KR102129367B1 - Compound for inducing the degradation of cereblon protein, preparation method thereof and pharmaceutical composition for use in preventing or treating cancer containing the same as an active ingredient - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for the prevention or treatment of cancer containing a compound for inducing the decomposition of a cerebron protein, a preparation method thereof, and an active ingredient thereof, to A-Linker-A or A-Linker-B according to the present invention The new compounds displayed can inhibit or decompose the cerebrone excellently, and contain it as an active ingredient to achieve an effect such as treatment, prevention or improvement from inhibiting or decomposing a cerebrone-related disease, preferably cerebrone. It has a useful effect as a pharmaceutical composition for the prevention or treatment of diseases that can be, for example, cancer, autoimmune diseases, or metabolic diseases.

Description

Compound for inducing the degradation of cereblon protein, preparation method thereof and pharmaceutical composition for use in preventing or treating cancer containing the same as an active ingredient}

The present invention relates to a pharmaceutical composition for preventing or treating cancer, which is a compound for inducing the degradation of a celebrative protein, a method for preparing the same, and an active ingredient thereof.

Cells degrade target proteins using the Ubiquitin-proteasome system (UPS) to maintain protein homeostasis. This is when the protein called E1, E2, E3 ligase transfers ubiquitin (Ub) composed of 76 amino acids to the target protein to be degraded, and polyubiquitination results in 26S proteasome. It is achieved through the process of cognizing and degrading target proteins. Among the ligase, more than 600 kinds of E3 ubiquitin ligase are known, and it is known that different proteins are decomposed according to the type of ligase.

On the other hand, of E3 ubiquitin ligase, cereblon (CRBN, Cereblon), when thalidomide, lenalidomide, pomalidomide, etc., known as immunomodulatory drugs (IMiD), are combined, Ikaros (transcription factor) ikaros), Aioros (aiolos) decomposes to show excellent anti-cancer effects, as well as effective in autoimmune disease diseases including lupus. Accordingly, the development of an immunomodulatory drug targeting Celebron itself has been actively conducted.

On the other hand, in addition to the role of E3 ubiquitin ligase, which is involved in the decomposition of specific proteins, Celebron, Professor Chul-Seung Park of Gwangju Institute of Science and Technology confirmed that CRBN inhibits AMPK activity, and when CRBN is inhibited, it is an energy sensor. When it was confirmed that AMPK was activated, the possibility of preventing or treating metabolic diseases such as obesity, fatty liver and diabetes was suggested from the induction of CRBN inhibition.

Furthermore, the research team of Prof. Seong-Kyu Park of Gwangju Institute of Science and Technology confirmed that CRBN is highly expressed in immune cells (T-cells), and when CRBN is deficient, the expression of potassium ion channels in T cells increases, thereby activating T cells. The results of this study were reported to control the sensitivity of T cells to antigens by regulating epigenetic gene expression. From the results of this study, it can be seen that induction of CRBN deficiency leads to an effect of increasing the activity of T cells by lowering the amount of CRBN overexpressed in T cells, and anti-cancer immunity from induction of CRBN deficiency that can cause such effects. It suggested the possibility of developing a therapeutic agent.

As can be seen from the background related to the above-mentioned E3 ubiquitin ligase CRBN, if induction or inhibition of cerebron is induced, useful effects can be achieved in cancer, autoimmune diseases, metabolic diseases, and the like.

However, there has been no development of a low-molecular drug targeting CRBN, and the conventional CRBN inhibitor has not achieved the desired pharmacological effect. In particular, the existing anti-cancer targeted therapeutics require a high inhibitory power to the target in order to inhibit the signal transmission of the target, and have a disadvantage in that a large amount must be administered for a long period of time in order to show a therapeutic effect, and also have resistance to drugs. It appears quickly, and there is a problem in that drug resistance occurs within a year after administration, thereby lowering the effect of the drug. In addition, since the cytotoxic therapeutic agent cannot directly act on the target in which cancer has occurred, there is a problem in that side effects are large and the therapeutic effect is small compared to the anticancer target therapeutic agent.

Therefore, a better therapeutic effect is achieved than an anti-cancer targeted therapeutic agent and a cytotoxic therapeutic agent, and new technology development is needed to overcome the problems such as drug resistance side effects. Therefore, it is required to develop a therapeutic agent that can achieve a pharmacological effect.

Against the background described above, a research team at Yale University (Craig Crews) recently developed a proteolysis targeting chimera (PROTAC) technology.

PROTAC is a novel therapeutic agent that is produced by linking an inhibitor or binder compound that binds to a specific protein and a ligand compound that specifically binds E3 ubiquitin ligase with various types of linkers, and PROTAC substances cause disease Since the target protein is degraded by targeting only, the occurrence of resistance to the drug is low, and if binding to the target protein is possible, sufficient therapeutic effect is achieved from the degradation of the active target protein, without high inhibitory activity on the target protein of PROTAC itself , As it can be applied to targets that have been difficult to achieve with inhibitory effects (undruggable target) with existing drugs, it has been spotlighted as a novel mechanism of disease treatment technology (Patent Document 1).

Accordingly, the present inventors have developed a new CRBN-PROTAC material by connecting thalidomide, a binding compound that binds to CRBN, and its derivatives and E3 ligase, in particular VHL ligand or CRBN ligand (thalidomide derivative), through various linkers, From this, it was confirmed that CRBN is successfully degraded, and in the future, it is not only utilized as a CRBN decomposition agent, but also a pharmaceutical composition or autoimmune disease prevention or treatment for the prevention or treatment of CRBN-related diseases, preferably metabolic diseases, autoimmune diseases or cancer. It was found that it can be useful as a pharmaceutical composition to complete the present invention.

WO 2013/106643 A2

An object of the present invention is to provide a compound that degrades cerebrone (CRBN).

Another object of the present invention is to provide a method for preparing the compound.

Another object of the present invention is to provide a pharmaceutical composition for the prevention or treatment of cerebron related diseases containing the compound as an active ingredient.

Another object of the present invention is to provide a pharmaceutical composition for preventing or treating cancer containing the compound as an active ingredient.

Another object of the present invention is to provide a pharmaceutical composition for the prevention or treatment of autoimmune diseases containing the compound as an active ingredient.

Another object of the present invention is to provide a pharmaceutical composition for the prevention or treatment of metabolic diseases containing the compound as an active ingredient.

Another object of the present invention is to provide a health functional food for preventing or improving cerebron-related diseases containing the compound as an active ingredient.

To solve the above object,

The present invention provides a compound represented by A-Linker-A or A-Linker-B, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

A is Cerebron E3 ubiquitin ligase binding moiety;

The linker is -(CH ₂ )-, -(C=O)-, -NH- and -O- is one or more selected from the group consisting of 3-20 connected linkers (linker),

The linking groups cannot be continuously connected to -O-; And

B is an E3 ubiquitin ligase binding moiety,

Here, Linker and A or B are chemically connected.

In addition, the present invention, as shown in Scheme 1 below,

Preparing a compound represented by A-Linker-V from the compound represented by U-Linker-V (step 1);

Preparing a compound represented by A-Linker-A or A-Linker-B from the compound represented by A-Linker-V prepared in step 1 (step 2); the A-Linker-A comprising or A method for preparing a compound represented by A-Linker-B is provided:

[Scheme 1]

(In Scheme 1,

A, Linker and B are as defined above; And

U or V are each independently NH ₂ or OH).

Furthermore, the present invention is to prevent or treat cereblon-related diseases containing the compound represented by A-Linker-A or A-Linker-B, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. It provides a pharmaceutical composition.

In addition, the present invention provides a pharmaceutical composition for preventing or treating cancer containing the compound represented by A-Linker-A or A-Linker-B, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. do.

Furthermore, the present invention is a pharmaceutical composition for the prevention or treatment of autoimmune diseases containing the compound represented by A-Linker-A or A-Linker-B, a stereoisomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient. Gives

In addition, the present invention provides a pharmaceutical composition for the prevention or treatment of metabolic diseases containing the compound represented by the A-Linker-A or A-Linker-B, a stereoisomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient. to provide.

Furthermore, the present invention prevents or improves cereblon-related diseases containing the compound represented by A-Linker-A or A-Linker-B, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. It provides a health functional food composition.

The novel compound represented by A-Linker-A or A-Linker-B according to the present invention can excellently inhibit or decompose celebrity, and contains it as an active ingredient to treat cerebron-related diseases, preferably celebrone. It has a useful effect as a pharmaceutical composition for the prevention or treatment of diseases, for example, cancer, autoimmune diseases, or metabolic diseases, in which effects such as treatment, prevention or improvement can be achieved from inhibition or degradation.

1 is a protein analysis result shown by Western blot in α-CRBN and α-Tubulin, using the inventive examples 1, 3, and 8 compounds as 0 to 10 μM.
2 is a DC ₅₀ graph showing proteolytic power according to the concentration of the compounds of Examples 1, 3, and 8 of the present invention.

Hereinafter, the present invention will be described in detail.

The following description should be understood as an example to aid the understanding of the present invention, and the spirit or scope of the present invention is not limited from the following description.

The present invention provides a compound represented by A-Linker-A or A-Linker-B, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

A is Cerebron E3 ubiquitin ligase binding moiety;

The linker is -(CH ₂ )-, -(C=O)-, -NH- and -O- is one or more selected from the group consisting of 3-20 connected linkers (linker),

The linking groups cannot be continuously connected to -O-; And

B is an E3 ubiquitin ligase binding moiety,

Here, Linker and A or B are chemically connected.

In this case, the chemical linkage may be, for example, a single bond, a double bond, or a covalent bond such as a triple bond.

Meanwhile,

Preferably, the A is thalidomide, lenalidomide, pomalidomide, analogs thereof, isomers thereof, or derivatives thereof.

More preferably,

A is one of the formulas represented by the following (a) to (g),

,

,

,

,

,

, 또는

,

,

,

,

,

, or

In the formulas (a), (b), (c), (d), (e), (f), and (g),

W is CH ₂ , CHR, C=O, SO ₂ , NH, or straight or branched alkyl of NC _1-10 ,

Each X is independently O, S, or H ₂ ,

Y is NH, NC _1-10 straight or branched chain alkyl, NC _6-10 aryl, N-heteroaryl (N, O, and 5-10 angles containing one or more heteroatoms selected from the group consisting of S) Ring heteroaryl), NC _3-10 cycloalkyl, N-heterocycloalkyl (3-10 heterocyclic alkyl containing 1 or more hetero atoms selected from the group consisting of N, O, and S), O, Or S,

Z is O, S, or H ₂ ,

G and G'are each independently selected from the group consisting of CH ₂ -heterocyclyl (N, O, and S) substituted or unsubstituted with H, C _1-10 linear or branched alkyl, OH, R' 3-10 heterocyclic heterocyclyl containing at least one hetero atom), or benzyl substituted or unsubstituted with R',

Q ₁ , Q ₂ , Q ₃ , and Q ₄ are each independently carbon substituted with R', or N,

A is C _1-10 straight or branched chain alkyl, C _3-10 cycloalkyl, or halogen

R is -CONR'R", -OR', -NR'R", -SR', -SO ₂ R', -SO ₂ NR'R", -CR'R"-, -CR'NR'R" -, -C _6-10 aryl, -heteroaryl (a 5- to 10-membered heteroaryl containing one or more hetero atoms selected from the group consisting of N, O, and S), -C _1-10 straight chain, or Branched chain alkyl, -C _3-10 cycloalkyl, -heterocyclyl ( _3-10 heterocyclic heterocyclyl containing at least one hetero atom selected from the group consisting of N, O, and S), -P( O)(OR')R", -P(O)R'R", -OP(O)(OR')R", -OP(O)R'R", -Cl, -F, -Br, -I, -CF ₃ , -CN, -NR'SO ₂ NR'R", -NR'CONR'R", -CONR'COR", -NR'C(=N-CN)NR'R",- C(=N-CN)NR'R", -NR'C(=N-CN)R", -NR'C(=CNO ₂ )NR'R", -SO ₂ NR'COR", -NO ₂ , -CO ₂ R', -C(C=N-OR')R", -CR'=CR'R", -CCR', -S(C=O)(C=N-R')R" , -SF ₅ or -OCF ₃ ,

R'and R" are one or more selected from the group consisting of H, C _1-10 linear or branched alkyl, C _3-10 cycloalkyl, C _6-10 aryl, heteroaryl (N, O, and S) 5-10-membered ring heteroaryl containing hetero atoms), heterocyclyl (3-10-membered ring heterocyclyl containing one or more hetero atoms selected from the group consisting of N, O, and S) Each independently selected from,

는 입체특이적(R 또는 S) 또는 비-입체특이적인 결합을 나타내고; 및

Represents stereospecific (R or S) or non-stereospecific binding; And

R _n is -(CH ₂ ) _m -NR ³ -, -(CH ₂ ) _m -O-, -O-(CH ₂ ) _m -(C=O)-NR ³ -or -NR ³ -(CH ₂ ) _m -(C=O)-NR ³ -,

Here again, m is an integer from 0 to 5,

R ³ is H, or unsubstituted or substituted C _1-10 linear or branched alkyl,

Here again, the substituted alkyl is substituted with a halogen, nitro, or cyano group, and R _n is covalently linked with a Linker.

More preferably,

,

,

, 또는

이되,A is

,

,

, or

This,

Wherein R ¹ is -(CH ₂ ) _n -NR ³ -, -(CH ₂ ) _n -O-, -O-(CH ₂ ) _n -(C=O)-NR ³ -or -NR ³ -( CH ₂ ) _n -(C=O)-NR ³ -,

Here again, n is an integer from 0 to 5,

R ² and R ³ are each independently H or unsubstituted or substituted C _1-10 linear or branched alkyl;

Here again, the substituted alkyl is substituted with a halogen, nitro, or cyano group.

More preferably,

,

,

,

,

,

,

, 또는

이되,A is

,

,

,

,

,

,

, or

This,

Wherein R ¹ is -(CH ₂ ) _n -NR ³ -, -(CH ₂ ) _n -O-, -O-(CH ₂ ) _n -(C=O)-NR ³ -or -NR ³ -( CH ₂ ) _n -(C=O)-NR ³ -,

Here again, n is an integer from 0 to 5,

R ² and R ³ are each independently H or unsubstituted or substituted C _1-10 linear or branched alkyl;

Here again, the substituted alkyl is substituted with a halogen, nitro, or cyano group.

Meanwhile, in the compound represented by A-Linker-A or A-Linker-B according to the present invention, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

Preferably, the Linker,

이되,

This,

Where a and i are independently 0 or 1;

B is an integer of 0-20;

C is 0 or 1;

D is an integer of 0-3;

E is 0 or 1;

F is an integer of 1-10;

G is 0 or 1;

H is an integer of 0-3;

J and k are independently integers of 0-5.

Meanwhile,

More preferably,

The Linker,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

, 또는

이다.

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

, or

to be.

On the other hand, in the compound represented by A-Linker-A or A-Linker-B according to the present invention, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

Preferably,

The B can be used without limitation as long as it is an E3 ubiquitin ligase binding moiety (ligand), wherein as an example of the E3 ubiquitin ligase, AMFR, APC/Cdc20, APC/Cdh1, C6orf157, Cbl, CBLL1, CHFR, CHIP , DTL, E6-AP, HACE1, HECW1, HECW2, HERC2, HUWE1, HYD, ITCH, LNX1, MARCH-I, MARCH-IV, MARCH-VII, MARCH-VIII, MDM2, MEKK1, MIB1, MIB2, MycBP2, NEDD4L , PELI1, Pirh2, PJA1, RFFL, RFWD2, Rictor, RNF5, RNF8, RNF19, RNF20, RNF34, RNF40, RNF138, RNF168, SCF/β-TrCP, SCF/FBW7, SCF/Skp2, SHPRH, SIAH1, SIAH2, SMURF1 , SMURF2, TOPORS, TRAF6, TRIM63, UBR2, UHRF2, VHL, WWP1, WWP2, or CRBN, and any combination moieties thereof can be applied to the present invention without limitation.

In one embodiment of the invention, the B may be a CRBN (cereblon) or VHL (von Hippel-Lindau) E3 ligase binding moiety.

In another embodiment of the invention,

B is a compound represented by Formula 1 below,

[Formula 1]

In Chemical Formula 1,

R ⁴ is OR ⁶ ,

R ⁵ is an optionally substituted or unsubstituted -NR ⁶ -(CH ₂ )oC _6-10 aryl-N, O, and 5-10 atom heteroaryl comprising one or more hetero atoms selected from the group consisting of S This,

The substituted -NR ⁶ -(CH ₂ )oC _6-10 aryl-N, O, and 5-10 atom heteroaryl including at least one hetero atom selected from the group consisting of S is a straight chain of C _1-10 Or substituted with branched alkyl,

Wherein R ⁶ is H or C _1-5 straight or branched chain alkyl, and o is 0-5;

R ⁷ is -CR ⁸ -NR ^9-

Here, R ⁸ is C _1-10 straight or branched chain alkyl, and R ⁹ is H or C _1-5 straight or branched chain alkyl.

More preferably,

이되,B is

This,

Wherein R ² and R ³ are each independently H, or unsubstituted or substituted C _1-10 linear or branched alkyl;

Here again, the substituted alkyl is substituted with a halogen, nitro, or cyano group.

Preferred examples of the compound represented by A-Linker-A or A-Linker-B according to the present invention include the following compounds.

(1) (2S,4R)-1-((S)-2-(7-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- 1amino)heptanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(2) (2S,4R)-1-((S)-2-(6-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- Ylamino)hexaneamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(3) (2S,4R)-1-((S)-2-(9-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- 1amino)nonanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(4) (2S,4R)-1-((S)-2-tert-butyl-17-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole -4-ylamino)-4-oxo-6,9,12,15-tetraoxa-3-azaheptadeca-1-noyl)-4-hydroxy-N-(4-(4-methylthiazole- 5-yl)benzyl)pyrrolidine-2-carboxamide;

(5) (2S,4R)-1-((S)-2-(2-(3-(2-(2-(2,6-dioxopiperidin-3-yl)-1,3-di Oxoisoindoline-4-ylamino)-2-oxoethoxy)propoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazole- 5-yl)benzyl)pyrrolidine-2-carboxamide;

(6) N ¹ -(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)-N ⁹ -((S)-1-(( 2S,4R)-4-hydroxy-2-(4-(4-methylthiazol-5-yl)benzylcarbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutane- 2-yl)nonanediamide;

(7) N ¹ -(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)-N ⁸ -((S)-1-(( 2S,4R)-4-hydroxy-2-(4-(4-methylthiazol-5-yl)benzylcarbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutane- 2-yl)octanediamide;

(8) N ¹ -(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)-N ⁷ -((S)-1-(( 2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxo Butan-2-yl)heptanediamide;

(9) N ¹ -(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)-N ¹⁴ -((S)-1-(( 2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxo Butan-2-yl)-3,6,9,12-tetraoxatetradecane-1,14-diamide;

(10) N ¹ -(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)-N ⁵ -((S)-1-(( 2S,4R)-4-hydroxy-2-(4-(4-methylthiazol-5-yl)benzylcarbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutane- 2-yl)glutaramide;

(11) N ¹ -((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)methyl)-N ⁷ -((S)-1 -((2S,4R)-4-hydroxy-2-(4-(4-methylthiazol-5-yl)benzylcarbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1- Oxobutan-2-yl)heptanediamide;

(12) (2S,4R)-1-((S)-2-(11-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- 1amino)undecanamido)-3.3-dimethylbutanyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(13) (2S,4R)-1-((S)-2-(8-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- Ylamino)octaneamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(14) (2S,4R)-1-((S)-2-(12-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- Ilamino)dodecaneamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide ;

(15) (2S,4R)-1-((S)-2-(2-(6-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole -4-ylamino)hexyloxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine -2-carboxamide;

(16) (2S,4R)-1-((S)-2-(10-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- 1amino)decanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

(17) (2S,4R)-1-((S)-2-tert-butyl-14-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole -4-ylamino)-4-oxo-6,9,12-trioxa-3-azatetradeca-1-noyl)-4-hydroxy-N-(4-(4-methylthiazole-5- 1)benzyl)pyrrolidine-2-carboxamide;

(18) (2S,4R)-1-((S)-2-(11-((3-(2,6-dioxopiperidin-3-yl)-2-methyl-4-oxo-3, 4-dihydroquinazolin-5-yl)amino)undecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl )Pyrrolidine-2-carboxamide;

(19) 4,4'-(nonane-1,9-diylbis(azanediyl))bis(2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione );

(20) (2S,4R)-1-((S)-2-(11-(2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole -4-ylamino)acetamido)undecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolid Dean-2-carboxamide;

(21) (2S,4R)-1-((S)-2-(11-(2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole -4-yloxy)acetamido)undecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolid Dean-2-carboxamide;

(22) (2S,4R)-1-((S)-2-(11-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5- Ilamino)undecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide ;

(23) 3,3'-(5,5'-(nonane-1,9-diylbis(azanediyl))bis(4-oxobenzo[d][1,2,3]triazine-5, 3(4H)-diyl))dipiperidine-2,6-dione;

(24) 2-(2,6-dioxopiperidin-3-yl)-4-(9-(3-(2,6-dioxopiperidin-3-yl)-4-oxo-3,4 -Dihydrobenzo[d][1,2,3]triazin-5-ylamino)nonylamino)isoindoline-1,3-dione; And

(25) (2S,4R)-1-((S)-2-(11-(3-(2,6-dioxopiperidin-3-yl)-4-oxo-3,4-dihydrobenzo [d][1,2,3]triazin-5-ylamino)undecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazole- 5-yl)benzyl)pyrrolidine-2-carboxamide.

The compound represented by A-Linker-A or A-Linker-B of the present invention can be used in the form of a pharmaceutically acceptable salt, and as the salt, an acid formed by a pharmaceutically acceptable free acid is added. Salt is useful. Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid and phosphorous acid, aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes It is obtained from non-toxic organic acids such as dioate, aromatic acids, aliphatic and aromatic sulfonic acids, acetic acid, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid and the like. The types of pharmaceutically non-toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, and eye Odide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, sube Late, sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitro benzoate, hydroxybenzoate, Methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, Glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and the like.

The acid addition salt according to the present invention can be prepared by a conventional method, for example, a derivative of A-Linker-A or A-Linker-B in an organic solvent such as methanol, ethanol, acetone, dichloromethane, acetonitrile, etc. The precipitate produced by dissolving and adding an organic acid or an inorganic acid can be produced by filtration and drying, or by distilling the solvent and excess acid under reduced pressure and drying to crystallize under an organic solvent.

In addition, bases can be used to make pharmaceutically acceptable metal salts. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess of an alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the inexpensive compound salt, and evaporating and drying the filtrate. At this time, it is suitable to manufacture sodium, potassium or calcium salts as metal salts. Further, the corresponding salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable negative salt (eg, silver nitrate).

Furthermore, the present invention includes all of the compounds represented by A-Linker-A or A-Linker-B and pharmaceutically acceptable salts thereof, as well as solvates, optical isomers, hydrates, etc., which can be prepared therefrom. .

In addition, as shown in Scheme 1 below,

Preparing a compound represented by A-Linker-V from the compound represented by U-Linker-V (step 1);

Preparing a compound represented by A-Linker-A or A-Linker-B from the compound represented by A-Linker-V prepared in step 1 (step 2); the A-Linker-A comprising or A method for preparing a compound represented by A-Linker-B is provided:

[Scheme 1]

(In Scheme 1,

A, Linker and B are as defined above; And

U or V are each independently NH ₂ or OH).

Hereinafter, a method for preparing a compound represented by A-Linker-A or A-Linker-B according to the present invention will be described in detail step by step.

In the method for preparing a compound represented by the formula A-Linker-A or A-Linker-B according to the present invention, the step 1 is a compound represented by A-Linker-V from the compound represented by U-Linker-V It is a manufacturing step.

At this time, the step is a step of introducing a ligand moiety for binding to the target protein to be inhibited or degraded of the compound of the present invention, cerebron, for example, a cereblon ligase represented by A in the linker It can be considered as the step of introducing the first ligand compound.

At this time, the linker and the linker A is a chemical bond, for example, may be a covalent bond, preferably a single bond, a double bond or a triple bond. Thus, the step of coupling the Linker and if A 1 is a linking group introducing method that can be used in the art may be used is not particularly limited, in the U-Linker-V, U is the case of the NH ₂ to A- Rosen, preferably a compound represented by AF, in one embodiment, in the Examples of the present invention, one exemplary compound of the compound represented by AF is 2-(2,6-dioxopiperidin-3-yl)- If 4-fluoroisoindoline-1,3-dione, U-Linker-V and A-halogen is reacted to produce a compound represented by A-Linker-V, the target compound of step 1, It is included in the manufacturing method of the present invention without limitation. On the other hand, when U is OH, a compound represented by A-NH ₂ , in one embodiment of the present invention as below, was used pomalidomide (Pomalidomide), U-Linker-V and A-NH ₂ Any method capable of producing a compound represented by A-Linker-V, the target compound of step 1 by reaction, is included in the production method of the present invention without limitation.

In addition, as the solvent usable in step 1, H ₂ O, ethanol, tetrahydrofuran (THF), dichloromethane, toluene, acetonitrile, dimethylformamide, mixtures thereof, and the like can be used, and preferably dimethylformamide (DMF) can be used.

In addition, the reaction temperature in the above step is not particularly limited, but preferably, it is preferably performed between the boiling points of the solvent at 80-100°C, and the reaction time is not particularly limited, but 5 hours or more, 10 hours or more, 20 hours or more It is preferred to react overnight.

In the method for preparing a compound represented by the formula A-Linker-A or A-Linker-B according to the present invention, step 2 is A-Linker- from the compound represented by A-Linker-V prepared in step 1 above This is a step for preparing a compound represented by A or A-Linker-B.

At this time, the step is a step of introducing A or B into the compound represented by A-Linker, ligand A or B can bind to celebrity or VHL E3 ubiquitin ligase, and multi-ubiquitin to target protein (cerebron) Induces polyubiquitination.

At this time, the A-Linker and A or B are connected to a chemical bond, for example, a covalent bond, preferably a single bond, a double bond or a triple bond. Therefore, step 2, which is a step of connecting A or B with A-Linker, is not limited, and in A-Linker-V, when V is NH ₂ , A-halogen or B-halogen, preferably AF Or a compound represented by BF, in one embodiment, in the Examples of the present invention, one exemplary compound of the compound represented by AF is 2-(2,6-dioxopiperidin-3-yl)-4-fluoro A compound represented by A-Linker-A or A-Linker-B, which is the desired compound of Step 1 by reacting A-Linker-V and A-halogen or B-halogen, which is a leusoindole-1,3-dione If it can be produced, it is included in the manufacturing method of the present invention without limitation. Meanwhile, when V is OH, A-NH ₂ or B-NH ₂ may be used, and in one embodiment, B-NH ₂ is (2R, 4R)-1-((R)-2-amino-3, 3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide, A-Linker-V and A-NH Any method capable of producing a compound represented by A-Linker-A or A-Linker-B, which is the target compound of Step 1 by reacting ₂ or B-NH ₂ , is included in the production method of the present invention without limitation.

In addition, as the solvent usable in step 1, H ₂ O, ethanol, tetrahydrofuran (THF), dichloromethane, toluene, acetonitrile, dimethylformamide, mixtures thereof, and the like can be used, and preferably dimethylformamide (DMF) can be used.

In addition, the reaction temperature in the above step is not particularly limited, but preferably is performed between the boiling point of the solvent at 10-40 ℃, the reaction time is not particularly limited, 5 hours or more, 10 hours or more, 20 hours or more It is preferred to react overnight.

The above production method may be more preferably prepared as in Example compound of the present invention, but the present invention is not limited thereto.

On the other hand, the manufacturing method described in this specification can be modified or changed reaction conditions, for example, reaction temperature, reaction time, and reaction step, in consideration of the yield of the compound prepared by those skilled in the art, and the reaction step is repeated or the order is changed. Can be performed.

In addition, using a conventional synthetic method known in the field of organic synthesis, the method for preparing a compound represented by A-Linker-A or A-Linker-B to be provided in the present invention is included in the scope of the present invention without limitation. It should be understood to be.

Furthermore, if a method capable of designing the moieties at both ends of each linker and the compound to be provided in the present invention is, for example, a cerebron protein binding ligand moiety on one side and an E3 ubiquitin ligase on the other side It should be understood that any manufacturing method of constructing and designing a ligand moiety and easily connecting it is included in the present invention.

For example, a change in the degree to which the compound of the present invention is composed of two or more units in series or in parallel is what the present invention seeks to achieve, on the one hand providing a moiety that binds to the serobron protein, and on the other hand By providing a moiety that binds to E3 ubiquitin ligase, it is intended to induce multiple ubiquitination with a celebrity protein. Compounds that can be derived from simple design modifications such as constituting two or more E3 ubiquitin ligase moieties, or conversely, one or more E3 ubiquitin ligase moieties to a celebrity-binding moiety of From this, if it is desired to achieve good inhibition or degradation of cerebron, as in the present invention, it should be understood that the present invention includes such alterations or modifications. That is, it should be understood that this is easily included in the present invention, changes and modifications to the extent that a person skilled in the art derives from the present invention.

On the other hand, the compound represented by A-Linker-A or A-Linker-B of the present invention binds to the target protein cerebrone as one A ligand moiety, and E3 as the other A or B ligand moiety. In combination with ubiquitin ligase, finally E3 ubiquitin ligase induces multiple ubiquitination to the target protein (cerebron), which is then probisome, e.g., 26S proteasome, multiubiquitinated protein ( Celebron) to achieve the effect of decomposing, and the pharmacological effect through the proteolysis is caused by actions related to all related diseases caused by Celebron, for example, abnormalities, hyperactivity, and the like of Celebron. Diseases, for example, cancer, for example, autoimmune diseases, for example, metabolic diseases, such as the conventional cerebron-related diseases, it can exhibit useful effects in all diseases identified.

In particular, the compound of the present invention is useful in that it is a protease drug (PROTAC) drug that can overcome problems such as side effects, resistance problems, and poor pharmacological activity of conventional drugs such as cell inhibitors and target inhibitors.

In addition, the compound of the present invention is a thredomide, lenalidomide, pomalidomide, an analog thereof, an isomer thereof, a derivative thereof, the cerebrone-binding moiety represented by A itself known as an immunomodulatory drug (IMiD) , As a step before the compound of the present invention induces decomposition to a celebrative protein, it exhibits a pharmacological effect as an immunomodulatory drug simply by being bound to celebrative.

Therefore, the compound represented by A-Linker-A or A-Linker-B of the present invention, its stereoisomer, or a pharmaceutically acceptable salt thereof, has a problem of inhibiting cerebrone as a known immunomodulatory drug and problems of conventional drugs. At the same time, the pharmacological effect as a proteolytic agent that can be overcome can be simultaneously achieved, exhibiting excellent synergistic effect in pharmacological activity, and at the same time, significantly improve the problems such as drug resistance and side effects.

In the present invention, in cancer, autoimmune disease or metabolic disease, the pharmacological activity of the compound represented by A-Linker-A or A-Linker-B of the present invention is very excellent, and the compound of the present invention is also used for the celebrity protein itself. As a result of decomposition, it has been experimentally confirmed that it can effectively solve disadvantages, resistance problems, etc. of existing targeted therapies and cell therapies.

Furthermore, the present invention is to prevent or treat cereblon-related diseases containing the compound represented by A-Linker-A or A-Linker-B, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. It provides a pharmaceutical composition.

The compound represented by A-Linker-A or A-Linker-B of the present invention exhibits inhibitory activity of a celebrative protein, and at the same time decomposes celebrative bar, a disease caused by celebratory (cerebron-related disease), It is possible to achieve excellent pharmacological effects on diseases resulting from celebrity abnormal activity, celebrative hyperactivity or activity induced by the mechanism of celebrity. As a specific exemplary disease, in the treatment of cancer, autoimmune disease, and metabolic disease, the compounds of the present invention can be used as an active ingredient of a pharmaceutical composition for prevention and improvement.

As can be seen from the description of the background art described above, cereblon (CRBN, Cereblon) among E3 ubiquitin ligase is combined with thalidomide, lenalidomide, pomalidomide, etc., also known as an immunomodulatory drug (IMiD), It decomposes transcription factors (ikaros) and ikaros (aiolos), which not only show excellent anticancer effects, but are also effective in autoimmune disease diseases including lupus. In the compound represented by A-Linker-A or A-Linker-B of the present invention, the part represented by A is thalidomide, lenalidomide, pomalidomide, analogs thereof, homoploids, derivatives thereof, and the same cancer Or, it has an excellent effect on autoimmune diseases, and on the other hand, in addition to the role of E3 ubiquitin ligase, which is involved in the decomposition of specific proteins, when the CRBN is suppressed, the energy sensor AMPK is activated, resulting in obesity, fatty liver, diabetes, etc. Prevention or treatment of metabolic diseases is possible.

Furthermore, when CRBN is suppressed or degraded to immune cells (T-cells), the amount of CRBN overexpressed in T cells is lowered to induce the effect of increasing the activity of T cells, and thus it can be used as an anticancer immunotherapy agent.

In addition, the present invention provides a pharmaceutical composition for preventing or treating cancer containing the compound represented by A-Linker-A or A-Linker-B, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. do.

At this time, the cancer refers to all cancer diseases that can be improved from inhibiting cerebron activity or decomposing the cerebron protein, and for non-limiting examples, the cancer is pseudomyxoma, intrahepatic biliary cancer, hepatoblastoma, liver cancer, thyroid cancer , Colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, cleft carcinoma, mycosis mycosis, acute myelogenous leukemia, acute lymphocytic leukemia, basal cell carcinoma, ovarian epithelial cancer, ovarian reproductive cell cancer, male breast cancer, brain cancer, pituitary adenoma, Multiple myeloma, gallbladder cancer, biliary tract cancer, colorectal cancer, chronic myelogenous leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, diffuse giant B cell lymphoma, barter swelling cancer, bladder cancer, peritoneal cancer, parathyroid cancer, adrenal cancer, non-sinusoidal cancer , Non-small cell lung cancer, non-Hodgkin's lymphoma, snow cancer, astrocytoma, small cell lung cancer, pediatric brain cancer, pediatric lymphoma, pediatric leukemia, small intestine cancer, meningioma, esophageal cancer, glioma, neuroblastoma, renal cancer, kidney cancer, heart cancer, duodenal cancer, Malignant soft tissue cancer, malignant bone cancer, malignant lymphoma, malignant mesothelioma, malignant melanoma, eye cancer, vulvar cancer, ureteral cancer, urethral cancer, primary cancer, gastric lymphoma, gastric cancer, gastric carcinoma, gastrointestinal interstitial cancer, Wilms' cancer, breast cancer , Sarcoma, penis cancer, pharyngeal cancer, chorionic disease, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone cancer, metastatic brain cancer, mediastinal cancer, rectal cancer, rectal carcinoma, vaginal cancer, spinal cord cancer, auditory nerve sheath, pancreatic cancer, Selected from the group consisting of salivary gland cancer, Kaposi's sarcoma, Paget's disease, tonsil cancer, squamous cell carcinoma, lung adenocarcinoma, lung cancer, pulmonary squamous cell carcinoma, skin cancer, anal cancer, rhabdomyosarcoma, larynx cancer, pleural cancer, and thymic cancer It may be one or more.

Furthermore, preferably the cancer is acute myeloid leukemia (AML); Chronic myelogenous leukemia (CML); Acute lymphoblastic leukemia (ALL); Chronic lymphocytic leukemia (CLL); Hodgkin's disease (HD); Non-Hodgkin's lymphoma (NHL); B-cell lymphoma; T-cell lymphoma; Multiple myeloma (MM); Amyloidosis; Waldenstrom megaglobulinemia; Myelodysplastic syndrome (MDS); Small lymphocyte lymphoma (SLL); Marginal zone lymphoma; Asymptomatic multiple myeloma; And it may be one or more selected from the group consisting of myeloproliferative syndrome.

As used herein, the term “cancer” establishes unregulated or dysregulated cell proliferation, reduced cellular differentiation, inadequate ability to invade surrounding tissue, and/or establishes new growth at ectopic sites. Refers to a cellular disorder characterized by the ability to. The term "cancer" includes, but is not limited to, solid tumors and blood-borne tumors (hematologic malignancy). The term "cancer" includes diseases of the skin, tissues, organs, bone, cartilage, blood, and blood vessels. The term "cancer" further includes primary and metastatic cancer.

The solid tumor is pancreatic cancer; Bladder cancer, including invasive bladder cancer; Colorectal cancer; Breast cancer, including thyroid cancer, stomach cancer, and metastatic breast cancer; Prostate cancer, including androgen-dependent and androgen-independent prostate cancer; Kidney cancer, including, for example, metastatic kidney cell carcinoma; Liver cancer, including, for example, hepatocellular carcinoma and intrahepatic bile ducts; Lung and bronchial cancers including non-small cell lung cancer (NSCLC), squamous epithelial lung cancer, bronchoalveolar carcinoma (BAC), adenocarcinoma of the lung, and small cell lung cancer (SCLC); Ovarian cancer, including, for example, advanced epithelial or primary peritoneal cancer; Cervical cancer; Uterine cancer including, for example, the uterine body and cervix; Endometrial cancer; Stomach cancer; Esophageal cancer; Head and neck cancers including, for example, squamous cell carcinoma of the head and neck, nasopharyngeal cancer, oral cavity and pharynx; Melanoma; Neuroendocrine cancer, including metastatic neuroendocrine tumors; Brain cancers, including, for example, glioma/glioblastoma, anaplastic oligodendrocyte glioma, adult glioblastoma polymorphism, and adult anaplastic astrocytoma; Metastatic neuroendocrine tumor; Bone cancer; And neuroendocrine, including soft tissue sarcoma.

The hematologic malignancy is acute myeloid leukemia (AML); Chronic myelogenous leukemia (CML) (including accelerated CML and CML subcellular phase (CML-BP)); Acute lymphoblastic leukemia (ALL); Chronic lymphocytic leukemia (CLL); Hodgkin's disease (HD); Non-Hodgkin's lymphoma (NHL) (including follicular lymphoma and mantle cell lymphoma); B-cell lymphoma (including diffuse large B-cell lymphoma (DLBCL)); T-cell lymphoma; Multiple myeloma (MM); Amyloidosis; Waldenstrom megaglobulinemia; Myelodysplastic syndrome (MDS) (including refractory anemia (RA), refractory anemia with coronary blasts (RARS) (excessive blast cells (RAEB), and refractory anemia with RAEB (RAEB-T) with transformation) ; Small lymphocyte lymphoma (SLL); Marginal zone lymphoma; Asymptomatic multiple myeloma; And myeloproliferative syndrome.

Furthermore, the present invention is a pharmaceutical composition for the prevention or treatment of autoimmune diseases containing the compound represented by A-Linker-A or A-Linker-B, a stereoisomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient. Gives

At this time, the autoimmune disease refers to all autoimmune diseases that can be improved from inhibiting cerebron activity or decomposing the cerebron protein, and for non-limiting examples, the autoimmune disease is immune neutropenia, Guillain-Barre syndrome, Epilepsy, autoimmune encephalitis, Isaac syndrome, birthmark syndrome, vulgar vesicular vesicle, deciduous celestial vesicle, vesicular vesicular vesicles, acquired epidermal vesicles, gestational pseudovesicles, mucose membrane-like vesicles, antiphospholipid syndrome, autoimmune anemia, autologous It may be one or more selected from the group consisting of immune grave disease, Goodpasture's syndrome, myasthenia gravis, multiple sclerosis, rheumatoid arthritis, lupus, idiopathic thrombocytopenic purpura (ITP), lupus nephritis and membranous nephropathy .

In addition, the present invention provides a pharmaceutical composition for the prevention or treatment of metabolic diseases containing the compound represented by the A-Linker-A or A-Linker-B, a stereoisomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient. to provide.

The metabolic disease refers to all metabolic diseases in which the effect of treatment or prevention can be achieved by inhibiting cerebron or decomposing cerebron protein, and non-limiting examples include obesity, type I diabetes, type II diabetes, and inappropriate history , Insulin resistance, hyperinsulinemia, hyperglycemia, dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia, metabolic syndrome X, vascular disease, atherosclerosis, coronary heart disease, cerebrovascular disease, heart failure , Peripheral vascular disease, and scars.

In the pharmaceutical composition according to the present invention described above, the compound represented by A-Linker-A or A-Linker-B, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof may be administered in various oral and parenteral forms during clinical administration. It can be administered in the form of an eggplant, and when formulated, it can be prepared using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, and surfactants.

Formulations for oral administration include, for example, tablets, pills, hard/soft capsules, liquids, suspensions, emulsifiers, syrups, granules, elixirs, troches, etc. , Dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine), lubricants (eg silica, talc, stearic acid and its magnesium or calcium salts and/or polyethylene glycols). Tablets may contain a binder such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidine, and, if desired, a boron such as starch, agar, alginic acid or its sodium salt, etc. It can contain an releasing or boiling mixture and/or absorbent, colorant, flavoring agent, and sweetening agent.

The pharmaceutical composition containing the compound represented by A-Linker-A or A-Linker-B as an active ingredient may be administered parenterally, and parenteral administration may include subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection. By injection method.

At this time, the compound represented by the A-Linker-A or A-Linker-B or a pharmaceutically acceptable salt thereof is mixed with water together with a stabilizer or buffer to prepare a solution or suspension for formulation into a formulation for parenteral administration. And it can be prepared in ampule or vial unit dosage form. The composition may be sterile and/or contain preservatives, stabilizers, hydrating or emulsifying accelerators, adjuvants such as salts and/or buffers for osmotic pressure control, and other therapeutically useful substances, conventional methods of mixing, granulation It can be formulated according to the chemical or coating method.

The example of the formulation is related to the conventional formulation example, it can be easily understood by those of ordinary skill in the art that the formulation of the present invention is not limited thereto.

Furthermore, the dosage of the compound represented by the A-Linker-A or A-Linker-B of the present invention or a pharmaceutically acceptable salt thereof to the human body is the age, weight, sex, dosage form, health condition and disease of the subject. It may vary depending on the degree, and based on an adult subject having a weight of 70 Kg, it is generally 0.1-1000 mg/day, preferably 1-500 mg/day, and also a predetermined time interval according to the judgment of a doctor or pharmacist It can also be administered in divided doses once to several times a day.

Furthermore, the present invention prevents or improves cereblon-related diseases containing the compound represented by A-Linker-A or A-Linker-B, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. It provides a health functional food composition.

At this time, the cerebron-related disease is a disease caused by cerebron-related disease (cerebron-related disease), cerebron abnormal activity, cerebron hyperactivity or activity induced by the mechanism of cerebrone, and is not limited to , Cancer, autoimmune diseases, and metabolic diseases.

The cancer refers to all cancer diseases that can be improved by inhibiting cerebron activity or decomposing the cerebron protein, and for non-limiting examples, the cancer is pseudomyxoma, intrahepatic biliary cancer, hepatoblastoma, liver cancer, thyroid cancer, colon cancer , Testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, celiac cancer, mycosis, acute myeloid leukemia, acute lymphocytic leukemia, basal cell carcinoma, ovarian epithelial cancer, ovarian reproductive cell cancer, male breast cancer, brain cancer, pituitary adenoma, multiple myeloma , Gallbladder cancer, Biliary tract cancer, Colon cancer, Chronic myelogenous leukemia, Chronic lymphocytic leukemia, Retinoblastoma, Choroid melanoma, Diffuse giant B cell lymphoma, Barter swelling cancer, Bladder cancer, Peritoneal cancer, Parathyroid cancer, Adrenal cancer, Non sinus cancer, Arsenic Cell lung cancer, non-Hodgkin's lymphoma, snow cancer, astrocytoma, small cell lung cancer, pediatric brain cancer, pediatric lymphoma, pediatric leukemia, small intestine cancer, meningioma, esophageal cancer, glioma, neuroblastoma, renal cancer, kidney cancer, heart cancer, duodenal cancer, malignant softening Tissue cancer, malignant bone cancer, malignant lymphoma, malignant mesothelioma, malignant melanoma, eye cancer, vulvar cancer, ureteral cancer, urethral cancer, primary site unknown cancer, gastric lymphoma, gastric cancer, gastric carcinoma, gastrointestinal stromal cancer, Wilms' cancer, breast cancer, sarcoma , Penile cancer, pharyngeal cancer, chorionic villus disease, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone cancer, metastatic brain cancer, mediastinal cancer, rectal cancer, rectal carcinoma, vaginal cancer, spinal cord cancer, auditory choroidoma, pancreatic cancer, salivary gland cancer , Kaposi's sarcoma, Paget's disease, tonsil cancer, squamous cell carcinoma, lung adenocarcinoma, lung cancer, lung squamous cell carcinoma, skin cancer, anal cancer, rhabdomyosarcoma, laryngeal cancer, pleural cancer, and thymic cancer 1 It may be more than a species.

The autoimmune disease refers to all autoimmune diseases that can be improved from inhibiting cerebron activity or decomposing the cerebron protein, and for non-limiting examples, the autoimmune disease is immune neutropenia, Guillain Barre syndrome, epilepsy, Autoimmune encephalitis, Isaac syndrome, birthmark syndrome, vulgar vesicular vesicles, deciduous celestial vesicles, vesicular vesicular vesicles, acquired epithelial vesicles, gestational pseudo blisters, mucos membrane pseudo blisters, antiphospholipid syndromes, autoimmune anemia, autoimmune yeah It may be one or more selected from the group consisting of Eve's disease, Goodpasture's syndrome, myasthenia gravis, multiple sclerosis, rheumatoid arthritis, lupus, idiopathic thrombocytopenic purpura (ITP), lupus nephritis and membranous nephropathy.

The metabolic disease refers to all metabolic diseases in which the effect of treatment or prevention can be achieved by inhibiting cerebron or decomposing cerebron protein, and non-limiting examples include obesity, type I diabetes, type II diabetes, and inappropriate history , Insulin resistance, hyperinsulinemia, hyperglycemia, dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia, metabolic syndrome X, vascular disease, atherosclerosis, coronary heart disease, cerebrovascular disease, heart failure , Peripheral vascular disease, and scars.

Furthermore, the present invention includes the step of administering a compound represented by A-Linker-A or A-Linker-B, a stereoisomer thereof or a pharmaceutically acceptable salt thereof to a subject in a therapeutically effective amount. It provides a method for treating cereblon-related diseases.

At this time, the cereblon-related disease refers to a disease that can be prevented or treated from inhibiting cereblon activity or decomposing a cereblon protein, as described herein, preferably Cancer, autoimmune disease or metabolic disease.

The therapeutically effective amount refers to an amount sufficient to treat, prevent or improve the symptoms or condition of a subject when administered into the body, depending on the administration method. In addition, the amount may vary depending on the weight, age, sex, condition, and family history of the subject to be administered, and in the present invention, the treatment method may determine a different amount of dose according to different conditions for each subject.

The "effective amount" is an amount effective to treat cereblon-related diseases, such as cancer, autoimmune diseases or metabolic diseases. In another embodiment, the “effective amount” of the compound is an amount that can inhibit Cereblon activity or degrade the celebrity protein.

The compounds and compositions according to the methods of the present invention can be administered using any amount and any route of administration effective for treating a disease. The exact amount required will vary from subject to subject, depending on the subject's species, age, and general condition, severity of infection, specific agent, mode of administration, and the like. The compounds of the present invention are frequently formulated in dosage unit form for ease of administration and uniformity of dosage. The expression “dosage unit form” as used herein means a physically discrete unit of agent suitable for the subject to be treated. It will also be understood that the total daily use of the compounds and compositions of the present invention will be determined by the attending physician within the scope of sound medical judgment. The specific effective dosage level for any particular subject or organism depends on various factors, including: the disease to be treated and the severity of the disease; The activity of the specific compound employed; Specific composition used; Age, weight, general health, subject's gender and diet; The time of administration, route of administration, and rate of excretion of the specific compound employed; Duration of treatment; The specific compound employed alone or co-administered drugs, and other factors well known in medical technology.

The term "subject" as used herein means an animal, for example a mammal, such as a human.

Hereinafter, the present invention will be described in detail by examples and experimental examples.

However, the following examples and experimental examples are merely illustrative of the present invention, and the contents of the present invention are not limited thereto.

<Example 1> (2S,4R)-1-((S)-2-(7-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole- 4-ylamino)heptanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carbox Preparation of amide

Step 1: Preparation of 7-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-ylamino)heptanoic acid

7-aminoheptanoic acid (158 mg, 1.09 mmol) and 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (300 mg, 1.09 mmol) in DMF ) Was dissolved, DIPEA (0.285 mL, 1.64 mmol) was added and stirred at room temperature. After completion of the reaction, the mixture was concentrated, diluted with EA and water, and the organic layer was extracted, washed with brine, and water was removed with MgSO ₄ , and then concentrated under reduced pressure. Separation and purification using silica gel column chromatography (MPLC, MeOH/DCM 10% 28 min) to 7-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole -4-ylamino)heptanoic acid (118 mg, 27%, yellow solid) was obtained.

LC/MS (ESI) m/z [M+H] ⁺ : 401.9, [MH] ^- : 399.9

¹ H NMR (CDCl ₃ , 300 MHz) δ 8.34 (s, 1H), 7.49 (dd, J = 8.5, 7.2 Hz, 1H), 7.09 (d, J = 7.1 Hz, 1H), 6.88 (d, J = 8.6 Hz, 1H), 6.29-6.18 (m, 1H), 4.96-4.87 (m, 1H), 3.32-3.22 (m, 2H), 2.94-2.65 (m, 3H), 2.36 (t, J = 7.3 Hz, 2H), 2.19-2.09 (m, 1H), 1.75-1.58 (m, 4H), 1.43 (t, J = 3.5 Hz, 4H).

Step 2: (2S,4R)-1-((S)-2-(7-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- Of 1-amino)heptanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide Produce

Compound prepared in step 1 above in DMF (30 mg, 0.074 mmol), (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N- (4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide hydrochloride (35 mg, 0.074 mmol), HATU (43 mg, 0.112 mmol) dissolved and DIPEA (0.052 mL, 0.299) mmol) and stirred at room temperature. After completion of the reaction, dilute with EA and water, extract the organic layer, wash with brine, remove water with MgSO ₄ and concentrate under reduced pressure. Separation and purification using silica gel column chromatography (MPLC, MeOH/DCM 6% 30 min) (2S,4R)-1-((S)-2-(7-(2-(2,6-dioxophyte) Peridin-3-yl)-1,3-dioxoisoindolin-4-ylamino)heptanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methyl Thiazole-5-yl)benzyl)pyrrolidine-2-carboxamide (10 mg, 17%, yellow solid) was obtained.

LC/MS (ESI) m/z [M+H] ⁺ : 814.6, [MH] ^- : 812.7

¹ H NMR (CDCl ₃ , 300 MHz) δ 10.00 (s, 1H), 8.68 (s, 1H), 7.61-7.53 (m, 1H), 7.47 (dd, J = 8.5, 7.1 Hz, 1H), 7.35 (S ,4H), 7.08 (d, J = 7.1 Hz, 1H), 6.87 (d, J = 8.5 Hz, 1H), 6.72 (d, J = 9.1 Hz, 1H), 6.24 (t, J = 5.7 Hz, 1H ), 4.89-4.81 (m, 1H), 4.65-4.54 (m, 4H), 4.32-4.23 (m, 1H), 4.06 (d, J = 11.3 Hz, 1H), 3.70-3.62 (m, 1H), 3.55 (s, 1H), 3.26 (q, J = 6.3 Hz, 2H), 2.87-2.75 (m, 2H), 2.74-2.62 (m, 1H), 2.52 (s, 3H), 2.50-2.42 (m, 1H), 2.23-2.06 (m, 4H), 1.84 (s, 1H), 1.68-1.52 (m, 4H), 1.44-1.28 (m, 5H), 1.25 (s, 3H), 0.93 (s, 9H) .

<Example 2> (2S,4R)-1-((S)-2-(6-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole- 4-ylamino)hexaneamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carbox Preparation of amide

Step 1: Preparation of 6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexanoic acid

6-aminohexanoic acid (119 mg, 0.905 mmol) and 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (250 mg, 0.905 mmol) in DMF ) Was dissolved, DIPEA (0.236 mL, 1.36 mmol) was added and stirred at room temperature. After completion of the reaction, the mixture was concentrated, diluted with EA and water, and the organic layer was extracted, washed with brine, and water was removed with MgSO ₄ , and then concentrated under reduced pressure. Separation and purification using silica gel column chromatography (MPLC, MeOH/DCM 10% 28 min) to 6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoin Doolin-4-yl)amino)hexanoic acid (60 mg, 17%, yellow solid) was obtained.

LC/MS (ESI) m/z [M+H] ⁺ : 388.6, [MH] ^- : 399.9

¹ H NMR (CDCl ₃ , 300 MHz) δ 8.39 (s, 1H), 7.50 (dd, J = 8.5, 7.2 Hz, 1H), 7.09 (d, J = 7.1 Hz, 1H), 6.88 (d, J = 8.5 Hz, 1H), 6.29-6.19 (m, 1H), 4.97-4.87 (m, 1H), 3.32-3.29 (m, 2H), 2.95-2.64 (m, 3H), 2.39 (t, J = 7.3 Hz, 2H), 2.19-2.08 (m, 1H), 1.76-1.61 (m, 4H), 1.55-1.41 (m, 2H).

Step 2: (2S,4R)-1-((S)-2-(6-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- Of monoamino)hexanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide Produce

Compound prepared in step 1 above in DMF (35 mg, 0.090 mmol), (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N- (4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide hydrochloride (42 mg, 0.090 mmol), HATU (52 mg, 0.136 mmol) dissolved and DIPEA (0.063 mL, 0.360) mmol) and stirred at room temperature. After completion of the reaction, the organic layer was extracted by diluting with EA and water, washed with brine, water was removed with MgSO ₄ and concentrated under reduced pressure. Separated and purified using silica gel column chromatography (MPLC, MeOH/DCM 6% 30 min) to (2S,4R)-1-((S)-2-(6-(2-(2,6-dioxophyte) Peridin-3-yl)-1,3-dioxoisoindolin-4-ylamino)hexanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methyl Thiazole-5-yl)benzyl)pyrrolidine-2-carboxamide (43 mg, 73%, yellow solid) was obtained.

LC/MS (ESI) m/z [M+H] ⁺ : 800.7, [MH] ^- : 798.7

¹ H NMR (300 MHz, CDCl ₃ ) δ 10.35 (s, 0.5H), 9.67 (s, 0.5H), 8.68 (s, 1H), 7.60 (t, J = 6.2 Hz, 1H), 7.54-7.40 ( m, 2H), 7.40-7.30 (m, 4H), 7.07 (t, J = 6.6 Hz, 1H), 6.86 (t, J = 7.8 Hz, 1H), 6.23-6.08 (m, 1H), 4.95-4.81 (m, 1H), 4.71-4.49 (m, 4H), 4.36-4.23 (m, 1H), 4.05 (d, J = 11.5 Hz, 1H), 3.64 (d, J = 11.1 Hz, 1H), 3.27- 3.14 (m, 2H), 2.86-2.62 (m, 3H), 2.51 (S,4H), 2.28-2.00 (m, 5H), 1.83 (s, 1H), 1.67-1.47 (m, 4H), 1.34 ( d, J = 9.4 Hz, 2H), 0.99-0.77 (m, 9H).

<Example 3> (2S,4R)-1-((S)-2-(9-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole- 4-ylamino)nonanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carbox Preparation of amide

Step 1: Preparation of 9-bromononanoic acid

9-bromononan-1-ol (2 g, 8.96 mmol) was added to the concentrated nitric acid (30 mL, 258 mmol) using a dropping funnel for 30 minutes, followed by stirring at room temperature for 4 hours. Thereafter, the mixture was heated to 80° C. and stirred for 1 hour. After completion of the reaction, the temperature was lowered to room temperature and diluted with tertiary distilled water. The organic layer was extracted with diethyl ether, dried over MgSO ₄ and concentrated to give 9-bromononanoic acid (1.57 g, 74%, brown oil).

¹ H NMR (DMSO, 300 MHz) δ 9.64 (s, 1H), 3.52 (t, J = 6.4 Hz, 2H), 2.19 (t, J = 6.8 Hz, 2H), 1.83-1.77 (m, 2H), 1.62 -1.17 (m, 10H).

Step 2: Preparation of 9-aminononanoic acid

The compound (1 g, 4.22 mmol) prepared in step 1 was added to an aqueous ammonium hydroxide solution (25% NH ₃ , 40 mL) and stirred at room temperature. After completion of the reaction, it was concentrated to obtain 9-aminononanoic acid (529 mg, 72%, brown oil).

Step 3: Preparation of 9-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)nonanoic acid

Compound prepared in Step 2 above in DMF (200 mg, 1.15 mmol), 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindole-1,3-dione (318 mg, 1.15 mmol) was added and DIPEA (0.301 mL, 1.73 mmol) was added, followed by stirring at 90°C. After completion of the reaction, it was concentrated, diluted with EA and water, and the organic layer was extracted, washed with brine, dried over MgSO ₄ and concentrated. Separation and purification using silica gel column chromatography (MPLC, EA/Hx 60%, 35 min) to 9-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoyi Soindoline-4-yl)amino)nonanoic acid (25 mg, 5%, yellow solid) is obtained.

LC/MS (ESI) m/z [M+H] ⁺ : 429.9, [MH] ^- : 427.9

¹ H NMR (CDCl ₃ , 300 MHz) δ 8.79 (s, 1H), 7.52-7.43 (m, 1H), 7.08 (d, J = 7.1 Hz, 1H), 6.87 (d, J = 8.5 Hz, 1H), 6.24 (s, 1H), 4.96-4.90 (m,, 1H), 3.26-3.23 (m, 2H), 2.94-2.65 (m, 3H), 2.34 (t, J = 7.4 Hz, 2H), 2.17-2.05 (m, 1H), 1.64 (d, J = 6.6 Hz, 5H), 1.34 (s, 9H).

Step 4: (2S,4R)-1-((S)-2-(9-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- Of monoamino)nonanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide Produce

Compound prepared in Step 3 above in DMF (25 mg, 0.058 mmol), (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N- (4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide hydrochloride (27 mg, 0.058 mmol), HATU (33 mg, 0.087 mmol) and DIPEA (0.041 mL, 0.233) mmol), and stirred at 90°C. After completion of the reaction, it was concentrated, diluted with EA and water, and the organic layer was extracted, washed with brine, dried over MgSO ₄ and concentrated. Separated and purified using silica gel column chromatography (MPLC, MeOH/DCM 6%, 30 min) to (2S,4R)-1-((S)-2-(9-(2-(2,6-diox) Sopiperidin-3-yl)-1,3-dioxoisoindolin-4-ylamino)nonaneamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4- Methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (17 mg, 35%, yellow solid).

LC/MS (ESI) m/z [M+H] ⁺ : 842.6, [MH] ^- : 840.7

¹ H NMR (300 MHz, CDCl ₃ ) δ 10.63 (s, 0.5H), 10.37 (s, 0.5H), 10.32 (s, 0.5H), 10.29 (s, 0.5H), 8.67 (s, 1H), 7.68-7.53 (m, 1H), 7.44 (t, J = 7.8 Hz, 1H), 7.38-7.30 (m, 3H), 7.03 (d, J = 7.1 Hz, 1H), 6.94-6.76 (m, 2H) , 6.22 (s, 1H), 4.98-4.78 (m, 1H), 4.69-4.44 (m, 4H), 4.34-4.09 (m, 2H), 4.05-3.90 (m, 1H), 3.69-3.56 (m, 1H), 3.28-3.11 (m, 2H), 2.83-2.56 (m, 3H), 2.52-2.32 (m, 4H), 2.22-1.96 (m, 4H), 1.66-1.44 (m, 4H), 1.40- 1.09 (m, 7H), 0.91 (s, 9H). LC/MS (ESI) m/z 842.6 [M+H] ⁺ , 840.7 [MH] ^-

<Example 4> (2S,4R)-1-((S)-2-tert-butyl-17-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoyi Soindoline-4-ylamino)-4-oxo-6,9,12,15-tetraoxa-3-azaheptadeca-1-noyl)-4-hydroxy-N-(4-(4-methylthia Preparation of zol-5-yl)benzyl)pyrrolidine-2-carboxamide

Step 1: Preparation of tert-butyl 14-amino-3,6,9,12-tetraoxatetradeca-1-noate

tert-butyl 14-iodo-3,6,9,12-tetraoxatetradeca-1-noate (315 mg, 0.753 mmol) was dissolved in DMF and sodium azide (147 mg, 2.26 mmol) was added to add 50°C. Stir in. After completion of the reaction, it was concentrated to obtain an azide compound in the crude product state, dissolved in ethanol, Pd(OH) ₂ (6 mg) was added, and the mixture was stirred under hydrogen gas. After completion of the reaction, celite was filtered using methanol, and then concentrated to give crude tert-butyl 14-amino-3,6,9,12-tetraoxatetradeca-1-noate (240 mg, quantitative). Yellow solid).

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 3.99 (s, 2H), 3.62-3.46 (m, 13H), 3.46-3.40 (m, 2H), 3.35 (t, J = 5.8 Hz, 7H), 2.63 (t, J = 5.8 Hz, 2H), 1.42 (s, 9H).

Step 2: tert-Butyl 14-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12 -Preparation of tetraoxatetradecanoate

Compound prepared in step 1 above in DMSO (100 mg, 0.325 mmol), 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindole-1,3-dione (90 mg, 0.325 mmol) was added, DIPEA (0.085 mL, 0.488 mmol) was added, followed by stirring at 90°C. After completion of the reaction, dilute with EA and water, extract the organic layer, wash with brine, remove water with MgSO ₄ and concentrate under reduced pressure. Separation and purification using silica gel column chromatography (MPLC, MeOH/DCM 5% 28 min) to tert-butyl 14-(2-(2,6-dioxopiperidin-3-yl)-1,3-di Oxoisoindoline-4-ylamino)-3,6,9,12-tetraoxatetradeca-1-noate (7 mg, 4%, yellow solid) is obtained.

LC/MS (ESI) m/z [M+H] ⁺ = 564.9 [MH] ^- = 562.9

Step 3: 14-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)-3,6,9,12-tetraoxa Preparation of tetradecanoic acid

Tert-butyl 14-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-ylamino)-3,6,9 in 40% TFA/DCM solution ,12-tetraoxatetradeca-1-noate (7 mg, 0.012 mmol) was added and stirred at room temperature. After completion of the reaction, it was concentrated to give 14-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12 -Tetraoxatetradecanoic acid (10 mg, crude product, brown oil) is obtained as crude product.

LC/MS (ESI) m/z [M+H] ⁺ = 508.8 [MH] ^- = 506.8

Step 4: (2S,4R)-1-((S)-2-(tert-butyl)-17-((2-(2,6-dioxapiperidin-3-yl)-1,3- Dioxoisoindolin-4-yl)amino)-4-oxo-6,9,12,15-tetraoxa-3-azaheptadecanoyl)-4-hydroxy-N-(4-(4-methylthia Preparation of zol-5-yl)benzyl)pyrrolidine-2-carboxamide

Compound prepared in Step 3 (6 mg, 0.012 mmol), (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4 -(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide hydrochloride (6 mg, 0.012 mmol) and HATU (7 mg, 0.018 mmol) were dissolved in DMF, followed by DIPEA (0.008 mL) , 0.048 mmol), and stirred at room temperature. After completion of the reaction, the mixture was concentrated, diluted with EA and water, and the organic layer was extracted, washed with brine, and water was removed with MgSO ₄ , and then concentrated under reduced pressure. Separated and purified using silica gel column chromatography (MPLC, MeOH/DCM 6%, 30 min) to (2S,4R)-1-((S)-2-(tert-butyl)-17-((2- (2,6-Dioxapiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)-4-oxo-6,9,12,15-tetraoxa-3-aza Heptadecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (3 mg, 27%, yellow solid) is obtained.

LC/MS (ESI) m/z [M+H] ⁺ : 921.8, [MH] ^- : 919.8

¹ H NMR (300 MHz, CDCl ₃ ) δ 9.29 (s, 1H), 8.68 (s, 1H), 7.63-7.43 (m, 2H), 7.42-7.32 (m, 3H), 7.32-7.27 (m, 1H ), 7.10 (d, J = 7.1 Hz, 1H), 6.95-6.86 (m, 1H), 6.52 (s, 1H), 4.93-4.79 (m, 1H), 4.72 (t, J = 8.0 Hz, 1H) , 4.64-4.45 (m, 2H), 4.37-4.20 (m, 1H), 4.17-4.06 (m, 1H), 4.04-3.97 (m, 1H), 3.79-3.54 (m, 12H), 3.52-3.38 ( m, 2H), 2.94-2.62 (m, 3H), 2.52 (s, 3H), 2.22-1.96 (m, 3H), 1.26 (s, 9H), 0.99-0.78 (m, 10H).

<Example 5> (2S,4R)-1-((S)-2-(2-(3-(2-(2-(2,6-dioxopiperidin-3-yl)-1,3) -Dioxoisoindolin-4-ylamino)-2-oxoethoxy)propoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthia Preparation of zol-5-yl)benzyl)pyrrolidine-2-carboxamide

Step 1: Preparation of di-tert-butyl 2,2'-(propane-1,3-diylbis(oxy))diacetate

Propane-1,3-diol (1 g, 13.1 mmol), tert-butyl 2-bromoacetate (21.5 g, 110.4 mmol), tetrabutyl ammonium hydrogen sulfate (445 mg) in toluene and NaOH aqueous solution (50 wt%) , 1.31 mmol) and stirred at room temperature for 16 hours. After completion of the reaction, diluted with ice water, extracted with EA, washed with brine, water was removed with MgSO ₄ and concentrated under reduced pressure. Separated and purified using silica gel column chromatography (MPLC, EA/Hx 30% 40 min) to di-tert-butyl 2,2'-(propane-1,3-diylbis(oxy)) diacetate (580 mg , 15%, colorless oil).

¹ H NMR (CDCl ₃ , 300 MHz) δ 3.96 (S,4H), 3.63 (t, J = 6.3 Hz, 4H), 1.94 (p, J = 6.3 Hz, 2H), 1.48 (s, 18H).

Step 2: Preparation of 2,2'-(propane-1,3-diylbis(oxy))diacetic acid

Di-tert-butyl 2,2'-(propane-1,3-diylbis(oxy)) diacetate (530 mg, 1.74 mmol) was added to a 40% TFA/DCM solution and stirred at room temperature. After completion of the reaction, it was concentrated to obtain 2,2'-(propane-1,3-diylbis(oxy))diacetic acid (631 mg, crude product, brown oil) as a crude product.

¹ H NMR (CDCl ₃ , 300 MHz) δ 10.12 (s, 2H), 4.21 (S,4H), 3.75 (t, J = 5.9 Hz, 4H), 2.08-1.90 (m, 2H).

Step 3: 2-(3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-2-oxo Preparation of ethoxy)propoxy)acetic acid

The compound (167 mg, 0.869 mmol) prepared in step 2 was dissolved in DCM, oxalyl chloride (0.373 mL, 4.35 mmol) was added, and DMF was added dropwise. After confirming that the acid chloride has been formed, it is concentrated. Dissolve in THF, add pomalidomide, and reflux. After completion of the reaction, the reaction was terminated with a 0.1 N HCl (aq.) solution, diluted with EA and water, and the organic layer was extracted, washed with brine, and water was removed with MgSO ₄ , and then concentrated under reduced pressure. The resulting solid was filtered with EA to give 2-(3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino) 2-Oxoethoxy)propoxy)acetic acid (54 mg, 28%, gray solid). LC/MS (ESI) m/z [M+H] ⁺ = 447.8 [MH] ^- = 445.8

¹ H NMR (CDCl ₃ , 300MHz) δ 10.41 (s, 1H), 8.96-8.78 (m, 1H), 8.65 (s, 1H), 7.81-7.66 (m, 1H), 7.62-7.50 (m, 1H) , 5.04-4.86 (m, 1H), 4.27-4.04 (m, 4H), 3.86 (t, J = 6.7 Hz, 2H), 3.74 (t, J = 6.0 Hz, 2H), 3.01-2.64 (m, 3H) ), 2.15-1.99 (m, 3H).

Step 4: (2S,4R)-1-((S)-2-(2-(3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3- Dioxoisoindoline-4-yl)amino)-2-oxoethoxy)propoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthia Preparation of zol-5-yl)benzyl)pyrrolidine-2-carboxamide

Compound prepared in step 3 (30 mg, 0.067 mmol), (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4 -(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide hydrochloride (31 mg, 0.067 mmol) and HATU (38 mg, 0.101 mmol) were dissolved in DMF, followed by DIPEA (0.047 mL) , 0.268 mmol), and stirred at room temperature. After completion of the reaction, the mixture was concentrated, diluted with EA and water, and the organic layer was extracted, washed with brine, and water was removed with MgSO ₄ , and then concentrated under reduced pressure. Separated and purified using silica gel column chromatography (MPLC, MeOH/DCM 6%, 30 min) to (2S,4R)-1-((S)-2-(2-(3-(2-((2 -(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)-2-oxoethoxy)propoxy)acetamido)-3,3- Dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (5 mg, 9%, white solid) is obtained.

LC/MS (ESI) m/z [M+H] ⁺ : 860.5, [MH] ^- : 858.7

¹ H NMR (CDCl ₃ , 500 MHz) δ 10.35 (s, 1H), 8.81 (d, J = 8.4 Hz, 1H), 8.68 (s, 1H), 7.76-7.68 (m, 1H), 7.62-7.53 (m , 1H), 7.40-7.35 (m, 4H), 7.32 (d, J = 9.5 Hz, 1H), 7.19 (d, J = 6.2 Hz, 1H), 4.95-4.84 (m, 1H), 4.67-4.59 ( m, 2H), 4.50 (s, 2H), 4.33-4.25 (m, 1H), 4.23-4.14 (m, 1H), 4.12-4.01 (m, 3H), 4.01-3.97 (m, 1H), 3.93- 3.85 (m, 1H), 3.82-3.73 (m, 2H), 3.65-3.56 (m, 2H), 2.88-2.57 (m, 3H), 2.53 (s, 3H), 2.40 (s, 1H), 2.19- 1.90 (m, 6H), 1.71-1.60 (m, 2H), 1.59-1.38 (m, 2H), 0.95 (s, 9H).

<Example 6> N ^One -(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)-N ⁹ -((S)-1-((2S,4R)-4-hydroxy-2-(4-(4-methylthiazol-5-yl)benzylcarbamoyl)pyrrolidin-1-yl)-3 Preparation of ,3-dimethyl-1-oxobutan-2-yl)nonanediamide

9-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-ylamino)-9-oxononanoic acid (30 mg, 0.068 mmol), (2S ,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine After -2-carboxamide hydrochloride (32 mg, 0.068 mmol) and HATU (39 mg, 0.101 mmol) were dissolved in DMF, DIPEA (0.047 mL, 0.272 mmol) was added, followed by stirring at room temperature. After completion of the reaction, the mixture was concentrated, diluted with EA and water, and the organic layer was extracted, washed with brine, and water was removed with MgSO ₄ , and then concentrated under reduced pressure. Separation and purification using silica gel column chromatography (MPLC, MeOH/DCM 6%, 30 min) to N ¹ -(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoyi Soindoline-4-yl)-N ⁹ -((R)-1-((2R,4R)-4-hydroxy-2-(4-(4-methylthiazol-5-yl)benzylcarbamoyl) Pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)nonanediamide (21 mg, 36%, white solid) is obtained.

LC/MS (ESI) m/z [M+H] ⁺ : 856.6, [MH] ^- : 854.7

¹ H NMR (300 MHz, CDCl ₃ ) δ 10.92 (s, 0.5H), 10.35 (s, 0.5H), 9.53 (s, 0.5H), 9.50 (s, 0.5H), 8.84 (d, J = 8.4 Hz, 0.5H), 8.79 (d, J = 8.4 Hz, 0.5H), 8.69 (s, 1H), 7.79-7.65 (m, 1H), 7.59-7.48 (m, 1H), 7.40-7.30 (m, 4H), 6.83 (d, J = 9.0 Hz, 0.5H), 6.63 (d, J = 9.0 Hz, 0.5H), 5.01-4.83 (m, 1H), 4.73-4.48 (m, 4H), 4.35-4.21 (m, 1H), 4.09 (t, J = 10.5 Hz, 1H), 3.70-3.59 (m, 1H), 2.89-2.60 (m, 3H), 2.57-2.36 (m, 6H), 2.23-2.06 (m , 4H), 1.91-1.65 (m, 2H), 1.63-1.51 (m, 2H), 1.51-1.41 (m, 2H), 1.40-1.16 (m, 7H), 1.00-0.81 (m, 9H). LC/MS (ESI) m/z 856.6 [M+H] ⁺ , 854.7 [MH] ^-

<Example 7> N ^One -(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)-N ⁸ -((S)-1-((2S,4R)-4-hydroxy-2-(4-(4-methylthiazol-5-yl)benzylcarbamoyl)pyrrolidin-1-yl)-3 Preparation of ,3-dimethyl-1-oxobutan-2-yl)octanediamide

8-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-ylamino)-8-oxooctanoic acid (30 mg, 0.070 mmol), (2S ,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine After -2-carboxamide hydrochloride (33 mg, 0.070 mmol) and HATU (40 mg, 0.105 mmol) were dissolved in DMF, DIPEA (0.049 mL, 0.279 mmol) was added, followed by stirring at room temperature. After completion of the reaction, it was concentrated, diluted with EA and water, and the organic layer was extracted, washed with brine, and water was removed with MgSO ₄ , and then concentrated under reduced pressure. Separation and purification using silica gel column chromatography (MPLC, MeOH/DCM 6%, 30 min) to N ¹ -(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoyi Soindoline-4-yl)-N ⁸ -((S)-1-((2S,4R)-4-hydroxy-2-(4-(4-methylthiazol-5-yl)benzylcarbamoyl) Pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)octanediamide (17 mg, 29%, white solid) is obtained.

LC/MS (ESI) m/z [M+H] ⁺ : 842.6, [MH] ^- : 840.7

¹ H NMR (300 MHz, CDCl ₃ ) δ 11.23 (s, 0.5H), 10.21 (s, 0.5H), 9.48 (d, J = 10.3 Hz, 1H), 8.77 (t, J = 9.0 Hz, 1H) , 8.72-8.65 (m, 1H), 7.77-7.66 (m, 1H), 7.61-7.47 (m, 1.5H), 7.40-7.29 (m, 4H), 7.03 (d, J = 9.0 Hz, 0.5H) , 6.59 (d, J = 9.0 Hz, 0.5H), 6.26-6.19 (m, 0.5H), 4.97-4.84 (m, 1H), 4.75-4.48 (m, 4H), 4.37-4.25 (m, 1H) , 4.18-4.04 (m, 1H), 3.69-3.57 (m, 2H), 2.91-2.61 (m, 3H), 2.57-2.40 (m, 5H), 2.32-2.06 (m, 4H), 2.06-1.97 ( m, 1H), 1.85 (t, J = 7.5 Hz, 1H), 1.79-1.68 (m, 1H), 1.68-1.52 (m, 3H), 1.44-1.32 (m, 3H), 0.97-0.83 (m, 9H). LC/MS (ESI) m/z 842.6 [M+H] ⁺ , 840.7 [MH] ^-

<Example 8> N ^One -(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)-N ⁷ -((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl) Preparation of -3,3-dimethyl-1-oxobutan-2-yl)heptanediamide

7-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-ylamino)-7-oxoheptanoic acid (50 mg, 0.120 mmol), (2S ,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine After dissolving -2-carboxamide hydrochloride (56 mg, 0.120 mmol) and HATU (68 mg, 0.180 mmol) in DMF, DIPEA (0.084 mL, 0.480 mmol) was added, followed by stirring at room temperature. After completion of the reaction, the mixture was concentrated, diluted with EA and water, and the organic layer was extracted, washed with brine, and water was removed with MgSO ₄ , and then concentrated under reduced pressure. Separation and purification using silica gel column chromatography (MPLC, MeOH/DCM 6%, 30 min) to N ¹ -(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoyi Soindoline-4-yl)-N ⁷ -((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)cover Moyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)heptanediamide (33 mg, 33%, white solid) is obtained.

LC/MS (ESI) m/z [M+H] ⁺ : 828.6, [MH] ^- : 826.7

¹ H NMR (CDCl ₃ , 300 MHz) δ 10.23 (s, 1H), 9.44 (s, 1H), 8.75 (d, J = 8.5 Hz, 1H), 8.68 (s, 1H), 7.68 (t, J = 7.9 Hz, 1H), 7.54 (dd, J = 10.5, 6.7 Hz, 2H), 7.35-7.32 (m, 4H), 6.76 (d, J = 9.1 Hz, 1H), 4.92-4.82 (m, 1H), 4.68 -4.53 (m, 4H), 4.91-4.84 (m, 1H), 4.07 (d, J = 11.3 Hz, 2H), 3.74-3.63 (m, 1H), 2.88-2.61 (m, 3H), 2.56-2.37 (m, 6H), 2.30-1.99 (m, 5H), 1.81-1.54 (m, 4H), 1.47-1.30 (m, 2H), 0.95 (s, 9H).

<Example 9> N ^One -(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)-N ¹⁴ -((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl) Preparation of -3,3-dimethyl-1-oxobutan-2-yl)-3,6,9,12-tetraoxatetradecane-1,14-diamide

Step 1: Preparation of di-tert-butyl 3,6,9,12-tetraoxatetradecanedioate

2-(2-(hydroxymethoxy)ethoxy)ethanol (1 g, 7.34 mmol), tert-butyl 2-bromoacetate (9.12 mL, 61.7 mmol), tetra in toluene and NaOH aqueous solution (50 wt%) Butyl ammonium hydrogen sulfate (249 mg, 0.734 mmol) was added and stirred at room temperature for 16 hours. After completion of the reaction, diluted with ice water, extracted with EA, washed with brine, water was removed with MgSO ₄ and concentrated under reduced pressure. Separated and purified using silica gel column chromatography (MPLC, EA/Hx 50% 40 min) to di-tert-butyl 3,6,9,12-tetraoxatetradecanedioate (1.24 g, 31%, colorless Oil).

¹ H NMR (CDCl ₃ , 300 MHz) δ 4.02 (S, 4H), 3.75-3.62 (m, 12H), 1.47 (s, 18H).

Step 2: Preparation of 3,6,9,12-tetraoxatetradecane-1,14-diionic acid

To the 40% TFA/DCM solution, the compound prepared in step 1 (450 mg, 1.48 mmol) was added and stirred at room temperature. After completion of the reaction, it is concentrated to obtain 3,6,9,12-tetraoxatetradecane-1,14-diionic acid 33 (502 mg, crude product, brown oil) as a crude product.

¹ H NMR (CDCl ₃ , 300 MHz) δ 10.14 (s, 1H), 4.23 (S,4H), 3.98-3.40 (m, 12H).

Step 3: 14-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)-14-oxo-3,6,9, Preparation of 12-tetraoxatetradecanoic acid

The compound (394 mg, 1.48 mmol) prepared in Step 2 was dissolved in DCM, oxalyl chloride (0.635 mL, 7.40 mmol) was added, and DMF was added dropwise. After confirming that the acid chloride has been formed, it is concentrated. Dissolve in THF, add pomalidomide (202 mg, 0.740 mmol), and reflux. After completion of the reaction, the reaction was terminated with a 0.1 N HCl (aq.) solution, diluted with EA and water, and the organic layer was extracted, washed with brine, removed with MgSO ₄ and concentrated under reduced pressure. Separated and purified by silica gel column chromatography (MPLC, MeOH/DCM 20% 40 min) to 14-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole- 4-yl)amino)-14-oxo-3,6,9,12-tetraoxatetradecanoic acid (78 mg, 20%, brown solid).

LC/MS (ESI) m/z [M+H] ⁺ = 522.8 [MH] ^- = 520.8

¹ H NMR (CDCl ₃ , 300 MHz) δ 10.47 (s, 1H), 9.18 (s, 1H), 8.84 (d, J = 8.4 Hz, 1H), 7.72 (t, J = 7.9 Hz, 1H), 7.57 ( d, J = 7.3 Hz, 1H), 5.07-4.92 (m, 1H), 4.29-4.05 (m, 8H), 3.87-3.78 (m, 4H), 3.78-3.61 (m, 17H), 3.57 (t, J = 5.7 Hz, 2H), 3.01-2.68 (m, 3H), 2.26-2.08 (m, 1H)

Step 4: N ^One -(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)-N ¹⁴ -((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl) Preparation of -3,3-dimethyl-1-oxobutan-2-yl)-3,6,9,12-tetraoxatetradecane-1,14-diamide

Compound prepared in step 3 (25 mg, 0.048 mmol), (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4 -(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide hydrochloride (22 mg, 0.048 mmol) and HATU (27 mg, 0.072 mmol) were dissolved in DMF, followed by DIPEA (0.033 mL) , 0.192 mmol), and stirred at room temperature. After completion of the reaction, the mixture was concentrated, diluted with EA and water, the organic layer was extracted, washed with brine, and water was removed with MgSO ₄ , and then concentrated under reduced pressure. Separation and purification using silica gel column chromatography (MPLC, MeOH/DCM 6%, 30 min) to N ¹ -(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoyi Soindoline-4-yl)-N ¹⁴ -((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)cover Moyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-3,6,9,12-tetraoxatetradecane-1,14-diamide (11 mg, 24%, ivory solid).

LC/MS (ESI) m/z [M+H] ⁺ : 935.5, [MH] ^- : 933.6

¹ H NMR (CDCl ₃ , 300 MHz) δ 10.50 (s, 1H), 8.87-8.79 (m, 1H), 8.68 (s, 1H), 7.76-7.67 (m, 1H), 7.59-7.52 (m, 1H) , 7.51-7.42 (m, 1H), 7.41-7.31 (m, 4H), 4.99-4.88 (m, 1H), 4.81-4.47 (m, 4H), 4.40-4.27 (m, 1H), 4.27-4.06 ( m, 4H), 4.06-3.95 (m, 2H), 3.79 (s, 3H), 3.75-3.52 (m, 12H), 2.90-2.59 (m, 3H), 2.56-2.38 (m, 4H), 2.22- 2.06 (m, 2H), 2.06-1.94 (m, 1H), 1.88-1.77 (m, 1H), 1.02-0.88 (m, 9H).

<Example 10> N ^One -(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)-N ⁵ -((S)-1-((2S,4R)-4-hydroxy-2-(4-(4-methylthiazol-5-yl)benzylcarbamoyl)pyrrolidin-1-yl)-3 Preparation of ,3-dimethyl-1-oxobutan-2-yl)glutaramide

Step 1: Preparation of 5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)-5-oxopentanoic acid

Dissolve amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (0.1 g, 0.37 mmol) in acetic acid (2 mL) and glutaric anhydride (0.046 g, 0.403 mmol) and potassium acetate (0.108 g, 1.1 mmol) were added, followed by stirring at 90°C for 2 hours. The reaction was terminated, and the reaction was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified to prepare a target compound.

1H NMR (300 MHz, DMSO) δ 11.14 (s, 1H), 9.72 (s, 1H), 8.44 (d, J = 8.4 Hz, 1H), 7.90-7.78 (m, 1H), 7.62 (d, J = 7.2 Hz, 1H), 5.15 (dd, J = 12.8, 5.4 Hz, 1H), 2.98-2.83 (m, 1H), 2.67-2.53 (m, 2H), 2.31 (t, J = 7.4 Hz, 2H), 2.24 (t, J = 7.4 Hz, 2H), 2.13-2.00 (m, 1H), 1.92-1.76 (m, 2H), 1.76-1.63 (m, 1H).

Step 2: N ^One -(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)-N ⁵ -((S)-1-((2S,4R)-4-hydroxy-2-(4-(4-methylthiazol-5-yl)benzylcarbamoyl)pyrrolidin-1-yl)-3 Preparation of ,3-dimethyl-1-oxobutan-2-yl)glutaramide

Compound prepared in Step 1 (25 mg, 0.048 mmol), (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4 -(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide hydrochloride (22 mg, 0.048 mmol) and HATU (27 mg, 0.072 mmol) were dissolved in DMF, followed by DIPEA (0.033 mL) , 0.192 mmol), and stirred at room temperature. After completion of the reaction, the mixture was concentrated, diluted with EA and water, the organic layer was extracted, washed with brine, and water was removed with MgSO4, and then concentrated under reduced pressure. Separation and purification using silica gel column chromatography (MPLC, MeOH/DCM 6%, 30 min) to N ¹ -(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoyi Soindoline-4-yl)-N ⁵ -((S)-1-((2S,4R)-4-hydroxy-2-(4-(4-methylthiazol-5-yl)benzylcarbamoyl) Pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)glutaramide is obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 10.25 (s, 0.5H), 10.03 (s, 0.5H), 8.77-8.63 (m, 2H), 7.72-7.61 (m, 1H), 7.61-7.48 (m , 2H), 7.36-7.29 (m, 4H), 6.85 (d, J = 9.0 Hz, 0.5H), 6.77 (d, J = 9.0 Hz, 0.5H), 4.95-4.84 (m, 1H), 4.69- 4.51 (m, 4H), 4.31-4.21 (m, 1H), 4.08-3.99 (m, 1H), 3.75-3.63 (m, 2H), 2.87-2.62 (m, 3H), 2.50 (s, 3H), 2.48-2.38 (m, 3H), 2.37-2.23 (m, 2H), 2.19-1.94 (m, 4H), 1.50-1.38 (m, 4H), 0.94 (s, 9H). LC/MS (ESI) m/z 800.3 [M+H] ⁺ , 798.2 [MH] ^-

<Example 11> N ^One -((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)methyl)-N ⁷ -((S)-1-((2S,4R)-4-hydroxy-2-(4-(4-methylthiazol-5-yl)benzylcarbamoyl)pyrrolidin-1-yl)-3 Preparation of ,3-dimethyl-1-oxobutan-2-yl)heptanediamide

In place of the glutaric anhydride used in Step 1 of Example 10, the target compound was prepared in a similar manner to Example 10, except that oxocan-2,8-dione was used.

¹ H NMR (500 MHz, CDCl ₃ ) δ 8.70 (d, J = 4.7 Hz, 1H), 7.81 (dd, J = 13.9, 6.2 Hz, 3H), 7.72 (t, J = 7.6 Hz, 1H), 7.44 -7.34 (m, 4H), 7.24-7.06 (m, 2H), 5.04-4.92 (m, 1H), 4.81-4.55 (m, 4H), 4.50 (m, 2H), 4.33 (td, J = 14.8, 4.9 Hz, 1H), 3.98 (t, J = 10.2 Hz, 1H), 3.62 (m, 1H), 2.85 (m, 2H), 2.80-2.58 (m, 1H), 2.52 (d, J = 5.7 Hz, 3H), 2.49-2.35 (m, 1H), 2.30-2.02 (m, 6H), 1.59-1.46 (m, 2H), 1.42 (m, 1H), 1.34-1.02 (m, 3H), 0.89 (d, J = 8.8 Hz, 9H); LC/MS (ESI) m/z 842 [M+H]+

<Example 12> (2S,4R)-1-((S)-2-(11-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole- 4-ylamino)undecanamido)-3.3-dimethylbutanyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide Manufacture of

The target compound was prepared in the same manner as in Example 1, except that 11-aminoundecanoic acid was used instead of 7-aminoheptanoic acid used in Step 1 of Example 1.

¹ H NMR (300 MHz, CDCl ₃ ) δ 9.92 (s, 0.5H), 9.86 (s, 0.5H), 8.69 (s, 1H), 7.56-7.44 (m, 2H), 7.40-7.30 (m, 4H ), 7.08 (d, J = 7.1 Hz, 1H), 6.92-6.84 (m, 1H), 6.67-6.55 (m, 1H), 6.30-6.20 (m, 1H), 4.96-4.79 (m, 1H), 4.73-4.47 (m, 4H), 4.36-4.23 (m, 1H), 4.15-4.04 (m, 1H), 3.67-3.57 (m, 1H), 3.33-3.19 (m, 2H), 2.89-2.59 (m , 3H), 2.57-2.46 (m, 4H), 2.22-1.98 (m, 4H), 1.70-1.59 (m, 2H), 1.59-1.47 (m, 2H), 1.47-1.36 (s, 2H), 1.36 -1.14 (m, 12H), 0.98-0.80 (m, 9H). LC/MS (ESI) m/z 871.7 [M+H] ⁺ , 869.8 [MH] ^-

<Example 13> (2S,4R)-1-((S)-2-(8-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole- 4-ylamino)octanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carbox Preparation of amide

The target compound was prepared in the same manner as in Example 1, except that 8-aminooctanoic acid was used instead of 7-aminoheptanoic acid used in Step 1 of Example 1.

¹ H NMR (300 MHz, CDCl ₃ ) δ 10.63 (s, 0.5H), 9.63 (s, 0.5H), 8.68 (s, 1H), 7.76-7.67 (m, 0.5H), 7.55-7.44 (m, 1.5H), 7.41-7.29 (m, 4H), 7.12-7.04 (m, 1H), 6.95-6.84 (m, 1.5H), 6.57 (d, J = 9.1 Hz, 0.5H), 6.32-6.21 (m , 1H), 4.96-4.82 (m, 1H), 4.72-4.50 (m, 4H), 4.36-4.22 (m, 1H), 4.17-4.03 (m, 1H), 3.63 (dd, J = 11.4, 3.5 Hz , 1H), 3.40-3.18 (m, 2H), 2.88-2.60 (m, 3H), 2.58-2.44 (m, 4H), 2.25-1.98 (m, 4H), 1.84-1.70 (m, 2H), 1.70 -1.50 (m, 4H), 1.50-1.19 (m, 5H), 0.99-0.80 (m, 9H). LC/MS (ESI) m/z 829.7 [M+H] ⁺ , 827.8 [MH] ^-

<Example 14> (2S,4R)-1-((S)-2-(12-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole- 4-ylamino)dodecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-car Preparation of Voxamide

The target compound was prepared in the same manner as in Example 1, except that 12-aminododecanoic acid was used instead of the 7-aminoheptanoic acid used in Step 1 of Example 1.

¹ H NMR (300 MHz, CDCl ₃ ) δ 10.14 (s, 0.5H), 9.96 (s, 0.5H), 8.69 (s, 1H), 7.64-7.42 (m, 2H), 7.42-7.30 (m, 4H ), 7.13-7.03 (m, 1H), 6.87 (d, J = 8.6 Hz, 1H), 6.71 (d, J = 9.0 Hz, 0.5H), 6.62 (d, J = 9.0 Hz, 0.5H), 6.24 (s, 1H), 4.96-4.76 (m, 1H), 4.72-4.48 (m, 3H), 4.36-4.21 (m, 1H), 4.12-4.00 (m, 1H), 3.70-3.58 (m, 1H) , 3.34-3.19 (m, 2H), 2.88-2.58 (m, 3H), 2.58-2.40 (m, 4H), 2.22-1.94 (m, 4H), 1.72-1.47 (m, 4H), 1.47-1.08 ( m, 14H), 0.99-0.77 (m, 9H). LC/MS (ESI) m/z 885.7 [M+H] ⁺ , 883.7 [MH] ^-

<Example 15> (2S,4R)-1-((S)-2-(2-(6-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoyi Soindoline-4-ylamino)hexyloxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pi Preparation of lollidine-2-carboxamide

The target compound was prepared in the same manner as in Example 1, except that 2-(6-aminohexyloxy)acetic acid was used instead of 7-aminoheptanoic acid used in Step 1 of Example 1.

¹ H NMR (300 MHz, CDCl ₃ ) δ 9.42 (s, 0.5H), 9.19 (s, 0.5H), 8.69 (s, 1H), 7.54-7.38 (m, 2H), 7.38-7.30 (m, 4H ), 7.25-7.17 (m, 1H), 7.07 (d, J = 7.1 Hz, 1H), 6.86 (d, J = 8.5 Hz, 1H), 6.32-6.19 (m, 1H), 4.97-4.84 (m, 1H), 4.76-4.63 (m, 1H), 4.61-4.44 (m, 3H), 4.38-4.24 (m, 1H), 4.07 (d, J = 10.9 Hz, 1H), 3.91 (s, 2H), 3.69 -3.59 (m, 1H), 3.56-3.37 (m, 3H), 3.33-3.18 (m, 2H), 2.89-2.62 (m, 3H), 2.56-2.39 (m, 4H), 2.19-2.01 (m, 2H), 1.93 (s, 1H), 1.76-1.53 (m, 4H), 1.53-1.34 (m, 4H), 0.95 (s, 9H). LC/MS (ESI) m/z 844.8 [M+H] ⁺ , 842.7 [MH] ^-

<Example 16> (2S,4R)-1-((S)-2-(10-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole- 4-ylamino)decanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carbox Preparation of amide

The target compound was prepared in the same manner as in Example 1, except that 10-aminodecanoic acid was used instead of the 7-aminoheptanoic acid used in Step 1 of Example 1.

¹ H NMR (300 MHz, CDCl ₃ ) δ 10.24 (s, 0.5H), 10.16 (s, 0.5H), 7.65-7.53 (m, 1H), 7.48 (t, J = 7.8 Hz, 1H), 7.42- 7.30 (m, 4H), 7.07 (d, J = 7.1 Hz, 1H), 6.88 (d, J = 8.5 Hz, 1H), 6.71 (dd, J = 9.1, 6.7 Hz, 1H), 6.31-6.18 (m , 1H), 4.97-4.81 (m, 1H), 4.73-4.49 (m, 4H), 4.36-4.24 (m, 1H), 4.11-4.03 (m, 1H), 3.68-3.57 (m, 1H), 3.35 -3.21 (m, 2H), 2.88-2.58 (m, 3H), 2.56-2.43 (m, 4H), 2.22-2.08 (m, 3H), 1.99-1.81 (m, 2H), 1.73-1.60 (m, 2H), 1.60-1.45 (m, 2H), 1.45-1.37 (m, 2H), 1.37-1.12 (m, 10H), 0.99-0.77 (m, 9H). LC/MS (ESI) m/z 857.1 [M+H] ⁺ , 855.0 [MH] ^-

<Example 17> (2S,4R)-1-((S)-2-tert-butyl-14-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoyi Soindoline-4-ylamino)-4-oxo-6,9,12-trioxa-3-azatetradeca-1-noyl)-4-hydroxy-N-(4-(4-methylthiazole- Preparation of 5-yl)benzyl)pyrrolidine-2-carboxamide

In place of tert-butyl 14-iodo-3,6,9,12-tetraoxatetradeca-1-noate, used in step 1 of Example 4 above, tert-butyl 2-(2-(2- Except that (2-iodoethoxy)ethoxy)ethoxy)acetate was used, the same procedure as in Example 4 was carried out to prepare the target compound.

¹ H NMR (300 MHz, CDCl ₃ ) δ 9.81-9.72 (m, 1H), 8.70 (s, 1H), 7.57-7.46 (m, 2H), 7.41-7.31 (m, 5H), 7.11 (d, J = 7.1 Hz, 1H), 6.90 (d, J = 8.5 Hz, 1H), 6.54 (d, J = 4.1 Hz, 1H), 4.95-4.82 (m, 1H), 4.76-4.66 (m, 1H), 4.66 -4.50 (m, 3H), 4.38-4.27 (m, 1H), 4.19-3.92 (m, 3H), 3.78-3.59 (m, 11H), 3.51-3.37 (m, 2H), 2.90-2.62 (m, 3H), 2.53 (d, J = 1.2 Hz, 3H), 2.52-2.41 (m, 1H), 2.22-2.09 (m, 1H), 1.91 (brs, merged with H2O, 1H), 0.97 (s, 9H) . LC/MS (ESI) m/z 877.1 [M+H] ⁺ , 875.0 [MH] ^-

<Example 18> (2S,4R)-1-((S)-2-(11-((3-(2,6-dioxopiperidin-3-yl)-2-methyl-4-oxo- 3,4-dihydroquinazolin-5-yl)amino)undecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl )Benzyl) Preparation of pyrrolidine-2-carboxamide

Instead of the 7-aminoheptanoic acid used in Step 1 of Example 1, 11-aminoundecanoic acid was used, and 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindole Except that 3-(5-fluoro-2-methyl-4-oxoquinazoline-3(4H)-yl)piperidine-2,6-dione was used instead of -1,3-dione , Was carried out as in Example 1 to prepare a target compound.

¹ H NMR (300 MHz, CD ₃ OD) δ 8.89 (s, 1H), 7.85-7.77 (m, 1H), 7.54-7.40 (m, 4H), 6.69 (d, J = 7.9 Hz, 1H), 6.55 (d, J = 8.5 Hz, 1H), 5.21-5.13 (m, 1H), 4.69-4.63 (m, 1H), 4.63-4.48 (m, 3H), 4.42-4.32 (m, 1H), 3.92 (d , J = 11.1 Hz, 1H), 3.82 (dd, J = 11.0, 3.9 Hz, 1H), 3.20 (t, J = 6.9 Hz, 2H), 2.92-2.70 (m, 4H), 2.63 (s, 3H) , 2.49 (s, 3H), 2.34-2.16 (m, 5H), 2.16-2.06 (m, 1H), 1.76-1.55 (m, 5H), 1.50-1.41 (m, 3H), 1.41-1.31 (m, 12H), 1.05 (s, 9H), 0.95-0.89 (m, 1H). LC/MS (ESI) m/z 884.1 [M+H] ⁺ , 882.1 [MH] ^-

<Example 19> 4,4'-(nonane-1,9-diylbis(azanediyl))bis(2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3 -Dion)

Step 1: Preparation of tert-butyl (9-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)nonyl)carbamate

tert-butyl (9-aminononyl)carbamate (212 mg, 0.82 mmol), 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindole-1,3-dione ( 227 mg, 0.82 mmol) and DIPEA (0.429 mL, 2.46 mmol) were dissolved in DMF (3 mL) and heated at 90°C. The reaction was diluted with ethyl acetate solution, and then washed with water. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, concentrated, and purified by column chromatography to obtain the target compound.

¹ H NMR (300 MHz, CDCl ₃ )δ8.14(s,1H),7.49(dd,J = 8.5, 7.1 Hz, 1H), 7.09 (d, J = 7.0 Hz, 1H), 6.88 (d, J = 8.6 Hz, 1H), 6.23 (t, J = 5.5 Hz, 1H), 4.97-4.86 (m, 1H), 4.52 (s, 1H), 3.26 (q, J = 6.6 Hz, 2H), 3.10 (q , J = 6.5 Hz, 2H), 2.94-2.65 (m, 3H), 2.19-2.09 (m, 1H), 1.72-1.63 (m, 2H), 1.55-1.38 (m, 13H), 1.38-1.23 (m , 8H).

Step 2: Preparation of 4-((9-aminononyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione hydrochloride

tert-butyl (9-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)nonyl)carbamate (0.112 g, 0.218 mmol) ), 4 N HCl/1,4-dioxane solution (2 mL), dichloromethane (1 mL) The mixed solution was stirred at room temperature, and then concentrated to 4-((9-aminononyl)amino)-2- (2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione hydrochloride was obtained.

Step 3: 4,4'-(nonane-1,9-diylbis(azanediyl))bis(2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione )

4-((9-aminononyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione hydrochloride (63 mg, 0.14 mmol), 2-( 2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (39 mg, 0.14 mmol), DIPEA (0.073 mL, 0.42 mmol) dissolved in DMF (1 mL) Then, it is heated at 90°C. The reaction was diluted with water, extracted with ethyl acetate and washed with brine. The organic layer was dried and concentrated with anhydrous magnesium sulfate, and then separated and purified by column chromatography to obtain 4,4'-(nonane-1,9-diylbis(azanediyl))bis(2-(2,6-dioxophyte) Peridin-3-yl)isoindoline-1,3-dione) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.42 (s, 1H), 8.29 (s, 1H), 7.48 (dd, J = 8.5, 7.1 Hz, 2H), 7.08 (d, J = 7.1 Hz, 2H) , 6.87 (d, J = 8.5 Hz, 2H), 6.24 (t, J = 5.5 Hz, 2H), 4.97-4.86 (m, 2H), 3.26 (q, J = 6.6 Hz, 4H), 2.92-2.66 ( m, 6H), 2.18-2.08 (m, 2H), 1.72-1.59 (m, 4H), 1.49-1.30 (m, 10H). LC/MS (ESI) m/z 671.8 [M+H] ⁺ , 669.0 [MH] ^-

<Example 20> (2S,4R)-1-((S)-2-(11-(2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoyi Soindolin-4-ylamino)acetamido)undecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl) Preparation of pyrrolidine-2-carboxamide

Step 1: Preparation of tert-butyl 11-aminoundecanoate

A solution of 11-aminoundecanoic acid (500 mg, 2.48 mmol) in thionyl chloride (24.80 ml, 24.8 mmol) was stirred at room temperature for 1.5 hours, after which excess thionyl chloride was removed under vacuum. To this residue was added a solution of NaHCO ₃ (458 mg, 5.45 mmol) in tBuOH (6 ml) under stirring, and the reaction mixture was stirred overnight at room temperature. The volatiles were removed under vacuum, and the residue was taken into EtOAc (30 ml) and NaOH (1M, aqueous) (20 ml). The combined organic layer was washed with water (30 ml) and brine (20 ml × 3), dried over MgSO ₄ and the solvent removed in vacuo to give the desired compound of step 1 (521 mg, 2.02 mmol, 81%) as a yellow transparent. Obtained as an oil.

Step 2: tert-Butyl 11-(2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-ylamino)acetamido)undecanoate Manufacture of

To a solution of the compound (50 mg, 0.194 mmol) prepared in step 1 above in DMF, 4-glycine thalidomide (64 mg, 0.194 mmol), HATU (110 mg, 0.291 mmol), DIPEA (0.135 mL, 0.776 mmol) It was added and stirred at room temperature for 2 hours. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layer was washed with brine, dried over MgSO ₄ and the solvent was removed in vacuo to give an oil. The crude mixture was purified by silica gel column chromatography using EtOAc/Hex=55% to give the desired compound of step 2 (71 mg, mixture) as a yellow solid.

Step 3: Preparation of 11-(2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-ylamino)acetamido)undecanoic acid

To a solution of the compound (71 mg, 0.124 mmol) prepared in step 2 above in DCM (2 ml), TFA (2 ml) was added and the resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated in vacuo to an oil. The crude mixture was purified by silica gel column chromatography using DCM/MeOH=7% to give the desired compound of step 3 (44mg, 0.085mmol, 44% during steps 2-3) as a yellow solid.

Step 4: (2S,4R)-1-((S)-2-(11-(2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole -4-ylamino)acetamido)undecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolid Preparation of Dean-2-carboxamide

To the solution of the compound (30mg, 0.058mmol) prepared in step 3 above in DMF, VHL ligand (27mg, 0.058mmol), HATU (33mg, 0.087mmol), DIPEA (0.040mL, 0.232mmol) were added overnight at room temperature. It was stirred. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layer was washed with brine, dried over MgSO ₄ and the solvent was removed in vacuo to give an oil. The crude mixture was purified on PREP TLC using MeOH / DCM = 5% to give the final target compound (10mg, 0.011mmol, 18%) as a yellow solid.

¹ H NMR (500 MHz, Chloroform- d ) δ 8.68 (d, J = 6.2 Hz, 1H), 7.62-7.52 (m, 2H), 7.40-7.32 (m, 4H), 7.22 (t, J = 7.8 Hz , 1H), 6.84 (t, J = 7.8 Hz, 1H), 6.70-6.56 (m, 2H), 4.93-4.84 (m, 1H), 4.72-4.53 (m, 4H), 4.31-4.22 (m, 1H) ), 4.08 (d, J = 11.5 Hz, 1H), 4.05-3.87 (m, 2H), 3.70-3.62 (m, 1H), 2.86-2.60 (m, 3H), 2.50 (s, 3H), 2.50- 2.44 (m, 1H), 2.22-2.01 (m, 4H), 1.60-1.48 (m, 2H), 1.49-1.38 (m, 2H), 1.34-1.23 (m, 3H), 1.23-0.97 (m, 13H) ), 0.93 (s, 9H). , LC/MS (ESI) m/z 927.2 [M + H] ⁺ , 925.1 [M-H] ^-

<Example 21> (2S,4R)-1-((S)-2-(11-(2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoyi Soindolin-4-yloxy)acetamido)undecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl) Preparation of pyrrolidine-2-carboxamide

Step 1: Preparation of tert-butyl 11-aminoundecanoate

A solution of 11-aminoundecanoic acid (500 mg, 2.48 mmol) in thionyl chloride (24.80 ml, 24.8 mmol) was stirred at room temperature for 1.5 hours, after which excess thionyl chloride was removed under vacuum. To this residue was added a solution of NaHCO ₃ (458 mg, 5.45 mmol) in tBuOH (6 ml) under stirring, and the reaction mixture was stirred overnight at room temperature. The volatiles were removed under vacuum, and the residue was taken into EtOAc (30 ml) and NaOH (1M, aqueous) (20 ml). The combined organic layer was washed with water (30 ml) and brine (20 ml × 3), dried over MgSO ₄ and the solvent removed in vacuo to give the desired compound of step 1 (521 mg, 2.02 mmol, 81%) as a yellow transparent. Obtained as an oil.

Step 2: tert-Butyl 11-(2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yloxy)acetamido)undecanoate Manufacture of

To a solution of the compound (50 mg, 0.194 mmol) prepared in step 1 above in DMF, 4-glycolic acid thalidomide (64 mg, 0.194 mmol), HATU (110 mg, 0.291 mmol), DIPEA (0.135 mL, 0.776 mmol) Was added and stirred at room temperature for 2 hours. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layer was washed with brine, dried over MgSO ₄ and the solvent was removed in vacuo to give an oil. The crude mixture was purified by silica gel column chromatography using EtOAc/Hex=55% to give the desired compound of step 2 (48 mg, mixture) as a beige solid.

Step 3: Preparation of 11-(2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yloxy)acetamido)undecanoic acid

To a solution of the compound (48 mg, 0.084 mmol) prepared in step 2 above in DCM (1 ml), TFA (1 ml) was added and the resulting mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated in vacuo to an oil. The crude mixture was purified by silica gel column chromatography using DCM/MeOH = 7% to give the desired compound of step 3 (29mg, 0.056mmol, 29% during steps 2-3) as a white solid.

Step 4: (2S,4R)-1-((S)-2-(11-(2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole -4-yloxy)acetamido)undecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolid Preparation of Dean-2-carboxamide

To the solution of the compound (30mg, 0.058mmol) prepared in step 3 above in DMF, VHL ligand (27mg, 0.058mmol), HATU (33mg, 0.087mmol), DIPEA (0.040mL, 0.232mmol) were added overnight at room temperature. It was stirred. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layer was washed with brine, dried over MgSO ₄ and the solvent was removed in vacuo to give an oil. The crude mixture was purified on PREP TLC using MeOH / DCM = 5% to give the final target compound (13mg, 0.014mmol, 24%) as a white solid.

¹ H NMR (500 MHz, Chloroform- d ) δ8.71-8.66 (m, 1H), 7.73 (q, J = 7.4 Hz, 1H), 7.63-7.60 (m, 0.5 H), 7.55-7.50 (m, 1.5H), 7.45 (t, J = 5.2 Hz, 1H), 7.38-7.30 (m, 4H), 7.23-7.17 (m, 0.5H), 4.97-4.90 (m, 0.5H), 4.87-4.80 (m , 1H), 4.70-4.51 (m, 6H), 4.32-4.18 (m, 1H), 4.12 (d, J = 11.6 Hz, 1H), 3.67-3.58 (m, 1H), 3.54-3.43 (m, 1H) ), 3.35-3.24 (m, 1H), 2.93-2.63 (m, 3H), 2.56-2.45 (m, 4H), 2.24-2.05 (m, 4H), 1.63-1.56 (m, 2H), 1.56-1.47 (m, 2H), 1.46-1.13 (m, 14H), 0.93 (s, 9H). , LC/MS (ESI) m/z 928.1 [M + H] ⁺ , 926.1 [M-H] ^-

<Example 22> (2S,4R)-1-((S)-2-(11-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole- 5-ylamino)undecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-car Preparation of Voxamide

Step 1: Preparation of tert-butyl 11-aminoundecanoate

A solution of 11-aminoundecanoic acid (500 mg, 2.48 mmol) in thionyl chloride (24.80 ml, 24.8 mmol) was stirred at room temperature for 1.5 hours, after which excess thionyl chloride was removed under vacuum. To this residue was added a solution of NaHCO ₃ (458 mg, 5.45 mmol) in tBuOH (6 ml) under stirring, and the reaction mixture was stirred overnight at room temperature. The volatiles were removed under vacuum, and the residue was taken into EtOAc (30 ml) and NaOH (1M, aqueous) (20 ml). The combined organic layer was washed with water (30 ml) and brine (20 ml × 3), dried over MgSO ₄ and the solvent removed in vacuo to give the desired compound of step 1 (521 mg, 2.02 mmol, 81%) as a yellow transparent. Obtained as an oil.

Step 2: Preparation of tert-butyl 11-(2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-ylamino)undecanoate

To a solution of the compound (86 mg, 0.334 mmol) prepared in step 1 above in DMSO, 5-F-thalidomide (61 mg, 0.223 mmol) and DIPEA (0.058 mL, 0.334 mmol) were added and stirred at 90°C overnight. Did. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layer was washed with brine, dried over MgSO ₄ and the solvent was removed in vacuo to give an oil. The crude mixture was purified by silica gel column chromatography using EtOAc/Hx=37% to give the desired compound of step 2 (38 mg, mixture) as a yellow solid.

Step 3: Preparation of 11-(2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-ylamino)undecanoic acid

To a solution of the compound (38 mg, 0.074 mmol) prepared in step 2 above in DCM (1 ml), TFA (1 ml) was added and the resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated in vacuo to an oil. The crude mixture was purified by silica gel column chromatography using DCM/MeOH=7% to give the desired compound of step 3 (12mg, 0.026mmol, 11% during steps 2-3) as a yellow solid.

Step 4: (2S,4R)-1-((S)-2-(11-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5- Ilamino)undecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide Manufacture of

To a solution of the compound (12mg, 0.026mmol) prepared in step 3 above in DMF, VHL-ligand (12mg, 0.026mmol), HATU (15mg, 0.039mmol), DIPEA (0.018mL, 0.104mmol) was added, and at room temperature Stir overnight. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layer was washed with brine, dried over MgSO ₄ and the solvent was removed in vacuo to give an oil. The crude mixture was purified on PREP TLC using MeOH / DCM = 5% to give the final target compound (12mg, 0.014mmol, 53%) as a yellow solid.

¹ H NMR (500 MHz, Chloroform- d ) δ8.68 (s, 1H), 7.66-7.61 (m, 0.5H), 7.59 (d, J = 8.2 Hz, 1H), 7.52 (t, J = 6.3 Hz , 0.5H), 7.39-7.32 (m, 4H), 6.98-6.93 (m, 1H), 6.79-6.77 (m, 0.5H), 6.73 (d, J = 8.4 Hz, 1H), 6.56-6.54 (m , 0.5H), 4.96-4.87 (m, 1H), 4.72 (t, J = 5.0 Hz, 1H), 4.70-4.65 (m, 1H), 4.65-4.57 (m, 1H), 4.57-4.50 (m, 2H), 4.12-4.04 (m, 1H), 3.68-3.60 (m, 1H), 2.91-2.61 (m, 3H), 2.56-2.46 (m, 4H), 2.21-2.05 (m, 4H), 1.62 ( p, J = 7.2 Hz, 2H), 1.58-1.48 (m, 2H), 1.43-1.29 (m, 5H), 1.30-1.11 (m, 11H), 0.91 (s, 9H).

<Example 23> 3,3'-(5,5'-(nonane-1,9-diylbis(azandiyl))bis(4-oxobenzo[d][1,2,3]triazine- Preparation of 5,3(4H)-diyl))dipiperidine-2,6-dione

In place of 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione, used in steps 1 and 4 of Example 19 above, application number 10- 3-(5-amino-4-oxobenzo[d][1,2,3]triazine-3(4H)-yl)piperidine-2,6-prepared as known from 2017-0184761 Except that dione was used, the same procedure as in Example 19 was carried out to prepare a target compound.

¹ H NMR (300 MHz, CDCl ₃ )δ8.74(s,1H),8.68(s,1H),8.15(t,J = 5.2 Hz, 2H), 7.67 (t, J = 8.2 Hz, 2H), 7.24 (d, J = 7.7 Hz, 2H), 6.77 (d, J = 8.5 Hz, 2H), 5.74-.64 (m, 2H), 3.25-.13 (m, 4H), 3.00-.84 (m , 6H), 2.41-.28 (m, 2H), 1.76-.62 (m, 6H), 1.49-.29 (m, 11H), 0.95-.79 (m, 1H).

<Example 24> 2-(2,6-dioxopiperidin-3-yl)-4-(9-(3-(2,6-dioxopiperidin-3-yl)-4-oxo-3 Preparation of ,4-dihydrobenzo[d][1,2,3]triazin-5-ylamino)nonylamino)isoindoline-1,3-dione

In place of 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione, used in step 1 of Example 19 above, application number 10-2017-0184761 3-(5-amino-4-oxobenzo[d][1,2,3]triazine-3(4H)-yl)piperidine-2,6-dione, prepared as known in the heading, Except for the point, it was carried out as in Example 19 above to prepare the target compound.

¹ H NMR (300 MHz, CDCl ₃ )δ8.452 (d,J = 6.1 Hz, 2H), 8.15 (s, 1H), 7.68 (t, J = 8.1 Hz, 1H), 7.48 (dd, J = 8.5 , 7.1 Hz, 1H), 7.24 (dd, J = 7.9, 0.8 Hz, 2H), 7.08 (d, J = 7.0 Hz, 1H), 6.88 (d, J = 8.5 Hz, 1H), 6.78 (d, J = 8.5 Hz, 1H), 6.24 (t, J = 5.6 Hz, 1H), 5.73-5.62 (m, 1H), 4.96-4.86 (m, 1H), 3.30-3.15 (m, 4H), 3.01-2.69 ( m, 6H), 2.39-2.29 (m, 1H), 2.17-2.08 (m, 1H), 1.75-1.61 (m, 4H), 1.49-1.30 (m, 10H).

<Example 25> (2S,4R)-1-((S)-2-(11-(3-(2,6-dioxopiperidin-3-yl)-4-oxo-3,4-di Hydrobenzo[d][1,2,3]triazine-5-ylamino)undecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthia Preparation of zol-5-yl)benzyl)pyrrolidine-2-carboxamide

Instead of the 7-aminoheptanoic acid used in Step 1 of Example 1, 11-aminoundecanoic acid was used, and 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindole In place of -1,3-dione, 3-(5-amino-4-oxobenzo[d][1,2,3]triazine-3, prepared as known from application number 10-2017-0184761 (4H)-yl) was carried out as in Example 1, except that the piperidine-2,6-dione was used to prepare the target compound.

¹ H NMR (300 MHz, CDCl ₃ )δ10.17(s,0.5H),9.74(s,0.5H),8.68(s,1H),8.25-8.13(m,1H),7.67(t,J = 8.1 Hz, 1H), 7.58-7.50 (m, 0.5H), 7.46 (t, J = 5.5 Hz, 0.5H), 7.40-7.30 (m, 4H), 7.23 (d, J = 7.7 Hz, 1H), 6.80-6.70 (m, 1.5H), 6.50 (d, J = 8.7 Hz, 1H), 5.72-5.62 (m, 0.5H), 5.56-5.46 (m, 0.5H), 4.72-4.50 (m, 4H) , 4.36-4.20 (m, 1H), 4.18-4.06 (m, 1H), 3.68-3.58 (m, 1H), 3.29 (s, 0.5H), 3.26-3.14 (m, 2.5H), 2.99-2.67 ( m, 3H), 2.58-2.45 (m, 4H), 2.37-2.23 (m, 1H), 2.23-2.07 (m, 3H), 1.61-1.49 (m, 2H), 1.49-1.38 (m, 2H), 1.38-1.16 (m, 12H), 0.98-0.87 (m, 9H).

The chemical structural formulas of the compounds prepared in Examples 1-25 are shown in Table 1 below.

Example constitutional formula Example constitutional formula One

14

2

15

3

16

4

17

5

18

6

19

7

20

8

21

9

22

10

23

11

24

12

25

13

<Experimental Example 1> Evaluation of cerebron (CRBN) proteolytic activity

In order to evaluate the cerebron (CRBN) proteolytic activity of the compound according to the present invention, experiments were conducted as follows.

Specifically, 5 x 10 ⁵ HEK293T cells were injected into each well of a 12-well plate. The next day, each well was treated with Example Compounds 1-22 to a final concentration of 10 nM, 30 nM, 100 nM, 300 nM, 1 μM, 3 μM, 10 μM. One well was treated with the same percentage of DMSO. After 24 hours of treatment, cells were collected and Western blotting was performed using NP40 Lysis buffer (20mM Tris, pH7.5, 150mM NaCl, 1% NP-40, 1mM EDTA, and protease inhibitor cocktail) to make cell lysates. And the results are shown in Table 2 below.

In addition, the results of analysis of cerebron protein for Examples 1, 3, and 8 are shown in FIG. 1, and the results of evaluating the decomposition ability of cerebron protein according to the concentrations of compounds treated in Examples 1, 3, and 8 (DC ₅₀ ) are shown in FIG. 2. Did.

Example Cerebron (CRBN) decomposition activity Example Cerebron (CRBN) decomposition activity One ++ 14 ++ 2 ++ 15 + 3 ++ 16 ++ 4 ++ 17 + 5 + 18 + 6 + 19 ++ 7 + 20 ++ 8 + 21 + 9 + 22 ++ 10 + 23 ++ 11 + 24 ++ 12 ++ 25 ++ 13 ++

++: decomposition to more than 50% at 300 nM concentration (> 50%) +: decomposition to less than 50% at 300 nM concentration (< 50%)

Looking at Table 2, the example compound according to the present invention can excellently decompose Celebron (CRBN) protein at a concentration of 300 nM, in particular Examples 1, 2, 3, 4, 12, 13, 14, 16 , 19, 20, 22, 23, 24, and 25 compounds can be seen that exhibit a decomposition activity of more than 50% at a concentration of 300 nM.

Therefore, the compound according to the present invention can excellently decompose celebrity (CRBN) protein to a concentration of nanomolar units, from which it can be effectively used for the prevention and treatment of cerebron (CRBN) related diseases.

Claims (10)

A compound represented by A-Linker-A or A-Linker-B, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
A is a cereblon E3 ubiquitin ligase binding moiety; And
The B is an E3 ubiquitin ligase binding moiety,
The cereblon E3 ubiquitin ligase binding moiety is

,

,

, or

ego,
Wherein R ¹ is -(CH ₂ ) _n -NR ³ -, -(CH ₂ ) _n -O-, -O-(CH ₂ ) _n -(C=O)-NR ³ -or -NR ³ -( CH ₂ ) _n -(C=O)-NR ³ -,
Here again, n is an integer from 0 to 2,
R ² and R ³ are each H;

The E3 ubiquitin ligase binding moiety

This,
Wherein R ² and R ³ are each H; And

The Linker,

This,
Where a and i are independently 0 or 1;
B is an integer of 0-3;
C is 0 or 1;
D is an integer of 0-3;
E is 0 or 1;
F is an integer of 1-5;
G is 0 or 1;
H is an integer of 0-3;
J and k are independently an integer of 0-5, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
delete According to claim 1,
The Linker,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

, or

A compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
delete According to claim 1,
The compound represented by A-Linker-A or A-Linker-B is a compound selected from the group consisting of the following compounds, stereoisomers thereof, or pharmaceutically acceptable salts thereof:
(1) (2S,4R)-1-((S)-2-(7-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- 1amino)heptanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;
(2) (2S,4R)-1-((S)-2-(6-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- Ylamino)hexaneamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;
(3) (2S,4R)-1-((S)-2-(9-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- 1amino)nonanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;
(4) (2S,4R)-1-((S)-2-tert-butyl-17-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole -4-ylamino)-4-oxo-6,9,12,15-tetraoxa-3-azaheptadeca-1-noyl)-4-hydroxy-N-(4-(4-methylthiazole- 5-yl)benzyl)pyrrolidine-2-carboxamide;
(5) (2S,4R)-1-((S)-2-(2-(3-(2-(2-(2,6-dioxopiperidin-3-yl)-1,3-di Oxoisoindoline-4-ylamino)-2-oxoethoxy)propoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazole- 5-yl)benzyl)pyrrolidine-2-carboxamide;
(6) N ¹ -(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)-N ⁹ -((S)-1-(( 2S,4R)-4-hydroxy-2-(4-(4-methylthiazol-5-yl)benzylcarbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutane- 2-yl)nonanediamide;
(7) N ¹ -(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)-N ⁸ -((S)-1-(( 2S,4R)-4-hydroxy-2-(4-(4-methylthiazol-5-yl)benzylcarbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutane- 2-yl)octanediamide;
(8) N ¹ -(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)-N ⁷ -((S)-1-(( 2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxo Butan-2-yl)heptanediamide;
(9) N ¹ -(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)-N ¹⁴ -((S)-1-(( 2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxo Butan-2-yl)-3,6,9,12-tetraoxatetradecane-1,14-diamide;
(10) N ¹ -(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)-N ⁵ -((S)-1-(( 2S,4R)-4-hydroxy-2-(4-(4-methylthiazol-5-yl)benzylcarbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutane- 2-yl)glutaramide;
(11) N ¹ -((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)methyl)-N ⁷ -((S)-1 -((2S,4R)-4-hydroxy-2-(4-(4-methylthiazol-5-yl)benzylcarbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1- Oxobutan-2-yl)heptanediamide;
(12) (2S,4R)-1-((S)-2-(11-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- 1amino)undecanamido)-3.3-dimethylbutanyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;
(13) (2S,4R)-1-((S)-2-(8-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- Ylamino)octaneamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;
(14) (2S,4R)-1-((S)-2-(12-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- Ilamino)dodecaneamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide ;
(15) (2S,4R)-1-((S)-2-(2-(6-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole -4-ylamino)hexyloxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine -2-carboxamide;
(16) (2S,4R)-1-((S)-2-(10-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- 1amino)decanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;
(17) (2S,4R)-1-((S)-2-tert-butyl-14-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole -4-ylamino)-4-oxo-6,9,12-trioxa-3-azatetradeca-1-noyl)-4-hydroxy-N-(4-(4-methylthiazole-5- 1)benzyl)pyrrolidine-2-carboxamide;
(18) (2S,4R)-1-((S)-2-(11-((3-(2,6-dioxopiperidin-3-yl)-2-methyl-4-oxo-3, 4-dihydroquinazolin-5-yl)amino)undecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl )Pyrrolidine-2-carboxamide;
(19) 4,4'-(nonane-1,9-diylbis(azanediyl))bis(2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione );
(20) (2S,4R)-1-((S)-2-(11-(2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole -4-ylamino)acetamido)undecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolid Dean-2-carboxamide;
(21) (2S,4R)-1-((S)-2-(11-(2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole -4-yloxy)acetamido)undecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolid Dean-2-carboxamide;
(22) (2S,4R)-1-((S)-2-(11-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5- Ilamino)undecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide ;
(23) 3,3'-(5,5'-(nonane-1,9-diylbis(azanediyl))bis(4-oxobenzo[d][1,2,3]triazine-5, 3(4H)-diyl))dipiperidine-2,6-dione;
(24) 2-(2,6-dioxopiperidin-3-yl)-4-(9-(3-(2,6-dioxopiperidin-3-yl)-4-oxo-3,4 -Dihydrobenzo[d][1,2,3]triazin-5-ylamino)nonylamino)isoindoline-1,3-dione; And
(25) (2S,4R)-1-((S)-2-(11-(3-(2,6-dioxopiperidin-3-yl)-4-oxo-3,4-dihydrobenzo [d][1,2,3]triazin-5-ylamino)undecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazole- 5-yl)benzyl)pyrrolidine-2-carboxamide.
As shown in Scheme 1 below,
Preparing a compound represented by A-Linker-V from the compound represented by U-Linker-V (step 1);
Preparing a compound represented by A-Linker-A or A-Linker-B from the compound represented by A-Linker-V prepared in step 1 (step 2); A-Linker of claim 1 comprising a Method for preparing a compound represented by A or A-Linker-B:
[Scheme 1]

(In Scheme 1,
A, Linker and B are as defined in claim 1; And
U or V are each independently NH ₂ or OH).
delete A pharmaceutical composition for preventing or treating cancer comprising the compound of claim 1, a stereoisomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.
A pharmaceutical composition for the prevention or treatment of an autoimmune disease comprising the compound of claim 1, a stereoisomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.
A pharmaceutical composition for the prevention or treatment of metabolic diseases comprising the compound of claim 1, a stereoisomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.

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