KR20190044499A - 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 cereblon protein degradation inducing compound, a method for manufacturing the same, and a pharmaceutical composition for preventing or treating cancer containing the same as an active component. A novel compound, represented by A-Linker-A or A-Linker-B according to the present invention, can remarkably inhibit or degrade cereblon, and thus, by containing the same as the active component, the present invention has an effect of being useful as the pharmaceutical composition for preventing or treating cereblon-related diseases, preferably diseases which have effects of treatment, prevention or alleviation by inhibiting or degrading cereblon such as cancer, autoimmune diseases or metabolic diseases.

Description

TECHNICAL FIELD [0001] The present invention relates to a pharmaceutical composition for the prevention or treatment of cancer, and a pharmaceutical composition for preventing or treating cancer, containing the same as an active ingredient}

The present invention relates to a degradation inducing compound for cerrebone protein, a process for producing the same, and a pharmaceutical composition for preventing or treating cancer containing the same as an active ingredient.

Cells digest the target protein using the ubiquitin-proteasome system (UPS) to maintain protein homeostasis. When a protein called E1, E2, or E3 ligase is ubiquitinated with ubiquitin (ubiquitin) composed of 76 amino acids to the target protein to be degraded, the 26S proteasome And then decomposing the target protein. More than 600 E3 ubiquitin ligases are known to be ligases, and it is known that the proteins degraded by ligase type are different.

Meanwhile, the E3 ubiquitin ligase CRBN (Cereblon), when combined with thalidomide, lenalidomide, and fomalidomide, known as immunomodulatory drugs (IMiD), binds to the transcription factor Icaros ikaros, and aiolos, which not only exerts excellent anti-cancer effects but also is effective for autoimmune diseases including lupus. Thus, development of an immunomodulating drug targeting Cerebrone itself has been actively carried out.

On the other hand, besides the role of E3 ubiquitin ligase which is involved in the degradation of a specific protein, Dr. Cheol Seung Park of Kwangju Institute of Science and Technology confirmed that CRBN inhibits the activity of AMPK. When CRBN is inhibited, AMPK was activated, suggesting the possibility of preventing or treating metabolic diseases such as obesity, fatty liver and diabetes from induction of CRBN inhibition.

In addition, the research team of Gwangju Institute of Science and Technology researchers confirmed that CRBN is expressed in the immune cells (T-cells). When CRBN is deficient, the expression of potassium ion channels is increased in T cells, , And that the sensitivity of T cells to antigens can be controlled by controlling the expression of these genes. From these results, it can be seen that the induction of CRBN deficiency induces the effect of increasing the activity of T cells by lowering the amount of CRBN overexpressed in T cells. From the induction of CRBN deficiency which induces such effect, Suggesting the possibility of developing therapeutic agents.

If the inhibition or deficiency of cerrebone is induced, as described in the background of the above-mentioned E3 ubiquitin ligase CRBN, effects useful for cancer, autoimmune diseases, metabolic diseases, etc. can be achieved.

However, there has been no development of low molecular drugs targeting CRBN, and the existing CRBN inhibitors have not achieved the desired level of pharmacological effect. In particular, existing anticancer target therapeutic agents have a disadvantage that they require a high inhibitory effect on the target in order to inhibit the signal transmission of the target, and that they must be administered for a long period of time in order to show a therapeutic effect. And the drug resistance is generated within one year after the administration to lower the effect of the drug. In addition, the cytotoxic therapeutic agent can not directly act on the cancer-causing target, so that side effects are more serious and the therapeutic effect is less than that of the anticancer target therapeutic agent.

Therefore, it is required to develop a new technology that can achieve superior therapeutic effect to the anticancer target therapeutic agent and the cytotoxic therapeutic agent and to overcome the problems such as side effects of drug resistance, and to prevent or defeat cerrebone to a desired level, It is necessary to develop a therapeutic agent which can achieve pharmacological effect.

In the background described above, a recent team from Yale University (Craig Crews) developed the Proteolysis Targeting Chimera (PROTAC) technology.

PROTAC is a novel therapeutic agent prepared by ligating an inhibitor or binder compound that binds to a specific protein and a ligand compound that specifically binds to E3 ubiquitin ligase with various kinds of linkers. Of the target protein is degraded by the targeted target protein, the resistance to the drug is low, and only the target protein can be bound to the target protein, a sufficient therapeutic effect is obtained from the degradation of the active target protein without the high inhibitory activity on the target protein of PROTAC itself , It can be applied to an undruggable target which is difficult to achieve an inhibitory effect as an existing drug, and thus it is attracting attention as a disease treatment technology of a novel mechanism (Patent Document 1).

Accordingly, the present inventors have developed a novel CRBN-PROTAC substance by linking a threidomide and a derivative thereof, which are binders to CRBN, and an E3 ligase, in particular, a VHL ligand or a CRBN ligand (a thalidomide derivative) It has been confirmed that CRBN is successfully degraded from this, and it is expected to be used not only as a CRBN decomposer but also as a pharmaceutical composition for prevention or treatment of CRBN related diseases, preferably metabolic diseases, autoimmune diseases or cancer, The present invention has been completed based on the findings that it can be useful as a pharmaceutical composition.

WO 2013/106643 A2

It is an object of the present invention to provide compounds that degrade cerebrone (CRBN).

Another object of the present invention is to provide a process for producing the above compound.

It is still another object of the present invention to provide a pharmaceutical composition for preventing or treating a cerrebone-related disease containing the above-mentioned compound as an active ingredient.

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

It is still another object of the present invention to provide a pharmaceutical composition for the prevention or treatment of autoimmune diseases containing the above-mentioned 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 above-mentioned compound as an active ingredient.

It is still another object of the present invention to provide a health functional food for preventing or ameliorating cerebellone-related diseases containing the above-mentioned compound as an active ingredient.

In order 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:

Wherein A is a Cerebron E3 ubiquitin ligase binding moiety;

The linker is a linker having 3 to 20 linkages selected from the group consisting of - (CH ₂ ) -, - (C═O) -, -NH- and -O-,

The linking group can not be linked to -O- in succession; And

Wherein B is an E3 ubiquitin ligase binding moiety,

Here, Linker and A or B are chemically linked.

The present invention also relates to a process for producing a compound represented by the formula (1)

(Step 1) of producing a compound represented by A-Linker-V from a compound represented by U-Linker-V;

A-Linker-A or a compound represented by A-Linker-A or A-Linker-B from the compound represented by A-Linker-V prepared in Step 1 above (Step 2) A-Linker-B < / RTI >

[Reaction Scheme 1]

(In the above Reaction Scheme 1,

A, Linker and B are as defined above; And

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

Furthermore, the present invention relates to the use of a compound represented by A-Linker-A or A-Linker-B, a stereoisomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient for the prevention or treatment of a Cereblon- A pharmaceutical composition is provided.

The present invention also provides a pharmaceutical composition for preventing or treating cancer comprising 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.

Further, the present invention relates to a pharmaceutical composition for preventing or treating autoimmune diseases, which comprises a compound represented by A-Linker-A or A-Linker-B, a stereoisomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient .

The present invention also relates to a pharmaceutical composition for preventing or treating a metabolic disease 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 to provide.

Furthermore, the present invention relates to the use of a compound represented by A-Linker-A or A-Linker-B, a stereoisomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient for the prevention or amelioration of a Cereblon- Or a pharmaceutically acceptable salt thereof.

The novel compounds represented by A-Linker-A or A-Linker-B according to the present invention can inhibit or decompose cerrebone to an excellent extent, and can be used as an effective ingredient for treating a cerrebone-related disease, There is a useful effect as a pharmaceutical composition for the prevention or treatment of diseases, for example, cancers, autoimmune diseases, or metabolic diseases in which effects such as treatment, prevention or amelioration from inhibition or degradation can be achieved.

FIG. 1 shows the results of protein analysis of the compounds of Examples 1, 3, and 8 of the present invention, expressed as 0- 10 .mu.M and Western blotting with .alpha.-CRBN and .alpha.-Tubulin.
2 is a DC ₅₀ graph showing the proteolytic potency according to the concentrations 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 examples for the purpose of helping 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:

Wherein A is a Cerebron E3 ubiquitin ligase binding moiety;

The linker is a linker having 3 to 20 linkages selected from the group consisting of - (CH ₂ ) -, - (C═O) -, -NH- and -O-,

The linking group can not be linked to -O- in succession; And

Wherein B is an E3 ubiquitin ligase binding moiety,

Here, Linker and A or B are chemically linked.

The chemical linkage may be, for example, a covalent bond such as a single bond, a double bond, or a triple bond.

Meanwhile,

Preferably, the A is Thalidomide, Lenalidomide, Pormalidomide, analogs thereof, their copper complexes, or derivatives thereof.

More preferably,

Wherein A is one of the following formulas (a) to (g)

,

,

,

,

,

, 또는

,

,

,

,

,

, or

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

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

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

Y is NH, a linear or branched alkyl of NC _1-10 , NC _6-10 aryl, N-heteroaryl (5-10 angles containing one or more heteroatoms selected from the group consisting of N, O, and S, unsubstituted heteroaryl), NC _3-9 cycloalkyl, heterocycloalkyl N- (N, O, and 3-10 containing at least one heteroatom selected from the group consisting of S, each unsubstituted heterocycloalkyl), O, Or S,

Z is O, S, or H ₂ ,

G and G 'are each independently selected from the group consisting of H, C _1-10 linear or branched alkyl, OH, substituted or unsubstituted CH ₂ -heterocyclyl (N, O, and S) Heterocyclyl of a 3-10 heterocycle containing one or more heteroatoms), or benzyl which is unsubstituted or substituted by R '

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

A is straight or branched chain alkyl of C _1-10 , 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 (heteroaryl of 5-10 heterocycle containing one or more heteroatoms selected from the group consisting of N, O, and S), -C _1-10 linear or branched alkyl, -C _3-9 cycloalkyl, - heterocyclyl (N, O, and 3-10 containing at least one heteroatom selected from the group consisting of S, each ring heterocyclyl), -P ( -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 _{independently} 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, (Heteroaryl of 5-10 heterocyclic rings containing heteroatoms), heterocyclyl (heterocyclyl of 3-10 heterocyclic rings containing at least one heteroatom selected from the group consisting of N, O, and S) , ≪ / RTI >

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

(R or S) or non-stereospecific linkages; 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,

Wherein R < ³ > is each H, or an unsubstituted or substituted C _1-10 straight chain or branched chain alkyl,

Here again, the substituted alkyl is substituted with a halogen, nitro, or cyano group, and R _n is covalently bonded to a linker.

More preferably,

,

,

, 또는

이되,A is

,

,

, or

However,

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,

Wherein R ² and R ³ are each independently H, or an unsubstituted or substituted C _1-10 straight chain or branched chain alkyl,

Here again, said substituted alkyl is substituted with halogen, nitro, or cyano.

More preferably,

,

,

,

,

,

,

, 또는

이되,A is

,

,

,

,

,

,

, or

However,

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,

Wherein R ² and R ³ are each independently H, or an unsubstituted or substituted C _1-10 straight chain or branched chain alkyl,

Here again, said substituted alkyl is substituted with halogen, nitro, or cyano.

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

Preferably, the linker comprises:

이되,

However,

Wherein a and i are independently 0 or 1;

B is an integer from 0 to 20;

Wherein c is 0 or 1;

D is an integer of 0-3;

E is 0 or 1;

F is an integer from 1 to 10;

G is 0 or 1;

H is an integer of 0-3;

J and k are independently an integer of 0-5.

Meanwhile,

More preferably,

The linker,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

, 또는

이다.

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

, or

to be.

On the other hand, in a 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 above B may be used without limitation as long as it is an E3 ubiquitin ligand binding ligand (ligand), wherein the E3 ubiquitin ligase is selected from 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 SCF / Skp2, SHPRH, SIAH1, SIAH2, SMURF1, SCF1, , SMURF2, TOPORS, TRAF6, TRIM63, UBR2, UHRF2, VHL, WWP1, WWP2, or CRBN, and can be used in the present invention without limitation as long as it is a binding moiety thereof.

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

In another embodiment of the present invention,

Wherein B is a compound represented by the following formula (1)

[Chemical Formula 1]

In Formula 1,

R ⁴ is OR ⁶ ,

R ⁵ is 5-10 membered heteroaryl comprising at least one heteroatom selected from the group consisting of optionally substituted or unsubstituted -NR ⁶ - (CH ₂ ) oC _6-10 aryl-N, O, and S However,

5-10 membered heteroaryl comprising at least one heteroatom selected from the group consisting of the substituted -NR ⁶ - (CH ₂ ) o C _6-10 aryl-N, O, and S is C _1-10 straight chain Or branched alkyl,

Wherein R < ⁶ > is H or a straight or branched chain alkyl of _1-5 , wherein o is 0-5;

R ⁷ is -CR ⁸ -NR ⁹ -

Wherein R ⁸ is a C _1-10 linear or branched alkyl and R ⁹ is H or a C _1-5 linear or branched alkyl.

More preferably,

이되,B is

However,

Wherein R ² and R ³ are each independently H or an unsubstituted or substituted C _1-10 straight chain or branched chain alkyl,

Here again, said substituted alkyl is substituted with halogen, nitro, or cyano.

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

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

(2) Synthesis of (2S, 4R) -1 - ((S) -2- (6- (2- (2,6-dioxopiperidin- Amino) hexanoamido) -3,3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide;

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

(4) Synthesis of (2S, 4R) -1 - ((S) -2-tert- butyl-17- (2- (2,6-dioxopiperidin- 4-ylamino) -4-oxo-6,9,12,15-tetraoxa-3-azaheptadec-l-nonyl) -4-hydroxy-N- (4- 5-yl) benzyl) pyrrolidine-2-carboxamide;

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

(6) N ¹ - (2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-4-yl) -N ⁹ - Pyrrolidin-l-yl) -3,3-dimethyl-l-oxobutane-l- 2-yl) nonanediamide;

(7) Synthesis of N ¹ - (2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-4-yl) -N ⁸ - Pyrrolidin-l-yl) -3,3-dimethyl-l-oxobutane-l- 2-yl) octanediamide;

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

(9) Synthesis of N ¹ - (2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-4-yl) -N ¹⁴ - (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin- 1 -yl) -3,3-dimethyl- Butan-2-yl) -3,6,9,12-tetraoxatetradecan-1,14-diamide;

(10) Synthesis of N ¹ - (2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-4-yl) -N ⁵ - Pyrrolidin-l-yl) -3,3-dimethyl-l-oxobutane-l- 2-yl) glutaramide;

^{(11) N 1 - ((} 2- (2,6- dioxide Sophie piperidine turned-3-yl) -1,3-stamp oksoyi 4-yl) ^{methyl) -N 7 - ((S)} -1 ((2S, 4R) -4-hydroxy-2- (4- (4-methylthiazol- 5- yl) benzylcarbamoyl) pyrrolidin- 1 -yl) -3,3- Oxobutan-2-yl) heptanediamide;

(12) Synthesis of (2S, 4R) -1 - ((S) -2- (11- (2- (2,6-dioxopiperidin- Undecanamido) -3,3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide;

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

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

(15) Synthesis of (2S, 4R) -1 - ((S) -2- (2- (6- (2- (2,6-dioxopiperidin- Yl) amino) hexyloxy) acetamido) -3,3-dimethylbutanoyl) -4-hydroxy-N- (4- Carboxamide;

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

(17) Synthesis of (2S, 4R) -1 - ((S) -2-tert- butyl- 14- (2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindoline Ylamino) -4-oxo-6,9,12-trioxa-3-azatetradec-l-nonyl) -4- Yl) benzyl) pyrrolidine-2-carboxamide;

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

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

(20) Synthesis of (2S, 4R) -1 - ((S) -2- (11- (2- (2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindoline Yl) amino) acetamido) undecanamido) -3,3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazol- Di-2-carboxamide;

(21) Synthesis of (2S, 4R) -1 - ((S) -2- (11- (2- (2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindoline -4-yloxy) acetamido) undecanamido) -3,3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazol- Di-2-carboxamide;

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

(23) Synthesis of 3,3 '- (5,5' - (nonan-1, 9-diylbis (azacyl)) bis (4-oxobenzo [d] [1,2,3] 3 (4H) -diyl)) dipiperidin-2,6-dione;

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

(25) Synthesis of (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- 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. As the salt, acid addition formed by a pharmaceutically acceptable free acid Salts are useful. Acid addition salts include those derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid and the like, aliphatic mono- and dicarboxylates, phenyl-substituted alkanoates, Derived from organic acids such as acetic acid, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid and the like. Examples of such pharmaceutically innocuous salts include, but are not limited to, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate chloride, bromide, But are not limited to, but are not limited to, but are not limited to, but are not limited to, but are not limited to, halides, halides, halides, halides, halides, halides, But are not limited to, lactose, sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, Methoxybenzoate, phthalate, terephthalate, benzene sulfonate, toluene sulfonate, chloro Such as benzenesulfonate, benzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate,? -Hydroxybutyrate, glycolate, maleate, 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, by reacting a derivative of A-Linker-A or A-Linker-B with an organic solvent such as methanol, ethanol, acetone, dichloromethane or acetonitrile Or by filtering and drying a precipitate formed by adding an organic acid or an inorganic acid, or by distilling a solvent and an excess acid under reduced pressure, followed by drying and crystallization in 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 amount of an alkali metal hydroxide or an alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is preferable for the metal salt to produce sodium, potassium or calcium salt. In addition, the corresponding salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable salt (such as silver nitrate).

Furthermore, the present invention encompasses not only the compound represented by A-Linker-A or A-Linker-B and its pharmaceutically acceptable salt, but also solvates, optical isomers, hydrates and the like which can be prepared therefrom .

Further, as shown in Reaction Scheme 1 below,

(Step 1) of producing a compound represented by A-Linker-V from a compound represented by U-Linker-V;

A-Linker-A or a compound represented by A-Linker-A or A-Linker-B from the compound represented by A-Linker-V prepared in Step 1 above (Step 2) A-Linker-B < / RTI >

[Reaction Scheme 1]

(In the above Reaction Scheme 1,

A, Linker and B are as defined above; And

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

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

In the process for producing a compound represented by the formula A-Linker-A or A-Linker-B according to the present invention, the step 1 is a step of reacting a compound represented by A-Linker-V from a compound represented by U- .

At this time, the above step is a step of introducing a ligand moiety for binding to cerrebone which is a target protein to be inhibited or decomposed of the compound of the present invention. For example, Cereblor ligase represented by A in Linker Can be considered as the step of introducing the ligand compound.

At this time, the bond to which the linker and A are connected may be a chemical bond, for example, a covalent bond, preferably a single bond, a double bond or a triple bond. Therefore, step 1, which is the step of connecting the linker with A, can be used without any particular limitation as long as it is a method of introducing a connector that can be used in the relevant field. In U-Linker-V, when U is NH ₂ , In one embodiment, in one embodiment of the invention, one exemplary compound of the compound represented by AF is 2- (2,6-dioxopiperidin-3-yl) - 3-dione, and U-Linker-V and A-halogen are reacted to produce a compound represented by A-Linker-V, which is a target compound of Step 1, by reacting 4-fluoroisoindoline- Are included in the production method of the present invention without limitation. On the other hand, when U is OH, a compound represented by A-NH ₂ , in an embodiment of the present invention, U-Linker-V and A-NH ₂ are used, Linker-V, which is the target compound of Step 1, by reacting the compound represented by the formula (1).

The solvent used in step 1 may be H ₂ O, ethanol, tetrahydrofuran (THF), dichloromethane, toluene, acetonitrile, dimethylformamide, or a mixture thereof. Preferred examples of the solvent include dimethylformamide (DMF) can be used.

The reaction temperature in the above step is not particularly limited, but is preferably carried out at a boiling point of the solvent at 80-100 ° C. The reaction time is not particularly limited, but is preferably 5 hours or more, 10 hours or more, 20 hours or more , It is preferable to react overnight.

Linker-A or A-Linker-B according to the present invention, the step 2 is a step of reacting the compound represented by A-Linker-V prepared in the step 1 with A-Linker- A or A-Linker-B.

The ligand A or B may bind to cerrebone or VHL E3 ubiquitin ligase, and the target protein (cerreon) may be conjugated with multiple ubiquitin Polyubiquitination is induced.

At this time, the bond to which A-Linker and A or B is connected may be a chemical bond, for example, a covalent bond, preferably a single bond, a double bond or a triple bond. Therefore, step 2, which is the step of connecting A-Linker with A or B, is not limited to A-Linker-V, preferably A-Linken or B-halogen when V is NH ₂ , Or BF, in an embodiment of the invention described below, one exemplary compound of the compound represented by AF is 2- (2,6-dioxopiperidin-3-yl) -4-fluoro 3-dione and reacting A-Linker-V and A-halogen or B-halogen to obtain the target compound of A-Linker-A or A-Linker-B Is included in the production method of the present invention without limitation. When V is OH, A-NH ₂ or B-NH ₂ can be used. In one embodiment, B-NH ₂ is (2R, 4R) -1 - ((R) 3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine- ₂ or B-NH ₂ to produce a compound represented by A-Linker-A or A-Linker-B, which is the target compound of Step 1, is included in the production method of the present invention without limitation.

The solvent used in step 1 may be H ₂ O, ethanol, tetrahydrofuran (THF), dichloromethane, toluene, acetonitrile, dimethylformamide, or a mixture thereof. Preferred examples of the solvent include dimethylformamide (DMF) can be used.

The reaction temperature in the above step is not particularly limited, but is preferably carried out at a boiling point of the solvent at 10-40 ° C. The reaction time is not particularly limited, but is preferably 5 hours or more, 10 hours or more, 20 hours or more , It is preferable to react overnight.

The above production process may be more preferably performed in accordance with the following examples of the present invention, but the present invention is not limited thereto.

Meanwhile, the manufacturing method described herein can modify or change the reaction conditions such as the reaction temperature, the reaction time, and the reaction step in consideration of the yield and the like of the compound produced by the person skilled in the art, and the reaction step is repeated or reversed .

Also, the method for producing a compound represented by A-Linker-A or A-Linker-B to be provided in the present invention using conventional synthetic methods in the field of organic synthesis known in the art is included in the scope of the present invention without limitation .

Further, if it is possible to design a moiety at both ends of a compound to be provided by each linker and a compound to be provided in the present invention, for example, a serovar protein binding ligand moiety on one side and E3 ubiquitin ligase It is to be understood that the present invention encompasses a manufacturing method in which a ligand moiety is constructed and easily connected and designed.

For example, a change in the degree to which a compound of the present invention is organized in tandem or in parallel above two units is intended to provide a moiety that the present invention is intended to combine with, on the one hand, E3 ubiquitin ligase to induce multiple ubiquitination with cerrelone protein, it is desirable to design the compound as serial or parallel repetition or modification or modification of the linking group, Compounds that can be derived from a simple design variant, such as two or more E3 ubiquitin ligase moieties, or, conversely, one E3 ubiquitin ligase moiety, constituting two or more serrebone binding moieties, and From this, it can be seen that, like the present invention, Aspect, the present invention is intended to include such changes or modifications. That is, it should be understood that changes and modifications in the extent to which those skilled in the art easily deduce from the present invention are included in the present invention.

Meanwhile, the compound represented by A-Linker-A or A-Linker-B of the present invention binds to a target protein, cerrebone, and the other A or B ligand moiety binds to E3 The protein is bound to ubiquitin ligase and ultimately the E3 ubiquitin ligase induces multiple ubiquitination with the target protein (cerreon), and then the protease, such as 26S proteasome, The effect of pharmacological effects through proteolysis can be further enhanced by the fact that all the related diseases caused by cerrebons, such as those caused by the abnormalities of cerrebone, hyperactivity, etc. Can be useful in any disease identified as a disease associated with conventional cerrecon, such as, for example, cancer, e.g., autoimmune diseases such as metabolic diseases have.

In particular, the compounds of the present invention are useful as protein cleavage inhibitors (PROTAC), which can overcome the problems of conventional drug side effects such as cell inhibitors, target inhibitors, resistance problems, and insufficient pharmacological activity.

In addition, the compound of the present invention is a compound of the present invention, wherein the cerreon binding moiety itself represented by A is a thalidomide, lenalidomide, fomalidomide, an analogue thereof, a copper myristate thereof, or a derivative thereof, which is known as an immunomodulatory drug (IMiD) , The compound of the present invention shows a pharmacological effect as an immunomodulatory drug by simply binding to cerrebone in a stage before inducing degradation to the cerrebone protein.

Therefore, the compound represented by A-Linker-A or A-Linker-B of the present invention, its stereoisomer or its pharmaceutically acceptable salt can be used as a conventional known immunoregulatory drug, It is possible to simultaneously achieve a pharmacological effect as a protein disintegrating agent which can be overcome, exhibiting excellent synergistic effect in pharmacological activity, and at the same time remarkably improving problems such as drug resistance and side effects.

In the present invention, the compound represented by the present invention A-Linker-A or A-Linker-B has excellent pharmacological activity in cancer, autoimmune disease or metabolic disease, And it has been confirmed experimentally that it is possible to effectively solve the disadvantages and resistance problems of conventional target therapeutic agents and cell therapeutic agents.

Furthermore, the present invention relates to the use of a compound represented by A-Linker-A or A-Linker-B, a stereoisomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient for the prevention or treatment of a Cereblon- A pharmaceutical composition is provided.

The compound represented by A-Linker-A or A-Linker-B of the present invention exhibits inhibitory activity of the cerrebone protein and decomposes cerrebone. The compound exhibiting the cerrebone-mediated disease (cerreone-related disease) An excellent pharmacological effect can be achieved on a disease caused by an activity above the cerrebone activity, an activity derived from the cerrebone and the activity or the mechanism of the cerrelone. As a specific example of the disease, in the treatment of cancer, autoimmune diseases, metabolic diseases, the compound of the present invention can be used as an active ingredient of a pharmaceutical composition for prevention and improvement.

As confirmed by the description of the background art described above, when E3 ubiquitin ligand CRBN (Cereblon) is combined with thalidomide, lenalidomide, and fomalidomide, which are known as immunomodulatory drugs (IMiD) It is effective for the autoimmune diseases including lupus as well as excellent anti-cancer effect by decomposing the transcription factors ikaros and aiolos. In the compounds represented by A-Linker-A or A-Linker-B according to the present invention, the moiety represented by A is a thalidomide, a lanalidomide, a fomalidomide, an analogue thereof, On the other hand, in addition to E3 ubiquitin ligase activity, which is involved in the degradation of a specific protein, cerreon inhibits CRBN and activates AMPK, which is an energy sensor, to be effective in obesity, fatty liver, diabetes mellitus It is possible to prevent or treat metabolic diseases.

Furthermore, inhibition or degradation of CRBN in immune cells (T-cells) may reduce the amount of CRBN overexpressed in T cells and induce the effect of increasing T cell activity, and thus can be used as an anti-cancer immunotherapeutic agent.

The present invention also provides a pharmaceutical composition for preventing or treating cancer comprising 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.

Herein, the cancer refers to all cancer diseases that can be improved from the inhibition of Celreon activity or the degradation of Celreon protein. Non-limiting examples of the cancer include caustic myxoma, intrahepatic bile duct cancer, hepatoblastoma, liver cancer, Cancer of the ovary, ovarian cancer, ovarian cancer, male breast cancer, brain cancer, pituitary adenoma, ovarian cancer, ovarian cancer, ovarian cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, Cholangiocarcinoma, diffuse large B cell lymphoma, bladder cancer, bladder cancer, peritoneal cancer, pituitary cancer, adenocarcinoma, sinus cancer, multiple myeloma, gallbladder cancer, bile duct cancer, colon cancer, chronic myelogenous leukemia, chronic lymphocytic leukemia, retinoblastoma, retinoblastoma, , Non-small cell lung cancer, non-Hodgkin's lymphoma, tongue cancer, astrocytoma, small cell lung cancer, pediatric brain cancer, pediatric lymphoma, childhood leukemia, small bowel cancer, meningioma, The present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prophylaxis of a neurodegenerative disease selected from the group consisting of a malignant melanoma, a malignant melanoma, a malignant melanoma, a malignant melanoma, Cancer of the uterus, endometrial cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone cancer, metastatic brain cancer, mediastinal cancer, rectal cancer, gastrointestinal cancer, gastric cancer, gastric cancer, gastric carcinoma, gastrointestinal stromal cancer, Wilms's tumor, breast cancer, sarcoma, Cancer of the lung, squamous cell carcinoma of the lung, squamous cell carcinoma of the lung, squamous cell carcinoma of the lung, rhabdomyosarcoma, rhabdomyosarcoma, squamous cell carcinoma, squamous cell carcinoma, Laryngeal cancer, pleural cancer, and thymus cancers.

Furthermore, preferably said cancer is acute myelogenous leukemia (AML); Chronic myelogenous leukemia (CML); Acute lymphocytic 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; Valgendrogmaglobulinemia; Myelodysplastic syndrome (MDS); Small lymphocytic lymphoma (SLL); Marginal lymphoma; Asymptomatic multiple myeloma; And bone marrow proliferative syndrome.

As used herein, the term " cancer " is used to establish unregulated or aberrantly regulated cell proliferation, reduced cellular differentiation, impaired ability to invade surrounding tissues, and / ≪ RTI ID = 0.0 > and / or < / RTI > The term " cancer " includes, but is not limited to, solid tumors and blood mediated tumors (hematologic malignant tumors). The term " cancer " includes diseases of the skin, tissues, organs, bone, cartilage, blood, and blood vessels. The term " cancer " further includes primary and metastatic cancers.

The solid tumor may be pancreatic cancer; Invasive bladder cancer containing bladder cancer; Colorectal cancer; Breast cancer including thyroid cancer, stomach cancer, metastatic breast cancer; Prostate cancer, including androgen-dependent and androgen-independent prostate cancer; Kidney cancer, including, for example, metastatic renal cell carcinoma; Liver cancer including hepatocellular carcinoma and intrahepatic bile duct; Lung and bronchial carcinoma, including non-small cell lung cancer (NSCLC), squamous cell lung cancer, bronchoalveolar alveolar 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; For example, uterine cancer including uterine body and cervix; Endometrial cancer; Gastric cancer; Esophagus cancer; For example, head and neck cancer including squamous cell carcinoma of the head and neck, nasopharyngeal cancer, oral cavity and pharynx; Melanoma; Neuroendocrine carcinoma, including metastatic neuroendocrine tumors; For example, brain tumors including glioma / glioblastomas, inverse dysplastic glomerulonephrosis, adult glioblastoma multiforme, and adult retroformed astrocytoma; Metastatic neuroendocrine tumors; Bone cancer; And neuroendocrine involvement including soft tissue sarcoma.

The hematological malignancies include acute myelogenous leukemia (AML); Chronic myelogenous leukemia (CML), including accelerated CML and CML aspirate (CML-BP); Acute lymphocytic 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; Valgendrogmaglobulinemia; (Including anemia of intractable anemia (RAE), hyperammonemia (RAEB), and transformation with accompanying RAEB (RAEB-T)) with mastitis formation syndrome (MDS) ; Small lymphocytic lymphoma (SLL); Marginal lymphoma; Asymptomatic multiple myeloma; And myeloproliferative syndrome.

Further, the present invention relates to a pharmaceutical composition for preventing or treating autoimmune diseases, which comprises a compound represented by A-Linker-A or A-Linker-B, a stereoisomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient .

Herein, the autoimmune disease refers to all autoimmune diseases that can be improved from the inhibition of cerreon activity or the degradation of cerrelone protein. Non-limiting examples of the autoimmune disease include immune neutrophilia, gilanvalescendrom, The present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of epilepsy, autoimmune encephalitis, autoimmune encephalitis, ischemic syndrome, birth palsy pemphigus, decidual pemphigus, (ITP), lupus nephritis, and membranous nephropathy. The present invention also relates to a method for the treatment and / or prophylaxis of a disease selected from the group consisting of: .

The present invention also relates to a pharmaceutical composition for preventing or treating a metabolic disease 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 to provide.

The metabolic disorder refers to all metabolic diseases in which the effect of treatment or prevention from inhibiting cerrebone or from degradation of cerrelone protein can be achieved, including but not limited to obesity, type I diabetes, type II diabetes, Hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia, metabolic syndrome X, vascular disease, atherosclerosis, coronary heart disease, cerebrovascular disease, heart failure, insulin resistance, hyperinsulinemia, hyperglycemia, dyslipidemia, , Peripheral vascular disease, and scarring.

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 orally or parenterally When formulated, it can be prepared using a diluent or excipient such as a commonly used filler, an extender, a binder, a wetting agent, a disintegrant, a surfactant, and the like.

Examples of formulations for oral administration include tablets, pills, light / soft capsules, liquids, suspensions, emulsions, syrups, granules, elixirs and troches, , Dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine), lubricants (such as silica, talc, stearic acid and its magnesium or calcium salts and / or polyethylene glycols). The tablets may contain binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidine and may optionally contain binders such as starch, agar, alginic acid or sodium salts thereof Release or boiling mixture and / or absorbent, colorant, flavor, and sweetening agent.

The pharmaceutical composition containing the compound represented by A-Linker-A or A-Linker-B as an active ingredient can be administered parenterally, and parenteral administration can be carried out by subcutaneous injection, intravenous injection, intramuscular injection, Injection method.

At this time, in order to formulate a formulation for parenteral administration, the compound represented by A-Linker-A or A-Linker-B or a pharmaceutically acceptable salt thereof is mixed with water together with a stabilizer or a buffer to prepare a solution or suspension And can be prepared in an ampoule or vial unit dosage form. The compositions may contain sterilized and / or preservatives, stabilizers, wettable or emulsifying accelerators, adjuvants such as salts and / or buffers for the control of osmotic pressure, and other therapeutically useful substances, Or may be formulated according to the coating method.

It should be understood by those skilled in the art that the formulations described above are only for the ordinary formulation examples, and that the formulations of the present invention are not limited thereto.

Further, the dosage of the compound represented by A-Linker-A or A-Linker-B of the present invention or a pharmaceutically acceptable salt thereof in the human body depends on the age, body weight, sex, dosage form, And is generally 0.1-1000 mg / day, preferably 1-500 mg / day, based on an adult subject having a body weight of 70 kg, and may be administered at a predetermined interval May be administered once to several times per day.

Furthermore, the present invention relates to the use of a compound represented by A-Linker-A or A-Linker-B, a stereoisomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient for the prevention or amelioration of a Cereblon- Or a pharmaceutically acceptable salt thereof.

Herein, the cerebellum-related disease is a disease caused by a cerebellar-mediated disease (cerebellar related disease), cerebellar abnormal activity, cerrebone and an activity induced by an activity or cerebellum mechanism, , Cancer, autoimmune diseases, and metabolic diseases.

The cancer refers to all cancers which can be improved from the inhibition of cervreon activity or the degradation of cervulone protein. Non-limiting examples of the cancer include caustic myxoma, intrahepatic bile duct cancer, hepatoblastoma, liver cancer, thyroid cancer, colon cancer , Testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, oral cancer, bacterial sarcoma, acute myelogenous leukemia, acute lymphoblastic leukemia, basal cell carcinoma, ovarian epithelial cancer, ovarian germ cell cancer, male breast cancer, brain cancer, pituitary adenoma, multiple myeloma , Gallbladder cancer, biliary cancer, colon cancer, chronic myelogenous leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, diffuse large B cell lymphoma, bladder cancer, bladder cancer, peritoneal cancer, parathyroid cancer, Neoplasm, neuroblastoma, neuroblastoma, neuroblastoma, neuroblastoma, neuroblastoma, neuroblastoma, neuroblastoma, neuroblastoma, papillary carcinoma, Malignant melanoma, malignant lymphoma, malignant mesothelioma, malignant melanoma, ovarian cancer, vulvar cancer, ureter cancer, urethral cancer, primary site unidentified cancer, gastric lymphoma, stomach cancer, Uterine sarcoma, uterine sarcoma, prostate cancer, metastatic brain cancer, metastatic brain cancer, mediastinal cancer, rectal cancer, rectal carcinoma, gastric adenocarcinoma, gastric adenocarcinoma, Cancer of the lung, squamous cell carcinoma of the lung, squamous cell carcinoma of the lung, squamous cell carcinoma of the lung, rhabdomyosarcoma, rhabdomyosarcoma, laryngeal carcinoma, pancreatic cancer, pancreatic cancer, Paget's disease, Paget's disease, Pleural cancer, and thymus cancers.

The autoimmune disease refers to all autoimmune diseases that can be improved from inhibiting ceerobron activity or degrading cerreline protein, and the autoimmune diseases include immune neutrophilia, gilanvalescendrom, epilepsy, Autoimmune hemolytic anemia, autoimmune hemolytic anemia, autoimmune hemolytic anemia, autoimmune hemolytic anemia, autoimmune hemolytic anemia, autoimmune encephalitis, autoimmune encephalitis, ischemic syndrome, idiopathic pemphigus, And may be one or more selected from the group consisting of idiopathic thrombocytopenic purpura (ITP), lupus nephritis and membranous nephropathy, for example, Eve disease, Goodpasture syndrome, myasthenia gravis, multiple sclerosis, rheumatoid arthritis,

The metabolic disorder refers to all metabolic diseases in which the effect of treatment or prevention from inhibiting cerrebone or from degradation of cerrelone protein can be achieved, including but not limited to obesity, type I diabetes, type II diabetes, Hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia, metabolic syndrome X, vascular disease, atherosclerosis, coronary heart disease, cerebrovascular disease, heart failure, insulin resistance, hyperinsulinemia, hyperglycemia, dyslipidemia, , Peripheral vascular disease, and scarring.

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

Herein, the Cereblon-related disease refers to a disease that can be prevented or treated from inhibiting Cereblon activity or degrading Cereblon protein, as described in the present specification, Cancer, autoimmune disease or metabolic disease.

The therapeutically effective amount refers to an amount sufficient to treat, prevent, or ameliorate the symptoms or conditions of the subject upon administration into the body, depending on the administration method. In addition, the amount may vary depending on the body weight, age, sex, condition, and family history of the subject to be administered. In the present invention, the treatment method can set different doses depending on different conditions.

Said " effective amount " is an amount effective to treat Cereblon-related diseases, such as cancer, autoimmune diseases or metabolic diseases. In another embodiment, an " effective amount " of a compound is an amount capable of inhibiting or destroying Cereblon activity.

The compounds and compositions according to the methods of the present invention may be administered using any amount and any route of administration effective in treating the disease. The exact amount required will vary from subject to subject depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its 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 " means a physically discrete unit of formulation suitable for the subject to be treated, as used herein. It will also be understood that the total daily usage 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 will depend on a variety of factors including: the severity of the disease and disorder to be treated; The activity of the specific compound employed; Specific composition; Age, weight, general health, gender and diet of the subject; The time of administration, the route of administration, and the rate of excretion of the particular compound employed; Duration of treatment; The particular compound used alone or coadministered, and other factors well known in the medical arts.

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

Hereinafter, the present invention will be described in detail with reference to Examples and Experimental Examples.

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

Example 1 Synthesis of (2S, 4R) -1 - ((S) -2- (7- (2- (2,6-dioxopiperidin- 3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine- Preparation of amide

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

(158 mg, 1.09 mmol) and 2- (2,6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1,3-dione (300 mg, 1.09 mmol DIPEA (0.285 mL, 1.64 mmol) was added thereto, followed by stirring at room temperature. After completion of the reaction, the reaction mixture was concentrated, diluted with EA and water, extracted with an organic layer, washed with brine, and water was removed with MgSO ₄ and concentrated under reduced pressure. The residue was purified and purified by silica gel column chromatography (MPLC, MeOH / DCM 10% for 28 minutes) to obtain 7- (2- (2,6- Ylamino) heptanoic acid (118 mg, 27%, yellow solid).

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

_{^{1 H NMR (CDCl 3, 300MHz}} ) 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 J = 7.3 Hz, 1H), 6.29-6.18 (m, 1H), 4.96-4.87 (m, 1H), 3.32-3.22 (m, 2H), 2.94-2.65 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-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide Produce

(30 mg, 0.074 mmol) and (2S, 4R) -1 - ((S) -2-amino-3,3-dimethylbutanoyl) -4-hydroxy- (35mg, 0.074mmol) and HATU (43mg, 0.112mmol) were dissolved, and DIPEA (0.052mL, 0.299mmol) was added to dissolve the hydrochloride salt of 4- (4-methylthiazol-5-yl) benzyl) pyrrolidine- mmol), and the mixture is stirred at room temperature. After completion of the reaction, the reaction mixture was diluted with EA and water, and the organic layer was extracted. The organic layer was washed with brine, and water was removed with MgSO ₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MPLC, MeOH / DCM 6% 30 min) to obtain (2S, 4R) -1 - ((S) -2- (7- (2- (4-methylpiperidin-3-yl) -1,3-dioxoisoindolin-4-ylamino) heptanamido) -3,3-dimethylbutanoyl) -4-hydroxy- 5-yl) benzyl) pyrrolidine-2-carboxamide (10 mg, 17%, yellow solid).

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

_{^{1 H NMR (CDCl 3, 300MHz}} ) 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 J = 5.7 Hz, 1H), 7.08 (d, J = 7.1 Hz, 1H), 6.87 (d, J = ), 4.89-4.81 (m, IH), 4.65-4.54 (m, 4H), 4.32-4.23 (m, IH), 4.06 (d, J = 11.3 Hz, 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 .

Example 2 Synthesis of (2S, 4R) -1 - ((S) -2- (6- (2- (2,6-dioxopiperidin- 3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine- Preparation of amide

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

To a DMF were added 6-aminohexanoic acid (119 mg, 0.905 mmol) and 2- (2,6-dioxopiperidin-3-yl) -4-fluoroisoindoline- ), DIPEA (0.236 mL, 1.36 mmol) was added thereto, and the mixture was stirred at room temperature. After completion of the reaction, the reaction mixture was concentrated, diluted with EA and water, extracted with an organic layer, washed with brine, and water was removed with MgSO ₄ and concentrated under reduced pressure. The residue was purified and purified by silica gel column chromatography (MPLC, MeOH / DCM 10% 28 min) to obtain 6 - ((2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoiso Yl) amino) hexanoic acid (60 mg, 17%, yellow solid).

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

_{^{1 H NMR (CDCl 3, 300MHz}} ) 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 J = 7.3 Hz, 1H), 6.29-6.19 (m, 1H), 4.97-4.87 (m, 1H), 3.32-3.29 (m, 2H), 2.95-2.64 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-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide Produce

(35 mg, 0.090 mmol) and (2S, 4R) -1 - ((S) -2-amino-3,3-dimethylbutanoyl) -4-hydroxy- (42 mg, 0.090 mmol) and HATU (52 mg, 0.136 mmol) were dissolved in DIPEA (0.063 mL, 0.360 mmol), and the mixture is stirred at room temperature. After completion of the reaction, the reaction mixture was diluted with EA and water, and the organic layer was extracted. The organic layer was washed with brine, water was removed with MgSO ₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MPLC, MeOH / DCM 6% 30 min) to obtain (2S, 4R) -1 - ((S) -2- (6- (2- 3-dioxoisoindolin-4-ylamino) hexanoamido) -3,3-dimethylbutanoyl) -4-hydroxy-N- (4- 5-yl) benzyl) pyrrolidine-2-carboxamide (43 mg, 73%, yellow solid).

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 (m, 1H), 4.71-4.49 (m, 4H), 4.36-4.23 (m, 1H), 4.05 (d, J = 11.5 Hz, 1H), 1.67-1.47 (m, 4H), 1.34 (m, 2H), 3.14 (m, 2H), 2.86-2.62 d, J = 9.4 Hz, 2H), 0.99-0.77 (m, 9H).

Example 3 Synthesis of (2S, 4R) -1 - ((S) -2- (9- (2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindoline- 3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine- Preparation of amide

Step 1: Preparation of 9-bromonic acid

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

^{1 H NMR (DMSO, 300MHz)} 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 - < / RTI > 1.17 (m, 10H).

Step 2: Preparation of 9-aminononanoic acid

The compound (1 g, 4.22 mmol) prepared in the above 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, the mixture was concentrated to obtain 9-aminononanic acid (529 mg, 72%, brown oil).

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

(200 mg, 1.15 mmol) and 2- (2,6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1,3-dione (318 mg, 1.15 mmol), and DIPEA (0.301 mL, 1.73 mmol) was added thereto, followed by stirring at 90 ° C. After completion of the reaction, the reaction mixture was concentrated, diluted with EA and water, extracted with an organic layer, washed with brine, dried over MgSO ₄ and concentrated. The residue was purified and purified by silica gel column chromatography (MPLC, EA / Hx 60%, 35 min) to give 9 - ((2- (2,6-dioxopiperidin- 4-yl) amino) nonanoic acid (25 mg, 5%, yellow solid).

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

_{^{1 H NMR (CDCl 3, 300MHz}} ) 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), J = 7.4 Hz, 2H), 2.17 - 2.05 (m, 2H), 6.24 (s, 1H), 4.96-4.90 (m, 1H), 1.64 (d, J = 6.6 Hz, 5H), 1.34 (s, 9H).

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

(25 mg, 0.058 mmol), (2S, 4R) -1 - ((S) -2-amino-3,3-dimethylbutanoyl) -4-hydroxy- (27 mg, 0.058 mmol) and HATU (33 mg, 0.087 mmol) were added to the mixture, and DIPEA (0.041 mL, 0.233 mmol) was added thereto, followed by stirring at 90 占 폚. After completion of the reaction, the reaction mixture was concentrated, diluted with EA and water, extracted with an organic layer, washed with brine, dried over MgSO ₄ and concentrated. The residue was purified by silica gel column chromatography (MPLC, MeOH / DCM 6%, 30 min) to obtain (2S, 4R) -1 - ((S) -2- (9- (2- Yl) amino) nonanamido) -3,3-dimethylbutanoyl) -4-hydroxy-N- (4- (4- 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 )? 10.63 (s, 0.5H), 10.37 (s, 0.5H), 10.32 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), 4.05-3.90 (m, 1H), 3.69-3.56 (m, 4H) 2H), 2.83-2.56 (m, 3H), 2.52-2.32 (m, 4H), 2.22-1.96 (m, 4H), 1.66-1.44 1.09 (m, 7 H), 0.91 (s, 9 H). LC / MS (ESI) m / z 842.6 [M + H] +, 840.7 [MH] -

Example 4 Synthesis of (2S, 4R) -1 - ((S) -2-tert-butyl-17- (2- (2,6-dioxopiperidin- 4-ylamino) -4-oxo-6,9,12,15-tetraoxa-3-azaheptadec-l-nonyl) -4-hydroxy-N- (4- 5-yl) benzyl) pyrrolidine-2-carboxamide

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

(315 mg, 0.753 mmol) was dissolved in DMF, sodium azide (147 mg, 2.26 mmol) was added, and the mixture was stirred at 50 占 폚 . After completion of the reaction, the reaction mixture was concentrated to obtain an azide compound in the form of a crude product. The azide compound was dissolved in ethanol, and Pd (OH) ₂ (6 mg) was added and stirred under hydrogen gas. After completion of the reaction, the reaction mixture was filtered through celite using methanol and then concentrated to obtain tert-butyl 14-amino-3,6,9,12-tetraoxatetradec-1-nooate (240 mg, quant. Yellow solid).

_{^{1 H NMR (DMSO-d 6}} , 300MHz) 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

(100 mg, 0.325 mmol) and 2- (2,6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1,3-dione (90 mg, 0.325 mmol) is added, DIPEA (0.085 mL, 0.488 mmol) is added and the mixture is stirred at 90 < 0 > C. After completion of the reaction, the reaction mixture was diluted with EA and water, and the organic layer was extracted, washed with brine, and water was removed with MgSO ₄ and concentrated under reduced pressure. The residue was purified and purified by silica gel column chromatography (MPLC, MeOH / DCM 5% 28 min) to give tert-butyl 14- (2- (2,6- dioxopiperidin- Yloxy) -3,6,9,12-tetraoxatetradec-1-nooate (7 mg, 4%, yellow solid).

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

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

To a solution of tert-butyl 14- (2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-4-ylamino) -3,6,9 , 12-tetraoxatetradec-1-nooate (7 mg, 0.012 mmol) was added and stirred at room temperature. After completion of the reaction, the solution was concentrated to obtain 14 - ((2- (2,6-dioxo-piperidin-3-yl) -1,3-dioxoisoindolin- - tetraoxatetradecanoic acid (10 mg, crude product, brown oil) as a 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- 4-yl) amino) -4-oxo-6,9,12,15-tetraoxa-3-azaheptadecanoyl) -4-hydroxy-N- (4- 5-yl) benzyl) pyrrolidine-2-carboxamide

(6 mg, 0.012 mmol) and (2S, 4R) -1 - ((S) -2-amino-3,3-dimethylbutanoyl) -4-hydroxy- (6 mg, 0.012 mmol) and HATU (7 mg, 0.018 mmol) were dissolved in DMF, and then DIPEA (0.008 mL, , 0.048 mmol), and the mixture is stirred at room temperature. After completion of the reaction, the reaction mixture was concentrated, diluted with EA and water, extracted with an organic layer, washed with brine, and water was removed with MgSO ₄ and concentrated under reduced pressure. (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- 2-carboxamide (3 mg, 27%, yellow solid) was obtained in the same manner as in Example 1, but using ethyl 2- (4- (4-methylthiazol-5-yl) benzyl) heptadecanoyl.

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 1H, J = 8.0 Hz, 1H), 7.10 (d, J = 7.1 Hz, 1H), 6.95-6.86 (m, , 4.64-4.45 (m, 2H), 4.37-4.20 (m, IH), 4.17-4.06 (m, IH), 4.04-3.97 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

Example 5 Synthesis of (2S, 4R) -1 - ((S) -2- (2- (3- (2- (2- (2,6-dioxopiperidin- 4-ylamino) -2-oxoethoxy) propoxy) acetamido) -3,3-dimethylbutanoyl) -4-hydroxy-N- (4- 5-yl) benzyl) pyrrolidine-2-carboxamide

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

(1 g, 13.1 mmol), tert-butyl 2-bromoacetate (21.5 g, 110.4 mmol) and tetrabutylammonium hydrogen sulfate (445 mg) were added to a solution of toluene and NaOH (50 wt% , 1.31 mmol), and the mixture is stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was diluted with ice water, extracted with EA, washed with brine, water was removed with MgSO ₄ and concentrated under reduced pressure. Separation and purification were carried out using silica gel column chromatography (MPLC, EA / Hx 30% 40 min) to obtain di-tert-butyl 2,2 '- (propane-1,3-diyl bis (oxy)) diacetate , 15%, colorless oil).

_{^{1 H NMR (CDCl 3, 300MHz}} ) 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, the mixture 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, 300MHz}} ) 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: To a solution of 2- (3- (2- ((2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin- Ethoxy) propoxy) acetic acid

The compound (167 mg, 0.869 mmol) prepared in the above step 2 is dissolved in DCM, and oxalyl chloride (0.373 mL, 4.35 mmol) is added, and a drop of DMF is added. After confirming that the acid chloride has been produced, concentrate it. After dissolving in THF, adding pomalidomide, reflux. After completion of the reaction, the reaction is terminated with 0.1 N HCl (aq.), And the reaction mixture is diluted with EA and water. The organic layer is extracted, washed with brine, water is removed with MgSO ₄ and concentrated under reduced pressure. The resulting solid was filtered through EA to give 2- (3- (2 - ((2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindol- -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)? 10.41 (s, 1H), 8.96-8.78 (m, 1H), 8.65 , 5.04-4.86 (m, 1H), 4.27-4.04 (m, 4H), 3.86 (t, J = 6.7 Hz, 2H), 3.74 ), 2.15-1.99 (m, 3H).

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

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

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

_{^{1 H NMR (CDCl 3, 500MHz}} ) 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 (m, 3H), 4.01-3.97 (m, 1H), 3.93-4.25 (m, 2H), 4.50 2H), 3.85-3.56 (m, 2H), 2.88-2.57 (m, 3H), 2.53 (s, 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- , 3-dimethyl-1-oxobutan-2-yl) nonanediamide

(30 mg, 0.068 mmol), (2S, < RTI ID = 0.0 > , 4R) -1 - ((S) -2-amino-3,3-dimethylbutanoyl) -4-hydroxy- -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 thereto, and the mixture was stirred at room temperature. After completion of the reaction, the reaction mixture was concentrated and diluted with EA and water. The organic layer was extracted, washed with brine, and water was removed with MgSO ₄ and concentrated under reduced pressure. Silica gel column chromatography separation using a (MPLC, MeOH / DCM 6% , 30 min), to give N ¹ - (2- (2,6- dioxide Sophie-3-yl) -1,3-oksoyi sweep ^{turned-4-yl) -N 9 - ((R)} -1 - ((2R, 4R) -4- hydroxy-2- (4- (4-methylthiazol-5-yl) benzyl carbamoyl) Yl) -3,3-dimethyl-1-oxobutan-2-yl) nonanediamide (21 mg, 36%, white solid).

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 (M, 1H), 7.59-7.48 (m, 1H), 7.40-7.30 (m, 1H), 8.79 (d, (M, 4H), 6.83 (d, J = 9.0 Hz, 0.5H), 6.63 (m, 3H), 2.57-2.36 (m, 6H), 2.23-2.06 (m, 1H), 4.09 (t, J = 10.5 Hz, 1H), 3.70-3.59 2H), 1.41-1.65 (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- , 3-dimethyl-1-oxobutan-2-yl) octanediamide

8-oxo-octanoic acid (30 mg, 0.070 mmol), (2S (4-fluoropyridin- , 4R) -1 - ((S) -2-amino-3,3-dimethylbutanoyl) -4-hydroxy- 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 thereto, and the mixture was stirred at room temperature. After completion of the reaction, the reaction 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 concentrated under reduced pressure. Silica gel column chromatography separation using a (MPLC, MeOH / DCM 6% , 30 min), to give N ¹ - (2- (2,6- dioxide Sophie-3-yl) -1,3-oksoyi sweep ^{turned-4-yl) -N 8 - ((S)} -1 - ((2S, 4R) -4- hydroxy-2- (4- (4-methylthiazol-5-yl) benzyl carbamoyl) 3-dimethyl-1-oxobutan-2-yl) octanediamide (17 mg, 29%, white solid).

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) , 7.72-8.65 (m, 1H), 7.77-7.66 (m, 1H), 7.61-7.47 (m, 1.5H), 7.40-7.29 , 6.59 (d, J = 9.0 Hz, 0.5H), 6.26-6.19 (m, 0.5H), 4.97-4.84 (m, IH), 4.75-4.48 (m, 4H), 4.37-4.25 , 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, 3H), 1.44-1.32 (m, 3H), 0.97-0.83 (m, 1H), 1.85 (t, J = 7.5 Hz, 1H), 1.79-1.68 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 Yl) benzyl) carbamoyl) pyrrolidin-1-yl) - ((2S, 4R) -4-hydroxy- -3,3-dimethyl-1-oxobutan-2-yl) heptanediamide

Yloamino) -7-oxoheptanoic acid (50 mg, 0.120 mmol), (2S (4-fluorobenzyloxy) , 4R) -1 - ((S) -2-amino-3,3-dimethylbutanoyl) -4-hydroxy- Carboxamide hydrochloride (56 mg, 0.120 mmol) and HATU (68 mg, 0.180 mmol) were dissolved in DMF, DIPEA (0.084 mL, 0.480 mmol) was added thereto, and the mixture was stirred at room temperature. After completion of the reaction, the reaction mixture was concentrated and diluted with EA and water. The organic layer was extracted, washed with brine, and water was removed with MgSO ₄ and concentrated under reduced pressure. Silica gel column chromatography separation using a (MPLC, MeOH / DCM 6% , 30 min), to give N ¹ - (2- (2,6- dioxide Sophie-3-yl) -1,3-oksoyi sweep turned-4-yl) -N ⁷ - ((S) -1 - ((2S, 4R) -4-hydroxy-2 - ((4- (4-methylthiazol-5-yl) benzyl) carbazole Yl) heptanediamide (33 mg, 33%, white solid). ≪ 1 >

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

_{^{1 H NMR (CDCl 3, 300MHz}} ) 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 1H), 4.92-4.82 (m, 1H), 4.68 (m, 1H), 7.54 (dd, J = 10.5, 6.7 Hz, 2H), 7.35-7.32 2H), 3.74-3.63 (m, 1H), 2.88-2.61 (m, 3H), 2.56-2.37 (m, (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: Synthesis of N ^One - (2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-4-yl) -N ¹⁴ Yl) benzyl) carbamoyl) pyrrolidin-1-yl) - ((2S, 4R) -4-hydroxy- -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

To a solution of 2- (2- (hydroxymethoxy) ethoxy) ethanol (1 g, 7.34 mmol), tert-butyl 2-bromoacetate (9.12 mL, 61.7 mmol), tetra Butylammonium hydrogen sulfate (249 mg, 0.734 mmol) was added thereto, and the mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was diluted with ice water, extracted with EA, washed with brine, and water was removed with MgSO ₄ and concentrated under reduced pressure. Separation and purification were performed using silica gel column chromatography (MPLC, EA / Hx 50% 40 min) to obtain di-tert-butyl 3,6,9,12-tetraoxatetradecanedioate (1.24 g, 31% Oil).

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

Step 2: Preparation of 3,6,9,12-tetraoxatetradecan-1,14-dione acid

To the 40% TFA / DCM solution was added the compound prepared in Step 1 (450 mg, 1.48 mmol) and the mixture was stirred at room temperature. After the reaction was completed, 3,6,9,12-tetraoxatetradecan-1,14-dione acid 33 (502 mg, crude product, brown oil) was obtained as a crude product.

¹ H NMR (CDCl ₃ , 300 MHz)? 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-dioxoisoindolin-4-yl) amino) Preparation of 12-tetraoxatetradecanoic acid

The compound prepared in Step 2 (394 mg, 1.48 mmol) is dissolved in DCM, and oxalyl chloride (0.635 mL, 7.40 mmol) is added and a drop of DMF is added. After confirming that the acid chloride has been produced, concentrate it. After dissolving in THF, formaldehydoid (202 mg, 0.740 mmol) was added and refluxed. After completion of the reaction, the reaction was terminated with a 0.1 N HCl (aq.) Solution. The reaction mixture was diluted with EA and water to extract an organic layer. The organic layer was washed with brine, water was removed with MgSO ₄ and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (MPLC, MeOH / DCM 20% 40 min) to obtain 14 - ((2- (2,6-dioxo-piperidin-3-yl) -1,3-dioxoisoindoline- 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, 300MHz}} ) 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 ( (m, 4H), 3.78-3.61 (m, 17H), 3.57 (t, < RTI ID = J = 5.7 Hz, 2H), 3.01-2.68 (m, 3H), 2.26-2.08 (m,

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

(25 mg, 0.048 mmol) and (2S, 4R) -1 - ((S) -2-amino-3,3-dimethylbutanoyl) -4-hydroxy- (22 mg, 0.048 mmol) and HATU (27 mg, 0.072 mmol) were dissolved in DMF, and then DIPEA (0.033 mL, , 0.192 mmol), and the mixture is stirred at room temperature. After completion of the reaction, the reaction mixture was concentrated, diluted with EA and water, extracted with an organic layer, washed with brine, and water was removed with MgSO ₄ and concentrated under reduced pressure. Silica gel column chromatography separation using a (MPLC, MeOH / DCM 6% , 30 min), to give N ¹ - (2- (2,6- dioxide Sophie-3-yl) -1,3-oksoyi sweep turned-4-yl) -N ¹⁴ - ((S) -1 - ((2S, 4R) -4-hydroxy-2 - ((4- (4-methylthiazol-5-yl) benzyl) carbazole Yl) -3,6,9,12-tetraoxatetradecan-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, 300MHz}} ) 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 2H), 3.79 (s, 3H), 3.75-3.52 (m, 12H), 2.90-2.59 (m, 3H), 2.56-2.38 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- , 3-dimethyl-1-oxobutan-2-yl) glutaramide

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

1,3-dione (0.1 g, 0.37 mmol) was dissolved 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 thereto, followed by stirring at 90 DEG 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, purified by separation, and the objective compound was prepared.

J = 8.4 Hz, 1H), 7.90-7.88 (m, 1H), 7.62 (d, J = (M, 2H), 2.31 (t, J = 7.4 Hz, 2H), 2.35-2.53 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- , 3-dimethyl-1-oxobutan-2-yl) glutaramide

(25 mg, 0.048 mmol) and (2S, 4R) -1 - ((S) -2-amino-3,3-dimethylbutanoyl) -4-hydroxy- (22 mg, 0.048 mmol) and HATU (27 mg, 0.072 mmol) were dissolved in DMF, and then DIPEA (0.033 mL, , 0.192 mmol), and the mixture is stirred at room temperature. After completion of the reaction, the reaction 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 concentrated under reduced pressure. Silica gel column chromatography separation using a (MPLC, MeOH / DCM 6% , 30 min), to give N ¹ - (2- (2,6- dioxide Sophie-3-yl) -1,3-oksoyi sweep ^{turned-4-yl) -N 5 - ((S)} -1 - ((2S, 4R) -4- hydroxy-2- (4- (4-methylthiazol-5-yl) benzyl carbamoyl) Pyrrolidin-1-yl) -3,3-dimethyl-1-oxobutan-2-yl) glutaramide.

^{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 = 9.0Hz, 0.5H), 4.95-4.84 2H), 2.87-2.62 (m, 3H), 2.50 (s, 3H), 4.51 (m, 4H), 4.31-4.21 (m, 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 Synthesis of 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- , 3-dimethyl-1-oxobutan-2-yl) heptanediamide

The target compound was prepared in a similar manner to Example 10, except that oxocane-2,8-dione was used instead of the glutaric anhydride used in Step 1 of Example 10 above.

^{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 2H), 4.33 (td, J = 14.8, m, 2H), 7.34 (m, 4H), 7.24-7. 2H), 2.80-2.58 (m, 1H), 2.52 (d, J = 5.7 Hz, 1H), 3.98 (m, (M, 3H), 2.49-2.35 (m, 1H), 2.30-2.02 (m, 6H), 1.59-1.46 J = 8.8 Hz, 9H); LC / MS (ESI) m / z 842 [M + H] < + &

Example 12 Synthesis of (2S, 4R) -1 - ((S) -2- (11- (2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindoline- -3-dimethylbutanal) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide Manufacturing

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 above.

^{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 1H), 7.08 (d, J = 7.1 Hz, 1H), 6.92-6.84 (m, 1H), 6.67-6.55 (M, 2H), 2.89-2.59 (m, 1H), 4.73-4.47 (m, 4H), 4.36-4.23 2H), 1.47-1. 36 (s, 2H), 1.36 (m, 2H), 2.57-2.46 (m, 4H) -1.14 (m, 12H), 0.98-0.80 (m, 9H). LC / MS (ESI) m / z 871.7 [M + H] +, 869.8 [MH] -

Example 13 Synthesis of (2S, 4R) -1 - ((S) -2- (8- (2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindoline- 3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine- Preparation of amide

The objective 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 above.

^{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), 6.57 (d, J = 9.1 Hz, 0.5H), 6.32-6.21 (m, 1H), 7.41-7.29 (m, 4H), 7.12-7.04 1H), 4.63-4.82 (m, 1H), 4.72-4.50 (m, 4H), 4.36-4.22 (M, 2H), 1.70 (m, 2H), 3.40-3.18 (m, 2H), 2.88-2.60 (m, 3H), 2.58-2.44 -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 Synthesis of (2S, 4R) -1 - ((S) -2- (12- (2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindoline- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carbaldehyde Preparation of Voxamide

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

^{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) (m, 1H), 4.96-4.76 (m, 1H), 4.72-4.48 (m, 3H), 4.36-4.21 , 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, 14H), 0.99-0.77 (m, 9H). LC / MS (ESI) m / z 885.7 [M + H] +, 883.7 [MH] -

Example 15 Synthesis of (2S, 4R) -1 - ((S) -2- (2- (6- (2- (2,6-dioxopiperidin- (4-methylthiazol-5-yl) benzyl) piperidin-4-ylamino) hexyloxy) acetamido) -3,3-dimethylbutanoyl) -4- 2-carboxamide < / RTI >

The procedure of Example 1 was repeated except for using 2- (6-aminohexyloxy) acetic acid instead of 7-aminoheptanoic acid used in Step 1 of Example 1 to prepare the target compound.

^{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 J = 8.5 Hz, 1H), 6.32-6.19 (m, 1H), 4.97-4.84 (m, 1H), 7.27-7.17 1H), 3.91 (s, 2H), 3.69 (m, 1H), 4.76-4.63 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 Synthesis of (2S, 4R) -1 - ((S) -2- (10- (2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindoline- 3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine- Preparation of amide

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

¹ H NMR (300 MHz, CDCl ₃ )? 10.24 (s, 0.5H), 10.16 (s, 0.5H), 7.65-7.53 J = 8.5 Hz, 1H), 6.71 (dd, J = 9.1, 6.7 Hz, 1H), 6.31-6.18 (m, (M, 1H), 3.97-4.81 (m, 1H), 4.73-4.49 (m, 4H), 4.36-4.24 2H), 1.73-1.60 (m, 3H), 2.32-2. 18 (m, 2H) 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 Synthesis of (2S, 4R) -1 - ((S) -2-tert-butyl-14- (2- (2,6- 4-ylamino) -4-oxo-6,9,12-trioxa-3-azatetradec-l-nonyl) -4-hydroxy-N- (4- 5-yl) benzyl) pyrrolidine-2-carboxamide

Butyl 2- (2- (2-tert-butyl-4-iodo-3-methylpyridazinone) was used in place of tert- butyl 14-iodo-3,6,9,12-tetraoxatetradec- (2-iodoethoxy) ethoxy) ethoxy) acetate was used instead of 2-bromo-2-methoxybenzoyl chloride.

^{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, 1 H), 6.90 (d, J = 8.5 Hz, 1 H), 6.54 (d, J = 4.1 Hz, 1 H), 4.95-4.82 2H), 2.90-2.62 (m, 3H), 3.48-3.57 (m, 3H) (M, 1H), 1.91 (brs, merged with H2O, lH), 0.97 (s, 9H), 2.53 (d, J = 1.2 Hz, 3H), 2.52-2.41 . LC / MS (ESI) m / z 877.1 [M + H] +, 875.0 [MH] -

Example 18 Synthesis of (2S, 4R) -1 - ((S) -2- (11 - ((3- (2,6-dioxopiperidin- Dihydroquinazolin-5-yl) amino) undecanamido) -3,3-dimethylbutanoyl) -4-hydroxy-N- (4- ) Benzyl) pyrrolidine-2-carboxamide < / RTI >

Amino heptanoic acid used in Step 1 of Example 1 was replaced with 11-amino undecanoic acid, and 2- (2,6-dioxopiperidin-3-yl) -4-fluoroisoindoline Except that 3- (5-fluoro-2-methyl-4-oxoquinazolin-3 (4H) -yl) piperidine-2,6-dione was used in place of , The procedure of Example 1 was repeated to produce the 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 2H), 2.92-2.70 (m, 4H), 2.63 (s, 3H), 3.20 (dd, J = 11.0, 3.9 Hz, , 2.49 (m, 3H), 2.34-2.16 (m, 5H), 2.16-2.06 (m, 1H), 1.76-1.55 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 Synthesis of 4,4 '- (nonan-1, 9-diylbis (azanediyl)) bis (2- (2,6-dioxopiperidin- - Dione)

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

(212 mg, 0.82 mmol), 2- (2,6-dioxopiperidin-3-yl) -4-fluoroisoindoline-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 占 폚. The reaction is diluted with ethyl acetate solution and washed with water. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, concentrated, and purified by column chromatography to obtain the desired 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 2H), 1.55-1.38 (m, 13H), 1.38-1.23 (m, 2H), 2.94-2.65 , 8H).

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

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

Step 3: Preparation of 4,4 '- (nonan-1, 9-diylbis (azanediyl)) bis (2- (2,6-dioxopiperidin- )

1,3-dione hydrochloride (63 mg, 0.14 mmol), 2- ((4-fluorophenyl) (39 mg, 0.14 mmol) and DIPEA (0.073 mL, 0.42 mmol) were dissolved in DMF (1 mL), and the mixture was stirred at room temperature for 2 hours Then, it is heated at 90 占 폚. The reaction was diluted with water, extracted with ethyl acetate and washed with brine. The organic layer was dried over anhydrous magnesium sulfate, concentrated, and then separated and purified by column chromatography to obtain 4,4 '- (nonan-1,9-diylbis (azanediyl)) bis (2- 3-yl) isoindoline-1,3-dione).

^{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 Synthesis of (2S, 4R) -1 - ((S) -2- (11- (2- (2- (2,6-dioxopiperidin- (4-methylthiazol-5-yl) benzyl) -3-methylbutanoyl) -4-hydroxy- Preparation of pyrrolidine-2-carboxamide

Step 1: Preparation of tert-butyl 11-aminoundecanoate

A solution of 11-amino undecanoic 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 in vacuo. A solution of _{NaHCO 3 (458 mg, 5.45 mmol} ) in tBuOH (6 ml) to the residue with stirring and the reaction mixture was stirred at room temperature overnight. The volatiles were removed in vacuo and the residue taken up in EtOAc (30 ml) and NaOH (1M, aq) (20 ml). The combined organic layers were washed with water (30 ml) and brine (20 ml x 3), dried over MgSO ₄ and the solvent removed in vacuo to give the desired compound (521 mg, 2.02 mmol, 81% As an oil.

Step 2: tert-Butyl 11- (2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-4-ylamino) acetamido) undecanoate Manufacturing

4-glycine thalidomide (64 mg, 0.194 mmol), HATU (110 mg, 0.291 mmol) and DIPEA (0.135 mL, 0.776 mmol) were added to a solution of the compound prepared in Step 1 (50 mg, 0.194 mmol) And the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, an oil was obtained and dried over MgSO ₄ and the solvent removed in vacuo. 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-dioxoisoindolin-4-ylamino) acetamido) undecanoic acid

To a solution of the compound prepared in Step 2 (71 mg, 0.124 mmol) 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 give an oil. The crude mixture was purified by silica gel column chromatography using DCM / MeOH = 7% to yield the desired compound of step 3 (44 mg, 0.085 mmol, 44% over step 2-3) as a yellow solid.

Step 4: (2S, 4R) -l - ((S) -2- (11- (2- (2- (2,6-Dioxopiperidin- Yl) amino) acetamido) undecanamido) -3,3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazol- Di-2-carboxamide &lt; / RTI &gt;

To a solution of the compound prepared in Step 3 (30 mg, 0.058 mmol) in DMF was added VHL ligand (27 mg, 0.058 mmol), HATU (33 mg, 0.087 mmol), DIPEA (0.040 mL, 0.232 mmol) Lt; / RTI &gt; The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, an oil was obtained and dried over MgSO ₄ and the solvent removed in vacuo. The crude mixture was purified on PREP TLC using MeOH / DCM = 5% to give the final desired compound (10 mg, 0.011 mmol, 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 2H), 4.93-4.84 (m, 1H), 4.72-4.53 (m, 4H), 4.31-4.22 (m, 1H), 6.84 (t, J = 7.8 Hz, ), 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- (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 Synthesis of (2S, 4R) -1 - ((S) -2- (11- (2- (2- (2,6-dioxopiperidin- 4-yloxy) acetamido) undecanamido) -3,3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazol- Preparation of pyrrolidine-2-carboxamide

Step 1: Preparation of tert-butyl 11-aminoundecanoate

A solution of 11-amino undecanoic 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 in vacuo. A solution of _{NaHCO 3 (458 mg, 5.45 mmol} ) in tBuOH (6 ml) to the residue with stirring and the reaction mixture was stirred at room temperature overnight. The volatiles were removed in vacuo and the residue taken up in EtOAc (30 ml) and NaOH (1M, aq) (20 ml). The combined organic layers were washed with water (30 ml) and brine (20 ml x 3), dried over MgSO ₄ and the solvent removed in vacuo to give the desired compound (521 mg, 2.02 mmol, 81% As an oil.

Step 2: tert-Butyl 11- (2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-4-yloxy) acetamido) undecanoate Manufacturing

(64 mg, 0.194 mmol), HATU (110 mg, 0.291 mmol) and DIPEA (0.135 mL, 0.776 mmol) were added to a solution of the compound prepared in Step 1 (50 mg, 0.194 mmol) And the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, an oil was obtained and dried over MgSO ₄ and the solvent removed in vacuo. 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 prepared in Step 2 (48 mg, 0.084 mmol) 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 give an oil. The crude mixture was purified by silica gel column chromatography using DCM / MeOH = 7% to yield the desired compound of step 3 (29 mg, 0.056 mmol, 29% over step 2-3) as a white solid.

Step 4: (2S, 4R) -l - ((S) -2- (11- (2- (2- (2,6-Dioxopiperidin- -4-yloxy) acetamido) undecanamido) -3,3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazol- Di-2-carboxamide &lt; / RTI &gt;

To a solution of the compound prepared in Step 3 (30 mg, 0.058 mmol) in DMF was added VHL ligand (27 mg, 0.058 mmol), HATU (33 mg, 0.087 mmol), DIPEA (0.040 mL, 0.232 mmol) Lt; / RTI &gt; The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, an oil was obtained and dried over MgSO ₄ and the solvent removed in vacuo. The crude mixture was purified on PREP TLC using MeOH / DCM = 5% to give the final desired compound (13 mg, 0.014 mmol, 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, IH), 4.12 (d, J = ), 3.35-3.24 (m, 1H), 2.93-2.63 (m, 3H), 2.56-2.45 (m, 4H), 2.24-2.05 (m, 2H), 1.46-1.13 (m, 14H), 0.93 (s, 9H). , LC / MS (ESI) m / z 928.1 [M + H] &lt; ⁺ &gt;, 926.1 [M-H] ^-

Example 22 Synthesis of (2S, 4R) -1 - ((S) -2- (11- (2- (2,6-dioxopiperidin- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carbaldehyde Preparation of Voxamide

Step 1: Preparation of tert-butyl 11-aminoundecanoate

A solution of 11-amino undecanoic 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 in vacuo. A solution of _{NaHCO 3 (458 mg, 5.45 mmol} ) in tBuOH (6 ml) to the residue with stirring and the reaction mixture was stirred at room temperature overnight. The volatiles were removed in vacuo and the residue taken up in EtOAc (30 ml) and NaOH (1M, aq) (20 ml). The combined organic layers were washed with water (30 ml) and brine (20 ml x 3), dried over MgSO ₄ and the solvent removed in vacuo to give the desired compound (521 mg, 2.02 mmol, 81% As an oil.

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

5-F-thalidomide (61 mg, 0.223 mmol) and DIPEA (0.058 mL, 0.334 mmol) were added to a solution of the compound prepared in Step 1 (86 mg, 0.334 mmol) in DMSO, Respectively. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, an oil was obtained and dried over MgSO ₄ and the solvent removed in vacuo. The crude mixture was purified by silica gel column chromatography using EtOAc / Hx = 37% to give the title 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 prepared in Step 2 (38 mg, 0.074 mmol) 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 give an oil. The crude mixture was purified by silica gel column chromatography using DCM / MeOH = 7% to yield the desired compound of step 3 (12 mg, 0.026 mmol, 11% over step 2-3) as a yellow solid.

Step 4: (2S, 4R) -l - ((S) -2- (11- (2- (2,6- Dioxopiperidin- 3-yl) -1,3-dioxoisoindoline- 3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide Manufacturing

(12 mg, 0.026 mmol), HATU (15 mg, 0.039 mmol) and DIPEA (0.018 mL, 0.104 mmol) were added to a solution of the compound prepared in Step 3 (12 mg, 0.026 mmol) in DMF at room temperature Lt; / RTI &gt; The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, an oil was obtained and dried over MgSO ₄ and the solvent removed in vacuo. The crude mixture was purified on PREP TLC using MeOH / DCM = 5% to give the final desired compound (12 mg, 0.014 mmol, 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 (M, 1H), 4.96-4.87 (m, 1H), 4.72 (t, J = 5.0 Hz, 1H), 4.70-4.65 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 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 Synthesis of 3,3 '- (5,5' - (nonan-1, 9-diylbis (acridine)) bis (4-oxobenzo [d] [1,2,3] triazine- 5,3 (4H) -diyl)) dipiperidine-2,6-dione

Instead of 2- (2,6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1,3-dione used in step 1 and step 4 of Example 19, (5-amino-4-oxobenzo [d] [1,2,3] triazine-3 (4H) -yl) piperidine- Dione, the target compound was prepared.

^{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), 2H), 6.74 (d, J = 8.5 Hz, 2H), 5.74-. 64 (m, 2H), 3.25-1.3 (m, 4H), 3.00- , 6H), 2.41-2.8 (m, 2H), 1.76-62 (m, 6H), 1.49-2.9 (m, 11H), 0.95-.

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

Instead of 2- (2,6-dioxopiperidin-3-yl) -4-fluoroisoroidine-1,3-dione used in step 1 of Example 19, (4H) -yl) piperidine-2,6-dione, prepared as described in Example 1, using 3- (5-amino-4-oxobenzo [d] [1,2,3] triazin- , The target compound was prepared.

^{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 = 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 Synthesis of (2S, 4R) -1 - ((S) -2- (11- (3- (2,6-dioxopiperidin- 3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiadiazol-5-yl) 5-yl) benzyl) pyrrolidine-2-carboxamide

Amino heptanoic acid used in Step 1 of Example 1 was replaced with 11-amino undecanoic acid, and 2- (2,6-dioxopiperidin-3-yl) -4-fluoroisoindoline (5-amino-4-oxobenzo [d] [1, 2,3] triazin-3-one, prepared as described in Application No. 10-2017-0184761, (4H) -yl) piperidin-2, 6-dione was used instead of 2-pyridylmethoxycarbonylpyridine.

¹ H NMR (300 MHz, CDCl ₃ )? 10.17 (s, 0.5H), 9.74 (s, 0.5H), 8.68 (s, 1H), 8.25-8.13 J = 5.5 Hz, 1H), 7.40-7.30 (m, 4H), 7.23 (d, J = 7.7 Hz, 1H) (M, 5H), 6.50 (d, J = 8.7 Hz, 1H), 5.72-5.62 , 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 2H), 1.49-1.38 (m, 2H), 1.49-1. 48 (m, 3H), 2.58-2.45 (m, 4H), 2.37-2.23 1.38-1.16 (m, 12H), 0.98-0.87 (m, 9H).

The chemical structures 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 proteolytic activity of cerrebone (CRBN)

In order to evaluate the cerreon (CRBN) proteolytic activity of the compounds according to the present invention, the following experiment was conducted.

Specifically, HEK293T cells were injected into each well of a 12-well plate at 5 × 10 ⁵ cells. On the next day, Example Compound 1-22 was treated to final concentrations of 10 nM, 30 nM, 100 nM, 300 nM, 1 μM, 3 μM and 10 μM in each well. One well was treated with the same percentage of DMSO. After 24 hours of treatment, the cells were collected and cell lysate was prepared using NP40 Lysis buffer (20 mM Tris, pH 7.5, 150 mM NaCl, 1% NP-40, 1 mM EDTA, and protease inhibitor cocktail) And the results are shown in Table 2 below.

In addition, the results of analysis of cerrebone protein for Examples 1, 3 and 8 are shown in Fig. 1, and the degree of proteolysis of cerrebone according to the concentration of treated compounds of Examples 1, 3 and 8 (DC ₅₀ ) Respectively.

Example Cerebrene (CRBN) degradative activity Example Cerebrene (CRBN) degradative 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 (> 50%) above 50% at 300 nM concentration +: Decrease (<50%) below 50% at 300 nM concentration

Table 2 shows that the compound of Example according to the present invention can decompose CRBN protein at a concentration of 300 nM, and in particular, the compounds of Examples 1, 2, 3, 4, 12, 13, 14, 16 , 19, 20, 22, 23, 24, and 25 exhibited greater than 50% degradation activity at a concentration of 300 nM.

Therefore, the compounds according to the present invention can decompose cerrebone (CRBN) protein to a high concentration in the nano-molar unit, and can be effectively used for the prevention and treatment of CRBN-related diseases.

Claims (10)

A-Linker-A or A-Linker-B, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
Wherein A is a Cerebron E3 ubiquitin ligase binding moiety;

The linker is a linker having 3 to 20 linkages selected from the group consisting of - (CH ₂ ) -, - (C═O) -, -NH- and -O-,
The linking group can not be linked to -O- in succession; And

Wherein B is an E3 ubiquitin ligase binding moiety,
Here, Linker and A or B are chemically linked.
The method according to claim 1,
Wherein A is Thalidomide, Lenalidomide, Pormalidomide, an analogue thereof, a copper complex thereof, or a derivative thereof;

The linker,

However,
Wherein a and i are independently 0 or 1;
B is an integer from 0 to 20;
Wherein c is 0 or 1;
D is an integer of 0-3;
E is 0 or 1;
F is an integer from 1 to 10;
G is 0 or 1;
H is an integer of 0-3;
J and k are independently an integer of 0-5; And

Wherein B is a compound represented by the following formula (1)
[Chemical Formula 1]

In Formula 1,
R ⁴ is OR ⁶ ;
R ⁵ is 5-10 membered heteroaryl comprising at least one heteroatom selected from the group consisting of optionally substituted or unsubstituted -NR ⁶ - (CH ₂ ) oC _6-10 aryl-N, O, and S However,
5-10 membered heteroaryl comprising at least one heteroatom selected from the group consisting of the substituted -NR ⁶ - (CH ₂ ) o C _6-10 aryl-N, O, and S is C _1-10 straight chain Or branched alkyl,
Wherein R &lt; ⁶ &gt; is H or a straight or branched chain alkyl of _1-5 , wherein o is 0-5;
R ⁷ is -CR ⁸ -NR ⁹ -
Wherein R ⁸ is a linear or branched alkyl of C _1-10 and R ⁹ is H or a straight or branched chain alkyl of C _1-5 , a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, Acceptable salts.
The method according to claim 1,
Wherein A is one of the following formulas (a) to (g)

,

,

,

,

,

, or

In the above formulas (a), (b), (c), (d), (e), (f) and (g)
W is CH ₂ , CHR, C = O, SO ₂ , NH, or a linear or branched alkyl of NC _1-10 ,
Each X is independently O, S, or H ₂ ,
Y is NH, a linear or branched alkyl of NC _1-10 , NC _6-10 aryl, N-heteroaryl (5-10 angles containing one or more heteroatoms selected from the group consisting of N, O, and S, unsubstituted heteroaryl), NC _3-9 cycloalkyl, heterocycloalkyl N- (N, O, and 3-10 containing at least one heteroatom selected from the group consisting of S, each unsubstituted heterocycloalkyl), O, Or S,
Z is O, S, or H ₂ ,
G and G 'are each independently selected from the group consisting of H, C _1-10 linear or branched alkyl, OH, substituted or unsubstituted CH ₂ -heterocyclyl (N, O, and S) Heterocyclyl of a 3-10 heterocycle containing one or more heteroatoms), or benzyl which is unsubstituted or substituted by R '
Q ₁ , Q ₂ , Q ₃ , and Q ₄ are each independently carbon substituted with R ', or N,
A is straight or branched chain alkyl of C _1-10 , 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 (heteroaryl of 5-10 heterocycle containing one or more heteroatoms selected from the group consisting of N, O, and S), -C _1-10 linear or branched alkyl, -C _3-9 cycloalkyl, - heterocyclyl (N, O, and 3-10 containing at least one heteroatom selected from the group consisting of S, each ring heterocyclyl), -P ( -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 _{independently} 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, (Heteroaryl of 5-10 heterocyclic rings containing heteroatoms), heterocyclyl (heterocyclyl of 3-10 heterocyclic rings containing at least one heteroatom selected from the group consisting of N, O, and S) , &Lt; / RTI &gt;

(R or S) or non-stereospecific linkages; 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 &lt; ³ &gt; -,
Here again, m is an integer from 0 to 5,
Wherein R &lt; ³ &gt; is each H, or an unsubstituted or substituted C _1-10 straight chain or branched chain alkyl,
Wherein said substituted alkyl is substituted with a halogen, nitro, or cyano group, and R _n is covalently bonded to a linker; And

The linker,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

, or

A stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
The method according to claim 1,
A is

,

,

, or

However,
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,
Wherein R ² and R ³ are each independently H, or an unsubstituted or substituted C _1-10 straight chain or branched chain alkyl,
Wherein said substituted alkyl is substituted with a halogen, nitro, or cyano group; And

B is

However,
Wherein R ² and R ³ are each independently H or an unsubstituted or substituted C _1-10 straight chain or branched chain alkyl,
Wherein said substituted alkyl is substituted with a halogen, nitro, or cyano group, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
The method 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, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
(1) Synthesis of (2S, 4R) -1 - ((S) -2- (7- (2- (2,6-dioxopiperidin- Amino) heptanamido) -3,3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide;
(2) Synthesis of (2S, 4R) -1 - ((S) -2- (6- (2- (2,6-dioxopiperidin- Amino) hexanoamido) -3,3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide;
(3) Synthesis of (2S, 4R) -1 - ((S) -2- (9- (2- (2,6-dioxopiperidin- Amino) nonanamido) -3,3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide;
(4) Synthesis of (2S, 4R) -1 - ((S) -2-tert- butyl-17- (2- (2,6-dioxopiperidin- 4-ylamino) -4-oxo-6,9,12,15-tetraoxa-3-azaheptadec-l-nonyl) -4-hydroxy-N- (4- 5-yl) benzyl) pyrrolidine-2-carboxamide;
(5) Synthesis of (2S, 4R) -1 - ((S) -2- (2- (3- (2- (2- (2,6-dioxopiperidin- 4-ylamino) -2-oxoethoxy) propoxy) acetamido) -3,3-dimethylbutanoyl) -4-hydroxy-N- (4- 5-yl) benzyl) pyrrolidine-2-carboxamide;
(6) N ¹ - (2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-4-yl) -N ⁹ - Pyrrolidin-l-yl) -3,3-dimethyl-l-oxobutane-l- 2-yl) nonanediamide;
(7) Synthesis of N ¹ - (2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-4-yl) -N ⁸ - Pyrrolidin-l-yl) -3,3-dimethyl-l-oxobutane-l- 2-yl) octanediamide;
(8) Synthesis of N ¹ - (2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-4-yl) -N ⁷ - (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin- 1 -yl) -3,3-dimethyl- Butan-2-yl) heptanediamide;
(9) Synthesis of N ¹ - (2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-4-yl) -N ¹⁴ - (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin- 1 -yl) -3,3-dimethyl- Butan-2-yl) -3,6,9,12-tetraoxatetradecan-1,14-diamide;
(10) Synthesis of N ¹ - (2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-4-yl) -N ⁵ - Pyrrolidin-l-yl) -3,3-dimethyl-l-oxobutane-l- 2-yl) glutaramide;
^{(11) N 1 - ((} 2- (2,6- dioxide Sophie piperidine turned-3-yl) -1,3-stamp oksoyi 4-yl) ^{methyl) -N 7 - ((S)} -1 ((2S, 4R) -4-hydroxy-2- (4- (4-methylthiazol- 5- yl) benzylcarbamoyl) pyrrolidin- 1 -yl) -3,3- Oxobutan-2-yl) heptanediamide;
(12) Synthesis of (2S, 4R) -1 - ((S) -2- (11- (2- (2,6-dioxopiperidin- Undecanamido) -3,3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide;
(13) Synthesis of (2S, 4R) -1 - ((S) -2- (8- (2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin- Amino) octanoamido) -3,3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide;
(14) Synthesis of (2S, 4R) -1 - ((S) -2- (12- (2- (2,6-dioxopiperidin- 3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide ;
(15) Synthesis of (2S, 4R) -1 - ((S) -2- (2- (6- (2- (2,6-dioxopiperidin- Yl) amino) hexyloxy) acetamido) -3,3-dimethylbutanoyl) -4-hydroxy-N- (4- Carboxamide;
(16) Synthesis of (2S, 4R) -1 - ((S) -2- (10- (2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin- Dimethylanilino) -3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide;
(17) Synthesis of (2S, 4R) -1 - ((S) -2-tert- butyl- 14- (2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindoline Ylamino) -4-oxo-6,9,12-trioxa-3-azatetradec-l-nonyl) -4- Yl) benzyl) pyrrolidine-2-carboxamide;
(18) (2S, 4R) -1 - ((S) -2- (11 - ((3- (2,6-dioxopiperidin- (4-methylthiazol-5-yl) amino) undecanamido) -3,3-dimethylbutanoyl) -4-hydroxy- ) Pyrrolidine-2-carboxamide;
(19) 4,4 '- (nonan-1, 9-diylbis (azanediyl)) bis (2- (2,6-dioxopiperidin-3- yl) isoindoline- );
(20) Synthesis of (2S, 4R) -1 - ((S) -2- (11- (2- (2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindoline Yl) amino) acetamido) undecanamido) -3,3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazol- Di-2-carboxamide;
(21) Synthesis of (2S, 4R) -1 - ((S) -2- (11- (2- (2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindoline -4-yloxy) acetamido) undecanamido) -3,3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazol- Di-2-carboxamide;
(22) Synthesis of (2S, 4R) -1 - ((S) -2- (11- (2- (2,6-dioxopiperidin- 3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide ;
(23) Synthesis of 3,3 '- (5,5' - (nonan-1, 9-diylbis (azacyl)) bis (4-oxobenzo [d] [1,2,3] 3 (4H) -diyl)) dipiperidin-2,6-dione;
(24) 2- (2,6-Dioxopiperidin-3-yl) -4- (9- (3- (2,6-dioxopiperidin- - dihydrobenzo [d] [1,2,3] triazin-5-ylamino) nonylamino) isoindoline-1,3-dione; And
(25) Synthesis of (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- 5-yl) benzyl) pyrrolidine-2-carboxamide.
As shown in Scheme 1 below,
(Step 1) of producing a compound represented by A-Linker-V from a compound represented by U-Linker-V;
A-Linker-A or A-Linker-B from the compound represented by A-Linker-V prepared in Step 1 above (Step 2). A or A-Linker-B:
[Reaction Scheme 1]

(In the above Reaction Scheme 1,
A, Linker and B are as defined in claim 1; And
U or V are each independently selected from NH ₂ or OH).
A pharmaceutical composition for the prophylaxis or treatment of a Cereblon-related disease containing the compound of claim 1, a stereoisomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.
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 preventing or treating an autoimmune disease, which comprises the compound of claim 1, a stereoisomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.
A pharmaceutical composition for preventing or treating a metabolic disease comprising the compound of claim 1, a stereoisomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.

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