionally protected by a protecting group 3 H or-NH 2 Or the group U represents-N 3 Alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, or any combination thereof; or the group U represents hydrogen.
In an embodiment of the present disclosure, the LIN represents:
-CH 2 -U；-(CH 2 ) 2 -U；-(CH 2 ) 3 -U；-(CH 2 ) 4 -U；-(CH 2 ) 5 -U；-(CH 2 ) 6 -U；-(CH 2 ) 7 -U；-(CH 2 ) 8 -U；-(CH 2 ) 9 -U；-(CH 2 ) 10 -U；-(CH 2 ) 11 -U；-(CH 2 ) 12 -U；-(CH 2 ) 13 -U；-(CH 2 ) 14 -U；-(CH 2 ) 15 -U；-(CH 2 ) 16 -U；-(CH 2 ) 17 -U；-(CH 2 ) 18 -U；-(CH 2 ) 19 -U；-(CH 2 ) 20 -U；-(CH 2 ) 21 -U；-(CH 2 ) 22 -U；-(CH 2 ) 23 -U；-(CH 2 ) 24 -U；-(CH 2 ) 25 -U；-(CH 2 ) 26 -U；-(CH 2 ) 27 -U；-(CH 2 ) 28 -U；-(CH 2 ) 29 -U; or- (CH) 2 ) 30 -U。
Wherein the group U represents-COOH, SO optionally protected by a protecting group 3 H or-NH 2 Or the group U represents-N 3 Alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, or any combination thereof; or the group U represents hydrogen.
In an embodiment of the present disclosure, the LIN represents:
-CH 2 -((CH 2 ) 2 -O)-CH 2 -U、-CH 2 -((CH 2 ) 2 -O) 2 -CH 2 -U、-CH 2 -((CH 2 ) 2 -O) 3 -CH 2 -U、-CH 2 -((CH 2 ) 2 -O) 4 -CH 2 -U、-CH 2 -((CH 2 ) 2 -O) 5 -CH 2 -U、-CH 2 -((CH 2 ) 2 -O) 6 -CH 2 -U、-CH 2 -((CH 2 ) 2 -O) 7 -CH 2 -U、-CH 2 -((CH 2 ) 2 -O) 8 -CH 2 -U、-CH 2 -((CH 2 ) 2 -O) 9 -CH 2 -U、-CH 2 -((CH 2 ) 2 -O) 10 -CH 2 -U、-CH 2 -((CH 2 ) 2 -O) 11 -CH 2 -U、-CH 2 -((CH 2 ) 2 -O) 12 -CH 2 -U、-CH 2 -((CH 2 ) 2 -O) 13 -CH 2 -U、-CH 2 -((CH 2 ) 2 -O) 14 -CH 2 -U、-CH 2 -((CH 2 ) 2 -O) 15 -CH 2 -U、-CH 2 -((CH 2 ) 2 -O) 16 -CH 2 -U、-CH 2 -((CH 2 ) 2 -O) 17 -CH 2 -U、-CH 2 -((CH 2 ) 2 -O) 18 -CH 2 -U、-CH 2 -((CH 2 ) 2 -O) 19 -CH 2 -U、-CH 2 -((CH 2 ) 2 -O) 20 -CH 2 -U、-((CH 2 ) 2 -O)-CH 2 -U、-((CH 2 ) 2 -O) 2 -CH 2 -U、-((CH 2 ) 2 -O) 3 -CH 2 -U、-((CH 2 ) 2 -O) 4 -CH 2 -U、-((CH 2 ) 2 -O) 5 -CH 2 -U、-((CH 2 ) 2 -O) 6 -CH 2 -U、-((CH 2 ) 2 -O) 7 -CH 2 -U、-((CH 2 ) 2 -O) 8 -CH 2 -U、-((CH 2 ) 2 -O) 9 -CH 2 -U、-((CH 2 ) 2 -O) 10 -CH 2 -U、-((CH 2 ) 2 -O) 11 -CH 2 -U、-((CH 2 ) 2 -O) 12 -CH 2 -U、-((CH 2 ) 2 -O) 13 -CH 2 -U、-((CH 2 ) 2 -O) 14 -CH 2 -U、-((CH 2 ) 2 -O) 15 -CH 2 -U、-((CH 2 ) 2 -O) 16 -CH 2 -U、-((CH 2 ) 2 -O) 17 -CH 2 -U、-((CH 2 ) 2 -O) 18 -CH 2 -U、-((CH 2 ) 2 -O) 19 -CH 2 -U、-((CH 2 ) 2 -O) 20 -CH 2 -U、-CH 2 -O-(CH 2 ) 2 -U、-CH 2 -(O(CH 2 ) 2 ) 2 -U、-CH 2 -(O(CH 2 ) 2 ) 3 -U、-CH 2 -(O(CH 2 ) 2 ) 4 -U、-CH 2 -(O(CH 2 ) 2 ) 5 -U、-CH 2 -(O(CH 2 ) 2 ) 6 -U、-CH 2 -(O(CH 2 ) 2 ) 7 -U、-CH 2 -(O(CH 2 ) 2 ) 8 -U、-CH 2 -(O(CH 2 ) 2 ) 9 -U、-CH 2 -(O(CH 2 ) 2 ) 10 -U、-(CH 2 ) 2 -O-(CH 2 ) 2 -U、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 2 -U、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 3 -U、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 4 -U、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 5 -U、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 6 -U、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 7 -U、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 8 -U、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 9 -U、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 10 -U、-(CH 2 ) 3 -O-(CH 2 ) 2 -U、-(CH 2 ) 3 -(O(CH 2 ) 2 ) 2 -U、-(CH 2 ) 3 -(O(CH 2 ) 2 ) 3 -U、-(CH 2 ) 3 -(O(CH 2 ) 2 ) 4 -U、-(CH 2 ) 3 -(O(CH 2 ) 2 ) 5 -U、-(CH 2 ) 3 -(O(CH 2 ) 2 ) 6 -U、-(CH 2 ) 3 -(O(CH 2 ) 2 ) 7 -U、-(CH 2 ) 3 -(O(CH 2 ) 2 ) 8 -U、-(CH 2 ) 3 -(O(CH 2 ) 2 ) 9 -U、-(CH 2 ) 3 -(O(CH 2 ) 2 ) 10 -U、-(CH 2 ) 4 -O-(CH 2 ) 2 -U、-(CH 2 ) 4 -(O(CH 2 ) 2 ) 2 -U、-(CH 2 ) 4 -(O(CH 2 ) 2 ) 3 -U、-(CH 2 ) 4 -(O(CH 2 ) 2 ) 4 -U、-(CH 2 ) 4 -(O(CH 2 ) 2 ) 5 -U、-(CH 2 ) 4 -(O(CH 2 ) 2 ) 6 -U、-(CH 2 ) 4 -(O(CH 2 ) 2 ) 7 -U、-(CH 2 ) 4 -(O(CH 2 ) 2 ) 8 -U、-(CH 2 ) 4 -(O(CH 2 ) 2 ) 9 -U、-(CH 2 ) 4 -(O(CH 2 ) 2 ) 10 -U、-CH 2 -O-(CH 2 ) 3 -U、-CH 2 -(O(CH 2 ) 3 ) 2 -U、-CH 2 -(O(CH 2 ) 3 ) 3 -U、-CH 2 -(O(CH 2 ) 3 ) 4 -U、-CH 2 -(O(CH 2 ) 3 ) 5 -U、-CH 2 -(O(CH 2 ) 3 ) 6 -U、-CH 2 -(O(CH 2 ) 3 ) 7 -U、-CH 2 -(O(CH 2 ) 3 ) 8 -U、-CH 2 -(O(CH 2 ) 3 ) 9 -U、-CH 2 -(O(CH 2 ) 3 ) 10 -U、-(CH 2 ) 2 -O-(CH 2 ) 3 -U、-(CH 2 ) 2 -(O(CH 2 ) 3 ) 2 -U、-(CH 2 ) 2 -(O(CH 2 ) 3 ) 3 -U、-(CH 2 ) 2 -(O(CH 2 ) 3 ) 4 -U、-(CH 2 ) 2 -(O(CH 2 ) 3 ) 5 -U、-(CH 2 ) 2 -(O(CH 2 ) 3 ) 6 -U、-(CH 2 ) 2 -(O(CH 2 ) 3 ) 7 -U、-(CH 2 ) 2 -(O(CH 2 ) 3 ) 8 -U、-(CH 2 ) 2 -(O(CH 2 ) 3 ) 9 -U、-(CH 2 ) 2 -(O(CH 2 ) 3 ) 10 -U、-(CH 2 ) 3 -O-(CH 2 ) 3 -U、-(CH 2 ) 3 -(O(CH 2 ) 3 ) 2 -U、-(CH 2 ) 3 -(O(CH 2 ) 3 ) 3 -U、-(CH 2 ) 3 -(O(CH 2 ) 3 ) 4 -U、-(CH 2 ) 3 -(O(CH 2 ) 3 ) 5 -U、-(CH 2 ) 3 -(O(CH 2 ) 3 ) 6 -U、-(CH 2 ) 3 -(O(CH 2 ) 3 ) 7 -U、-(CH 2 ) 3 -(O(CH 2 ) 3 ) 8 -U、-(CH 2 ) 3 -(O(CH 2 ) 3 ) 9 -U、-(CH 2 ) 3 -(O(CH 2 ) 3 ) 10 -U、-CH 2 -O-(CH 2 ) 2 -O-(CH 2 ) 3 -U、-CH 2 -(O(CH 2 ) 2 ) 2 -(O(CH 2 ) 3 ) 2 -U、-CH 2 -(O(CH 2 ) 2 ) 3 -(O(CH 2 ) 3 ) 3 -U、-CH 2 -(O(CH 2 ) 2 ) 4 -(O(CH 2 ) 3 ) 4 -U、-CH 2 -(O(CH 2 ) 2 ) 5 -(O(CH 2 ) 3 ) 5 -U、-CH 2 -(O(CH 2 ) 2 ) 6 -(O(CH 2 ) 3 ) 6 -U、-(CH 2 ) 2 -O-(CH 2 ) 2 -O-(CH 2 ) 3 -U、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 2 -(O(CH 2 ) 3 ) 2 -U、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 3 -(O(CH 2 ) 3 ) 3 -U、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 4 -(O(CH 2 ) 3 ) 4 -U、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 5 -(O(CH 2 ) 3 ) 5 -U、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 6 -(O(CH 2 ) 3 ) 6 -U、-(CH 2 ) 3 -O-(CH 2 ) 2 -O-(CH 2 ) 3 -U、-(CH 2 ) 3 -(O(CH 2 ) 2 ) 2 -(O(CH 2 ) 3 ) 2 -U、-(CH 2 ) 3 -(O(CH 2 ) 2 ) 3 -(O(CH 2 ) 3 ) 3 -U、-(CH 2 ) 3 -(O(CH 2 ) 2 ) 4 -(O(CH 2 ) 3 ) 4 -U、-(CH 2 ) 3 -(O(CH 2 ) 2 ) 5 -(O(CH 2 ) 3 ) 5 -U、-(CH 2 ) 3 -(O(CH 2 ) 2 ) 6 -(O(CH 2 ) 3 ) 6 -U、-CH 2 -O-(CH 2 ) 3 -O-(CH 2 ) 2 -U、-CH 2 -(O(CH 2 ) 3 ) 2 -(O(CH 2 ) 2 ) 2 -U、-CH 2 -(O(CH 2 ) 3 ) 3 -(O(CH 2 ) 2 ) 3 -U、-CH 2 -(O(CH 2 ) 3 ) 4 -(O(CH 2 ) 2 ) 4 -U、-CH 2 -(O(CH 2 ) 3 ) 5 -(O(CH 2 ) 2 ) 5 -U、-CH 2 -(O(CH 2 ) 3 ) 6 -(O(CH 2 ) 2 ) 6 -U、-(CH 2 ) 2 -O-(CH 2 ) 3 -O-(CH 2 ) 2 -U、-(CH 2 ) 2 -(O(CH 2 ) 3 ) 2 -(O(CH 2 ) 2 ) 2 -U、-(CH 2 ) 2 -(O(CH 2 ) 3 ) 3 -(O(CH 2 ) 2 ) 3 -U、-(CH 2 ) 2 -(O(CH 2 ) 3 ) 4 -(O(CH 2 ) 2 ) 4 -U、-(CH 2 ) 2 -(O(CH 2 ) 3 ) 5 -(O(CH 2 ) 2 ) 5 -U、-(CH 2 ) 2 -(O(CH 2 ) 3 ) 6 -(O(CH 2 ) 2 ) 6 -U、-(CH 2 ) 3 -O-(CH 2 ) 3 -O-(CH 2 ) 2 -U、-(CH 2 ) 3 -(O(CH 2 ) 3 ) 2 -(O(CH 2 ) 2 ) 2 -U、-(CH 2 ) 3 -(O(CH 2 ) 3 ) 3 -(O(CH 2 ) 2 ) 3 -U、-(CH 2 ) 3 -(O(CH 2 ) 3 ) 4 -(O(CH 2 ) 2 ) 4 -U、-(CH 2 ) 3 -(O(CH 2 ) 3 ) 5 -(O(CH 2 ) 2 ) 5 -U、-(CH 2 ) 3 -(O(CH 2 ) 3 ) 6 -(O(CH 2 ) 2 ) 6 -U、-CH 2 -O-(CH 2 ) 2 -O-CH 2 -U、-(CH 2 ) 2 -O-(CH 2 ) 2 -O-CH 2 -U、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 2 -O-(CH 2 ) 3 -U、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 3 -O-(CH 2 ) 3 -U、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 4 -O-(CH 2 ) 3 -U、-(CH 2 ) 5 -(O(CH 2 ) 2 ) 2 -O-(CH 2 ) 5 -U, or- (CH) 2 ) 5 -(O(CH 2 ) 2 ) 2 -O-(CH 2 ) 6 -U；
Wherein the group U represents an optionally protected groupProtected COOH, SO 3 H or NH 2 Or the group U represents N 3 Alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, or any combination thereof; or the group U represents hydrogen.
In one embodiment of the disclosure, the LIN is an alkylene-U, the alkylene (preferably C) 1-30 Alkylene chains, particularly preferably C 2 -C 29 Alkylene chain, C 2 -C 28 Alkylene chain, C 2 -C 27 Alkylene chain, C 2 -C 26 Alkylene chain, C 2 -C 25 Alkylene chain, C 2 -C 24 Alkylene chain, C 2 -C 23 Alkylene chain, C 2 -C 22 Alkylene chain, C 2 -C 21 Alkylene chain, C 2 -C 20 Alkylene chain, C 2 -C 19 Alkylene chain, C 2 -C 18 Alkylene chain, C 2 -C 17 Alkylene chain, C 2 -C 16 Alkylene chain, C 2 -C 15 Alkylene chain, C 2 -C 14 Alkylene chain, C 2 -C 13 Alkylene chain, C 2 -C 12 Alkylene chain, C 2 -C 11 Alkylene chain, C 2 -C 10 Alkylene chain, C 2 -C 9 Alkylene chain, C 2 -C 8 Alkylene chain, C 2 -C 7 Alkylene chain, C 2 -C 6 Alkylene chain, C 2 -C 5 Alkylene chain, C 2 -C 4 Alkylene chain, or C 2 -C 3 Alkylene chain) is a straight or branched alkylene chain substituted one or more times with one or more substituents selected from the group consisting of hydroxyl, amino, thiol, halogen, or combinations thereof; wherein the group U represents COOH, SO optionally protected by a protecting group 3 H or NH 2 Or the group U represents N 3 Alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, or any combination thereof; or the group U represents hydrogen. In a sub-embodiment of the disclosure, the number of substituents may be, for example, 1 to 30, 1 to 25, 1 to 20, or 1 to 15,1 to 10,1 to 9,1 to 8,1 to 7,1-6,1-5,1-4,1-3, or 1-2, or 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3,2, or 1.
In an embodiment of the present disclosure, the LIN represents-C 1-30 Alkylene chain-U, said C 1-30 The alkylene chain is a straight or branched C chain substituted with one or more substituents selected from hydroxy, amino, mercapto, halogen or combinations thereof 1-30 An alkylene chain; wherein the group U represents COOH, SO optionally protected by a protecting group 3 H or NH 2 Or the group U represents N 3 Alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, or any combination thereof; or the group U represents hydrogen. In a sub-embodiment of the disclosure, the number of substituents may be, for example, 1-30, 1-25, 1-20, or 1-15,1-10,1-9,1-8,1-7,1-6,1-5,1-4,1-3, or 1-2, or 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3,2, or 1.
In an embodiment of the present disclosure, the LIN represents: - (CH) 2 ) n11 -triazolyl- (CH) 2 ) n12 -U、-(CH 2 ) n11 -triazolyl- (CH) 2 ) n12 -(O(CH 2 ) n13 ) m11 -U、-(CH 2 ) n11 -(O(CH 2 ) n12 ) m11 -O-(CH 2 ) n13 -triazolyl- (CH) 2 ) n14 -(O(CH 2 ) n15 ) m12 -O-(CH 2 ) n16 -U、-(CH 2 ) n11 -triazolyl- (CH) 2 ) n12 -(O(CH 2 ) n13 ) m11 -O-(CH 2 ) n14 -U or- (CH) 2 ) n11 -(O(CH 2 ) n12 ) m11 -O-(CH 2 ) n13 -triazolyl- (CH) 2 ) n14 -U; and
n11, n12, n13, n14, n15, n16, m11, m12 each independently represent an integer of 1,2,3, 4,5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20;
whereinThe group U represents COOH, SO optionally protected by a protecting group 3 H or NH 2 Or the group U represents N 3 Alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, or any combination thereof; or the group U represents hydrogen.
In an embodiment of the present disclosure, the LIN represents: - (CH) 2 ) 3 -triazolyl- (CH) 2 ) 5 -U、-(CH 2 ) 2 -triazolyl- (CH) 2 ) 5 -U、-CH 2 -triazolyl- (CH) 2 ) 5 -U、-(CH 2 ) 2 -triazolyl- (CH) 2 ) 4 -U、-(CH 2 ) 3 -triazolyl- (CH) 2 ) 2 -O(CH 2 ) 2 -U、-(CH 2 ) 2 -triazolyl- (CH) 2 ) 2 -O(CH 2 ) 2 -U or-CH 2 -triazolyl- (CH) 2 ) 2 -O(CH 2 ) 2 -U; wherein the group U represents COOH, SO optionally protected by a protecting group 3 H or NH 2 Or the group U represents N 3 Alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, or any combination thereof; or the group U represents hydrogen.
In an embodiment of the present disclosure, the LIN represents: -CH 2 CONHCH 2 -U、-(CH 2 ) 2 CONH(CH 2 ) 2 -U、-(CH 2 ) 3 CONH(CH 2 ) 3 -U、-(CH 2 ) 3 CONH(CH 2 ) 4 -U、-(CH 2 ) 4 CONH(CH 2 ) 4 -U、-(CH 2 ) 5 CONH(CH 2 ) 5 -U、-(CH 2 ) 6 CONH(CH 2 ) 7 -U、-(CH 2 ) 6 CONH(CH 2 ) 6 -U、-(CH 2 ) 7 CONH(CH 2 ) 7 -U、-(CH 2 ) 8 CONH(CH 2 ) 8 -U、-(CH 2 ) 9 CONH(CH 2 ) 9 -U、-(CH 2 ) 10 CONH(CH 2 ) 10 -U、-(CH 2 ) 2 CONH(CH 2 ) 5 -U、-(CH 2 ) 2 CONH(CH 2 ) 3 -U、-(CH 2 ) 2 CONH(CH 2 ) 4 -U, or- (CH) 2 ) 2 CONH(CH 2 ) 2 -O-(CH 2 ) 2 -U; wherein the group U represents COOH, SO optionally protected by a protecting group 3 H or NH 2 Or the group U represents N 3 Alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, or any combination thereof; or the group U represents hydrogen.
In an embodiment of the present disclosure, the LIN represents: -CH 2 NHCOCH 2 -U、-(CH 2 ) 2 NHCO(CH 2 ) 2 -U、-(CH 2 ) 3 NHCO(CH 2 ) 3 -U、-(CH 2 ) 3 NHCO(CH 2 ) 4 -U、-(CH 2 ) 4 NHCO(CH 2 ) 4 -U、-(CH 2 ) 5 NHCO(CH 2 ) 5 -U、-(CH 2 ) 6 NHCO(CH 2 ) 7 -U、-(CH 2 ) 6 NHCO(CH 2 ) 6 -U、-(CH 2 ) 7 NHCO(CH 2 ) 7 -U、-(CH 2 ) 8 NHCO(CH 2 ) 8 -U、-(CH 2 ) 9 NHCO(CH 2 ) 9 -U、-(CH 2 ) 10 NHCO(CH 2 ) 10 -U、-(CH 2 ) 2 NHCO(CH 2 ) 5 -U、-(CH 2 ) 2 NHCO(CH 2 ) 3 -U、-(CH 2 ) 2 NHCO(CH 2 ) 4 -U、-(CH 2 ) 4 NHCO(CH 2 ) 8 -U or- (CH) 2 ) 2 NHCO(CH 2 ) 2 -O-(CH 2 ) 2 -U; wherein the group U represents COOH, SO optionally protected by a protecting group 3 H or NH 2 Or the group U represents N 3 Alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, or any combination thereof; or the group U represents hydrogen.
In an embodiment of the present disclosure, the LIN represents-alkylene-U, wherein the alkylene is straightC of a chain or branched chain 1-30 Alkylene and the group U represents N 3 Alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, or any combination thereof.
In an embodiment of the present disclosure, the amount of organic base in the reaction is 0.1 to 10 equivalents, calculated on the molar amount of the compound of formula (II). Preferably, the amount of organic base is 0.1 to 9 equivalents, preferably 0.5 to 8 equivalents, 0.5 to 7 equivalents, 0.5 to 6 equivalents, 0.5 to 5 equivalents, 1 to 4 equivalents, 1 to 3 equivalents, calculated on the molar amount of the compound of formula (II).
In an embodiment of the present disclosure, in the reaction, the amount of the compound of formula (III) is 0.5 to 1.5 equivalents (preferably 0.5 equivalents, 0.6 equivalents, 0.7 equivalents, 0.8 equivalents, 0.9 equivalents, 1 equivalent, 1.1 equivalents, 1.2 equivalents, 1.3 equivalents, 1.4 equivalents, or 1.5 equivalents) calculated on the molar amount of the compound of formula (II).
In one embodiment of the present disclosure, the reaction is carried out with or without the addition of a solvent. The solvent can be appropriately selected as needed by those skilled in the art. Preferably, the solvent includes, but is not limited to, NMP, DMF, CH 3 And (C) CN. In one embodiment of the present disclosure, the reaction is carried out without the addition of a solvent, wherein the organic base is used as the sole solvent.
In one embodiment of the present disclosure, the reaction is carried out at a temperature of 10-150 ℃. In one embodiment of the disclosure, the temperature is 20-140 ℃,70-130 ℃,80-120 ℃,90-110 ℃, or 80-100 ℃.
In one embodiment of the disclosure, when leaving group R 1 When representing p-toluenesulfonyloxy, the method may further comprise first reacting the compound of formula (III) with NaI to convert the compound of formula (III) to an iodide, i.e.
I-LIN formula (IV);
and (3) further carrying out amino alkylation reaction on the compound of the formula (IV) and the amino of the compound of the formula (II) in the presence of an organic base to selectively obtain the compound of the formula (I).
In an embodiment of the present disclosure, in the case that the group U of the compound of formula (III) is protected by a protecting group, the method of the present disclosure may further include a step of deprotecting the protected group U of the compound of formula (I).
The present disclosure also provides compounds of formula (I),
Figure BDA0002099337960000121
wherein LIN represents-alkylene-U, wherein
The alkylene group is a linear or branched alkylene group optionally interrupted one or more times by one or more groups selected from: o, CONH, NHCO, NH, alkynylene, alkenylene, cycloalkylene, arylene, heterocyclylene, heteroarylene, or any combination thereof, wherein the linear or branched alkylene is optionally substituted with one or more substituents, and
the group U represents COOH, SO optionally protected by a protecting group 3 H or NH 2 (ii) a Or
The group U represents N 3 Alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, or any combination thereof; or
The group U represents hydrogen.
In one embodiment of the compounds of formula (I) of the present disclosure, the LIN represents:
-C 1-30 alkylene-U, - (CH) 2 ) n1 -(O(CH 2 ) n2 ) m1 -U，-(CH 2 ) n1 -(O(CH 2 ) n2 ) m1 -(O(CH 2 ) n3 ) m2 -U，-(CR a1 R a2 ) n1 -(O(CR a3 R a4 ) n2 ) m1 -U，-(CR a5 R a6 ) n1 -(O(CR a7 R a8 ) n2 ) m1 -(O(CR a9 R a10 ) n3 ) m2 -U，-(CH 2 ) n1 -(CONH-(CH 2 ) n2 ) m1 -U，-(CH 2 ) n1 -(CONH-(CH 2 ) n2 ) m1 -(O(CH 2 ) n3 ) m2 -U，-(CH 2 ) n1 -(O(CH 2 ) n2 ) m1 -O-(CH 2 ) n3 -CONH-(CH 2 ) n4 -(O(CH 2 ) n5 ) m2 -O-(CH 2 ) n6 -U，-(CR a11 R a12 ) n1 -(O(CR a13 R a14 ) n2 ) m1 -O-(CR a15 R a16 ) n3 -CONH-(CR a17 R a18 ) n4 -(O(CR a19 R a20 ) n5 ) m2 -O-(CR a21 R a22 ) n6 -U，-(CR a23 R a24 ) n1 -CONH-(O(CR a25 R a26 ) n2 ) m1 -U，-(CH 2 ) n1 -(NHCO-(CH 2 ) n2 ) m1 -U，-(CH 2 ) n1 -(NHCO-(CH 2 ) n2 ) m1 -(O(CH 2 ) n3 ) m2 -U, a linear or branched-alkylene chain interrupted one or more times by one or more alkynylene, alkenylene, cycloalkylene, arylene, heterocyclylene or heteroarylene groups or any combination thereof-U, or- (CH) interrupted one or more times in its carbon chain by one or more arylene or heterocyclylene or heteroarylene groups or any combination thereof 2 ) n1 -(O(CH 2 ) n2 ) m1 -U；
Wherein R is a1 、R a2 、R a3 、R a4 、R a5 、R a6 、R a7 、R a8 、R a9 、R a10 、R a11 、R a12 、R a13 、R a14 、R a15 、R a16 、R a17 、R a18 、R a19 、R a20 、R a21 、R a22 、R a23 、R a24 、R a25 、R a26 Each independently represents H, straight-chain or branched C 1-10 Alkyl or C 3-10 Cycloalkyl, wherein R is when in the same said LIN a1 、R a2 、R a3 、R a4 Or R is a5 、R a6 、R a7 、R a8 、R a9 、R a10 Or R is a11 、R a12 、R a13 、R a14 、R a15 、R a16 、R a17 、R a18 、R a19 、R a20 、R a21 、R a22 Or R is a23 、R a24 、R a25 、R a26 Not H at the same time; and
n1, n2, n3, n4, n5, n6, m1, m2 each independently represent an integer 1,2,3, 4,5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20;
wherein the group U represents-COOH, -SO optionally protected by a protecting group 3 H or-NH 2 (ii) a Or the group U represents N 3 Alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, or any combination thereof; or the group U represents hydrogen.
In one embodiment of the compound of formula (I) described in this disclosure, the LIN is preferably-C 1-30 alkylene-U. In one embodiment of the present disclosure, the LIN is preferably-methylene-U or-C 2-30 alkylene-U, wherein said C 2-30 Alkylene being straight-chain or branched C 2-30 Alkylene (preferably C) 2 -C 29 Alkylene chain, C 2 -C 28 Alkylene chain, C 2 -C 27 Alkylene chain, C 2 -C 26 Alkylene chain, C 2 -C 25 Alkylene chain, C 2 -C 24 Alkylene chain, C 2 -C 23 Alkylene chain, C 2 -C 22 Alkylene chain, C 2 -C 21 Alkylene chain, C 2 -C 20 Alkylene chain, C 2 -C 19 Alkylene chain, C 2 -C 18 Alkylene chain, C 2 -C 17 Alkylene chain, C 2 -C 16 Alkylene chain, C 2 -C 15 Alkylene chain, C 2 -C 14 Alkylene chain, C 2 -C 13 Alkylene chain, C 2 -C 12 Alkylene chain, C 2 -C 11 Alkylene chain, C 2 -C 10 Alkylene chain, C 2 -C 9 Alkylene chain, C 2 -C 8 Alkylene chain, C 2 -C 7 Alkylene chain, C 2 -C 6 Alkylene chain, C 2 -C 5 Alkylene chain, C 2 -C 4 Alkylene chain, or C 2 -C 3 An alkylene chain) and the group U represents-COOH, -SO optionally protected by a protecting group 3 H or-NH 2 Or the group U represents-N 3 Alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, or any combination thereof; or the group U represents hydrogen.
In one embodiment of the compounds of formula (I) of the present disclosure, the LIN represents:
-CH 2 -U；-(CH 2 ) 2 -U；-(CH 2 ) 3 -U；-(CH 2 ) 4 -U；-(CH 2 ) 5 -U；-(CH 2 ) 6 -U；-(CH 2 ) 7 -U；-(CH 2 ) 8 -U；-(CH 2 ) 9 -U；-(CH 2 ) 10 -U；-(CH 2 ) 11 -U；-(CH 2 ) 12 -U；-(CH 2 ) 13 -U；-(CH 2 ) 14 -U；-(CH 2 ) 15 -U；-(CH 2 ) 16 -U；-(CH 2 ) 17 -U；-(CH 2 ) 18 -U；-(CH 2 ) 19 -U；-(CH 2 ) 20 -U；-(CH 2 ) 21 -U；-(CH 2 ) 22 -U；-(CH 2 ) 23 -U；-(CH 2 ) 24 -U；-(CH 2 ) 25 -U；-(CH 2 ) 26 -U；-(CH 2 ) 27 -U；-(CH 2 ) 28 -U；-(CH 2 ) 29 -U; or- (CH) 2 ) 30 -U。
Wherein the group U represents-COOH, SO optionally protected by a protecting group 3 H or-NH 2 Or the group U represents-N 3 Alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, or any combination thereof; or the group U represents hydrogen.
In one embodiment of the compounds of formula (I) of the present disclosure, the LIN represents:
-CH 2 -((CH 2 ) 2 -O)-CH 2 -U、-CH 2 -((CH 2 ) 2 -O) 2 -CH 2 -U、-CH 2 -((CH 2 ) 2 -O) 3 -CH 2 -U、-CH 2 -((CH 2 ) 2 -O) 4 -CH 2 -U、-CH 2 -((CH 2 ) 2 -O) 5 -CH 2 -U、-CH 2 -((CH 2 ) 2 -O) 6 -CH 2 -U、-CH 2 -((CH 2 ) 2 -O) 7 -CH 2 -U、-CH 2 -((CH 2 ) 2 -O) 8 -CH 2 -U、-CH 2 -((CH 2 ) 2 -O) 9 -CH 2 -U、-CH 2 -((CH 2 ) 2 -O) 10 -CH 2 -U、-CH 2 -((CH 2 ) 2 -O) 11 -CH 2 -U、-CH 2 -((CH 2 ) 2 -O) 12 -CH 2 -U、-CH 2 -((CH 2 ) 2 -O) 13 -CH 2 -U、-CH 2 -((CH 2 ) 2 -O) 14 -CH 2 -U、-CH 2 -((CH 2 ) 2 -O) 15 -CH 2 -U、-CH 2 -((CH 2 ) 2 -O) 16 -CH 2 -U、-CH 2 -((CH 2 ) 2 -O) 17 -CH 2 -U、-CH 2 -((CH 2 ) 2 -O) 18 -CH 2 -U、-CH 2 -((CH 2 ) 2 -O) 19 -CH 2 -U、-CH 2 -((CH 2 ) 2 -O) 20 -CH 2 -U、-((CH 2 ) 2 -O)-CH 2 -U、-((CH 2 ) 2 -O) 2 -CH 2 -U、-((CH 2 ) 2 -O) 3 -CH 2 -U、-((CH 2 ) 2 -O) 4 -CH 2 -U、-((CH 2 ) 2 -O) 5 -CH 2 -U、-((CH 2 ) 2 -O) 6 -CH 2 -U、-((CH 2 ) 2 -O) 7 -CH 2 -U、-((CH 2 ) 2 -O) 8 -CH 2 -U、-((CH 2 ) 2 -O) 9 -CH 2 -U、-((CH 2 ) 2 -O) 10 -CH 2 -U、-((CH 2 ) 2 -O) 11 -CH 2 -U、-((CH 2 ) 2 -O) 12 -CH 2 -U、-((CH 2 ) 2 -O) 13 -CH 2 -U、-((CH 2 ) 2 -O) 14 -CH 2 -U、-((CH 2 ) 2 -O) 15 -CH 2 -U、-((CH 2 ) 2 -O) 16 -CH 2 -U、-((CH 2 ) 2 -O) 17 -CH 2 -U、-((CH 2 ) 2 -O) 18 -CH 2 -U、-((CH 2 ) 2 -O) 19 -CH 2 -U、-((CH 2 ) 2 -O) 20 -CH 2 -U、-CH 2 -O-(CH 2 ) 2 -U、-CH 2 -(O(CH 2 ) 2 ) 2 -U、-CH 2 -(O(CH 2 ) 2 ) 3 -U、-CH 2 -(O(CH 2 ) 2 ) 4 -U、-CH 2 -(O(CH 2 ) 2 ) 5 -U、-CH 2 -(O(CH 2 ) 2 ) 6 -U、-CH 2 -(O(CH 2 ) 2 ) 7 -U、-CH 2 -(O(CH 2 ) 2 ) 8 -U、-CH 2 -(O(CH 2 ) 2 ) 9 -U、-CH 2 -(O(CH 2 ) 2 ) 10 -U、-(CH 2 ) 2 -O-(CH 2 ) 2 -U、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 2 -U、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 3 -U、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 4 -U、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 5 -U、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 6 -U、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 7 -U、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 8 -U、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 9 -U、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 10 -U、-(CH 2 ) 3 -O-(CH 2 ) 2 -U、-(CH 2 ) 3 -(O(CH 2 ) 2 ) 2 -U、-(CH 2 ) 3 -(O(CH 2 ) 2 ) 3 -U、-(CH 2 ) 3 -(O(CH 2 ) 2 ) 4 -U、-(CH 2 ) 3 -(O(CH 2 ) 2 ) 5 -U、-(CH 2 ) 3 -(O(CH 2 ) 2 ) 6 -U、-(CH 2 ) 3 -(O(CH 2 ) 2 ) 7 -U、-(CH 2 ) 3 -(O(CH 2 ) 2 ) 8 -U、-(CH 2 ) 3 -(O(CH 2 ) 2 ) 9 -U、-(CH 2 ) 3 -(O(CH 2 ) 2 ) 10 -U、-(CH 2 ) 4 -O-(CH 2 ) 2 -U、-(CH 2 ) 4 -(O(CH 2 ) 2 ) 2 -U、-(CH 2 ) 4 -(O(CH 2 ) 2 ) 3 -U、-(CH 2 ) 4 -(O(CH 2 ) 2 ) 4 -U、-(CH 2 ) 4 -(O(CH 2 ) 2 ) 5 -U、-(CH 2 ) 4 -(O(CH 2 ) 2 ) 6 -U、-(CH 2 ) 4 -(O(CH 2 ) 2 ) 7 -U、-(CH 2 ) 4 -(O(CH 2 ) 2 ) 8 -U、-(CH 2 ) 4 -(O(CH 2 ) 2 ) 9 -U、-(CH 2 ) 4 -(O(CH 2 ) 2 ) 10 -U、-CH 2 -O-(CH 2 ) 3 -U、-CH 2 -(O(CH 2 ) 3 ) 2 -U、-CH 2 -(O(CH 2 ) 3 ) 3 -U、-CH 2 -(O(CH 2 ) 3 ) 4 -U、-CH 2 -(O(CH 2 ) 3 ) 5 -U、-CH 2 -(O(CH 2 ) 3 ) 6 -U、-CH 2 -(O(CH 2 ) 3 ) 7 -U、-CH 2 -(O(CH 2 ) 3 ) 8 -U、-CH 2 -(O(CH 2 ) 3 ) 9 -U、-CH 2 -(O(CH 2 ) 3 ) 10 -U、-(CH 2 ) 2 -O-(CH 2 ) 3 -U、-(CH 2 ) 2 -(O(CH 2 ) 3 ) 2 -U、-(CH 2 ) 2 -(O(CH 2 ) 3 ) 3 -U、-(CH 2 ) 2 -(O(CH 2 ) 3 ) 4 -U、-(CH 2 ) 2 -(O(CH 2 ) 3 ) 5 -U、-(CH 2 ) 2 -(O(CH 2 ) 3 ) 6 -U、-(CH 2 ) 2 -(O(CH 2 ) 3 ) 7 -U、-(CH 2 ) 2 -(O(CH 2 ) 3 ) 8 -U、-(CH 2 ) 2 -(O(CH 2 ) 3 ) 9 -U、-(CH 2 ) 2 -(O(CH 2 ) 3 ) 10 -U、-(CH 2 ) 3 -O-(CH 2 ) 3 -U、-(CH 2 ) 3 -(O(CH 2 ) 3 ) 2 -U、-(CH 2 ) 3 -(O(CH 2 ) 3 ) 3 -U、-(CH 2 ) 3 -(O(CH 2 ) 3 ) 4 -U、-(CH 2 ) 3 -(O(CH 2 ) 3 ) 5 -U、-(CH 2 ) 3 -(O(CH 2 ) 3 ) 6 -U、-(CH 2 ) 3 -(O(CH 2 ) 3 ) 7 -U、-(CH 2 ) 3 -(O(CH 2 ) 3 ) 8 -U、-(CH 2 ) 3 -(O(CH 2 ) 3 ) 9 -U、-(CH 2 ) 3 -(O(CH 2 ) 3 ) 10 -U、-CH 2 -O-(CH 2 ) 2 -O-(CH 2 ) 3 -U、-CH 2 -(O(CH 2 ) 2 ) 2 -(O(CH 2 ) 3 ) 2 -U、-CH 2 -(O(CH 2 ) 2 ) 3 -(O(CH 2 ) 3 ) 3 -U、-CH 2 -(O(CH 2 ) 2 ) 4 -(O(CH 2 ) 3 ) 4 -U、-CH 2 -(O(CH 2 ) 2 ) 5 -(O(CH 2 ) 3 ) 5 -U、-CH 2 -(O(CH 2 ) 2 ) 6 -(O(CH 2 ) 3 ) 6 -U、-(CH 2 ) 2 -O-(CH 2 ) 2 -O-(CH 2 ) 3 -U、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 2 -(O(CH 2 ) 3 ) 2 -U、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 3 -(O(CH 2 ) 3 ) 3 -U、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 4 -(O(CH 2 ) 3 ) 4 -U、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 5 -(O(CH 2 ) 3 ) 5 -U、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 6 -(O(CH 2 ) 3 ) 6 -U、-(CH 2 ) 3 -O-(CH 2 ) 2 -O-(CH 2 ) 3 -U、-(CH 2 ) 3 -(O(CH 2 ) 2 ) 2 -(O(CH 2 ) 3 ) 2 -U、-(CH 2 ) 3 -(O(CH 2 ) 2 ) 3 -(O(CH 2 ) 3 ) 3 -U、-(CH 2 ) 3 -(O(CH 2 ) 2 ) 4 -(O(CH 2 ) 3 ) 4 -U、-(CH 2 ) 3 -(O(CH 2 ) 2 ) 5 -(O(CH 2 ) 3 ) 5 -U、-(CH 2 ) 3 -(O(CH 2 ) 2 ) 6 -(O(CH 2 ) 3 ) 6 -U、-CH 2 -O-(CH 2 ) 3 -O-(CH 2 ) 2 -U、-CH 2 -(O(CH 2 ) 3 ) 2 -(O(CH 2 ) 2 ) 2 -U、-CH 2 -(O(CH 2 ) 3 ) 3 -(O(CH 2 ) 2 ) 3 -U、-CH 2 -(O(CH 2 ) 3 ) 4 -(O(CH 2 ) 2 ) 4 -U、-CH 2 -(O(CH 2 ) 3 ) 5 -(O(CH 2 ) 2 ) 5 -U、-CH 2 -(O(CH 2 ) 3 ) 6 -(O(CH 2 ) 2 ) 6 -U、-(CH 2 ) 2 -O-(CH 2 ) 3 -O-(CH 2 ) 2 -U、-(CH 2 ) 2 -(O(CH 2 ) 3 ) 2 -(O(CH 2 ) 2 ) 2 -U、-(CH 2 ) 2 -(O(CH 2 ) 3 ) 3 -(O(CH 2 ) 2 ) 3 -U、-(CH 2 ) 2 -(O(CH 2 ) 3 ) 4 -(O(CH 2 ) 2 ) 4 -U、-(CH 2 ) 2 -(O(CH 2 ) 3 ) 5 -(O(CH 2 ) 2 ) 5 -U、-(CH 2 ) 2 -(O(CH 2 ) 3 ) 6 -(O(CH 2 ) 2 ) 6 -U、-(CH 2 ) 3 -O-(CH 2 ) 3 -O-(CH 2 ) 2 -U、-(CH 2 ) 3 -(O(CH 2 ) 3 ) 2 -(O(CH 2 ) 2 ) 2 -U、-(CH 2 ) 3 -(O(CH 2 ) 3 ) 3 -(O(CH 2 ) 2 ) 3 -U、-(CH 2 ) 3 -(O(CH 2 ) 3 ) 4 -(O(CH 2 ) 2 ) 4 -U、-(CH 2 ) 3 -(O(CH 2 ) 3 ) 5 -(O(CH 2 ) 2 ) 5 -U、-(CH 2 ) 3 -(O(CH 2 ) 3 ) 6 -(O(CH 2 ) 2 ) 6 -U、-CH 2 -O-(CH 2 ) 2 -O-CH 2 -U、-(CH 2 ) 2 -O-(CH 2 ) 2 -O-CH 2 -U、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 2 -O-(CH 2 ) 3 -U、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 3 -O-(CH 2 ) 3 -U、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 4 -O-(CH 2 ) 3 -U、-(CH 2 ) 5 -(O(CH 2 ) 2 ) 2 -O-(CH 2 ) 5 -U, or- (CH) 2 ) 5 -(O(CH 2 ) 2 ) 2 -O-(CH 2 ) 6 -U；
Wherein the group U represents COOH, SO optionally protected by a protecting group 3 H or NH 2 Or the group U represents N 3 Alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, or any combination thereof; or the group U represents hydrogen.
In one embodiment of the compound of formula (I) of the present disclosure, the LIN is an alkylene-U, the alkylene (preferably C) 1-30 Alkylene chain, particularly preferably C 2 -C 29 Alkylene chain, C 2 -C 28 Alkylene chain, C 2 -C 27 Alkylene chain, C 2 -C 26 Alkylene chain, C 2 -C 25 Alkylene chain, C 2 -C 24 Alkylene chain, C 2 -C 23 Alkylene chain, C 2 -C 22 Alkylene chain, C 2 -C 21 Alkylene chain, C 2 -C 20 Alkylene chain, C 2 -C 19 Alkylene chain, C 2 -C 18 Alkylene chain, C 2 -C 17 Alkylene chain, C 2 -C 16 Alkylene chain, C 2 -C 15 Alkylene chain, C 2 -C 14 Alkylene chain, C 2 -C 13 Alkylene chain, C 2 -C 12 Alkylene chain, C 2 -C 11 Alkylene chain, C 2 -C 10 Alkylene chain, C 2 -C 9 Alkylene chain, C 2 -C 8 Alkylene chain, C 2 -C 7 Alkylene chain, C 2 -C 6 Alkylene chain, C 2 -C 5 Alkylene chain, C 2 -C 4 Alkylene chain, or C 2 -C 3 Alkylene chain) is a straight or branched alkylene chain substituted one or more times with one or more substituents selected from the group consisting of hydroxy, amino, mercapto, halogen, or combinations thereof; wherein the group U represents COOH, SO optionally protected by a protecting group 3 H or NH 2 Or the group U represents N 3 Alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, or any combination thereof; or the group U represents hydrogen. In a sub-embodiment of the disclosure, the number of substituents may be, for example, 1-30, 1-25, 1-20, or 1-15,1-10,1-9,1-8,1-7,1-6,1-5,1-4,1-3, or 1-2, or 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3,2, or 1.
In one embodiment of the compound of formula (I) of the present disclosure, the LIN represents-C 1-30 Alkylene chain-U, said C 1-30 The alkylene chain is a straight or branched C chain substituted with one or more substituents selected from hydroxy, amino, mercapto, halogen or combinations thereof 1-30 An alkylene chain; wherein the group U represents COOH, SO optionally protected by a protecting group 3 H or NH 2 Or the group U represents N 3 Alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, or any combination thereof; or the group U represents hydrogen. In a sub-embodiment of the disclosure, the number of substituents may be, for example, 1-30, 1-25, 1-20, or 1-15,1-10,1-9,1-8,1-7,1-6,1-5,1-4,1-3, or 1-2, or 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3,2, or 1.
In one embodiment of the compounds of formula (I) of the present disclosure, the LIN represents: - (CH) 2 ) n11 -triazolyl- (CH) 2 ) n12 -U、-(CH 2 ) n11 -triazolyl- (CH) 2 ) n12 -(O(CH 2 ) n13 ) m11 -U、-(CH 2 ) n11 -(O(CH 2 ) n12 ) m11 -O-(CH 2 ) n13 -triazolyl- (CH) 2 ) n14 -(O(CH 2 ) n15 ) m12 -O-(CH 2 ) n16 -U、-(CH 2 ) n11 -triazolyl- (CH) 2 ) n12 -(O(CH 2 ) n13 ) m11 -O-(CH 2 ) n14 -U or- (CH) 2 ) n11 -(O(CH 2 ) n12 ) m11 -O-(CH 2 ) n13 -triazolyl- (CH) 2 ) n14 -U; and
n11, n12, n13, n14, n15, n16, m11, m12 each independently represent an integer of 1,2,3, 4,5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20;
wherein the group U represents COOH, SO optionally protected by a protecting group 3 H or NH 2 Or the group U represents N 3 Alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, or any combination thereof; or the group U represents hydrogen.
In one embodiment of the compounds of formula (I) of the present disclosure, the LIN represents: - (CH) 2 ) 3 -triazolyl- (CH) 2 ) 5 -U、-(CH 2 ) 2 -triazolyl- (CH) 2 ) 5 -U、-CH 2 -triazolyl- (CH) 2 ) 5 -U、-(CH 2 ) 2 -triazolyl- (CH) 2 ) 4 -U、-(CH 2 ) 3 -triazolyl- (CH) 2 ) 2 -O(CH 2 ) 2 -U、-(CH 2 ) 2 -triazolyl- (CH) 2 ) 2 -O(CH 2 ) 2 -U or-CH 2 -triazolyl- (CH) 2 ) 2 -O(CH 2 ) 2 -U; wherein the group U represents COOH, SO optionally protected by a protecting group 3 H or NH 2 Or the group U represents N 3 Alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, or any combination thereof; or the group U represents hydrogen.
In one embodiment of the compounds of formula (I) of the present disclosure, the LIN represents: -CH 2 CONHCH 2 -U、-(CH 2 ) 2 CONH(CH 2 ) 2 -U、-(CH 2 ) 3 CONH(CH 2 ) 3 -U、-(CH 2 ) 3 CONH(CH 2 ) 4 -U、-(CH 2 ) 4 CONH(CH 2 ) 4 -U、-(CH 2 ) 5 CONH(CH 2 ) 5 -U、-(CH 2 ) 6 CONH(CH 2 ) 7 -U、-(CH 2 ) 6 CONH(CH 2 ) 6 -U、-(CH 2 ) 7 CONH(CH 2 ) 7 -U、-(CH 2 ) 8 CONH(CH 2 ) 8 -U、-(CH 2 ) 9 CONH(CH 2 ) 9 -U、-(CH 2 ) 10 CONH(CH 2 ) 10 -U、-(CH 2 ) 2 CONH(CH 2 ) 5 -U、-(CH 2 ) 2 CONH(CH 2 ) 3 -U、-(CH 2 ) 2 CONH(CH 2 ) 4 -U, or- (CH) 2 ) 2 CONH(CH 2 ) 2 -O-(CH 2 ) 2 -U; wherein the group U represents COOH, SO optionally protected by a protecting group 3 H or NH 2 Or the group U represents N 3 Alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, or any combination thereof; or the group U represents hydrogen.
In one embodiment of the compounds of formula (I) of the present disclosure, the LIN represents: -CH 2 NHCOCH 2 -U、-(CH 2 ) 2 NHCO(CH 2 ) 2 -U、-(CH 2 ) 3 NHCO(CH 2 ) 3 -U、-(CH 2 ) 3 NHCO(CH 2 ) 4 -U、-(CH 2 ) 4 NHCO(CH 2 ) 4 -U、-(CH 2 ) 5 NHCO(CH 2 ) 5 -U、-(CH 2 ) 6 NHCO(CH 2 ) 7 -U、-(CH 2 ) 6 NHCO(CH 2 ) 6 -U、-(CH 2 ) 7 NHCO(CH 2 ) 7 -U、-(CH 2 ) 8 NHCO(CH 2 ) 8 -U、-(CH 2 ) 9 NHCO(CH 2 ) 9 -U、-(CH 2 ) 10 NHCO(CH 2 ) 10 -U、-(CH 2 ) 2 NHCO(CH 2 ) 5 -U、-(CH 2 ) 2 NHCO(CH 2 ) 3 -U、-(CH 2 ) 2 NHCO(CH 2 ) 4 -U、-(CH 2 ) 4 NHCO(CH 2 ) 8 -U or- (CH) 2 ) 2 NHCO(CH 2 ) 2 -O-(CH 2 ) 2 -U; wherein the group U represents COOH, SO optionally protected by a protecting group 3 H or NH 2 Or the group U represents N 3 Alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, or any combination thereof; or the group U represents hydrogen.
In one embodiment of the compounds of formula (I) of the present disclosure, the LIN represents: -alkylene-U, wherein the alkylene is a linear or branched C 1-30 Alkylene and the group U represents N 3 Alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, or any combination thereof.
In one embodiment of the present disclosure, when the group U in LIN of the compound of formula (I) represents SO 3 H, SO of said compound of formula (I) 3 H can be further converted to SO as required by subsequent synthetic schemes 2 Cl。
The compounds of formula (I) described in the present disclosure are preferably selected from the compounds listed in table 1:
TABLE 1
Figure BDA0002099337960000171
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Figure BDA0002099337960000181
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Figure BDA0002099337960000191
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Figure BDA0002099337960000201
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Figure BDA0002099337960000211
Definition of
The term "halogen atom" or "halogen", as used herein, alone or in combination, refers to fluorine, chlorine, bromine or iodine, and is preferably I, br or Cl.
The term "alkyl" as used herein, alone or in combination, refers to a straight or branched chain alkyl group. The term "C x -C y Alkyl "(x and y are each an integer) means a straight or branched chain alkyl group containing x to y carbon atoms. The term "C" used in this disclosure, alone or in combination 1-10 Alkyl "refers to a straight or branched chain alkyl group containing 1 to 10 carbon atoms. C of the present disclosure 1-10 The alkyl group is preferably C 1-9 Alkyl, more preferably C 1-8 Alkyl, still more preferably C 2-8 Alkyl, more preferably C 1-7 Alkyl, even more preferably C 1-6 Alkyl radical, C 1-5 Alkyl, or C 1-4 An alkyl group. Representative examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. The term "C" of the present disclosure 1-3 Alkyl "refers to an alkyl group containing 1 to 3 carbon atoms, representative examples of which include methyl, ethyl, n-propyl, and isopropyl.
The term "alkylene" (which is used interchangeably with "alkylene chain") used herein, alone or in combination, refers to a straight or branched chain divalent saturated hydrocarbon group consisting of carbon and hydrogen atoms. The term "C x -C y Alkylene "or" C x-y Alkylene "(x and y are each an integer) means a straight or branched chain alkylene group containing x to y carbon atoms. C of the present disclosure 1 -C 30 Alkylene is preferably C 1 -C 29 Alkylene radical, C 1 -C 28 Alkylene radical, C 1 -C 27 Alkylene radical, C 1 -C 26 Alkylene radical, C 1 -C 25 Alkylene oxideBase, C 1 -C 24 Alkylene radical, C 1 -C 23 Alkylene radical, C 1 -C 22 Alkylene radical, C 1 -C 21 Alkylene radical, C 1 -C 20 Alkylene radical, C 1 -C 19 Alkylene radical, C 1 -C 18 Alkylene radical, C 1 -C 17 Alkylene radical, C 1 -C 16 Alkylene radical, C 1 -C 15 Alkylene radical, C 1 -C 14 Alkylene radical, C 1 -C 13 Alkylene radical, C 1 -C 12 Alkylene radical, C 1 -C 11 Alkylene radical, C 1 -C 10 Alkylene radical, C 1 -C 9 Alkylene radical, C 1 -C 8 Alkylene radical, C 1 -C 7 Alkylene radical, C 1 -C 6 Alkylene radical, C 1 -C 5 Alkylene radical, C 1 -C 4 Alkylene radical, C 1 -C 3 Alkylene, or C 1 -C 2 An alkylene group. Representative examples include, but are not limited to, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, tert-butylene, pentylene, isopentylene, neopentylene, pentylene, hexylene, heptylene, octylene, nonylene, decylene, undecylene, dodecylene, tridecylene, tetradecylene, pentadecylene, hexadecylene, heptadecylene, octadecylene, nonadecylene, eicosylene, heneicosylene, docosylene, tricosylene, tetracosylene, pentacosylene, hexacosylene, heptacosylene, octacosylene, nonacosylene, and triacontylene.
The term "arylene" as used herein, alone or in combination, refers to a divalent aromatic hydrocarbon group containing 5 to 14 carbon atoms and optionally containing one or more fused rings, such as phenylene or naphthylene or fluorenylene. In the present disclosure, the "arylene" is an optionally substituted arylene. Substituted arylene means arylene substituted 1 to 3 times with a substituent selected from C 1-3 Alkyl radical, C 1-3 Alkoxy, halogen, amino or hydroxy.
The term "C" as used herein, alone or in combination 1-3 Alkoxy "means a straight or branched chain alkoxy group containing 1 to 3 carbon atoms. C 1-3 Representative examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, and isopropoxy. Methoxy and ethoxy are preferred.
The term "cycloalkyl", as used herein, alone or in combination, refers to saturated and partially unsaturated (i.e., having one or more double bonds, but not fully conjugated) monocyclic or bicyclic hydrocarbon groups having from 3 to 12 carbon atoms. The term "C 3-10 Cycloalkyl "refers to saturated and partially unsaturated (i.e., having one or more double bonds, but not fully conjugated) monocyclic or bicyclic cycloalkyl groups having 3 to 10 carbon atoms. Representative examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, decahydronaphthalene, octahydropentalene, octahydro-1H-indene, and spirocyclic groups.
The term "cycloalkylene" as used herein, alone or in combination, refers to a saturated and partially unsaturated (i.e., having one or more double bonds, but not fully conjugated) monocyclic or bicyclic hydrocarbon divalent radicals having from 3 to 12 carbon atoms. Representative examples of cycloalkylene groups include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, cyclopentenylene, cyclohexylene, cyclohexenylene, cycloheptenylene, cyclooctenylene, decahydronaphthalenylene, octahydrocyclopentadienylene, octahydro-1H-indeneene, spirocyclylene.
The term "heteroaryl", as used herein, alone or in combination, refers to a 5-to 10-membered monocyclic or bicyclic aromatic ring group containing 1 or more (e.g., 1 to 6, or 1 to 5, or 1 to 4, or 1 to 3) heteroatoms independently selected from oxygen, nitrogen and sulfur. Representative examples of such heteroaryl groups include, but are not limited to, furyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothienyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, benzo [2,1,3] oxadiazolyl, benzo [2,1,3] thiadiazolyl, benzo [1,2,3] thiadiazolyl, quinolyl, isoquinolyl, naphthyridinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, pyrazolo [1,5-a ] pyridyl, pyrazolo [1,5-a ] pyrimidinyl, imidazo [1,2-a ] pyridyl, 1H-pyrrolo [3,2-b ] pyridyl, 1H-pyrrolo [2,3-b ] pyridyl, 4H-pyrrolo [1, 2-b ] pyridyl, and 1,2, 4H-pyrrolo [3,2-b ] pyridyl. The heteroaryl group may be unsubstituted or substituted according to a well-defined definition.
The term "heteroarylene" as used herein, alone or in combination, refers to a 5-to 10-membered monocyclic or bicyclic divalent aromatic ring radical containing 1 or more (e.g., 1 to 6, or 1 to 5, or 1 to 4, or 1 to 3) heteroatoms independently selected from oxygen, nitrogen and sulfur. Representative examples of such heteroarylene groups include, but are not limited to, furanylene, oxazolene, isoxazolene, oxadiazolene, thienylene, thiazolyl, isothiazolene, thiadiazolene, pyrrolylene, imidazolyl, pyrazolyl, triazolene, pyridylene, pyrimidylene, pyridazinylene, pyrazinylene, indolyl, isoindolene, benzofuranylene, isobenzofuranylene, benzothiophene, indazolene, benzimidazolene, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolene, benzoisothiazolene, and mixtures thereof benzotriazolylene, benzolene [2,1,3] oxadiazolyl, benzolene [2,1,3] thiadiazolyl, benzolene [1,2,3] thiadiazolyl, quinolylene, isoquinolylene, naphthyrylene, cinnoline, quinazolinylene, quinoxalylene, phthalazinylene, pyrazolo [1,5-a ] pyridylidene, pyrazolo [1,5-a ] pyrimidylidene, imidazo [1,2-a ] pyridylidene, 1H-pyrrolo [3,2-b ] pyridylidene, 1H-pyrrolo [2,3-b ] pyridylidene, 4H-fluoro [3,2-b ] pyrrylylidene, pyrrolo [2,1-b ] thiazolylidene, and imidazo [2,1-b ] thiazolylidene. The heteroarylene group may be unsubstituted or substituted, as appropriate to the explicit definition.
The term "heterocyclyl", as used herein, alone or in combination, refers to a 4-to 6-membered saturated monocyclic group containing one or more heteroatoms independently selected from sulfur, oxygen and nitrogen. Representative examples of such heterocyclyl groups include, but are not limited to, azetidinyl, oxetanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, triazolyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and dioxacyclohexyl. The heterocyclyl group may be unsubstituted or substituted as specifically defined.
The term "heterocyclylene" as used herein, alone or in combination, refers to a 4-to 6-membered saturated divalent monocyclic group containing one or more heteroatoms independently selected from sulfur, oxygen, and nitrogen. Representative examples of such heterocyclylene groups include, but are not limited to, azetidinylene, oxetanylene, pyrrolidinylene, imidazolidinylene, pyrazolylene, triazolylene, tetrahydrofurylene, tetrahydrothienyl, tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, piperidylene, piperazinyl, morpholinylene, thiomorpholinylene, and dioxacyclohexyl. The heterocyclylene group may be unsubstituted or substituted as specifically defined.
The term "alkynylene" as used herein, alone or in combination, refers to a straight or branched chain divalent hydrocarbon radical containing from 2 to 10 (preferably 2 to 6, more preferably 2 to 4) carbon atoms having one or more carbon-carbon triple bonds. Examples of preferred alkynylene groups include, but are not limited to, ethynylene, 1-propynylene, 1-butynylene, and 1, 3-diynylene.
The term "alkynyl", as used herein, alone or in combination, refers to a straight or branched chain hydrocarbon radical containing from 2 to 10 (preferably 2 to 6, more preferably 2 to 4) carbon atoms having one or more carbon-carbon triple bonds. Examples of preferred alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 1-butynyl, and 1, 3-diynyl.
The term "alkenylene" as used herein, alone or in combination, refers to a straight or branched chain divalent hydrocarbon radical containing 2 to 10 (preferably 2 to 6, more preferably 2 to 4) carbon atoms with one or more carbon-carbon double bonds. Examples of preferred alkenylene groups include, but are not limited to, ethenylene (e.g., -CH = CH-), 1-propenylene, 1-butenylene.
The term "alkenyl" as used herein, alone or in combination, refers to a straight or branched chain hydrocarbon group (preferably containing 2 to 40 carbon atoms, more preferably 2 to 35, 2 to 30, 2 to 25, 2 to 20, 2 to 15, 2 to 10, 2 to 6 or 2 to 5 carbon atoms, especially preferably 2 to 4 or 2 to 3 carbon atoms) having one or more carbon-carbon double bonds. Examples of preferred alkenyl groups include, but are not limited to, vinyl, propenyl, allyl, 1-butenyl, 2-butenyl, 3-butenyl, isobutenyl, pentenyl, n-penta-2, 4-dienyl, 1-methyl-but-1-enyl, 2-methyl-but-1-enyl, 3-methyl-but-1-enyl, 1-methyl-but-2-enyl, 2-methyl-but-2-enyl, 3-methyl-but-2-enyl, 1-methyl-but-3-enyl, 2-methyl-but-3-enyl, 3-methyl-but-3-enyl, hexenyl, heptenyl, octenyl, n-oct-2-enyl, nonenyl, decenyl, n-dodec-2-enyl, isododec-enyl, n-dodec-2-enyl, n-octadec-4-enyl or 3,7, 11-tetramethyl-2, 6, 10-undecadienyl.
The term "leaving group", used herein, alone or in combination, is a term well known to those skilled in the art, which may also be referred to as a leaving group, is a molecular fragment (ionic or neutral molecule) that carries a pair of electron-leaving groups from a reactant in a chemical reaction, and is a term used in nucleophilic substitution reactions and elimination reactions. Common ionic leaving groups are Cl - 、Br - 、I - And sulfonic acid esters (e.g., p-toluenesulfonate, tsO) - ) Neutral molecule leaving groups are water, ammonia and alcohol. In the present disclosure, one skilled in the art can select an appropriate leaving group as desired, such as, but not limited to, halogen, methanesulfonyloxy, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy, or the like.
The term "organic base" as used herein, alone or in combination, is generally defined as an organic compound containing an amino group in the molecule, such as an amine compound. In the present disclosure, the organic base includes, but is not limited to, triethylamine, dimethylamine, tri-tert-butylamine, N-dimethylaniline, DIPEA, N-diethylethylamine, DMAP, pyridine, quinoline, morpholine, and NMM.
The term "protecting group" as used herein, alone or in combination, is an agent capable of protecting a group (e.g., carboxy, amino, sulfonyl). The use of protecting groups in organic reactions is common, and protection of groups such as hydroxyl, amino, and the like is common.
The term "room temperature" herein refers to ambient temperature, such as, but not limited to, temperatures of 20-30 ℃.
The disclosed process of reacting lenalidomide with a suitable alkylating agent in the presence of an organic base can yield aminoalkylated products with high selectivity as compared to inorganic bases. The present disclosure provides examples using a plurality of organic bases and inorganic bases, respectively, and the results show that the alkylation reaction in the presence of organic bases of the process of the present disclosure can obtain the desired aminoalkylated product with high selectivity, while the alkylation reaction in the presence of inorganic bases can not obtain the desired aminoalkylated product, but only obtain the N-alkylated product of glutarimide, as shown in scheme 5 below and table 2.
Figure BDA0002099337960000251
TABLE 2
Figure BDA0002099337960000252
a HPLC yield. b The reaction was carried out at 110 ℃.
Examples
In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present disclosure. The present disclosure may be practiced without some or all of these specific details. In other instances, well known process operations have not been described in detail in order not to unnecessarily obscure the present disclosure. While the disclosure will be described in conjunction with specific embodiments, it will be understood that they are not intended to limit the disclosure to these embodiments.
The following abbreviations are used throughout the specification and examples:
boc tert-butoxycarbonyl
DCM dichloromethane
DIPEA N, N-diisopropylethylamine
DMAP 4-dimethylaminopyridine
DMF N, N-dimethylformamide
equiv equivalent of
ESI electrospray ionization
HPLC high performance liquid chromatography
HRMS high resolution mass spectrometry
LC-MS liquid chromatography-mass spectrometry combination
LRMS low resolution mass spectrometry
LC liquid chromatography
NMM N-methylmorpholine
NMP N-methylpyrrolidone
1 H NMR hydrogen nuclear magnetic resonance spectrum
rt Room temperature
TFA trifluoroacetic acid
t Bu tert-butyl
THF tetrahydrofuran
TLC thin layer chromatography
TMS trimethylsilyl group
In an embodiment of the present invention, 1 h NMR spectra were determined using a Bruker-500MHz type NMR spectrometer, using CD containing 0.1% TMS 3 OD as a solvent, wherein 1 H NMR Spectroscopy in CD 3 OD (δ =3.31 ppm) as internal standard; or by containing0.1% of CDCl of TMS 3 As a solvent, wherein 1 H NMR spectrum in CDCl 3 (δ =7.26 ppm) as an internal standard; or using DMSO-d containing 0.03% of TMS 6 As a solvent, wherein 1 H NMR spectra in DMSO-d 6 (δ =2.50 ppm) as an internal standard; the LRMS spectra were determined on an AB Triple 4600 mass spectrometer, the HPLC preparation was determined on a SHIMADZU LC-20AP instrument, and the HPLC purity was determined on a SHIMADZU LC-30AP or Waters 1525 instrument. All reactions are carried out in an air atmosphere unless otherwise specified; the reaction was followed by TLC or LC-MS.
Solvent and reagent treatments were as follows:
1. solvents used in the reaction, such as DCM, DMF, NMP, anhydrous EtOH, anhydrous MeOH and the like, are purchased from the national pharmaceutical group;
HPLC preparation used preparative CH 3 CN and deionized water;
3. lenalidomide was purchased directly.
Other reagents and drugs were purchased from the manufacturer and used without specific reference.
General synthetic method
General synthesis scheme a:
the preparation method of the terminal carboxylic acid substituted lenalidomide alkyl carbon chain series derivative comprises the following steps:
Figure BDA0002099337960000271
lenalidomide (259.3mg, 1mmol, 1equiv), bromo-tert-butyl ester (1.2mmol, 1.2equiv) and N, N-diisopropylethylamine (387.7mg, 3mmol, 3equiv) were added together to a 25mL reaction tube, followed by NMP (5 mL) and reacted in an oil bath at 110 ℃ for 12h. The reaction was allowed to cool to room temperature and then prepared using a C18 reverse phase column, eluting (v/v): acetonitrile/(water +0.1% =10% -100%, evaporate acetonitrile under reduced pressure, get intermediate after lyophilizing; the compound was then added to a 25mL single-neck flask, followed by the addition of 1mL of dichloromethane and 3mL of trifluoroacetic acid, and stirred at room temperature for 1h. And (4) evaporating the reaction solvent under reduced pressure, adding water and freeze-drying to obtain the final target compound.
General synthesis scheme B1:
preparation method of terminal carboxylic acid substituted lenalidomide polyethylene glycol (PEG) series derivatives 1:
Figure BDA0002099337960000272
the OTs-substituted tert-butyl ester (1 equiv) and sodium iodide (2 equiv) were added together in a 25mL egg-shaped flask followed by acetone (5 mL) and refluxed in a 60 ℃ oil bath for 2h. Acetone was spin dried, followed by the addition of NMP (3 mL), lenalidomide (0.8 equiv) and N, N-diisopropylethylamine (3 equiv), and an oil bath at 110 ℃ for 12h. The reaction was allowed to cool to room temperature and then prepared using a C18 reverse phase column, eluting (v/v): acetonitrile/(water +0.1% =10% -100%, evaporate acetonitrile under reduced pressure, get intermediate after lyophilizing; the compound was then added to a 25mL single-neck flask, followed by the addition of 1mL of dichloromethane and 3mL of trifluoroacetic acid, and stirred at room temperature for 1h. The reaction solvent is evaporated under reduced pressure, and the final target compound is obtained by adding water and freeze-drying.
General synthesis scheme B2:
preparation of terminal carboxylic acid substituted lenalidomide polyethylene glycol (PEG) series derivatives method 2:
Figure BDA0002099337960000273
Figure BDA0002099337960000281
lenalidomide (1 equiv), OTs-substituted tert-butyl ester (1.2 equiv) and N, N-diisopropylethylamine (3 equiv) were added together in a 25mL reaction tube, followed by NMP (5 mL) and an oil bath at 80 ℃ for 6h. The reaction was allowed to cool to room temperature and then prepared using a C18 reverse phase column, eluting (v/v): acetonitrile/(water +0.1% =10% -100%, evaporate acetonitrile under reduced pressure, get intermediate after lyophilizing; the compound was then added to a 25mL single-neck flask, followed by the addition of 1mL of dichloromethane and 3mL of trifluoroacetic acid, and stirred at room temperature for 1h. And (3) decompressing and distilling off the reaction solvent, adding water and freeze-drying to obtain the final target compound.
General synthesis scheme C:
the preparation method of the terminal amino-substituted lenalidomide alkyl carbon chain series derivative comprises the following steps:
Figure BDA0002099337960000282
lenalidomide (259.3mg, 1mmol, 1equiv), N-t-butoxycarbonyl-bromoalkylamine (1.2mmol, 1.2equiv) and N, N-diisopropylethylamine (387.7mg, 3mmol, 3equiv) were added together in a 25mL reaction tube, followed by NMP (5 mL) and reacted in an oil bath at 110 ℃ for 12 hours. The reaction was allowed to cool to room temperature and then prepared using a C18 reverse phase column, eluting (v/v): acetonitrile/(water +0.1% =10% -100%, evaporate acetonitrile under reduced pressure, get intermediate after lyophilizing; the compound was then added to a 25mL single-neck flask, followed by the addition of 1mL of dichloromethane and 3mL of trifluoroacetic acid, and stirred at room temperature for 1h. The reaction solvent is evaporated under reduced pressure, and the final target compound is obtained by adding water and freeze-drying.
General synthesis scheme D:
Figure BDA0002099337960000283
lenalidomide (20mg, 0.073mmol, 1equiv), N-propyl bromide (18.9mg, 0.0876mmol, 1.2equiv) and N, N-diisopropylethylamine (29.9mg, 0.219mmol, 3equiv) were added together to a 10mL reaction tube, followed by NMP (2 mL) and reacted in an oil bath at 110 ℃ for 6 hours. The reaction was allowed to cool to room temperature and then prepared using a C18 reverse phase column, eluting (v/v): acetonitrile/(water +0.1% tfa) =10% -100%, acetonitrile was distilled off under reduced pressure, and the final target compound was obtained after lyophilization.
Example 1: preparation of (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) aminoacetic acid ((2- (2, 6-dioxoperidin-3-yl) -1-oxoisoindolin-4-yl) glycine; SIAIS 1204057)
Following the procedure of scheme A, lenalidomide (259.3mg, 1mmol, 1equiv), tert-butyl 2-bromoacetate (1.2mmol, 1.2equiv) and N, N-diisopropylethylamine (387.7mg, 3mmol, 3equiv) were charged together in a 25mL reaction tube, withThen NMP (5 mL) was added and the reaction was carried out in an oil bath at 110 ℃ for 12 hours. The reaction was allowed to cool to room temperature and then prepared using a C18 reverse phase column, eluent (v/v): acetonitrile/(water +0.1% =10% -100%, evaporate acetonitrile under reduced pressure, get intermediate after lyophilizing; this compound was then added to a 25mL single-necked flask, followed by the addition of 1mL of dichloromethane and 3mL of trifluoroacetic acid, and stirred at room temperature for 1h. The reaction solvent was evaporated under reduced pressure, and water was added to lyophilize to obtain the target compound, SIAIS1204057 (yellow solid, 203mg, yield 64%); 1 h NMR (500mhz, dmso) δ 11.01 (s, 1H), 7.28 (t, J =7.7hz, 1h), 6.98 (d, J =7.3hz, 1h), 6.66 (d, J =8.0hz, 1h), 5.94 (s, 1H), 5.12 (dd, J =13.3,5.1hz, 1h), 4.26 (d, J =17.0hz, 1h), 4.16 (d, J =17.0hz, 1h), 3.92 (s, 2H), 2.98-2.85 (m, 1H), 2.62 (d, J =17.0hz, 1h), 2.39-2.26 (m, 1H), 2.08-1.99 (m, 1H); HRMS (ESI) m/z calculated value C 15 H 16 N 3 O 5 + [M+H] + 318.1084; found 318.1098.
Example 2: preparation of 3- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) propanoic acid (3- ((2- (2, 6-dioxoperidin-3-yl) -1-oxoisoindolin-4-yl) amino) propanoic acid; SIAIS 1204059)
According to scheme a, the target compound sias 1204059 was prepared under appropriate conditions understood in the art using the same method as in example 1, except that the tert-butyl bromide used was tert-butyl 3-bromopropionate. The obtained target compound SIAIS1204059 is yellow solid, 54mg, and the yield is 16%; 1 h NMR (500mhz, dmso) δ 11.00 (s, 1H), 7.31 (t, J =7.7hz, 1h), 6.96 (d, J =7.4hz, 1h), 6.79 (d, J =8.0hz, 1h), 5.11 (dd, J =13.3,5.1hz, 1h), 4.21 (d, J =17.0hz, 1h), 4.12 (d, J =17.0hz, 1h), 4.08 (s, 1H), 3.37 (t, J =6.9hz, 2h), 2.98-2.86 (m, 1H), 2.65-2.57 (m, 1H), 2.54 (t, J =6.9hz, 2h), 2.33-2.26 (m, 1H), 2.07-1.99 (m, 1H); HRMS (ESI) m/z calculated value C 16 H 18 N 3 O 5 + [M+H] + 332.1241; found 332.1259.
Example 3: preparation of 4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) butanoic acid (4- ((2- (2, 6-dioopioridin-3-yl) -1-oxoisoindolin-4-yl) amino) butanoic acid; SIAIS 1204085)
According to scheme a, the target compound sias 1204085 was prepared under appropriate conditions understood in the art using the same method as in example 1, except that the tert-butyl bromide used was tert-butyl 4-bromobutyrate. The obtained target compound SIAIS1204085 is yellow solid, 215mg and the yield is 62%; 1 h NMR (500mhz, dmso) δ 11.01 (s, 1H), 7.28 (t, J =7.7hz, 1h), 6.93 (d, J =7.3hz, 1h), 6.77 (d, J =8.0hz, 1h), 5.11 (dd, J =13.3,5.1hz, 1h), 4.23 (d, J =17.0hz, 1h), 4.13 (d, J =17.0hz, 1h), 4.01 (s, 1H), 3.14 (t, J =7.0hz, 2h), 2.98-2.86 (m, 1H), 2.66-2.58 (d, J =17.6hz, 1h), 2.34 (t, J =7.3hz, 2h), 2.32-2.24 (m, 1H), 2.08-1.98 (m, 1H), 1.85 (m, 1H); HRMS (ESI) m/z calculated value C 17 H 20 N 3 O 5 + [M+H] + 346.1379; found 346.1414.
Example 4: preparation of 5- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) pentanoic acid (5- ((2- (2, 6-dioopioridin-3-yl) -1-oxoisoindolin-4-yl) amino) pentanoic acid; SIAIS 184047)
According to scheme a, the title compound, siis 184047, was prepared under appropriate conditions understood in the art, using the same procedure as in example 1, except that the bromo-tert-butyl ester used was tert-butyl 5-bromovalerate. The obtained target compound SIAIS184047 is yellow solid, 215mg and 60% of yield; 1 h NMR (500mhz, dmso) δ 11.00 (s, 1H), 7.28 (t, J =7.7hz, 1h), 6.92 (t, J =10.9hz, 1h), 6.76 (d, J =8.0hz, 1h), 5.11 (dd, J =13.3,5.1hz, 1h), 5.07 (s, 1H), 4.23 (d, J =17.2hz, 1h), 4.13 (d, J =17.1hz, 1h), 3.13 (d, J =6.4hz, 2h), 2.97 to 2.87 (m, 1H), 2.61 (d, J =16.7hz, 1h), 2.38 to 2.21 (m, 3H), 2.06 to 1.98 (m, 1H), 1.67 to 1.55 (m, 4H); HRMS (ESI) m/z calculated value C 18 H 22 N 3 O 5 + [M+H] + 416.2180; found 416.2189.
Example 5: preparation of 6- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) hexanoic acid (6- ((2- (2, 6-dioxoperidin-3-yl) -1-oxoisoindolin-4-yl) amino) hexanoic acid; SIAIS 1204061)
According to scheme A, the same procedure as in example 1 was adopted, under appropriate conditions understood in the artStandard compound SIAIS1204061, except that tert-butyl bromo-ester was used which was tert-butyl 6-bromohexanoate. The obtained target compound SIAIS1204061 was a yellow solid, 268mg, yield 72%; 1 h NMR (500mhz, dmso) δ 11.01 (s, 1H), 7.29 (t, J =7.7hz, 1h), 6.94 (d, J =7.4hz, 1h), 6.76 (d, J =8.0hz, 1h), 5.11 (dd, J =13.3,5.1hz, 1h), 4.24 (d, J =17.0hz, 1h), 4.14 (d, J =17.0hz, 1h), 4.05 (s, 1H), 3.12 (t, J =7.0hz, 2h), 2.98-2.87 (m, 1H), 2.66-2.58 (m, 1H), 2.35-2.25 (m, 1H), 2.22 (t, J =7.0hz, 2h), 2.07-2.00 (m, 1H), 1.63-1.50 (m, 1H), 1.37-2H (m, 1H); HRMS (ESI) m/z calculated value C 19 H 24 N 3 O 5 + [M+H] + 374.1710; found 374.1720.
Example 6: preparation of 7- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) heptanoic acid (7- ((2- (2, 6-dioopioridin-3-yl) -1-oxoisoindolin-4-yl) amino) heptanic acid; SIAIS 1204063)
According to scheme a, the target compound sias 1204063 was prepared under appropriate conditions understood in the art, using the same method as in example 1, except that the tert-butyl bromide used was tert-butyl 7-bromoheptanoate. The obtained target compound SIAIS1204063 is yellow solid, 252mg, and the yield is 65%; 1 h NMR (500mhz, dmso) δ 11.00 (s, 1H), 7.28 (t, J =7.7hz, 1h), 6.93 (d, J =7.3hz, 1h), 6.75 (d, J =8.0hz, 1h), 5.11 (dd, J =13.2,5.0hz, 1h), 4.23 (d, J =17.0hz, 1h), 4.13 (d, J =17.0hz, 1h), 3.11 (t, J =7.0hz, 2h), 2.98-2.84 (m, 1H), 2.67-2.57 (m, 1H), 2.35-2.25 (m, 1H), 2.20 (t, J =7.3hz, 2h), 2.07-1.99 (m, 1H), 1.63-1.46 (m, 4H), 1.42-1.42 (m, 4H, 27.42H); HRMS (ESI) m/z calculated value C 20 H 26 N 3 O 5 + [M+H] + 388.1867; found 388.1878.
Example 7: preparation of 2- (2- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) ethoxy) acetic acid (2- (2- ((2- (2, 6-dioxoperidin-3-yl) -1-oxoisoindolin-4-yl) amino) ethoxy) acetic acid (SIAIS 4111205)
According to the procedure of scheme B1, tert-butyl 2- (2- (tosyloxy) ethoxy) acetate (1 equiv) and sodium iodide (2 equiv) were added together in a 25mL egg-shaped flask followed by the addition of propyleneKetone (5 mL), oil bath reflux reaction at 60 ℃ for 2h. Acetone was spin dried, followed by the addition of NMP (3 mL), lenalidomide (0.8 equiv) and N, N-diisopropylethylamine (3 equiv), and an oil bath at 110 ℃ for 12h. The reaction was allowed to cool to room temperature and then prepared using a C18 reverse phase column, eluting (v/v): acetonitrile/(water +0.1% =10% -100%, evaporate acetonitrile under reduced pressure, get intermediate after lyophilizing; the compound was then added to a 25mL single-neck flask, followed by the addition of 1mL of dichloromethane and 3mL of trifluoroacetic acid, and stirred at room temperature for 1h. Evaporating the reaction solvent under reduced pressure, adding water, and lyophilizing to obtain the target compound SIAIS1204115 (yellow solid, 134mg, yield 77%); 1 H NMR(500MHz,DMSO)δ 1 h NMR (500mhz, dmso) δ 11.00 (s, 1H), 7.29 (t, J =7.7hz, 1h), 6.95 (d, J =6.9hz, 1h), 6.80 (d, J =8.0hz, 1h), 5.12 (dd, J =13.3,5.1hz, 1h), 4.24 (d, J =17.1hz, 1h), 4.13 (d, J =17.0hz, 1h), 4.02 (s, 2H), 3.65 (t, J =5.9hz, 2h), 3.32 (t, J =5.9hz, 2h), 2.97-2.89 (m, 1H), 2.65-2.58 (m, 1H), 2.33-2.25 (m, 1H), 2.06-2.02 (m, 1H); HRMS (ESI) m/z calculated value C 17 H 20 N 3 O 6 + [M+H] + 362.1347; found 362.1344.
Example 7-1: preparation of 2- (2- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) ethoxy) acetic acid (2- (2- ((2- (2, 6-dioxoperidin-3-yl) -1-oxoisoindolin-4-yl) amino) ethoxy) acetic acid (SIAIS 4111205)
Following the procedure of scheme B2, lenalidomide (1 equiv), tert-butyl 2- (2- (tosyloxy) ethoxy) acetate (1.2 equiv) and N, N-diisopropylethylamine (3 equiv) were added together in a 25mL reaction tube followed by NMP (5 mL) and an 80 ℃ oil bath for 6h. The reaction was allowed to cool to room temperature and then prepared using a C18 reverse phase column, eluting (v/v): acetonitrile/(water +0.1% tfa) =10% -100%, evaporating acetonitrile under reduced pressure, and lyophilizing to obtain an intermediate; this compound was then added to a 25mL single-necked flask, followed by the addition of 1mL of dichloromethane and 3mL of trifluoroacetic acid, and stirred at room temperature for 1h. Evaporating the reaction solvent under reduced pressure, adding water, and lyophilizing to obtain final target compound SIAIS1204115 (yellow solid, 11.1mg, yield 40%); 1 H NMR(500MHz,DMSO)δ 1 H NMR(500MHz,DMSO)δ11.01(s,1H),7.27(t,J＝7.7Hz,1H),6.93(d,J＝6.9Hz,1H),6.78(d,J＝8.0Hz,1H),5.11(dd, J =13.3,5.1hz, 1h), 4.23 (d, J =17.1hz, 1h), 4.12 (d, J =17.0hz, 1h), 4.01 (s, 2H), 3.63 (t, J =5.9hz, 2h), 3.31 (t, J =5.9hz, 2h), 2.96-2.88 (m, 1H), 2.64-2.57 (m, 1H), 2.33-2.23 (m, 1H), 2.06-2.01 (m, 1H); HRMS (ESI) m/z calculated value C 17 H 20 N 3 O 6 + [M+H] + 362.1347; found 362.1339.
Example 8: preparation of 2- (2- (2- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) ethoxy) ethoxy) acetic acid (2- (2- (2- ((2- (2, 6-diozoperidin-3-yl) -1-oxosoindolin-4-yl) amino) ethoxy) acetic acid (acetyloxy) ethoxy) acetic acid; (SIAIS 1204123)
The title compound, siis 1204123, was prepared according to scheme B1, using the same procedure as in example 7, under appropriate conditions understood in the art, except that the OTs-substituted tert-butyl ester used was tert-butyl 2- (2- (2- (tosyloxy) ethoxy) acetate. The obtained target compound SIAIS1204123 is yellow liquid, 139mg, yield 80%; 1 h NMR (500mhz, dmso) δ 11.00 (s, 1H), 7.33-7.24 (m, 1H), 6.94 (t, J =8.2hz, 1h), 6.81 (d, J =7.9hz, 1h), 5.11 (dd, J =13.3,5.1hz, 1h), 4.23 (d, J =17.1hz, 1h), 4.14 (d, J =17.1hz, 1h), 4.04-4.01 (m, 2H), 3.62-3.56 (m, 6H), 3.32 (t, J =5.9hz, 2h), 2.95-2.88 (m, 1H), 2.62 (d, J =17.6hz, 1h), 2.35-2.28 (m, 1H), 2.07-2.00 (m, 1H); HRMS (ESI) m/z calculated value C 19 H 24 N 3 O 7 + [M+H] + 406.1609; found, 406.1618.
Example 9: preparation of 2- (2- (2- (2- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) ethoxy) ethoxy) ethoxy) acetic acid (2- (2- (2- (2- ((2- (2, 6-dioxoperidin-3-yl) -1-oxoisoindolin-4-yl) amino) ethoxy) ethoxy) ethoxy) acetic acid; (SIAIS 1204127)
The title compound, siis 1204127, was prepared according to scheme B1, using the same procedure as in example 7, under appropriate conditions understood in the art, except that the OTs-substituted tert-butyl ester used was tert-butyl 2- (2- (2- (2- (tosyloxy) ethoxy) acetate. The obtained target compound SIAIS1204127 is yellow liquid, 124mg, and the yield is 72%; 1 H NMr (500mhz, dmso) δ 11.00 (s, 1H), 7.29 (t, J =7.7hz, 1h), 6.94 (d, J =7.4hz, 1h), 6.81 (d, J =8.0hz, 1h), 5.11 (dd, J =13.3,5.1hz, 1h), 4.23 (d, J =17.1hz, 1h), 4.13 (d, J =17.1hz, 1h), 4.01 (s, 2H), 3.60-3.51 (m, 10H), 3.34-3.30 (m, 2H), 2.97-2.87 (m, 1H), 2.62 (d, J =16.9hz, 1h), 2.36-2.28 (m, 1H), 2.07-2.01 (m, 1H); HRMS (ESI) m/z calculated value C 21 H 28 N 3 O 8 + [M+H] + 450.1871; found 450.1879.
Example 10: preparation of 14- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) -3,6,9,12-tetraoxatetradecanoic acid (14- ((2- (2, 6-dioopioridin-3-yl) -1-oxosoindolin-4-yl) amino) -3,6,9, 12-tetraoxaradanoic acid; SIAIS 1204131)
The title compound, SIAIS1204131, was prepared according to scheme B1, using the same procedure as in example 7, under appropriate conditions understood in the art, except that the OTs-substituted tert-butyl ester used was tert-butyl 14- (tosyloxy) -3,6,9, 12-tetraoxatetradecane. The obtained target compound SIAIS1204131 was a yellow liquid, 134mg, yield 79%. 1 H NMR (500mhz, dmso) δ 11.00 (s, 1H), 7.29 (t, J =7.7hz, 1h), 6.96 (d, J =7.3hz, 1h), 6.82 (d, J =8.0hz, 1h), 5.11 (dd, J =13.3,5.1hz, 2h), 4.24 (d, J =17.1hz, 1h), 4.13 (d, J =17.1hz, 1h), 4.01 (s, 2H), 3.64-3.46 (m, 14H), 3.32 (t, J =5.9hz, 2h), 2.99-2.86 (m, 1H), 2.62 (d, J =16.9hz, 1h), 2.31 (qd, J =13.3,4.4hz, 1h), 2.07-2.00 (m, 1H); HRMS (ESI) m/z calculated value C 23 H 32 N 3 O 9 + [M+H] + 494.2133; found 494.2144.
Example 11: preparation of 14- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) -3,6,9,12-tetraoxatetradecanoic acid (14- ((2- (2, 6-dioopioridin-3-yl) -1-oxosoindolin-4-yl) amino) -3,6,9, 12-tetraoxaradanoic acid; SIAIS 1204135)
The title compound, SIAIS1204135, was prepared according to scheme B1, using the same procedure as in example 7, under appropriate conditions as understood in the art, except that the OTs-substituted tert-butyl ester used was tert-butyl 17- (tosyloxy) -3,6,9,12, 15-pentaoxaheptadecane. What is needed isThe target compound SIAIS1204135 was obtained as a yellow liquid, 127mg, 75% yield. 1 H NMR (500mhz, dmso) δ 11.01 (s, 1H), 7.29 (t, J =7.7hz, 1h), 6.95 (d, J =6.9hz, 1h), 6.80 (d, J =6.9hz, 1h), 5.11 (dd, J =13.3,5.1hz, 1h), 4.24 (d, J =17.1hz, 1h), 4.14 (d, J =17.1hz, 1h), 4.01 (s, 2H), 3.62-3.46 (m, 18H), 3.32 (t, J =5.9hz, 2h), 2.96-2.88 (m, 1H), 2.62 (d, J =16.6hz, 1h), 2.37-2.25 (m, 1H), 2.08-2.00 (m, 1H); HRMS (ESI) m/z calculated value C 25 H 36 N 3 O 10 + [M+H] + 538.2395; found 538.2403.
Example 12: preparation of 3- (4- ((3-aminopropyl) amino) -1-oxoisoindolin-2-yl) piperidine-2,6-dione (3- (4- ((3-aminopropy) amino) -1-oxoisoindolin-2-yl) piperidine-2,6-dione; SIAIS 1204071)
Following the procedure of scheme C, lenalidomide (259.3mg, 1mmol, 1equiv), (3-bromopropyl) carbamic acid tert-butyl ester (1.2mmol, 1.2equiv) and N, N-diisopropylethylamine (387.7mg, 3mmol, 3equiv) were added together in a 25mL reaction tube, followed by NMP (5 mL) and reacted in an oil bath at 110 ℃ for 12h. The reaction was allowed to cool to room temperature and then prepared using a C18 reverse phase column, eluting (v/v): acetonitrile/(water +0.1% =10% -100%, evaporate acetonitrile under reduced pressure, get intermediate after lyophilizing; this compound was then added to a 25mL single-necked flask, followed by the addition of 1mL of dichloromethane and 3mL of trifluoroacetic acid, and stirred at room temperature for 1h. Evaporating the reaction solvent under reduced pressure, adding water, and lyophilizing to obtain SIAIS1204071 (yellow liquid, 159mg, 50%) 1 H NMR (500mhz, dmso) δ 11.01 (s, 1H), 7.93 (s, 1H), 7.71 (s, 2H), 7.31 (t, J =7.7hz, 1h), 6.96 (d, J =7.4hz, 1h), 6.79 (d, J =8.1hz, 1h), 5.12 (dd, J =13.2,5.1hz, 1h), 4.21 (d, J =17.0hz, 1h), 4.12 (d, J =17.0hz, 1h), 3.22 (t, J =6.4hz, 2h), 2.98-2.92 (m, 1H), 2.92-2.87 (m, 2H), 2.67-2.58 (m, 1H), 2.34-2.23 (m, 1H), 2.08-2.00 (m, 1H), 1.88-1H (m, 1H), 1.79 (m, 1H); HRMS (ESI) m/z calculated value C 16 H 21 N 4 O 3 + [M+H] + 317.1608; found 317.1616.
Example 13: preparation of 3- (4- ((4-aminobutyl) amino) -1-oxoisoindolin-2-yl) piperidine-2,6-dione (3- (4- ((4-aminobutyl) amino) -1-oxoisoindolin-2-yl) piperidine-2,6-dione; SIAIS 1204073)
According to scheme C, the title compound siasi 1204073 was prepared under appropriate conditions understood in the art, using the same procedure as in example 12, except that the N-tert-butoxycarbonyl-bromoalkylamine used was tert-butyl (4-bromobutyl) carbamate. The obtained target compound SIAIS1204073 is yellow liquid, 60mg, and the yield is 18%; 1 h NMR (500mhz, dmso) δ 11.01 (s, 1H), 7.87 (s, 1H), 7.69 (s, 2H), 7.29 (t, J =7.7hz, 1h), 6.94 (d, J =7.3hz, 1h), 6.77 (d, J =8.0hz, 1h), 5.13 (dd, J =13.3,5.1hz, 1h), 4.22 (d, J =17.1hz, 1h), 4.11 (d, J =17.1hz, 1h), 3.25-3.12 (m, 2H), 3.00-2.88 (m, 1H), 2.88-2.75 (m, 2H), 2.67-2.57 (m, 1H), 2.33-2.22 (m, 1H), 2.10-1.98 (m, 1H), 1.66-1H (m, 4.50H); HRMS (ESI) m/z calculated value C 17 H 23 N 4 O 3 + [M+H] + 331.1765; found 331.1784.
Example 14: preparation of 3- (4- ((5-aminopentyl) amino) -1-oxoisoindolin-2-yl) piperidine-2,6-dione (3- (4- ((5-aminopentyl) amino) -1-oxoisoindolin-2-yl) piperidine-2,6-dione; SIAIS 1204075)
According to scheme C, the target compound sias 1204075 was prepared under appropriate conditions understood in the art by the same method as in example 12, except that t-butyloxycarbonyl-bromoalkylamine used was t-butyl (5-bromopentyl) carbamate. The obtained target compound SIAIS1204075 is yellow liquid, 234mg and the yield is 68%; 1 h NMR (500mhz, dmso) δ 11.01 (s, 1H), 7.69 (s, 3H), 7.29 (t, J =7.7hz, 1h), 6.94 (d, J =7.1hz, 1h), 6.75 (d, J =8.0hz, 1h), 5.12 (dd, J =13.3,5.1hz, 1h), 4.23 (d, J =17.1hz, 1h), 4.13 (d, J =17.1hz, 1h), 3.13 (t, J =7.0hz, 2h), 2.98-2.88 (m, 1H), 2.84-2.75 (m, 2H), 2.67-2.57 (m, 1H), 2.35-2.22 (m, 1H), 2.08-1.99 (m, 1H), 1.65-1.51 (m, 4.51, 1H), 1.45-1H (m, 1H); HRMS (ESI) m/z calculated value C 18 H 25 N 4 O 3 + [M+H] + 345.1921; found 345.1939.
Example 15: preparation of 3- (4- ((6-aminohexyl) amino) -1-oxoisoindolin-2-yl) piperidine-2,6-dione (3- (4- ((6-aminohexyl) amino) -1-oxoisoindolin-2-yl) piperidine-2,6-dione; SIAIS 1204077)
According to scheme C, the target compound sias 1204077 was prepared under appropriate conditions understood in the art by the same method as in example 12, except that t-butyloxycarbonyl-bromoalkylamine was used which was t-butyl (6-bromohexyl) carbamate. The obtained target compound SIAIS1204077 is yellow liquid, 243mg, and the yield is 76%; 1 h NMR (500mhz, dmso) δ 11.01 (s, 1H), 7.67 (s, 3H), 7.29 (t, J =7.7hz, 1h), 6.93 (d, J =6.9hz, 1h), 6.75 (d, J =7.8hz, 1h), 5.12 (dd, J =13.3,5.1hz, 1h), 4.23 (d, J =17.1hz, 1h), 4.12 (d, J =17.1hz, 1h), 3.13 (t, J =7.0hz, 2h), 2.98-2.87 (m, 1H), 2.82-2.72 (m, 2H), 2.67-2.57 (m, 1H), 2.35-2.23 (m, 1H), 2.08-2.00 (m, 1H), 1.62-1.49 (m, 4H), 1.43-2.29H, 1 (m, 4H); HRMS (ESI) m/z calculated value C 19 H 27 N 4 O 3 + [M+H] + 359.2078; found 359.2090.
Example 16: preparation of 3- (4- ((7-aminoheptyl) amino) -1-oxoisoindolin-2-yl) piperidine-2,6-dione (3- (4- ((7-aminoheptyl) amino) -1-oxoisoindolin-2-yl) piperidine-2,6-dione; SIAIS 1204079)
According to scheme C, the same procedure as in example 12 was followed to prepare the target compound sias 1204079 under appropriate conditions as understood in the art, except that the N-tert-butoxycarbonyl-bromoalkylamine used was tert-butyl (7-bromoheptyl) carbamate. The obtained target compound SIAIS1204079 is yellow liquid, 283mg, and the yield is 76%; 1 h NMR (500mhz, dmso) δ 11.01 (s, 1H), 7.68 (s, 3H), 7.29 (t, J =7.7hz, 1h), 6.93 (t, J =7.2hz, 1h), 6.75 (d, J =8.0hz, 1h), 5.12 (dd, J =13.3,5.1hz, 1h), 4.23 (d, J =17.1hz, 1h), 4.12 (d, J =17.1hz, 1h), 3.12 (t, J =7.1hz, 2h), 2.98-2.87 (m, 1H), 2.83-2.72 (m, 2H), 2.66-2.58 (m, 1H), 2.35-2.23 (m, 1H), 2.08-1.99 (m, 1H), 1.62-1.55 (m, 2H), 1.55-1.49 (m, 2H), 1.40-1.34 (m, 2H), 1.34-1.29 (m, 4H); HRMS (ESI) m/z calculated value C 20 H 29 N 4 O 3 + [M+H] + 373.2234; found 373.2242.
Example 17: preparation of 3- (4- ((8-aminooctyl) amino) -1-oxoisoindolin-2-yl) piperidine-2,6-dione (3- (4- ((8-aminoctyl) amino) -1-oxoisoindolin-2-yl) piperidine-2,6-dione; SIAIS 1204081)
According to scheme C, the same procedure as in example 12 was followed to prepare the target compound SIAIS1204081 under appropriate conditions as understood in the art, except that the N-t-butoxycarbonyl-bromoalkylamine used was t-butyl (8-bromooctyl) carbamate. The obtained target compound SIAIS1204081 is a yellow liquid, 274mg, and the yield is 71%; 1 h NMR (500mhz, dmso) δ 11.01 (s, 1H), 7.66 (s, 3H), 7.28 (t, J =7.7hz, 1h), 6.93 (d, J =7.3hz, 1h), 6.74 (d, J =8.0hz, 1h), 5.12 (dd, J =13.3,5.1hz, 1h), 4.23 (d, J =17.1hz, 1h), 4.12 (d, J =17.1hz, 1h), 3.20-3.01 (m, 2H), 2.99-2.85 (m, 1H), 2.83-2.69 (m, 2H), 2.66-2.58 (m, 1H), 2.35-2.23 (m, 1H), 2.11-1.95 (m, 1H), 1.65-1.43 (m, 4.43, 1.43-1H), 1.6.25H (m, 1H); HRMS (ESI) m/z calculated value C 21 H 31 N 4 O 3 + [M+H] + 387.2391; found 387.2382.
Example 18: preparation of 3- (1-oxo-4- (propylamino) isoindolin-2-yl) piperidine-2,6-dione (3- (1-oxo-4- (propyllamino) isoindolin-2-yl) piperidine-2,6-dione; SIAIS 1204083A)
Lenalidomide (20mg, 0.073mmol, 1equiv), N-propyl bromide (18.9mg, 0.0876mmol, 1.2equiv) and N, N-diisopropylethylamine (29.9mg, 0.219mmol, 3equiv) were added together to a 10mL reaction tube according to the method of scheme D, followed by NMP (2 mL) and reacted in an oil bath at 110 ℃ for 6h. The reaction was allowed to cool to room temperature and then prepared using a C18 reverse phase column, eluting (v/v): acetonitrile/(water +0.1% tfa) =10% -100%, acetonitrile was distilled off under reduced pressure, and the target compound siis 1204083A (yellow solid, 18.5mg, 84%) was obtained after lyophilization; 1 h NMR (500mhz, dmso) δ 11.00 (s, 1H), 7.28 (t, J =7.7hz, 1h), 6.92 (d, J =7.4hz, 1h), 6.74 (d, J =8.0hz, 1h), 5.58 (s, 1H), 5.11 (dd, J =13.3,5.1hz, 1h), 4.23 (d, J =17.1hz, 1h), 4.13 (d, J =17.1hz, 1h), 3.09 (t, J =6.7hz, 2h), 2.98-2.86 (m, 1H), 2.66-2.58 (m, 1H), 2.35-2..24 (qd, J =13.0,4.2hz, 1h), 2.08-1.98 (m, 1H), 1.64-1.52 (m, 2H), 3.94, 94, 0.94H, 7H); HRMS (ESI) m/z calculated value C 16 H 20 N 3 O 3 + [M+H] + 302.1499; found 302.1508.
Comparative example:
Figure BDA0002099337960000351
according to scheme E, lenalidomide (20mg, 0.073mmol, 1equiv), n-propyl bromide (18.9mg, 0.0876mmol, 1.2equiv), KI (3.8mg, 0.0146mmol, 0.2equiv) and potassium carbonate (21.3mg, 0.146mmol, 3equiv) were added together in a 10mL reaction tube, followed by acetonitrile (2 mL) and refluxed in an oil bath at 100 ℃ for 2h. The reaction was cooled to room temperature, and acetonitrile was evaporated under reduced pressure, followed by preparation using a C18 reverse phase column, eluent (v/v): acetonitrile/(Water +0.1% TFA) =10% -100%, and after lyophilization, the compound 3- (4-amino-1-oxoisoindolin-2-yl) -1-propylpiperidine-2,6-dione (3- (4-amino-1-oxoisoindolin-2-yl) -1-propylpiperidine-2,6-dione; SIAIS 1204083B) (yellow solid, 12.8mg, 58%) 1 H NMR (500mhz, dmso) δ 7.23 (t, J =7.6hz, 1h), 6.98 (d, J =6.9hz, 1h), 6.86 (d, J =7.6hz, 1h), 5.18 (dd, J =13.4,5.1hz, 1h), 4.22 (d, J =17.1hz, 1h), 4.11 (d, J =17.1hz, 1h), 3.68-3.50 (m, 2H), 3.08-2.96 (m, 1H), 2.83-2.71 (m, 1H), 2.35-2.24 (m, 1H), 2.09-1.99 (m, 1H), 1.52-1.40 (m, 2H), 0.83 (t, J =7.5hz, 3h); HRMS (ESI) m/z calculated value C 16 H 20 N 3 O 3 + [M+H] + 302.1499; found 302.1511.
The disclosure is not limited by the embodiments shown and described above, but may be varied within the scope of the claims.
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Claims (11)

1. A process for the preparation of a compound of formula (I),
Figure FDA0004019074610000011
wherein LIN represents-alkylene-U, wherein
The alkylene group is a linear or branched alkylene group optionally interrupted one or more times by one or more groups selected from: o, CONH, NHCO, NH, alkynylene, alkenylene, cycloalkylene, arylene, heterocyclylene, heteroarylene, or any combination thereof, wherein the linear or branched alkylene is optionally substituted with one or more substituents, and
the group U represents-COOH, -SO optionally protected by a protecting group 3 H or-NH 2 (ii) a Or
The group U represents-N 3 Alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, or any combination thereof; or
The group U represents hydrogen;
said process comprising the step of subjecting the amino group of the compound of formula (II) to aminoalkylation with a compound of formula (III) in the presence of an organic base to selectively obtain a compound of formula (I),
Figure FDA0004019074610000012
wherein R is 1 Represents a leaving group, and LIN represents-alkylene-U, wherein
The alkylene group is a linear or branched alkylene group optionally interrupted one or more times by one or more groups selected from: o, CONH, NHCO, NH, alkynylene, alkenylene, cycloalkylene, arylene, heterocyclylene, heteroarylene, or any combination thereof, wherein the linear or branched alkylene is optionally substituted with one or more substituents, and
the group U represents COOH, SO optionally protected by a protecting group 3 H or NH 2 (ii) a Or
The group U represents-N 3 Alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, or any combination thereof; or
The group U represents hydrogen;
wherein the organic base is selected from one or more of the following: triethylamine, N-Diisopropylethylamine (DIPEA), pyridine and N-methylmorpholine (NMM).
2. The method of claim 1, wherein R is 1 Represents halogen, mesyloxy, trifluoromethanesulfonyloxy or p-toluenesulfonyloxy.
3. The method of claim 1 or 2, wherein the LIN represents:
-C 1-30 alkylene-U, - (CH) 2 ) n1 -(O(CH 2 ) n2 ) m1 -U，-(CH 2 ) n1 -(O(CH 2 ) n2 ) m1 -(O(CH 2 ) n3 ) m2 -U，-(CR a1 R a2 ) n1 -(O(CR a3 R a4 ) n2 ) m1 -U，-(CR a5 R a6 ) n1 -(O(CR a7 R a8 ) n2 ) m1 -(O(CR a9 R a10 ) n3 ) m2 -U，-(CH 2 ) n1 -(CONH-(CH 2 ) n2 ) m1 -U，-(CH 2 ) n1 -(CONH-(CH 2 ) n2 ) m1 -(O(CH 2 ) n3 ) m2 -U，-(CH 2 ) n1 -(O(CH 2 ) n2 ) m1 -O-(CH 2 ) n3 -CONH-(CH 2 ) n4 -(O(CH 2 ) n5 ) m2 -O-(CH 2 ) n6 -U，-(CR a11 R a12 ) n1 -(O(CR a13 R a14 ) n2 ) m1 -O-(CR a15 R a16 ) n3 -CONH-(CR a17 R a18 ) n4 -(O(CR a19 R a20 ) n5 ) m2 -O-(CR a21 R a22 ) n6 -U，-(CR a23 R a24 ) n1 -CONH-(O(CR a25 R a26 ) n2 ) m1 -U，-(CH 2 ) n1 -(NHCO-(CH 2 ) n2 ) m1 -U，-(CH 2 ) n1 -(NHCO-(CH 2 ) n2 ) m1 -(O(CH 2 ) n3 ) m2 -U, a linear or branched-alkylene chain interrupted one or more times by one or more alkynylene, alkenylene, cycloalkylene, arylene, heterocyclylene or heteroarylene groups or any combination thereof-U, or- (CH) interrupted one or more times in its carbon chain by one or more arylene or heterocyclylene or heteroarylene groups or any combination thereof 2 ) n1 -(O(CH 2 ) n2 ) m1 -U；
Wherein R is a1 、R a2 、R a3 、R a4 、R a5 、R a6 、R a7 、R a8 、R a9 、R a10 、R a11 、R a12 、R a13 、R a14 、R a15 、R a16 、R a17 、R a18 、R a19 、R a20 、R a21 、R a22 、R a23 、R a24 、R a25 、R a26 Each independently represents H, straight-chain or branched C 1-10 Alkyl or C 3-10 Cycloalkyl, wherein R is when in the same said LIN a1 、R a2 、R a3 、R a4 Or R is a5 、R a6 、R a7 、R a8 、R a9 、R a10 Or R is a11 、R a12 、R a13 、R a14 、R a15 、R a16 、R a17 、R a18 、R a19 、R a20 、R a21 、R a22 Or R is a23 、R a24 、R a25 、R a26 Not H at the same time; and
n1, n2, n3, n4, n5, n6, m1, m2 each independently represent an integer of 1,2,3, 4,5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.
4. The method of claim 3, wherein the LIN represents:
-CH 2 -U；-(CH 2 ) 2 -U；-(CH 2 ) 3 -U；-(CH 2 ) 4 -U；-(CH 2 ) 5 -U；-(CH 2 ) 6 -U；-(CH 2 ) 7 -U；-(CH 2 ) 8 -U；-(CH 2 ) 9 -U；-(CH 2 ) 10 -U；-(CH 2 ) 11 -U；-(CH 2 ) 12 -U；-(CH 2 ) 13 -U；-(CH 2 ) 14 -U；-(CH 2 ) 15 -U；-(CH 2 ) 16 -U；-(CH 2 ) 17 -U；-(CH 2 ) 18 -U；-(CH 2 ) 19 -U；-(CH 2 ) 20 -U；-(CH 2 ) 21 -U；-(CH 2 ) 22 -U；-(CH 2 ) 23 -U；-(CH 2 ) 24 -U；-(CH 2 ) 25 -U；-(CH 2 ) 26 -U；-(CH 2 ) 27 -U；-(CH 2 ) 28 -U；-(CH 2 ) 29 -U; or- (CH) 2 ) 30 -U。
5. The method of claim 1, wherein the LIN represents:
-CH 2 -((CH 2 ) 2 -O)-CH 2 -U、-CH 2 -((CH 2 ) 2 -O) 2 -CH 2 -U、-CH 2 -((CH 2 ) 2 -O) 3 -CH 2 -U、-CH 2 -((CH 2 ) 2 -O) 4 -CH 2 -U、-CH 2 -((CH 2 ) 2 -O) 5 -CH 2 -U、-CH 2 -((CH 2 ) 2 -O) 6 -CH 2 -U、-CH 2 -((CH 2 ) 2 -O) 7 -CH 2 -U、-CH 2 -((CH 2 ) 2 -O) 8 -CH 2 -U、-CH 2 -((CH 2 ) 2 -O) 9 -CH 2 -U、-CH 2 -((CH 2 ) 2 -O) 10 -CH 2 -U、-CH 2 -((CH 2 ) 2 -O) 11 -CH 2 -U、-CH 2 -((CH 2 ) 2 -O) 12 -CH 2 -U、-CH 2 -((CH 2 ) 2 -O) 13 -CH 2 -U、-CH 2 -((CH 2 ) 2 -O) 14 -CH 2 -U、-CH 2 -((CH 2 ) 2 -O) 15 -CH 2 -U、-CH 2 -((CH 2 ) 2 -O) 16 -CH 2 -U、-CH 2 -((CH 2 ) 2 -O) 17 -CH 2 -U、-CH 2 -((CH 2 ) 2 -O) 18 -CH 2 -U、-CH 2 -((CH 2 ) 2 -O) 19 -CH 2 -U、-CH 2 -((CH 2 ) 2 -O) 20 -CH 2 -U、-((CH 2 ) 2 -O)-CH 2 -U、-((CH 2 ) 2 -O) 2 -CH 2 -U、-((CH 2 ) 2 -O) 3 -CH 2 -U、-((CH 2 ) 2 -O) 4 -CH 2 -U、-((CH 2 ) 2 -O) 5 -CH 2 -U、-((CH 2 ) 2 -O) 6 -CH 2 -U、-((CH 2 ) 2 -O) 7 -CH 2 -U、-((CH 2 ) 2 -O) 8 -CH 2 -U、-((CH 2 ) 2 -O) 9 -CH 2 -U、-((CH 2 ) 2 -O) 10 -CH 2 -U、-((CH 2 ) 2 -O) 11 -CH 2 -U、-((CH 2 ) 2 -O) 12 -CH 2 -U、-((CH 2 ) 2 -O) 13 -CH 2 -U、-((CH 2 ) 2 -O) 14 -CH 2 -U、-((CH 2 ) 2 -O) 15 -CH 2 -U、-((CH 2 ) 2 -O) 16 -CH 2 -U、-((CH 2 ) 2 -O) 17 -CH 2 -U、-((CH 2 ) 2 -O) 18 -CH 2 -U、-((CH 2 ) 2 -O) 19 -CH 2 -U、-((CH 2 ) 2 -O) 20 -CH 2 -U、-CH 2 -O-(CH 2 ) 2 -U、-CH 2 -(O(CH 2 ) 2 ) 2 -U、-CH 2 -(O(CH 2 ) 2 ) 3 -U、-CH 2 -(O(CH 2 ) 2 ) 4 -U、-CH 2 -(O(CH 2 ) 2 ) 5 -U、-CH 2 -(O(CH 2 ) 2 ) 6 -U、-CH 2 -(O(CH 2 ) 2 ) 7 -U、-CH 2 -(O(CH 2 ) 2 ) 8 -U、-CH 2 -(O(CH 2 ) 2 ) 9 -U、-CH 2 -(O(CH 2 ) 2 ) 10 -U、-(CH 2 ) 2 -O-(CH 2 ) 2 -U、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 2 -U、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 3 -U、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 4 -U、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 5 -U、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 6 -U、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 7 -U、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 8 -U、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 9 -U、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 10 -U、-(CH 2 ) 3 -O-(CH 2 ) 2 -U、-(CH 2 ) 3 -(O(CH 2 ) 2 ) 2 -U、-(CH 2 ) 3 -(O(CH 2 ) 2 ) 3 -U、-(CH 2 ) 3 -(O(CH 2 ) 2 ) 4 -U、-(CH 2 ) 3 -(O(CH 2 ) 2 ) 5 -U、-(CH 2 ) 3 -(O(CH 2 ) 2 ) 6 -U、-(CH 2 ) 3 -(O(CH 2 ) 2 ) 7 -U、-(CH 2 ) 3 -(O(CH 2 ) 2 ) 8 -U、-(CH 2 ) 3 -(O(CH 2 ) 2 ) 9 -U、-(CH 2 ) 3 -(O(CH 2 ) 2 ) 10 -U、-(CH 2 ) 4 -O-(CH 2 ) 2 -U、-(CH 2 ) 4 -(O(CH 2 ) 2 ) 2 -U、-(CH 2 ) 4 -(O(CH 2 ) 2 ) 3 -U、-(CH 2 ) 4 -(O(CH 2 ) 2 ) 4 -U、-(CH 2 ) 4 -(O(CH 2 ) 2 ) 5 -U、-(CH 2 ) 4 -(O(CH 2 ) 2 ) 6 -U、-(CH 2 ) 4 -(O(CH 2 ) 2 ) 7 -U、-(CH 2 ) 4 -(O(CH 2 ) 2 ) 8 -U、-(CH 2 ) 4 -(O(CH 2 ) 2 ) 9 -U、-(CH 2 ) 4 -(O(CH 2 ) 2 ) 10 -U、-CH 2 -O-(CH 2 ) 3 -U、-CH 2 -(O(CH 2 ) 3 ) 2 -U、-CH 2 -(O(CH 2 ) 3 ) 3 -U、-CH 2 -(O(CH 2 ) 3 ) 4 -U、-CH 2 -(O(CH 2 ) 3 ) 5 -U、-CH 2 -(O(CH 2 ) 3 ) 6 -U、-CH 2 -(O(CH 2 ) 3 ) 7 -U、-CH 2 -(O(CH 2 ) 3 ) 8 -U、-CH 2 -(O(CH 2 ) 3 ) 9 -U、-CH 2 -(O(CH 2 ) 3 ) 10 -U、-(CH 2 ) 2 -O-(CH 2 ) 3 -U、-(CH 2 ) 2 -(O(CH 2 ) 3 ) 2 -U、-(CH 2 ) 2 -(O(CH 2 ) 3 ) 3 -U、-(CH 2 ) 2 -(O(CH 2 ) 3 ) 4 -U、-(CH 2 ) 2 -(O(CH 2 ) 3 ) 5 -U、-(CH 2 ) 2 -(O(CH 2 ) 3 ) 6 -U、-(CH 2 ) 2 -(O(CH 2 ) 3 ) 7 -U、-(CH 2 ) 2 -(O(CH 2 ) 3 ) 8 -U、-(CH 2 ) 2 -(O(CH 2 ) 3 ) 9 -U、-(CH 2 ) 2 -(O(CH 2 ) 3 ) 10 -U、-(CH 2 ) 3 -O-(CH 2 ) 3 -U、-(CH 2 ) 3 -(O(CH 2 ) 3 ) 2 -U、-(CH 2 ) 3 -(O(CH 2 ) 3 ) 3 -U、-(CH 2 ) 3 -(O(CH 2 ) 3 ) 4 -U、-(CH 2 ) 3 -(O(CH 2 ) 3 ) 5 -U、-(CH 2 ) 3 -(O(CH 2 ) 3 ) 6 -U、-(CH 2 ) 3 -(O(CH 2 ) 3 ) 7 -U、-(CH 2 ) 3 -(O(CH 2 ) 3 ) 8 -U、-(CH 2 ) 3 -(O(CH 2 ) 3 ) 9 -U、-(CH 2 ) 3 -(O(CH 2 ) 3 ) 10 -U、-CH 2 -O-(CH 2 ) 2 -O-(CH 2 ) 3 -U、-CH 2 -(O(CH 2 ) 2 ) 2 -(O(CH 2 ) 3 ) 2 -U、-CH 2 -(O(CH 2 ) 2 ) 3 -(O(CH 2 ) 3 ) 3 -U、-CH 2 -(O(CH 2 ) 2 ) 4 -(O(CH 2 ) 3 ) 4 -U、-CH 2 -(O(CH 2 ) 2 ) 5 -(O(CH 2 ) 3 ) 5 -U、-CH 2 -(O(CH 2 ) 2 ) 6 -(O(CH 2 ) 3 ) 6 -U、-(CH 2 ) 2 -O-(CH 2 ) 2 -O-(CH 2 ) 3 -U、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 2 -(O(CH 2 ) 3 ) 2 -U、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 3 -(O(CH 2 ) 3 ) 3 -U、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 4 -(O(CH 2 ) 3 ) 4 -U、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 5 -(O(CH 2 ) 3 ) 5 -U、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 6 -(O(CH 2 ) 3 ) 6 -U、-(CH 2 ) 3 -O-(CH 2 ) 2 -O-(CH 2 ) 3 -U、-(CH 2 ) 3 -(O(CH 2 ) 2 ) 2 -(O(CH 2 ) 3 ) 2 -U、-(CH 2 ) 3 -(O(CH 2 ) 2 ) 3 -(O(CH 2 ) 3 ) 3 -U、-(CH 2 ) 3 -(O(CH 2 ) 2 ) 4 -(O(CH 2 ) 3 ) 4 -U、-(CH 2 ) 3 -(O(CH 2 ) 2 ) 5 -(O(CH 2 ) 3 ) 5 -U、-(CH 2 ) 3 -(O(CH 2 ) 2 ) 6 -(O(CH 2 ) 3 ) 6 -U、-CH 2 -O-(CH 2 ) 3 -O-(CH 2 ) 2 -U、-CH 2 -(O(CH 2 ) 3 ) 2 -(O(CH 2 ) 2 ) 2 -U、-CH 2 -(O(CH 2 ) 3 ) 3 -(O(CH 2 ) 2 ) 3 -U、-CH 2 -(O(CH 2 ) 3 ) 4 -(O(CH 2 ) 2 ) 4 -U、-CH 2 -(O(CH 2 ) 3 ) 5 -(O(CH 2 ) 2 ) 5 -U、-CH 2 -(O(CH 2 ) 3 ) 6 -(O(CH 2 ) 2 ) 6 -U、-(CH 2 ) 2 -O-(CH 2 ) 3 -O-(CH 2 ) 2 -U、-(CH 2 ) 2 -(O(CH 2 ) 3 ) 2 -(O(CH 2 ) 2 ) 2 -U、-(CH 2 ) 2 -(O(CH 2 ) 3 ) 3 -(O(CH 2 ) 2 ) 3 -U、-(CH 2 ) 2 -(O(CH 2 ) 3 ) 4 -(O(CH 2 ) 2 ) 4 -U、-(CH 2 ) 2 -(O(CH 2 ) 3 ) 5 -(O(CH 2 ) 2 ) 5 -U、-(CH 2 ) 2 -(O(CH 2 ) 3 ) 6 -(O(CH 2 ) 2 ) 6 -U、-(CH 2 ) 3 -O-(CH 2 ) 3 -O-(CH 2 ) 2 -U、-(CH 2 ) 3 -(O(CH 2 ) 3 ) 2 -(O(CH 2 ) 2 ) 2 -U、-(CH 2 ) 3 -(O(CH 2 ) 3 ) 3 -(O(CH 2 ) 2 ) 3 -U、-(CH 2 ) 3 -(O(CH 2 ) 3 ) 4 -(O(CH 2 ) 2 ) 4 -U、-(CH 2 ) 3 -(O(CH 2 ) 3 ) 5 -(O(CH 2 ) 2 ) 5 -U、-(CH 2 ) 3 -(O(CH 2 ) 3 ) 6 -(O(CH 2 ) 2 ) 6 -U、-CH 2 -O-(CH 2 ) 2 -O-CH 2 -U、-(CH 2 ) 2 -O-(CH 2 ) 2 -O-CH 2 -U、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 2 -O-(CH 2 ) 3 -U、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 3 -O-(CH 2 ) 3 -U、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 4 -O-(CH 2 ) 3 -U、-(CH 2 ) 5 -(O(CH 2 ) 2 ) 2 -O-(CH 2 ) 5 -U, or- (CH) 2 ) 5 -(O(CH 2 ) 2 ) 2 -O-(CH 2 ) 6 -U。
6. A method according to claim 1 or 2, wherein LIN represents-alkylene-U, wherein said alkylene is a linear or branched C 1-30 Alkylene and the group U represents N 3 Alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, or any combination thereof.
7. The process of claim 1 or 2, wherein the reaction is carried out at a temperature of 10-150 ℃.
8. The process according to claim 1 or 2, wherein in the reaction the amount of organic base is 0.1 to 10 equivalents, calculated on the molar amount of the compound of formula (II).
9. The process of claim 1 or 2, wherein the amount of the compound of formula (III) in the reaction is 0.5 to 1.5 equivalents, calculated on the molar amount of the compound of formula (II).
10. The process according to claim 1 or 2, wherein the reaction is carried out without addition of a solvent, wherein the organic base is used as the sole solvent.
11. The method of claim 1, wherein the compound of formula (I) is selected from:
2- (2- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) ethoxy) acetic acid;
3- (2- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) ethoxy) propionic acid;
2- (2- (2- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) ethoxy) acetic acid;
3- (2- (2- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) ethoxy) propionic acid;
2- (2- (2- (2- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) ethoxy) acetic acid;
3- (2- (2- (2- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) ethoxy) propionic acid;
14- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) -3,6,9,12-tetraoxatetradecanoic acid;
1- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) -3,6,9, 12-tetraoxapentadecane-15-carboxylic acid;
17- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) -3,6,9,12, 15-pentaoxaheptadecanoic acid;
1- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) -3,6,9,12, 15-pentaoxaoctadecane-18-oic acid;
3- (3- (2- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) ethoxy) propionylamino) propionic acid;
(2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) aminoacetic acid;
3- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) propionic acid;
4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) butanoic acid;
5- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) pentanoic acid;
6- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) hexanoic acid;
7- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) heptanoic acid;
8- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) octanoic acid;
9- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) nonanoic acid;
10- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) decanoic acid;
11- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) undecanoic acid;
12- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) dodecanoic acid;
13- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) tridecanoic acid;
14- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) tetradecanoic acid;
15- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) pentadecanoic acid;
3- (6- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) hexanoylamino) propionic acid;
3- (4- ((2- (2-aminoethoxy) ethyl) amino) -1-oxoisoindolin-2-yl) piperidine-2,6-dione;
3- (4- ((2- (2- (2-aminoethoxy) ethoxy) ethyl) amino) -1-oxoisoindolin-2-yl) piperidine-2,6-dione;
3- (4- ((2- (2- (2- (2-aminoethoxy) ethoxy) ethyl) amino) -1-oxoisoindolin-2-yl) piperidine-2,6-dione;
3- (4- ((14-amino-3, 6,9, 12-tetraoxatetradecyl) amino) -1-oxoisoindolin-2-yl) piperidine-2,6-dione;
3- (4- ((17-amino-3, 6,9,12, 15-pentaoxaheptadecyl) amino) -1-oxoisoindolin-2-yl) piperidine-2,6-dione;
4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) ethoxy) ethyl) amino) -4-oxobutanoic acid;
3- (4- ((2-aminoethyl) amino) -1-oxoisoindolin-2-yl) piperidine-2,6-dione;
3- (4- ((3-aminopropyl) amino) -1-oxoisoindolin-2-yl) piperidine-2,6-dione;
3- (4- ((4-aminobutyl) amino) -1-oxoisoindolin-2-yl) piperidine-2,6-dione;
3- (4- ((5-aminopentyl) amino) -1-oxoisoindolin-2-yl) piperidine-2,6-dione;
3- (4- ((6-aminohexyl) amino) -1-oxoisoindolin-2-yl) piperidine-2,6-dione;
3- (4- ((7-aminoheptyl) amino) -1-oxoisoindolin-2-yl) piperidine-2,6-dione;
3- (4- ((8-aminooctyl) amino) -1-oxoisoindolin-2-yl) piperidine-2,6-dione;
4- ((5- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) pentyl) amino) -4-oxobutanoic acid;
3- (4- ((2- (2-azidoethoxy) ethyl) amino) -1-oxoisoindolin-2-yl) piperidine-2,6-dione;
3- (4- ((2- (2- (2-azidoethoxy) ethoxy) ethyl) amino) -1-oxoisoindolin-2-yl) piperidine-2,6-dione;
3- (4- ((2- (2- (2- (2-azidoethoxy) ethoxy) ethyl) amino) -1-oxoisoindolin-2-yl) piperidine-2,6-dione;
3- (4- ((14-azido-3, 6,9, 12-tetraoxatetradecyl) amino) -1-oxoisoindolin-2-yl) piperidine-2,6-dione;
3- (4- ((17-azido-3, 6,9,12, 15-pentaoxaheptadecyl) amino) -1-oxoisoindolin-2-yl) piperidine-2,6-dione;
4- (1- (2- (2- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) ethoxy) ethyl) -1H-1,2, 3-triazol-4-yl) butanoic acid;
3- (4- ((2-azidoethyl) amino) -1-oxoisoindolin-2-yl) piperidine-2,6-dione;
3- (4- ((3-azidopropyl) amino) -1-oxoisoindolin-2-yl) piperidine-2,6-dione;
3- (4- ((4-azidobutyl) amino) -1-oxoisoindolin-2-yl) piperidine-2,6-dione;
3- (4- ((5-azidopentyl) amino) -1-oxoisoindolin-2-yl) piperidine-2,6-dione;
3- (4- ((6-azidohexyl) amino) -1-oxoisoindolin-2-yl) piperidine-2,6-dione;
3- (4- ((8-azidooctyl) amino) -1-oxoisoindolin-2-yl) piperidine-2,6-dione;
4- (1- (5- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) pentyl) -1H-1,2, 3-triazol-4-yl) butanoic acid;
2- (2- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) ethoxy) ethane-1-sulfonic acid;
2- (2- (2- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) ethoxy) ethane-1-sulfonic acid;
2- (2- (2- (2- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) ethoxy) ethane-1-sulfonic acid;
14- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) -3,6,9, 12-tetraoxatetradecane-1-sulfonic acid;
17- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) -3,6,9,12, 15-pentaoxaheptadecane-1-sulfonic acid;
2- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) ethane-1-sulfonic acid;
3- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) propane-1-sulfonic acid;
4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) butane-1-sulfonic acid;
5- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) pentane-1-sulfonic acid;
6- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) hexane-1-sulfonic acid; and
7- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) heptane-1-sulfonic acid.
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