[go: up one dir, main page]
More Web Proxy on the site http://driver.im/

WO2019078522A1 - Cereblon protein degradation inducing compound, preparation method therefor and pharmaceutical composition for preventing or treating cancer, containing same as active ingredient - Google Patents

Cereblon protein degradation inducing compound, preparation method therefor and pharmaceutical composition for preventing or treating cancer, containing same as active ingredient Download PDF

Info

Publication number
WO2019078522A1
WO2019078522A1 PCT/KR2018/011782 KR2018011782W WO2019078522A1 WO 2019078522 A1 WO2019078522 A1 WO 2019078522A1 KR 2018011782 W KR2018011782 W KR 2018011782W WO 2019078522 A1 WO2019078522 A1 WO 2019078522A1
Authority
WO
WIPO (PCT)
Prior art keywords
dioxopiperidin
linker
synthesis
hydroxy
benzyl
Prior art date
Application number
PCT/KR2018/011782
Other languages
French (fr)
Korean (ko)
Inventor
황종연
하재두
조성윤
김필호
박병철
김선홍
김정훈
박성구
Original Assignee
한국화학연구원
한국생명공학연구원
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 한국화학연구원, 한국생명공학연구원 filed Critical 한국화학연구원
Publication of WO2019078522A1 publication Critical patent/WO2019078522A1/en

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/4035—Isoindoles, e.g. phthalimide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

  • 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.
  • E1 ubiquitin-proteasome system
  • E2 ubiquitin-proteasome system
  • 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.
  • ubiquitin ubiquitin
  • More than 600 E3 ubiquitin ligases are known to be ligases, and it is known that the proteins degraded by ligase type are different.
  • E3 ubiquitin ligase CRBN Cereblon
  • IMD immunomodulatory drugs
  • CRBN is expressed in the immune cells (T-cells).
  • T-cells the immune cells
  • 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.
  • CRBN inhibitors have not achieved the desired level of pharmacological effect.
  • 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.
  • the drug resistance is generated within one year after the administration to lower the effect of the drug.
  • 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.
  • 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.
  • 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 (WO 2013/106643 A2), which can be applied to an undruggable target which is difficult to achieve an inhibitory effect as an existing drug.
  • 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.
  • Another object of the present invention is to provide a process for producing the above compound.
  • 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.
  • 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.
  • the present invention provides a compound represented by A-Linker-A or A-Linker-B, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
  • A is 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
  • B is an E3 ubiquitin ligase binding moiety
  • 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 >
  • U or V are each independently selected from NH 2 or OH).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the present invention provides a compound represented by A-Linker-A or A-Linker-B, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
  • A is 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
  • B is an E3 ubiquitin ligase binding moiety
  • 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.
  • the A is Thalidomide, Lenalidomide, Pormalidomide, analogs thereof, their copper complexes, or derivatives thereof.
  • A is one of the following formulas (a) to (g)
  • 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", -
  • 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 >
  • n is an integer from 0 to 5
  • R < 3 > is each H, or an unsubstituted or substituted C 1-10 straight chain or branched chain alkyl
  • substituted alkyl is substituted with a halogen, nitro, or cyano group, and R n is covalently bonded to a linker.
  • A is , , , or However,
  • n is an integer from 0 to 5
  • R 2 and R 3 are each independently H, or an unsubstituted or substituted C 1-10 straight chain or branched chain alkyl
  • said substituted alkyl is substituted with halogen, nitro, or cyano.
  • A is , , , , , , or However,
  • n is an integer from 0 to 5
  • R 2 and R 3 are each independently H, or an unsubstituted or substituted C 1-10 straight chain or branched chain alkyl
  • said substituted alkyl is substituted with halogen, nitro, or cyano.
  • the linker comprises:
  • a and i are independently 0 or 1;
  • B is an integer from 0 to 20;
  • 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.
  • 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 mo
  • B may be CRBN (cereblon) or VHL (von Hippel-Lindau) E3 ligand binding moiety.
  • 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
  • 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
  • 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,
  • R < 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 -
  • 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.
  • R 2 and R 3 are each independently H or an unsubstituted or substituted C 1-10 straight chain or branched chain alkyl
  • said substituted alkyl is substituted with halogen, nitro, or cyano.
  • A-Linker-A or A-Linker-B include the following compounds.
  • 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.
  • 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.
  • 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
  • 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.
  • an organic solvent such as methanol, ethanol, acetone, dichloromethane or acetonitrile
  • 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.
  • the corresponding salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable salt (such as silver nitrate).
  • 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 .
  • 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 >
  • U or V are each independently selected from NH 2 or OH).
  • the step 1 is a step of reacting a compound represented by A-Linker-V from a compound represented by U- .
  • 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.
  • Cereblor ligase represented by A in Linker Can be considered as the step of introducing the ligand compound.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • A-NH 2 or B-NH 2 can be used.
  • 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.
  • 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 .
  • 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 .
  • 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.
  • 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.
  • 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.
  • 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.
  • PROTAC protein cleavage inhibitors
  • 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) ,
  • IMD immunomodulatory drug
  • 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.
  • the compound represented by A-Linker-A or A-Linker-B of the present invention 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.
  • 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.
  • 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.
  • the compound of the present invention 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.
  • 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.
  • the moiety represented by A is a thalidomide, a lanalidomide, a fomalidomide, an analogue thereof,
  • 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.
  • 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.
  • 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, retinoblastom
  • 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.
  • AML acute myelogenous leukemia
  • CML Chronic myelogenous leukemia
  • ALL acute lymphocytic leukemia
  • CLL Chronic lymphocytic leukemia
  • HD Hodgkin's disease
  • NHL Non-Hodgkin's lymphoma
  • cancer includes, but is not limited to, solid tumors and blood mediated tumors (hematologic malignant tumors).
  • " cancer &quot 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,
  • 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; A
  • 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 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.
  • 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
  • a diluent or excipient such as a commonly used filler, an extender, a binder, a wetting agent, a disintegrant, a surfactant, and the like.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 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
  • 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,
  • ITP idiopathic thrombocytopenic purpura
  • lupus nephritis and membranous nephropathy
  • 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.
  • 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.
  • 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.
  • the amount may vary depending on the body weight, age, sex, condition, and family history of the subject to be administered.
  • 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.
  • 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.
  • 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.
  • subject means an animal, such as a mammal, such as a human.
  • Step 1 Preparation of 7- (2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-4-ylamino) heptanoic acid
  • 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
  • Step 1 Preparation of 6 - ((2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-4-yl) amino)
  • 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
  • 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).
  • 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)
  • 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
  • Step 1 Preparation of tert-butyl 14-amino-3,6,9,12-tetraoxatetradec-1 -noate
  • Step 2 tert-Butyl 14 - ((2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-4- yl) amino) -3,6,9,12 - Preparation of tetraoxatetradecanoate
  • Step 3 14 - ((2- (2,6-Dioxopiperidin-3-yl) -1,3-dioxoisoindolin-4- yl) amino) -3,6,9,12- Preparation of tetradecanoic acid
  • 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
  • Step 1 Preparation of di-tert-butyl 2,2 '- (propane-1,3-diylbis (oxy)) diacetate
  • Step 2 Preparation of 2,2 '- (propane-1,3-diylbis (oxy)) diacetic acid
  • 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.
  • 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
  • Step 1 Preparation of di-tert-butyl 3,6,9,12-tetraoxatetradecanedioate
  • 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.
  • Step 4 N1- (2- (2,6-Dioxopiperidin-3-yl) -1,3-dioxoisoindolin- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin- 1 -yl) -3,3-dimethyl-1-oxobutane- 2-yl) -3,6,9,12-tetraoxatetradecan-1,14-diamide
  • 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.
  • Step 2 N1- (2- (2,6-Dioxopiperidin-3-yl) -1,3-dioxoisoindolin- Pyrrolidin-1-yl) -3,3-dimethyl-1-oxobutane-2- (4-methyl- Yl) glutaramide < / RTI >
  • 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.
  • 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.
  • 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.
  • 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.
  • Example 1 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.
  • 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.
  • Step 1 Preparation of tert-butyl (9 - ((2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-4-yl) amino)
  • 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
  • DIPEA 0.073 mL, 0.42 mmol
  • Step 2 tert-Butyl 11- (2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-4-ylamino) acetamido) undecanoate Manufacturing
  • Step 3 Preparation of 11- (2- (2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-4-ylamino) acetamido) undecanoic acid
  • Step 4 (2S, 4R) -l - ((S) -2- (11- (2- (2- (2- (2,6-Dioxopiperidin- Yl) amino) acetamido) undecanamido) -3,3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazol- Di-2-carboxamide < / RTI >
  • Step 2 tert-Butyl 11- (2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-4-yloxy) acetamido) undecanoate Manufacturing
  • Step 3 Preparation of 11- (2- (2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-4-yloxy) acetamido) undecanoic acid
  • Step 4 (2S, 4R) -l - ((S) -2- (11- (2- (2- (2- (2,6-Dioxopiperidin- -4-yloxy) acetamido) undecanamido) -3,3-dimethylbutanoyl) -4-hydroxy-N- (4- (4-methylthiazol- Di-2-carboxamide < / RTI >
  • Step 2 Preparation of tert-butyl 11- (2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-5-ylamino) undecanoate
  • Step 3 Preparation of 11- (2- (2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-5-ylamino) undecanoic acid
  • 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
  • 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.
  • 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
  • Example Compound 1-22 was treated to final concentrations of 10 nM, 30 nM, 100 nM, 300 nM, 1 ⁇ M, 3 ⁇ M and 10 ⁇ M in each well.
  • One well was treated with the same percentage of DMSO.
  • 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.
  • Example Cerebrene (CRBN) degradative activity 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 ++
  • 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.
  • 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.
  • CRBN cerrebone
  • 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.
  • 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.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to a cereblon protein degradation inducing compound, a preparation method therefor and a pharmaceutical composition for preventing or treating cancer, containing the same as an active ingredient. 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 an active ingredient, the present invention is useful as a pharmaceutical composition for preventing or treating cereblon-related diseases, preferably diseases, such as cancer, autoimmune diseases or metabolic diseases, in which effects such as treatment, prevention or alleviation can be achieved by inhibiting or degrading cereblon.

Description

세레브론 단백질의 분해 유도 화합물, 이의 제조방법 및 이를 유효성분으로 함유하는 암의 예방 또는 치료용 약학적 조성물A pharmaceutical composition for the prevention or treatment of cancers containing it as an active ingredient
본 발명은 세레브론 단백질의 분해 유도 화합물, 이의 제조방법 및 이를 유효성분으로 함유하는 암의 예방 또는 치료용 약학적 조성물에 관한 것이다.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.
세포는 단백질-항상성(protein homeostasis)을 유지하기 위해 유비퀴틴-프로테아좀 시스템(Ubiquitin-proteasome system, UPS)을 이용하여 표적 단백질을 분해한다. 이는 E1, E2, E3 리가제라 불리는 단백질이 76개의 아미노산으로 이루어진 유비퀴틴(Ub)을, 분해하고자 하는 표적단백질(substrate)에 전달하여 다중유비퀴틴화(polyubiquitination) 시키면, 26S 프로테아좀(proteasome)이 이를 인지하여 표적 단백질을 분해하는 과정을 통해서 이루어진다. 리가제 중 E3 유비퀴틴 리가제는 600여종 이상 알려져 있으며, 리가제 종류에 따라 분해되는 단백질이 다르다고 알려져 있다.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.
한편, E3 유비퀴틴 리가제 중 세레브론(CRBN, Cereblon)은 면역조절약물(Immunomodulatory drug, IMiD)로 알려진 탈리도마이드, 레날리도마이드, 포말리도마이드 등이 결합하면, 전사요인(transcription factor)인 이카로스(ikaros), 에이오로스(aiolos)를 분해 시켜 우수한 항암 효과를 보일 뿐만 아니라, 루푸스를 포함하는 자가면역질환 질환에 효과가 있다. 이에, 세레브론 자체를 표적하는 면역조절약물 개발이 활발히 이루어지고 있다.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.
또 다른 한편, 세레브론은 특정 단백질의 분해에 관여하는 E3 유비퀴틴 리가제 역할외에도, 광주과학기술원 박철승 교수연구팀은 CRBN이 AMPK의 활성을 억제함을 확인하였고, CRBN을 억제하였을 경우에는, 에너지센서인 AMPK가 활성화됨을 확인한 바, 이러한 CRBN 억제 유도로부터 비만, 지방간, 당뇨병 등 대사질환의 예방 또는 치료 가능성을 제시하였다.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.
나아가, 광주과학기술원 박성규 교수 연구팀은 면역세포(T-세포)에 CRBN이 많이 발현되어 있음을 확인하였고, CRBN이 결핍되면 T 세포에서 칼륨 이온채널의 발현이 증가하고, 이를 통해 T 세포가 활성화되는 것을 확인하였으며, 이와 같은 후성적 유전자 발현 조절을 통해 항원에 대한 T세포의 민감도를 조절 할 수 있다는 연구 결과를 보고하였다. 이와 같은 연구 결과로부터, CRBN 결핍의 유도는 T세포에 과발현 되어 있는 CRBN의 양을 낮추어 T세포의 활성을 증가시키는 효과를 유도됨을 알 수 있고, 이러한 효과를 야기할 수 있는 CRBN 결핍 유도로부터 항암면역치료제 개발 가능성을 제시하였다.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.
상술된 E3 유비퀴틴 리가제인 CRBN과 관련한 배경기술로부터 알 수 있듯이, 세레브론의 억제 또는 결핍을 유도한다면, 암, 자가면역질환, 대사질환, 등에 유용한 효과가 달성될 수 있다.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.
그러나, 아직까지 CRBN을 표적한 저분자 약물 개발이 전무하고, 또한 기존의 CRBN 억제제는 목적하는 수준의 약리 효과가 달성되지 못하고 있다. 특히, 기존의 항암 표적 치료제는 표적의 신호 전달을 저해하기 위해서는 표적에 대한 높은 저해력이 요구되며, 치료효과를 보이기 위해서는 많은 양을 오랜 기간 투여해야 하는 단점을 가지고 있고, 또한 약물에 대한 내성이 빠르게 나타나, 투여 후 1년 이내에 약물 내성이 발생하여 약물의 효과를 낮추게 되는 문제점이 있다. 또한, 세포독성 치료제는 암이 발생한 표적에 직접 작용할 수 없어, 상기 항암 표적 치료제와 비교하여 부작용 발생이 크고, 치료효가 적은 문제가 있다.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.
따라서, 항암 표적 치료제, 세포독성 치료제 보다 우수한 치료효과가 달성되고, 약물 내성 부작용 등의 문제점을 극복할 수 있는 새로운 기술 개발이 요구되며, 세레브론을 목적하는 수준으로 저해 또는 결핍시켜, 목적하는 수준으로 약리효과가 달성될 수 있는 치료제 개발이 요구된다.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.
상술된 배경에서, 최근 예일대학교의 연구팀(Craig Crews)이 단백질 분해 유도제(Proteolysis Targeting Chimera, PROTAC)기술을 개발하였다.In the background described above, a recent team from Yale University (Craig Crews) developed the Proteolysis Targeting Chimera (PROTAC) technology.
PROTAC은 특정 단백질에 결합하는 저해제(inhibitor) 또는 결합인자(binder) 화합물과 E3 유비퀴틴 리가아제에 특징적으로 결합하는 리간드 화합물을 다양한 종류의 링커로 연결하여 제조되는 신규 치료제로서, PROTAC 물질은 질병의 원인이 되는 표적 단백질만을 타깃하여 분해하기 때문에 약물에 대한 내성발생이 낮고, 표적 단백질에 결합만 가능하다면, PROTAC 자체의 대상 단백질에 대한 높은 저해활성 없이도, 활성표적 단백질 분해로부터 충분한 치료효과가 달성되는 바, 기존 약물로는 저해효과가 달성이 어려웠던 표적(undruggable target)에도 적용이 가능한 바, 신규한 메카니즘의 질환 치료기술로 각광받고 있다(WO 2013/106643 A2).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 (WO 2013/106643 A2), which can be applied to an undruggable target which is difficult to achieve an inhibitory effect as an existing drug.
이에, 본 발명자들은 CRBN에 결합하는 결합 화합물(binder)인 탈리도마이드 및 이의 유도체와 E3 리가제, 특히 VHL 리간드 또는 CRBN 리간드(탈리도마이드 유도체)를 다양한 링커를 통해 연결하여 신규 CRBN-PROTAC 물질을 개발하였고, 이로부터 성공적으로 CRBN이 분해되는 것을 확인 하였으며, 향후 CRBN 분해제로의 활용 뿐만 아니라, CRBN 관련 질환, 바람직하게 대사질환, 자가면역질환 또는 암의 예방 또는 치료용 약학적 조성물 또는 자가면역질환 예방 또는 치료용 약학적 조성물로 유용할 수 있음을 규명하여 본 발명을 완성하였다.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.
본 발명의 목적은 세레브론(CRBN) 분해하는 화합물을 제공하는 것이다.It is an object of the present invention to provide compounds that degrade cerebrone (CRBN).
본 발명의 다른 목적은 상기 화합물의 제조방법을 제공하는 것이다.Another object of the present invention is to provide a process for producing the above compound.
본 발명의 또 다른 목적은 상기 화합물을 유효성분으로 함유하는 세레브론 관련 질환의 예방 또는 치료용 약학적 조성물을 제공하는 것이다.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.
본 발명의 다른 목적은 상기 화합물을 유효성분으로 함유하는 암의 예방 또는 치료용 약학적 조성물을 제공하는 것이다.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.
본 발명의 또 다른 목적은 상기 화합물을 유효성분으로 함유하는 자가면역질환의 예방 또는 치료용 약학적 조성물을 제공하는 것이다.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.
본 발명의 다른 목적은 상기 화합물을 유효성분으로 함유하는 대사질환의 예방 또는 치료용 약학적 조성물을 제공하는 것이다.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.
본 발명의 또 다른 목적은 상기 화합물을 유효성분으로 함유하는 세레브론 관련 질환의 예방 또는 개선용 건강기능식품을 제공하는 것이다.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.
상기 목적을 해결하기 위해,In order to solve the above object,
본 발명은 A-Linker-A 또는 A-Linker-B로 표시되는 화합물, 이의 입체 이성질체, 또는 이의 약학적으로 허용 가능한 염을 제공한다:The present invention provides a compound represented by A-Linker-A or A-Linker-B, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
상기 A는 세레브론(Cerebron) E3 유비퀴틴 리가아제 결합 모이어티(moiety)이고;Wherein A is a Cerebron E3 ubiquitin ligase binding moiety;
상기 Linker는 -(CH2)-, -(C=O)-, -NH- 및 -O-로 이루어진 군으로부터 선택되는 1종 이상이 3-20개 연결된 연결기(linker)이되,The linker is a linker having 3 to 20 linkages selected from the group consisting of - (CH 2 ) -, - (C═O) -, -NH- and -O-,
상기 연결기는 연속하여 -O-로 연결될 수 없고; 및The linking group can not be linked to -O- in succession; And
상기 B는 E3 유비퀴틴 리가아제 결합 모이어티(moiety)이고,Wherein B is an E3 ubiquitin ligase binding moiety,
여기서 Linker와 A 또는 B는 화학적으로 연결된다.Here, Linker and A or B are chemically linked.
또한, 본 발명은 하기 반응식 1에 나타난 바와 같이,The present invention also relates to a process for producing a compound represented by the formula (1)
U-Linker-V로 표시되는 화합물로부터 A-Linker-V로 표시되는 화합물을 제조하는 단계(단계 1);(Step 1) of producing a compound represented by A-Linker-V from a compound represented by U-Linker-V;
상기 단계 1에서 제조한 A-Linker-V로 표시되는 화합물로부터 A-Linker-A 또는 A-Linker-B로 표시되는 화합물을 제조하는 단계(단계 2);를 포함하는 상기 A-Linker-A 또는 A-Linker-B로 표시되는 화합물의 제조방법을 제공한다: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 >
[반응식 1][Reaction Scheme 1]
Figure PCTKR2018011782-appb-I000001
Figure PCTKR2018011782-appb-I000001
(상기 반응식 1에 있어서,(In the above Reaction Scheme 1,
A, Linker 및 B는 상기에서 정의한 바와 같고; 및A, Linker and B are as defined above; And
U 또는 V는 각각 독립적으로 NH2 또는 OH이다).U or V are each independently selected from NH 2 or OH).
나아가, 본 발명은 상기 A-Linker-A 또는 A-Linker-B로 표시되는 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 세레브론(Cereblon) 관련 질환의 예방 또는 치료용 약학적 조성물을 제공한다.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.
또한, 본 발명은 상기 A-Linker-A 또는 A-Linker-B로 표시되는 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 암의 예방 또는 치료용 약학적 조성물을 제공한다.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.
나아가, 본 발명은 상기 A-Linker-A 또는 A-Linker-B로 표시되는 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 자가면역질환의 예방 또는 치료용 약학적 조성물을 제공한다.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 .
또한, 본 발명은 상기 A-Linker-A 또는 A-Linker-B로 표시되는 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 대사질환의 예방 또는 치료용 약학적 조성물을 제공한다.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.
나아가, 본 발명은 상기 A-Linker-A 또는 A-Linker-B로 표시되는 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 세레브론(Cereblon) 관련 질환의 예방 또는 개선용 건강기능식품 조성물을 제공한다.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.
본 발명에 따른 A-Linker-A 또는 A-Linker-B로 표시되는 신규 화합물은 세레브론을 우수하게 저해하거나 분해시킬 수 있는 바, 이를 유효성분으로 함유하여 세레브론 관련 질환, 바람직하게 세레브론을 저해 또는 분해하는 것으로부터 치료, 예방 또는 개선과 같은 효과가 달성될 수 있는 질환, 예를 들어, 암, 자가면역질환, 또는 대사질환의 예방 또는 치료용 약학적 조성물로서 유용한 효과가 있다.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.
도 1은 본 발명 실시예 1, 3, 및 8 화합물을 0 내지 10 μM로 하여, α-CRBN 및 α-Tubulin에서 웨스턴 블롯하여 나타낸 단백질 분석 결과이다.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.
도 2는 본 발명 실시예 1, 3, 및 8 화합물의 농도에 따른 단백질 분해력을 도시한 DC50 그래프이다.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.
이하, 본 발명을 상세히 설명한다.Hereinafter, the present invention will be described in detail.
이하의 설명은 본 발명의 이해를 돕기 위한 예시로서 이해되어야 하며, 본 발명의 사상 또는 범주가 하기의 설명으로부터 제한되는 것은 아니다.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.
본 발명은 A-Linker-A 또는 A-Linker-B로 표시되는 화합물, 이의 입체 이성질체, 또는 이의 약학적으로 허용 가능한 염을 제공한다:The present invention provides a compound represented by A-Linker-A or A-Linker-B, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
상기 A는 세레브론(Cerebron) E3 유비퀴틴 리가아제 결합 모이어티(moiety)이고;Wherein A is a Cerebron E3 ubiquitin ligase binding moiety;
상기 Linker는 -(CH2)-, -(C=O)-, -NH- 및 -O-로 이루어진 군으로부터 선택되는 1종 이상이 3-20개 연결된 연결기(linker)이되,The linker is a linker having 3 to 20 linkages selected from the group consisting of - (CH 2 ) -, - (C═O) -, -NH- and -O-,
상기 연결기는 연속하여 -O-로 연결될 수 없고; 및The linking group can not be linked to -O- in succession; And
상기 B는 E3 유비퀴틴 리가아제 결합 모이어티(moiety)이고,Wherein B is an E3 ubiquitin ligase binding moiety,
여기서 Linker와 A 또는 B는 화학적으로 연결된다.Here, Linker and A or B are chemically linked.
이때, 상기의 화학적인 연결은 예를 들어 단일결합, 이중결합, 또는 삼중결합과 같은 공유결합일 수 있다.The chemical linkage may be, for example, a covalent bond such as a single bond, a double bond, or a triple bond.
한편,Meanwhile,
바람직하게, 상기 A는 탈리도마이드(Thalidomide), 레날리도마이드(Lenalidomide), 포말리도마이드(Pormalidomide), 이들의 유사체, 이들의 동배체, 또는 이들의 유도체이다.Preferably, the A is Thalidomide, Lenalidomide, Pormalidomide, analogs thereof, their copper complexes, or derivatives thereof.
더욱 바람직하게,More preferably,
상기 A는 하기 (a) 내지 (g)로 표시되는 화학식 중 하나이고,Wherein A is one of the following formulas (a) to (g)
Figure PCTKR2018011782-appb-I000002
,
Figure PCTKR2018011782-appb-I000003
,
Figure PCTKR2018011782-appb-I000004
,
Figure PCTKR2018011782-appb-I000005
,
Figure PCTKR2018011782-appb-I000006
,
Figure PCTKR2018011782-appb-I000007
, 또는
Figure PCTKR2018011782-appb-I000008
Figure PCTKR2018011782-appb-I000002
,
Figure PCTKR2018011782-appb-I000003
,
Figure PCTKR2018011782-appb-I000004
,
Figure PCTKR2018011782-appb-I000005
,
Figure PCTKR2018011782-appb-I000006
,
Figure PCTKR2018011782-appb-I000007
, or
Figure PCTKR2018011782-appb-I000008
상기 화학식 (a), (b), (c), (d), (e), (f), 및 (g)에 있어서,In the above formulas (a), (b), (c), (d), (e), (f) and (g)
W는 CH2, CHR, C=O, SO2, NH, 또는 N-C1-10의 직쇄 또는 분지쇄의 알킬이고,W is CH 2 , CHR, C = O, SO 2 , NH, or a linear or branched alkyl of NC 1-10 ,
각각의 X는 독립적으로 O, S, 또는 H2이고,Each X is independently O, S, or H 2 ,
Y는 NH, N-C1-10의 직쇄 또는 분지쇄 알킬, N-C6-10 아릴, N-헤테로아릴(N, O, 및 S로 이루어진 군으로부터 선택되는 1종 이상의 헤테로 원자를 포함하는 5-10각환의 헤테로아릴), N-C3-10 사이클로알킬, N-헤테로사이클로알킬(N, O, 및 S로 이루어진 군으로부터 선택되는 1종 이상의 헤테로 원자를 포함하는 3-10각환의 헤테로사이클로알킬), O, 또는 S이고,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,
Z는 O, S, 또는 H2이고,Z is O, S, or H 2 ,
G 및 G'는 각각 독립적으로 H, C1-10의 직쇄 또는 분지쇄 알킬, OH, R'로 치환 또는 비치환된 CH2-헤테로사이클릴(N, O, 및 S로 이루어진 군으로부터 선택되는 1종 이상의 헤테로 원자를 포함하는 3-10각환의 헤테로사이클릴), 또는 R'로 치환 또는 비치환된 벤질이고,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 '
Q1, Q2, Q3, 및 Q4는 각각 독립적으로 R'로 치환된 탄소, 또는 N 이고,Q 1 , Q 2 , Q 3 , and Q 4 are each independently carbon substituted with R ', or N,
A는 C1-10의 직쇄 또는 분지쇄 알킬, C3-10 사이클로알킬, 또는 할로젠이고,A is straight or branched chain alkyl of C 1-10 , C 3-10 cycloalkyl, or halogen,
R은 -CONR'R", -OR', -NR'R", -SR', -SO2R', -SO2NR'R", -CR'R"-, -CR'NR'R"-, -C6-10아릴, -헤테로아릴(N, O, 및 S로 이루어진 군으로부터 선택되는 1종 이상의 헤테로 원자를 포함하는 5-10각환의 헤테로아릴), -C1-10의 직쇄 또는 분지쇄 알킬, -C3-10사이클로알킬, -헤테로사이클릴(N, O, 및 S로 이루어진 군으로부터 선택되는 1종 이상의 헤테로 원자를 포함하는 3-10각환의 헤테로사이클릴), -P(O)(OR')R", -P(O)R'R", -OP(O)(OR')R", -OP(O)R'R", -Cl, -F, -Br, -I, -CF3, -CN, -NR'SO2NR'R", -NR'CONR'R", -CONR'COR", -NR'C(=N-CN)NR'R", -C(=N-CN)NR'R", -NR'C(=N-CN)R", -NR'C(=CNO2)NR'R", -SO2NR'COR", -NO2, -CO2R', -C(C=N-OR')R", -CR'=CR'R", -CCR', -S(C=O)(C=N-R')R", -SF5 또는 -OCF3이고,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' 및 R"는 H, C1-10의 직쇄 또는 분지쇄 알킬, C3-10사이클로알킬, C6-10아릴, 헤테로아릴(N, O, 및 S로 이루어진 군으로부터 선택되는 1종 이상의 헤테로 원자를 포함하는 5-10각환의 헤테로아릴), 헤테로사이클릴(N, O, 및 S로 이루어진 군으로부터 선택되는 1종 이상의 헤테로 원자를 포함하는 3-10각환의 헤테로사이클릴)로 구성된 군에서 각각 독립적으로 선택되고,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 >
Figure PCTKR2018011782-appb-I000009
는 입체특이적(R 또는 S) 또는 비-입체특이적인 결합을 나타내고; 및
Figure PCTKR2018011782-appb-I000009
(R or S) or non-stereospecific linkages; And
Rn은 -(CH2)m-NR3-, -(CH2)m-O-, -O-(CH2)m-(C=O)-NR3- 또는 -NR3-(CH2)m-(C=O)-NR3-이고,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 > -,
다시 여기서, m은 0 내지 5의 정수이고,Here again, m is an integer from 0 to 5,
상기 R3는 각각 H, 또는 비치환 또는 치환된 C1-10의 직쇄 또는 분지쇄의 알킬이고,Wherein R < 3 > is each H, or an unsubstituted or substituted C 1-10 straight chain or branched chain alkyl,
다시 여기서, 상기 치환된 알킬은 할로겐, 니트로, 또는 시아노기로 치환되고, Rn은 Linker와 공유결합된다.Here again, the substituted alkyl is substituted with a halogen, nitro, or cyano group, and R n is covalently bonded to a linker.
보다 바람직하게,More preferably,
상기 A는
Figure PCTKR2018011782-appb-I000010
,
Figure PCTKR2018011782-appb-I000011
,
Figure PCTKR2018011782-appb-I000012
, 또는
Figure PCTKR2018011782-appb-I000013
이되,A is
Figure PCTKR2018011782-appb-I000010
,
Figure PCTKR2018011782-appb-I000011
,
Figure PCTKR2018011782-appb-I000012
, or
Figure PCTKR2018011782-appb-I000013
However,
여기서 상기 R1은 -(CH2)n-NR3-, -(CH2)n-O-, -O-(CH2)n-(C=O)-NR3- 또는 -NR3-(CH2)n-(C=O)-NR3-이고,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 -
다시 여기서, n은 0 내지 5의 정수이고,Here again, n is an integer from 0 to 5,
상기 R2 및 R3는 각각 독립적으로 H, 또는 비치환 또는 치환된 C1-10의 직쇄 또는 분지쇄의 알킬이고,Wherein R 2 and R 3 are each independently H, or an unsubstituted or substituted C 1-10 straight chain or branched chain alkyl,
다시 여기서, 상기 치환된 알킬은 할로겐, 니트로, 또는 시아노기로 치환된다.Here again, said substituted alkyl is substituted with halogen, nitro, or cyano.
더욱 바람직하게,More preferably,
상기 A는
Figure PCTKR2018011782-appb-I000014
,
Figure PCTKR2018011782-appb-I000015
,
Figure PCTKR2018011782-appb-I000016
,
Figure PCTKR2018011782-appb-I000017
,
Figure PCTKR2018011782-appb-I000018
,
Figure PCTKR2018011782-appb-I000019
,
Figure PCTKR2018011782-appb-I000020
, 또는
Figure PCTKR2018011782-appb-I000021
이되,A is
Figure PCTKR2018011782-appb-I000014
,
Figure PCTKR2018011782-appb-I000015
,
Figure PCTKR2018011782-appb-I000016
,
Figure PCTKR2018011782-appb-I000017
,
Figure PCTKR2018011782-appb-I000018
,
Figure PCTKR2018011782-appb-I000019
,
Figure PCTKR2018011782-appb-I000020
, or
Figure PCTKR2018011782-appb-I000021
However,
여기서 상기 R1은 -(CH2)n-NR3-, -(CH2)n-O-, -O-(CH2)n-(C=O)-NR3- 또는 -NR3-(CH2)n-(C=O)-NR3-이고,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 -
다시 여기서, n은 0 내지 5의 정수이고,Here again, n is an integer from 0 to 5,
상기 R2 및 R3는 각각 독립적으로 H, 또는 비치환 또는 치환된 C1-10의 직쇄 또는 분지쇄의 알킬이고,Wherein R 2 and R 3 are each independently H, or an unsubstituted or substituted C 1-10 straight chain or branched chain alkyl,
다시 여기서, 상기 치환된 알킬은 할로겐, 니트로, 또는 시아노기로 치환된다.Here again, said substituted alkyl is substituted with halogen, nitro, or cyano.
한편, 본 발명에 따른 A-Linker-A 또는 A-Linker-B로 표시되는 화합물, 이의 입체 이성질체, 또는 이의 약학적으로 허용 가능한 염에 있어서,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,
바람직하게, 상기 Linker는,Preferably, the linker comprises:
Figure PCTKR2018011782-appb-I000022
이되,
Figure PCTKR2018011782-appb-I000022
However,
여기서, 상기 a 및 i는 독립적으로 0 또는 1이고;Wherein a and i are independently 0 or 1;
상기 b는 0-20의 정수이고;B is an integer from 0 to 20;
상기 c는 0 또는 1이고;Wherein c is 0 or 1;
상기 d는 0-3의 정수이고;D is an integer of 0-3;
상기 e는 0 또는 1이고;E is 0 or 1;
상기 f는 1-10의 정수이고;F is an integer from 1 to 10;
상기 g는 0 또는 1이고;G is 0 or 1;
상기 h는 0-3의 정수이고;H is an integer of 0-3;
상기 j 및 k는 독립적으로 0-5의 정수이다.J and k are independently an integer of 0-5.
한편,Meanwhile,
보다 바람직하게,More preferably,
상기 Linker는,The linker,
Figure PCTKR2018011782-appb-I000023
,
Figure PCTKR2018011782-appb-I000024
,
Figure PCTKR2018011782-appb-I000025
,
Figure PCTKR2018011782-appb-I000026
,
Figure PCTKR2018011782-appb-I000027
,
Figure PCTKR2018011782-appb-I000028
,
Figure PCTKR2018011782-appb-I000029
,
Figure PCTKR2018011782-appb-I000030
,
Figure PCTKR2018011782-appb-I000031
,
Figure PCTKR2018011782-appb-I000032
,
Figure PCTKR2018011782-appb-I000033
,
Figure PCTKR2018011782-appb-I000034
,
Figure PCTKR2018011782-appb-I000035
,
Figure PCTKR2018011782-appb-I000036
,
Figure PCTKR2018011782-appb-I000037
,
Figure PCTKR2018011782-appb-I000038
,
Figure PCTKR2018011782-appb-I000039
,
Figure PCTKR2018011782-appb-I000040
,
Figure PCTKR2018011782-appb-I000041
, 또는
Figure PCTKR2018011782-appb-I000042
이다.
Figure PCTKR2018011782-appb-I000023
,
Figure PCTKR2018011782-appb-I000024
,
Figure PCTKR2018011782-appb-I000025
,
Figure PCTKR2018011782-appb-I000026
,
Figure PCTKR2018011782-appb-I000027
,
Figure PCTKR2018011782-appb-I000028
,
Figure PCTKR2018011782-appb-I000029
,
Figure PCTKR2018011782-appb-I000030
,
Figure PCTKR2018011782-appb-I000031
,
Figure PCTKR2018011782-appb-I000032
,
Figure PCTKR2018011782-appb-I000033
,
Figure PCTKR2018011782-appb-I000034
,
Figure PCTKR2018011782-appb-I000035
,
Figure PCTKR2018011782-appb-I000036
,
Figure PCTKR2018011782-appb-I000037
,
Figure PCTKR2018011782-appb-I000038
,
Figure PCTKR2018011782-appb-I000039
,
Figure PCTKR2018011782-appb-I000040
,
Figure PCTKR2018011782-appb-I000041
, or
Figure PCTKR2018011782-appb-I000042
to be.
또 다른 한편, 본 발명에 따른 A-Linker-A 또는 A-Linker-B로 표시되는 화합물, 이의 입체 이성질체, 또는 이의 약학적으로 허용 가능한 염에 있어서,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,
바람직하게,Preferably,
상기 B는 E3 유비퀴틴 리가제 결합 모이어티(리간드)라면 제한없이 사용될 수있고, 여기서, 상기 E3 유비퀴틴 리가제로의 일예로, AMFR, APC/Cdc20, APC/Cdh1, C6orf157, Cbl, CBLL1, CHFR, CHIP, DTL, E6-AP, HACE1, HECW1, HECW2, HERC2, HUWE1, HYD, ITCH, LNX1, MARCH-I, MARCH-IV, MARCH-VII, MARCH-VIII, MDM2, MEKK1, MIB1, MIB2, MycBP2, NEDD4L, PELI1, Pirh2, PJA1, RFFL, RFWD2, Rictor, RNF5, RNF8, RNF19, RNF20, RNF34, RNF40, RNF138, RNF168, SCF/β-TrCP, SCF/FBW7, SCF/Skp2, SHPRH, SIAH1, SIAH2, SMURF1, SMURF2, TOPORS, TRAF6, TRIM63, UBR2, UHRF2, VHL, WWP1, WWP2, 또는 CRBN일 수 있고, 이의 결합 뫼어티라면 제한없이 본 발명에 적용하여 사용할 수 있다.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.
본 발명의 일 구체예에서는, 상기 B는 CRBN(cereblon) 또는 VHL(von Hippel-Lindau) E3 리가제 결합 모이어티일 수 있다.In one embodiment of the present invention, B may be CRBN (cereblon) or VHL (von Hippel-Lindau) E3 ligand binding moiety.
본 발명의 또 다른 구체예에서는,In another embodiment of the present invention,
상기 B는 하기 화학식 1로 표시되는 화합물이되,Wherein B is a compound represented by the following formula (1)
[화학식 1][Chemical Formula 1]
Figure PCTKR2018011782-appb-I000043
Figure PCTKR2018011782-appb-I000043
상기 화학식 1에 있어서,In Formula 1,
R4은 OR6이고,R 4 is OR 6 ,
R5는 선택적으로 치환 또는 비치환된 -NR6-(CH2)o-C6-10아릴-N, O, 및 S로이루어진 군으로부터 선택되는 1종 이상의 헤테로 원자를 포함하는 5-10원자 헤테로아릴이되,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,
상기 치환된 -NR6-(CH2)o-C6-10아릴-N, O, 및 S로이루어진 군으로부터 선택되는 1종 이상의 헤테로 원자를 포함하는 5-10원자 헤테로아릴은 C1-10의 직쇄 또는 분지쇄의 알킬로 치환되고,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,
여기서, 상기 R6는 H 또는 C1-5의 직쇄 또는 분지쇄의 알킬이고, 상기 o는 0-5이고;Wherein R < 6 > is H or a straight or branched chain alkyl of 1-5 , wherein o is 0-5;
R7는 -CR8-NR9-이되,R 7 is -CR 8 -NR 9 -
여기서, R8는 C1-10의 직쇄 또는 분지쇄의 알킬이고, R9는 H 또는 C1-5의 직쇄 또는 분지쇄의 알킬이다.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.
더욱 바람직하게,More preferably,
상기 B는
Figure PCTKR2018011782-appb-I000044
이되,B is
Figure PCTKR2018011782-appb-I000044
However,
여기서 상기 R2 및 R3는 각각 독립적으로 H, 또는 비치환 또는 치환된 C1-10의 직쇄 또는 분지쇄의 알킬이고,Wherein R 2 and R 3 are each independently H or an unsubstituted or substituted C 1-10 straight chain or branched chain alkyl,
다시 여기서, 상기 치환된 알킬은 할로겐, 니트로, 또는 시아노기로 치환된다.Here again, said substituted alkyl is substituted with halogen, nitro, or cyano.
본 발명에 따른 A-Linker-A 또는 A-Linker-B로 표시되는 화합물의 바람직한 예로는 하기 화합물을 들 수 있다.Preferred examples of the compound represented by A-Linker-A or A-Linker-B according to the present invention include the following compounds.
(1) (2S,4R)-1-((S)-2-(7-(2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일아미노)헵탄아미도)-3,3-디메틸부타노일)-4-히드록시-N-(4-(4-메틸티아졸-5-일)벤질)피롤리딘-2-카복스아미드;(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) (2S,4R)-1-((S)-2-(6-(2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일아미노)헥산아미도)-3,3-디메틸부타노일)-4-히드록시-N-(4-(4-메틸티아졸-5-일)벤질)피롤리딘-2-카복스아미드;(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) (2S,4R)-1-((S)-2-(9-(2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일아미노)노난아미도)-3,3-디메틸부타노일)-4-히드록시-N-(4-(4-메틸티아졸-5-일)벤질)피롤리딘-2-카복스아미드;(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) (2S,4R)-1-((S)-2-tert-부틸-17-(2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일아미노)-4-옥소-6,9,12,15-테트라옥사-3-아자헵타데카-1-노일)-4-히드록시-N-(4-(4-메틸티아졸-5-일)벤질)피롤리딘-2-카복스아미드;(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) (2S,4R)-1-((S)-2-(2-(3-(2-(2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일아미노)-2-옥소에톡시)프로폭시)아세트아미도)-3,3-디메틸부타노일)-4-히드록시-N-(4-(4-메틸티아졸-5-일)벤질)피롤리딘-2-카복스아미드;(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) N1-(2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일)-N9-((S)-1-((2S,4R)-4-히드록시-2-(4-(4-메틸티아졸-5-일)벤질카바모일)피롤리딘-1-일)-3,3-디메틸-1-옥소부탄-2-일)노난디아미드;(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) N1-(2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일)-N8-((S)-1-((2S,4R)-4-히드록시-2-(4-(4-메틸티아졸-5-일)벤질카바모일)피롤리딘-1-일)-3,3-디메틸-1-옥소부탄-2-일)옥탄디아미드;(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) N1-(2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일)-N7-((S)-1-((2S,4R)-4-히드록시-2-((4-(4-메틸티아졸-5-일)벤질)카바모일)피롤리딘-1-일)-3,3-디메틸-1-옥소부탄-2-일)헵탄디아미드;(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) N1-(2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일)-N14-((S)-1-((2S,4R)-4-히드록시-2-((4-(4-메틸티아졸-5-일)벤질)카바모일)피롤리딘-1-일)-3,3-디메틸-1-옥소부탄-2-일)-3,6,9,12-테트라옥사테트라데칸-1,14-디아미드;(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) N1-(2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일)-N5-((S)-1-((2S,4R)-4-히드록시-2-(4-(4-메틸티아졸-5-일)벤질카바모일)피롤리딘-1-일)-3,3-디메틸-1-옥소부탄-2-일)글루타르아미드;(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) N1-((2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일)메틸)-N7-((S)-1-((2S,4R)-4-히드록시-2-(4-(4-메틸티아졸-5-일)벤질카바모일)피롤리딘-1-일)-3,3-디메틸-1-옥소부탄-2-일)헵탄디아미드; (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) (2S,4R)-1-((S)-2-(11-(2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일아미노)운데칸아미도)-3.3-디메틸부탄오일)-4-히드록시-N-(4-(4-메틸티아졸-5-일)벤질)피롤리딘-2-카복스아미드;(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) (2S,4R)-1-((S)-2-(8-(2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일아미노)옥탄아미도)-3,3-디메틸부타노일)-4-히드록시-N-(4-(4-메틸티아졸-5-일)벤질)피롤리딘-2-카복스아미드;(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) (2S,4R)-1-((S)-2-(12-(2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일아미노)도데칸아미도)-3,3-디메틸부타노일)-4-히드록시-N-(4-(4-메틸티아졸-5-일)벤질)피롤리딘-2-카복스아미드;(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) (2S,4R)-1-((S)-2-(2-(6-(2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일아미노)헥실옥시)아세트아미도)-3,3-디메틸부타노일)-4-히드록시-N-(4-(4-메틸티아졸-5-일)벤질)피롤리딘-2-카복스아미드;(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) (2S,4R)-1-((S)-2-(10-(2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일아미노)데칸아미도)-3,3-디메틸부타노일)-4-히드록시-N-(4-(4-메틸티아졸-5-일)벤질)피롤리딘-2-카복스아미드;(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) (2S,4R)-1-((S)-2-tert-부틸-14-(2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일아미노)-4-옥소-6,9,12-트리옥사-3-아자테트라데카-1-노일)-4-히드록시-N-(4-(4-메틸티아졸-5-일)벤질)피롤리딘-2-카복스아미드;(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- 디옥소피페리딘-3-일)-2-메틸-4-옥소-3,4-디히드로퀴나졸린-5-일)아미노)운데칸아미도)-3,3-디메틸부타노일)-4-히드록시-N-(4-(4-메틸티아졸-5-일)벤질)피롤리딘-2-카르복스아미드;(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'-(노난-1,9-디일비스(아자네디일))비스(2-(2,6-디옥소피페리딘-3-일)이소인돌린-1,3-디온);(19) 4,4 '- (nonan-1, 9-diylbis (azanediyl)) bis (2- (2,6-dioxopiperidin-3- yl) isoindoline- );
(20) (2S,4R)-1-((S)-2-(11-(2-(2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일아미노)아세트아미도)운데칸아미도)-3,3-디메틸부타노일)-4-히드록시-N-(4-(4-메틸티아졸-5-일)벤질)피롤리딘-2-카복스아미드;(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) (2S,4R)-1-((S)-2-(11-(2-(2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일옥시)아세트아미도)운데칸아미도)-3,3-디메틸부타노일)-4-히드록시-N-(4-(4-메틸티아졸-5-일)벤질)피롤리딘-2-카복스아미드;(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) (2S,4R)-1-((S)-2-(11-(2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-5-일아미노)운데칸아미도)-3,3-디메틸부타노일)-4-히드록시-N-(4-(4-메틸티아졸-5-일)벤질)피롤리딘-2-카복스아미드;(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) 3,3'-(5,5'-(노난-1,9-디일비스(아잔디일))비스(4-옥소벤조[d][1,2,3]트리아진-5,3(4H)-디일))디피페리딘-2,6-디온;(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-디옥소피페리딘-3-일)-4-(9-(3-(2,6-디옥소피페리딘-3-일)-4-옥소-3,4-디히드로벤조[d][1,2,3]트리아진-5-일아미노)노닐아미노)이소인돌린-1,3-디온; 및(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) (2S,4R)-1-((S)-2-(11-(3-(2,6-디옥소피페리딘-3-일)-4-옥소-3,4-디히드로벤조[d][1,2,3]트리아진-5-일아미노)운데칸아미도)-3,3-디메틸부타노일)-4-히드록시-N-(4-(4-메틸티아졸-5-일)벤질)피롤리딘-2-카복스아미드.(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.
본 발명의 A-Linker-A 또는 A-Linker-B로 표시되는 화합물은 약학적으로 허용 가능한 염의 형태로 사용할 수 있으며, 염으로는 약학적으로 허용 가능한 유리산(free acid)에 의해 형성된 산 부가염이 유용하다. 산 부가염은 염산, 질산, 인산, 황산, 브롬화수소산, 요드화수소산, 아질산, 아인산 등과 같은 무기산류, 지방족 모노 및 디카르복실레이트, 페닐-치환된 알카노에이트, 하이드록시 알카노에이트 및 알칸디오에이트, 방향족 산류, 지방족 및 방향족 설폰산류 등과 같은 무독성 유기산, 아세트산, 안식향산, 구연산, 젖산, 말레인산, 글루콘산, 메탄설폰산, 4-톨루엔설폰산, 주석산, 푸마르산 등과 같은 유기산으로부터 얻는다. 이러한 약학적으로 무독한 염의 종류로는 설페이트, 피로설페이트, 바이설페이트, 설파이트, 바이설파이트, 니트레이트, 포스페이트, 모노하이드로겐 포스페이트, 다이하이드로겐 포스페이트, 메타포스페이트, 피로포스페이트 클로라이드, 브로마이드, 아이오다이드, 플루오라이드, 아세테이트, 프로피오네이트, 데카노에이트, 카프릴레이트, 아크릴레이트, 포메이트, 이소부티레이트, 카프레이트, 헵타노에이트, 프로피올레이트, 옥살레이트, 말로네이트, 석시네이트, 수베레이트, 세바케이트, 푸마레이트, 말리에이트, 부틴-1,4-디오에이트, 헥산-1,6-디오에이트, 벤조에이트, 클로로벤조에이트, 메틸벤조에이트, 디니트로 벤조에이트, 하이드록시벤조에이트, 메톡시벤조에이트, 프탈레이트, 테레프탈레이트, 벤젠설포네이트, 톨루엔설포네이트, 클로로벤젠설포네이트, 크실렌설포네이트, 페닐아세테이트, 페닐프로피오네이트, 페닐부티레이트, 시트레이트, 락테이트, β-하이드록시부티레이트, 글리콜레이트, 말레이트, 타트레이트, 메탄설포네이트, 프로판설포네이트, 나프탈렌-1-설포네이트, 나프탈렌-2-설포네이트, 만델레이트 등을 포함한다.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.
본 발명에 따른 산 부가염은 통상의 방법으로 제조할 수 있으며, 예를 들면 A-Linker-A 또는 A-Linker-B의 유도체를 메탄올, 에탄올, 아세톤, 디클로로메탄, 아세토니트릴 등과 같은 유기용매에 녹이고 유기산 또는 무기산을 가하여 생성된 침전물을 여과, 건조시켜 제조하거나, 용매와 과량의 산을 감압 증류한 후 건조시켜 유기용매 하에서 결정화시켜서 제조할 수 있다.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.
또한, 염기를 사용하여 약학적으로 허용가능한 금속염을 만들 수 있다. 알칼리 금속 또는 알칼리 토금속 염은 예를 들면 화합물을 과량의 알칼리 금속 수산화물 또는 알칼리 토금속 수산화물 용액 중에 용해하고, 비용해 화합물 염을 여과하고, 여액을 증발, 건조시켜 얻는다. 이때, 금속염으로는 나트륨, 칼륨 또는 칼슘염을 제조하는 것이 제약상 적합하다. 또한, 이에 대응하는 염은 알칼리 금속 또는 알칼리 토금속 염을 적당한 음염(예, 질산은)과 반응시켜 얻는다.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).
나아가, 본 발명은 상기 A-Linker-A 또는 A-Linker-B로 표시되는 화합물 및 이의 약학적으로 허용가능한 염뿐만 아니라, 이로부터 제조될 수 있는 용매화물, 광학 이성질체, 수화물 등을 모두 포함한다.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 .
또한, 하기 반응식 1에 나타난 바와 같이,Further, as shown in Reaction Scheme 1 below,
U-Linker-V로 표시되는 화합물로부터 A-Linker-V로 표시되는 화합물을 제조하는 단계(단계 1);(Step 1) of producing a compound represented by A-Linker-V from a compound represented by U-Linker-V;
상기 단계 1에서 제조한 A-Linker-V로 표시되는 화합물로부터 A-Linker-A 또는 A-Linker-B로 표시되는 화합물을 제조하는 단계(단계 2);를 포함하는 상기 A-Linker-A 또는 A-Linker-B로 표시되는 화합물의 제조방법을 제공한다: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 >
[반응식 1][Reaction Scheme 1]
Figure PCTKR2018011782-appb-I000045
Figure PCTKR2018011782-appb-I000045
(상기 반응식 1에 있어서,(In the above Reaction Scheme 1,
A, Linker 및 B는 상기에서 정의한 바와 같고; 및A, Linker and B are as defined above; And
U 또는 V는 각각 독립적으로 NH2 또는 OH이다).U or V are each independently selected from NH 2 or OH).
이하, 본 발명에 따른 A-Linker-A 또는 A-Linker-B로 표시되는 화합물의 제조방법을 단계별로 상세히 설명한다.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.
본 발명에 따른 화학식 A-Linker-A 또는 A-Linker-B로 표시되는 화합물의 제조방법에 있어서, 상기 단계 1은 U-Linker-V로 표시되는 화합물로부터 A-Linker-V로 표시되는 화합물을 제조하는 단계이다.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- .
이때, 상기 단계는 본 발명 화합물의 저해 또는 분해하고자 하는 표적 단백질인 세레브론에 결합하기 위한 리간드 모이어티를 도입하는 단계로, 예를 들어 연결기(Linker)에 A로 표시되는 세레브론(Cereblon) 리가제 리간드 화합물의 도입 단계로 생각될 수 있다.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.
이때, Linker와 A가 연결되는 결합은 화학적인 결합으로, 예를 들어, 공유결합, 바람직하게 단일결합, 이중결합 또는 삼중결합일 수 있다. 따라서, 상기 Linker와 A를 연결하는 단계인 단계 1은 해당 분야에 사용될 수 있는 연결기 도입 방법이라면 특별히 제한되지 않고 사용될 수 있으며, U-Linker-V에 있어서, U가 NH2인 경우는 A-할로젠, 바람직하게 A-F로 표시되는 화합물, 일 실시예로 하기 본 발명의 실시예에서, A-F로 표시되는 화합물의 하나의 예시 화합물은 2-(2,6-디옥소피페리딘-3-일)-4-플루오로이소인돌린-1,3-디온이고, U-Linker-V 및 A-할로젠을 반응시켜 단계 1의 목적 화합물인 A-Linker-V로 표시되는 화합물을 제조할 수 있는 방법이라면, 제한없이 본 발명의 제조방법에 포함된다. 한편, U가 OH인 경우, A-NH2로 표시되는 화합물, 일 실시예로 하기 본 발명의 실시예에서, 포말리도마이드(Pomalidomide)를 사용하였고, U-Linker-V 및 A-NH2을 반응시켜 단계 1의 목적 화합물인 A-Linker-V로 표시되는 화합물을 제조할 수 있는 방법이라면, 제한없이 본 발명의 제조방법에 포함된다.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).
또한, 상기 단계 1에서 사용 가능한 용매로는 H2O, 에탄올, 테트라하이드로퓨란(THF), 디클로로메탄, 톨루엔, 아세토니트릴, 디메틸포름아미드, 이의 혼합물 등을 사용할 수 있고, 바람직하게는 디메틸포름아미드(DMF)를 사용할 수 있다.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.
또한, 상기 단계에서 반응온도는 특별히 제한되지 않으나, 바람직하게 80-100℃에서 용매의 비등점 사이에서 수행하는 것이 바람직하고, 반응시간은 특별한 제약은 없으나, 5시간 이상, 10시간 이상, 20시간 이상, 밤새 동안 반응하는 것이 바람직하다.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.
본 발명에 따른 화학식 A-Linker-A 또는 A-Linker-B로 표시되는 화합물의 제조방법에 있어서, 상기 단계 2는 상기 단계 1에서 제조한 A-Linker-V로 표시되는 화합물로부터 A-Linker-A 또는 A-Linker-B로 표시되는 화합물을 제조하는 단계이다.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.
이때, 상기 단계는 A-Linker로 표시되는 화합물에 A 또는 B를 도입하는 단계로, 리간드 A 또는 B는 세레브론 또는 VHL E3 유비퀴틴 리가제와 결합할 수 있고, 표적 단백질(세레브론)에 다중유비퀴틴화(Polyubiquitination)를 유도한다.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.
이때, A-Linker와 A 또는 B가 연결되는 결합은 화학적인 결합으로, 예를 들어, 공유결합, 바람직하게 단일결합, 이중결합 또는 삼중결합일 수 있다. 따라서, 상기 A-Linker와 A 또는 B를 연결하는 단계인 단계 2는 비제한적으로, A-Linker-V에 있어서, V가 NH2인 경우는 A-할로젠 또는 B-할로젠, 바람직하게 A-F 또는 B-F로 표시되는 화합물, 일 실시예로 하기 본 발명의 실시예에서, A-F로 표시되는 화합물의 하나의 예시 화합물은 2-(2,6-디옥소피페리딘-3-일)-4-플루오로이소인돌린-1,3-디온이고, A-Linker-V 및 A-할로젠 또는 B-할로젠을 반응시켜 단계 1의 목적 화합물인 A-Linker-A 또는 A-Linker-B로 표시되는 화합물을 제조할 수 있는 방법이라면, 제한없이 본 발명의 제조방법에 포함된다. 한편, V가 OH인 경우, A-NH2 또는 B-NH2를 사용할 수 있고, 일 실시예로 B-NH2는 (2R,4R)-1-((R)-2-아미노-3,3-디메틸부타노일)-4-히드록시-N-(4-(4-메틸티아졸-5-일)벤질)피롤리딘-2-카복스아미드이고, A-Linker-V 및 A-NH2 또는 B-NH2을 반응시켜 단계 1의 목적 화합물인 A-Linker-A 또는 A-Linker-B로 표시되는 화합물을 제조할 수 있는 방법이라면, 제한없이 본 발명의 제조방법에 포함된다.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.
또한, 상기 단계 1에서 사용 가능한 용매로는 H2O, 에탄올, 테트라하이드로퓨란(THF), 디클로로메탄, 톨루엔, 아세토니트릴, 디메틸포름아미드, 이의 혼합물 등을 사용할 수 있고, 바람직하게는 디메틸포름아미드(DMF)를 사용할 수 있다.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.
또한, 상기 단계에서 반응온도는 특별히 제한되지 않으나, 바람직하게 10-40℃에서 용매의 비등점 사이에서 수행하는 것이 바람직하고, 반응시간은 특별한 제약은 없으나, 5시간 이상, 10시간 이상, 20시간 이상, 밤새 동안 반응하는 것이 바람직하다.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.
상기의 제조방법은 보다 바람직하게 하기 본 발명의 실시예 화합물과 같이 제조할 수 있으나, 본 발명이 이에 제한되는 것은 아니다.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.
한편, 본 명세서에 기재된 제조방법은 당업자가 제조되는 화합물의 수율 등을 고려하여, 반응 조건, 예를 들어 반응 온도, 반응시간, 반응 단계를 수정하거나 변경할 수 있고, 반응 단계는 반복되거나 순서가 바뀌어 수행될 수 있다.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 .
또한, 종래 알려진 유기합성 분야에서의 통상적인 합성방법을 사용하여, 본 발명에서 제공하고자 하는 A-Linker-A 또는 A-Linker-B로 표시되는 화합물의 제조방법은 제한없이 본 발명의 범주로 포함되는 것으로 이해되어야 한다.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 .
나아가, 각각의 연결기(Linker)와 본 발명에서 제공하고자 하는 화합물의 양단의 모이어티를 설계할 수 있는 방법이라면, 예를들어 한쪽으로 세레브론 단백질 결합 리간드 모이어티를, 다른 한편으로 E3 유비퀴틴 리가제 리간드 모이어티를 구성하고, 이를 용이하게 연결하여 설계하는 제조 방법이라면 본 발명에 포함되는 것으로 이해되어야 한다.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.
예를 들어, 본 발명 화합물을 2 단위(unit) 이상으로 직렬 또는 병렬로 구성하는 정도의 변경은 본 발명이 달성하고자 하는 바가, 한편으로 세로브론 단백질과 결합하는 모이어티를 제공하고, 다른 한편으로 E3 유비퀴틴 리가제와 결합하는 모이어티를 제공하여, 세레브론 단백질로 다중유비퀴틴화를 유도하고자 하는 것을 목적하는 바, 상기 변경과 같이 화합물의 설계를 직렬 또는 병렬 반복 또는 연결기를 변형 또는 수정하여, 하나의 세레브론 결합 모이어티에, 두개 이상의 E3 유비퀴틴 리가제 모이어티로 구성하거나, 반대로 하나의 E3 유비퀴틴 리가제 모이어티에 두개 이상의 세레브론 결합 모이어티를 구성하는 것과 같은 간단한 설계 변형으로 도출될 수 있는 화합물 및 이로부터 본 발명과 같이, 세레브론의 우수한 저해 또는 분해를 달성하고자 한다면, 본 발명은 이러한 변경 또는 수정을 포함하는 것으로 이해되어야 한다. 즉, 이건 발명에서 용이하게 당업자가 도출해내는 정도의 변경과 수정은, 본 발명에 포함되는 것으로 이해되어야 한다.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.
한편, 본 발명의 A-Linker-A 또는 A-Linker-B로 표시되는 화합물은 한 편의 A 리간드 모이어티로는 표적 단백질인 세레브론과 결합하고, 다른 한 편의 A 또는 B 리간드 모이어티로는 E3 유비퀴틴 리가제와 결합하여, 최종적으로 E3 유비퀴틴 리가제가 표적 단백질(세레브론)로 다중유비퀴틴화를 유도시키고, 이 후 단백질 분해 효소, 예를 들어 26S 프로테아좀(proteasome)에 다중유비퀴틴화된 단백질(세레브론)을 인식시켜, 분해시키는 효과를 달성하는데, 이러한 단백질 분해를 통한 약리 효과는, 세레브론으로 기인하는 모든 관련 질병, 예를 들어, 세레브론의 이상, 과활성, 등과 같은 작용으로부터 야기되는 질환, 예를 들어, 암, 예를 들어, 자가면역질환, 예를 들어 대사질환과 같은, 종래 세레브론과 관련된 질환으로 규명된 모든 질환에서 유용한 효과를 나타낼 수 있다.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.
특히, 본 발명의 화합물이 세포저해제, 표적저해제와 같은 종래 약의 부작용 문제, 내성 문제, 미비한 약리활성과 같은 문제점을 극복할 수 있는, 단백질 분해제(PROTAC) 약물이라는 점에서, 유용하다.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.
또한, 본 발명 화합물은 A로 표시되는 세레브론 결합 모이어티 자체가 면역조절약물(Immunomodulatory drug, IMiD)로 알려진 탈리도마이드, 레날리도마이드, 포말리도마이드, 이의 유사체, 이의 동배체, 이의 유도체인 바, 본 발명 화합물이 세레브론 단백질에 분해를 유도하기 전 단계로, 단순히 세레브론에 결합되는 것만으로도 면역조절약물로서의 약리효과를 나타낸다.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.
따라서, 본 발명 A-Linker-A 또는 A-Linker-B로 표시되는 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용 가능한 염은, 종래 알려진 면역조절약물로서의 세레브론 저해 효과와, 종래 약물의 문제점을 극복할 수 있는 단백질 분해제로서의 약리 효과를 동시에 달성할 수 있는 바, 약리 활성에서 우수한 시너지 효과를 나타내고, 동시에 약의 내성, 부작용과 같은 문제점을 현저히 개선시킨다.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.
본 발명에서는, 암, 자가면역질환 또는 대사질환에 있어서, 본 발명 A-Linker-A 또는 A-Linker-B로 표시되는 화합물의 약리활성은 매우 우수하며, 또한 본 발명 화합물은 세레브론 단백질 자체를 분해시키는 바, 기존의 표적치료제, 세포치료제 등의 단점, 내성문제 등을 효과적으로 해결할 수 있음을 실험적으로 확인하였다.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.
나아가, 본 발명은 상기 A-Linker-A 또는 A-Linker-B로 표시되는 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 세레브론(Cereblon) 관련 질환의 예방 또는 치료용 약학적 조성물을 제공한다.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.
본 발명의 A-Linker-A 또는 A-Linker-B로 표시되는 화합물은 세레브론 단백질의 저해 활성을 나타냄과 동시에, 세레브론을 분해하는 바, 세레브론에 기인한 질환(세레브론 관련 질환), 세레브론 이상활성, 세레브론 과활성 또는 세레브론의 기작에 의해 유도되는 활성으로부터 야기되는 질환에 우수한 약리효과를 달성할 수 있다. 구체적인 예시의 질환으로, 암, 자가면역 질환, 대사질환의 치료에서, 본 발명 화합물은 예방, 개선을 위한 약학적 조성물의 유효성분으로 사용될 수 있다.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.
상술된 배경기술의 기재에서 확인되듯이, E3 유비퀴틴 리가제 중 세레브론(CRBN, Cereblon)은 면역조절약물(Immunomodulatory drug, IMiD)로 알려진 탈리도마이드, 레날리도마이드, 포말리도마이드 등이 결합하면, 전사요인(transcription factor)인 이카로스(ikaros), 에이오로스(aiolos)를 분해 시켜 우수한 항암 효과를 보일 뿐만 아니라, 루푸스를 포함하는 자가면역질환 질환에 효과가 있다. 본 발명 A-Linker-A 또는 A-Linker-B로 표시되는 화합물에서 A로 표시되는 부분은 탈리도마이드, 레날리도마이드, 포말리도마이드, 이의 유사체, 이으 동배체, 이의 유도체인 바, 동일하게 암 또는 자가면역질환에 우수한 효과를 나타내고, 또 다른 한편, 세레브론은 특정 단백질의 분해에 관여하는 E3 유비퀴틴 리가제 역할외에도, CRBN을 억제하였을 경우, 에너지센서인 AMPK가 활성화되어 비만, 지방간, 당뇨병 등 대사질환의 예방 또는 치료가 가능하다.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.
나아가, 면역세포(T-세포)에 CRBN을 억제 또는 분해하면 T세포에 과발현 되어 있는 CRBN의 양을 낮추어 T세포의 활성을 증가시키는 효과를 유도하여 항암면역치료제로 사용 가능하다.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.
또한, 본 발명은 상기 A-Linker-A 또는 A-Linker-B로 표시되는 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 암의 예방 또는 치료용 약학적 조성물을 제공한다.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.
이때, 상기 암은 세레브론 활성을 억제 또는 세레브론 단백질을 분해하는 것으로부터 호전될 수 있는 모든 암 질환을 말하며, 비제한적인 예로, 상기 암은 가성점액종, 간내 담도암, 간모세포종, 간암, 갑상선암, 결장암, 고환암, 골수이형성증후군, 교모세포종, 구강암, 구순암, 균상식육종, 급성골수성백혈병, 급성림프구성백혈병, 기저세포암, 난소상피암, 난소생식세포암, 남성유방암, 뇌암, 뇌하수체선종, 다발성골수종, 담낭암, 담도암, 대장암, 만성골수성백혈병, 만성림프구백혈병, 망막모세포종, 맥락막흑색종, 미만성거대B세포림프종, 바터팽대부암, 방광암, 복막암, 부갑상선암, 부신암, 비부비동암, 비소세포폐암, 비호지킨림프종, 설암, 성상세포종, 소세포폐암, 소아뇌암, 소아림프종, 소아백혈병, 소장암, 수막종, 식도암, 신경교종, 신경모세포종, 신우암, 신장암, 심장암, 십이지장암, 악성 연부조직 암, 악성골암, 악성림프종, 악성중피종, 악성흑색종, 안암, 외음부암, 요관암, 요도암, 원발부위불명암, 위림프종, 위암, 위유암종, 위장관간질암, 윌름스암, 유방암, 육종, 음경암, 인두암, 임신융모질환, 자궁경부암, 자궁내막암, 자궁육종, 전립선암, 전이성 골암, 전이성뇌암, 종격동암, 직장암, 직장유암종, 질암, 척수암, 청신경초종, 췌장암, 침샘암, 카포시 육종, 파제트병, 편도암, 편평상피세포암, 폐선암, 폐암, 폐편평상피세포암, 피부암, 항문암, 횡문근육종, 후두암, 흉막암, 및 흉선암으로 이루어진 군으로부터 선택되는 1종 이상일 수 있다.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.
나아가, 바람직하게 상기 암은 급성 골수 백혈병(AML); 만성적 골수성 백혈병(CML); 급성 림프아구성 백혈병(ALL); 만성적 림프구성 백혈병(CLL); 호지킨 질환(HD); 비-호지킨 림프종(NHL); B-세포 림프종; T-세포 림프종; 다발성 골수종(MM); 아밀로이드증; 발덴스트롬 거대글로불린혈증; 골수이형성 증후군(MDS); 작은 림프구 림프종(SLL); 변연부 림프종; 무증상 다발성 골수종; 및 골수증식성 증후군으로 이루어진 군으로부터 선택되는 1종 이상일 수 있다.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.
본 명세서에서 사용된 바와 같이, 용어 "암"은 조절되지 않는 또는 이상조절된 세포 증식, 감소된 세포성 분화, 주위의 조직에 침입하는 부절적한 능력, 및/또는 이소성 부위에서 신규 성장을 확립하는 능력을 특징으로 하는 세포성 장애를 의미한다. 용어 "암"은 비제한적으로, 고형 종양 및 혈액매개 종양 (혈액성 악성종양)을 포함한다. 용어 "암"은 피부, 조직, 기관, 골, 연골, 혈액, 및 혈관의 질환을 포함한다. 용어 "암"은 추가로, 1차 및 전이암을 포함한다.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.
상기 고형 종양은 췌장암; 침습성 방광암 포함하는 방광암; 결장직장암; 갑상선암, 위암, 전이성 유방암을 포함하는 유방암; 안드로겐-의존적 및 안드로겐-독립적인 전립선암을 포함하는 전립선암; 예를 들면, 전이성 신장 세포 암종을 포함하는 신장암; 예를 들면 간세포 암 및 간내 담관을 포함하는 간암; 비-소세포 폐암 (NSCLC), 편평상피 폐암, 세기관지폐포 암종 (BAC), 폐의 선암종, 및 소세포 폐암 (SCLC)을 포함하는 폐 및 기관지 암; 예를 들면, 진행성 상피성 또는 1차 복막 암을 포함하는 난소암; 자궁경부암; 예를 들면 자궁 체부 및 자궁 경부를 포함하는 자궁암; 자궁내막 암; 위암; 식도암; 예를 들면, 두경부의 편평상피 세포 암종, 비인두 암, 구강 및 인두를 포함하는 두경부 암; 흑색종; 전이성 신경내분비 종양을 포함하는 신경내분비 암; 예를 들면, 신경아교종/교모세포종, 역형성 희소돌기아교세포종, 성인 교모세포종 다형성, 및 성인 역형성 별아교세포종을 포함하는 뇌암; 전이성 신경내분비 종양; 골 암이고; 그리고 연조직 육종을 포함하는 신경내분비를 포함한다.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.
상기 혈액성 악성종양은 급성 골수 백혈병 (AML); 만성적 골수성 백혈병 (CML) (가속화된 CML 및 CML 아세포기 (CML-BP) 포함); 급성 림프아구성 백혈병 (ALL); 만성적 림프구성 백혈병 (CLL); 호지킨 질환 (HD); 비-호지킨 림프종 (NHL) (여포성 림프종 및 외투 세포 림프종 포함); B-세포 림프종 (미만성 큰 B-세포 림프종 (DLBCL) 포함); T-세포 림프종; 다발성 골수종 (MM); 아밀로이드증; 발덴스트롬 거대글로불린혈증; 골수이형성 증후군 (MDS) (난치의 빈혈 (RA), 관상 철아구 (RARS)를 갖는 난치의 빈혈 (과다 모세포 (RAEB), 및 형질전환 동반 RAEB (RAEB-T)를 갖는 난치의 빈혈) 포함); 작은 림프구 림프종 (SLL); 변연부 림프종; 무증상 다발성 골수종; 및 골수증식성 증후군을 포함한다.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.
나아가, 본 발명은 상기 A-Linker-A 또는 A-Linker-B로 표시되는 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 자가면역질환의 예방 또는 치료용 약학적 조성물을 제공한다.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 .
이때, 상기 자가면역질환은 세레브론 활성을 억제 또는 세레브론 단백질을 분해하는 것으로부터 호전될 수 있는 모든 자가면역질환을 말하며, 비제한적인 예로, 상기 자가면역질환은 면역성 호중구감소증, 길랑바레 신드롬, 간질, 자가면역 뇌염, 아이삭 신드롬, 모반 신드롬, 심상성천포창, 낙엽성천포창, 수포성류천포창, 후천성표피수포증, 임신성 유사수포창, 뮤코스 막 유사수포창, 항인지질 신드롬, 자가면역 빈혈, 자가면역 그래이브 병, 굿파스튜어 증후군, 중증근무력증, 다발성경화증, 류마티스성 관절염, 루프스, 특발성 혈소판 감소성 자반증(idiopathic thrombocytopenic purpura, ITP), 루프스 신염 및 막성 신병증으로 구성된 군에서 선택되는 하나 이상일 수 있다.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: .
또한, 본 발명은 상기 A-Linker-A 또는 A-Linker-B로 표시되는 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 대사질환의 예방 또는 치료용 약학적 조성물을 제공한다.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.
상기 대사질환은, 세레브론을 억제 또는 세레브론 단백질의 분해로부터 치료 또는 예방의 효과가 달성될 수 있는 모든 대사질환을 말하며, 비제한적인 예로, 비만, Ⅰ형 당뇨병, Ⅱ형 당뇨병, 부적합한 내당력, 인슐린 내성, 고인슐린혈증, 고혈당증, 이상지질혈증, 고지질혈증, 고중성지방혈증, 고콜레스테롤혈증, 이상지질혈증, 대사 증후군 X, 혈관 질환, 죽상경화증, 관상심장질환, 대뇌혈관질환, 심부전증, 말초혈관질환, 및 반흔에서 선택되는 1종 이상일 수 있다.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.
상술된 본 발명에 따른 약학적 조성물에 있어서, 상기 A-Linker-A 또는 A-Linker-B로 표시되는 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용 가능한 염은 임상 투여시에 경구 및 비경구의 여러 가지 제형으로 투여될 수 있는데, 제제화할 경우에는 보통 사용하는 충전제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 제조될 수 있다.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.
경구 투여용 제형으로는 예를 들면 정제, 환제, 경/연질 캅셀제, 액제, 현탁제, 유화제, 시럽제, 과립제, 엘릭시르제, 트로키제 등이 있는데, 이들 제형은 유효성분 이외에 희석제(예: 락토즈, 덱스트로즈, 수크로즈, 만니톨, 솔비톨, 셀룰로즈 및/또는 글리신), 활택제(예: 실리카, 탈크, 스테아르산 및 그의 마그네슘 또는 칼슘염 및/또는 폴리에틸렌 글리콜)를 함유하고 있다. 정제는 마그네슘 알루미늄 실리케이트, 전분 페이스트, 젤라틴, 메틸셀룰로즈, 나트륨 카복시메틸셀룰로즈 및/또는 폴리비닐피롤리딘 등과 같은 결합제를 함유할 수 있으며, 경우에 따라 전분, 한천, 알긴산 또는 그의 나트륨 염 등과 같은 붕해제 또는 비등 혼합물 및/또는 흡수제, 착색제, 향미제, 및 감미제를 함유할 수 있다.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.
상기 A-Linker-A 또는 A-Linker-B로 표시되는 화합물을 유효 성분으로 하는 약학적 조성물은 비경구 투여할 수 있으며, 비경구 투여는 피하주사, 정맥주사, 근육 내 주사 또는 흉부 내 주사를 주입하는 방법에 의하였다. 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.
이때, 비경구 투여용 제형으로 제제화하기 위하여 상기 A-Linker-A 또는 A-Linker-B로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염을 안정제 또는 완충제와 함께 물에 혼합하여 용액 또는 현탁액으로 제조하고, 이를 앰플 또는 바이알 단위 투여형으로 제조할 수 있다. 상기 조성물은 멸균되고/되거나 방부제, 안정화제, 수화제 또는 유화 촉진제, 삼투압 조절을 위한 염 및/또는 완충제 등의 보조제, 및 기타 치료적으로 유용한 물질을 함유할 수 있으며, 통상적인 방법인 혼합, 과립화 또는 코팅 방법에 따라 제제화할 수 있다.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.
상기 제제화의 예시는 통상적인 제제예에 관한 것일 뿐, 본 발명의 제제화가 이에 제한되지는 않음을 통상의 기술지식을 가진 자라면 용이하게 이해할 수 있다.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.
나아가, 본 발명의 상기 A-Linker-A 또는 A-Linker-B로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염의 인체에 대한 투여량은 대상의 나이, 몸무게, 성별, 투여형태, 건강상태 및 질환 정도에 따라 달라질 수 있으며, 몸무게가 70Kg인 성인 대상를 기준으로 할 때, 일반적으로 0.1-1000 mg/일이며, 바람직하게는 1-500 mg/일이며, 또한 의사 또는 약사의 판단에 따라 일정시간 간격으로 1일 1회 내지 수회로 분할 투여할 수도 있다.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.
나아가, 본 발명은 상기 A-Linker-A 또는 A-Linker-B로 표시되는 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 세레브론(Cereblon) 관련 질환의 예방 또는 개선용 건강기능식품 조성물을 제공한다.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.
이때, 상기 세레브론 관련 질환은 세레브론에 기인한 질환(세레브론 관련 질환), 세레브론 이상활성, 세레브론 과활성 또는 세레브론의 기작에 의해 유도되는 활성으로부터 야기되는 질환으로, 비제한적인 예로, 암, 자가면역질환, 및 대사질환이다.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.
상기 암은 세레브론 활성을 억제 또는 세레브론 단백질을 분해하는 것으로부터 호전될 수 있는 모든 암 질환을 말하며, 비제한적인 예로, 상기 암은 가성점액종, 간내 담도암, 간모세포종, 간암, 갑상선암, 결장암, 고환암, 골수이형성증후군, 교모세포종, 구강암, 구순암, 균상식육종, 급성골수성백혈병, 급성림프구성백혈병, 기저세포암, 난소상피암, 난소생식세포암, 남성유방암, 뇌암, 뇌하수체선종, 다발성골수종, 담낭암, 담도암, 대장암, 만성골수성백혈병, 만성림프구백혈병, 망막모세포종, 맥락막흑색종, 미만성거대B세포림프종, 바터팽대부암, 방광암, 복막암, 부갑상선암, 부신암, 비부비동암, 비소세포폐암, 비호지킨림프종, 설암, 성상세포종, 소세포폐암, 소아뇌암, 소아림프종, 소아백혈병, 소장암, 수막종, 식도암, 신경교종, 신경모세포종, 신우암, 신장암, 심장암, 십이지장암, 악성 연부조직 암, 악성골암, 악성림프종, 악성중피종, 악성흑색종, 안암, 외음부암, 요관암, 요도암, 원발부위불명암, 위림프종, 위암, 위유암종, 위장관간질암, 윌름스암, 유방암, 육종, 음경암, 인두암, 임신융모질환, 자궁경부암, 자궁내막암, 자궁육종, 전립선암, 전이성 골암, 전이성뇌암, 종격동암, 직장암, 직장유암종, 질암, 척수암, 청신경초종, 췌장암, 침샘암, 카포시 육종, 파제트병, 편도암, 편평상피세포암, 폐선암, 폐암, 폐편평상피세포암, 피부암, 항문암, 횡문근육종, 후두암, 흉막암, 및 흉선암으로 이루어진 군으로부터 선택되는 1종 이상일 수 있다.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.
상기 자가면역질환은 세레브론 활성을 억제 또는 세레브론 단백질을 분해하는 것으로부터 호전될 수 있는 모든 자가면역질환을 말하며, 비제한적인 예로, 상기 자가면역질환은 면역성 호중구감소증, 길랑바레 신드롬, 간질, 자가면역 뇌염, 아이삭 신드롬, 모반 신드롬, 심상성천포창, 낙엽성천포창, 수포성류천포창, 후천성표피수포증, 임신성 유사수포창, 뮤코스 막 유사수포창, 항인지질 신드롬, 자가면역 빈혈, 자가면역 그래이브 병, 굿파스튜어 증후군, 중증근무력증, 다발성경화증, 류마티스성 관절염, 루프스, 특발성 혈소판 감소성 자반증(idiopathic thrombocytopenic purpura, ITP), 루프스 신염 및 막성 신병증으로 구성된 군에서 선택되는 하나 이상일 수 있다. 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,
상기 대사질환은, 세레브론을 억제 또는 세레브론 단백질의 분해로부터 치료 또는 예방의 효과가 달성될 수 있는 모든 대사질환을 말하며, 비제한적인 예로, 비만, Ⅰ형 당뇨병, Ⅱ형 당뇨병, 부적합한 내당력, 인슐린 내성, 고인슐린혈증, 고혈당증, 이상지질혈증, 고지질혈증, 고중성지방혈증, 고콜레스테롤혈증, 이상지질혈증, 대사 증후군 X, 혈관 질환, 죽상경화증, 관상심장질환, 대뇌혈관질환, 심부전증, 말초혈관질환, 및 반흔에서 선택되는 1종 이상일 수 있다.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.
나아가, 본 발명은 상기 A-Linker-A 또는 A-Linker-B로 표시되는 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용 가능한 염을 치료학적으로 유효한 양으로 대상(subject)에게 투여하는 단계를 포함하는 세레브론(Cereblon) 관련 질환의 치료 방법을 제공한다.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.
이때, 상기 세레브론(Cereblon) 관련 질환은 본 명세서에서 설명된 바와 같이, 세레브론(Cereblon) 활성을 저해 또는 세레브론(Cereblon) 단백질을 분해하는 것으로부터 예방 또는 치료할 수 있는 질환을 말하고, 바람직하게 암, 자가면역질환 또는 대사질환이다.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.
상기 치료학적 유효량은 투여 방법에 따라, 체내로 투여시 대상(subject)의 증상 또는 상태를 치료, 예방 또는 개선시킬 수 있을 정도의 양을 말한다. 또한 상기 양은 투여하는 대상의 체중, 나이, 성별, 상태, 가족력에 따라 상이할 수 있고, 본 발명에서 상기 치료 방법은 이처럼 대상별로 상이한 조건에 따라 다른 양의 투여량을 정할 수 있다.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.
상기 "유효한 양"은 세레브론(Cereblon) 관련 질환, 예를 들어 암, 자가면역질환 또는 대사질환을 치료하는데 유효한 양이다. 다른 구체예에서, 화합물의 "유효한 양"은 세레브론(Cereblon) 활성을 억제 또는 세레브론 단백질을 분해시킬수 있는 양이다.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.
본 발명의 방법에 따른 화합물 및 조성물은 질환을 치료하는데 유효한 임의의 양 및 임의의 투여 경로를 사용하여 투여될 수 있다. 필요한 정확한 양은 대상(subject)의 종, 연령, 및 일반적인 병태, 감염의 중증도, 특정한 제제, 그것의 투여 방식, 등에 따라 대상별로 변할 것이다. 본 발명의 화합물은 복용량의 투여 용이성 및 균일성에 대해 투약량 단위 형태로 빈번하게 제형화된다. 표현 "투약량 단위 형태"는, 본 명세서에서 사용된 바와 같이 치료될 대상에 적절한 제제의 물리적으로 별개의 단위를 의미한다. 또한, 본 발명의 화합물 및 조성물의 총 일일 사용량이 건전한 의료 판단의 범위 내에 주치의에 의해 결정될 것으로 이해될 것이다. 임의의 특정한 대상 또는 유기체에 대한 특정 유효한 투여 수준은 하기를 포함하는 다양한 인자에 의존된다: 치료될 질환 및 질환의 중증도; 이용된 특정 화합물의 활성; 특정 조성물 이용된; 연령, 체중, 일반적인 건강, 대상의 성별 및 다이어트; 투여 시간, 투여 경로, 및 이용된 특정 화합물의 배출 속도; 치료의 지속시간; 이용된 특정 화합물 단독 또는 공동투여된 약물, 및 의료 기술에서 잘 알려진 이 외의 요인.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.
용어 "대상(subject)"은, 본 명세서에서 사용된 바와 같이, 동물, 예를 들면 포유동물, 예컨대 인간을 의미한다.The term " subject ", as used herein, means an animal, such as a mammal, such as a human.
이하, 본 발명을 실시예 및 실험예에 의하여 상세히 설명한다.Hereinafter, the present invention will be described in detail with reference to Examples and Experimental Examples.
단, 하기 실시예 및 실험예는 본 발명을 예시하는 것일 뿐, 본 발명의 내용이 이에 한정되는 것은 아니다.However, the following examples and experimental examples are illustrative of the present invention, and the present invention is not limited thereto.
<실시예 1> (2S,4R)-1-((S)-2-(7-(2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일아미노)헵탄아미도)-3,3-디메틸부타노일)-4-히드록시-N-(4-(4-메틸티아졸-5-일)벤질)피롤리딘-2-카복스아미드의 제조Example 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
Figure PCTKR2018011782-appb-I000046
Figure PCTKR2018011782-appb-I000046
단계 1: 7-(2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일아미노)헵탄산의 제조Step 1: Preparation of 7- (2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-4-ylamino) heptanoic acid
DMF에 7-아미노헵탄산(158 mg, 1.09 mmol)과 2-(2,6-디옥소피페리딘-3-일)-4-플루오로이소인돌린-1,3-디온(300 mg, 1.09 mmol)을 녹인 후, DIPEA(0.285 mL, 1.64 mmol)를 넣고 실온에서 교반한다. 반응 종결 후, 농축하여 EA와 물로 희석하여 유기층을 추출하고 염수로 씻어주고, MgSO4로 물을 제거한 후, 감압농축한다. 실리카겔 컬럼 크로마토그래피(MPLC, MeOH/DCM 10% 28 분)를 이용하여 분리, 정제하여 7-(2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일아미노)헵탄산(118 mg, 27%, 황색 고체)을 얻었다.(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, [M-H]- : 399.9LC / MS (ESI) m / z [M + H] +: 401.9, [MH] -: 399.9
1H NMR (CDCl3, 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 Hz, 1H), 6.29-6.18 (m, 1H), 4.96-4.87 (m, 1H), 3.32-3.22 (m, 2H), 2.94-2.65 (m, 3H), 2.36 (t, J = 7.3 Hz, 2H), 2.19-2.09 (m, 1H), 1.75-1.58 (m, 4H), 1.43 (t, J = 3.5 Hz, 4H). 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).
단계 2: (2S,4R)-1-((S)-2-(7-(2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일아미노)헵탄아미도)-3,3-디메틸부타노일)-4-히드록시-N-(4-(4-메틸티아졸-5-일)벤질)피롤리딘-2-카복스아미드의 제조Step 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
DMF에 상기 단계 1에서 제조한 화합물(30 mg, 0.074 mmol), (2S,4R)-1-((S)-2-아미노-3,3-디메틸부타노일)-4-히드록시-N-(4-(4-메틸티아졸-5-일)벤질)피롤리딘-2-카복스아미드 염산염(35 mg, 0.074 mmol), HATU (43 mg, 0.112 mmol)을 녹이고 DIPEA(0.052 mL, 0.299 mmol)를 가한 뒤 실온에서 교반한다. 반응 종결 후, EA와 물로 희석하여 유기층을 추출하고 염수로 씻어주고, MgSO4로 물을 제거한 후, 감압농축한다. 실리카겔 컬럼 크로마토그래피(MPLC, MeOH/DCM 6% 30 min)를 이용하여 분리, 정제하여 (2S,4R)-1-((S)-2-(7-(2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일아미노)헵탄아미도)-3,3-디메틸부타노일)-4-히드록시-N-(4-(4-메틸티아졸-5-일)벤질)피롤리딘-2-카복스아미드(10 mg, 17%, 황색 고체)를 얻었다.(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, [M-H]- : 812.7LC / MS (ESI) m / z [M + H] +: 814.6, [MH] -: 812.7
1H NMR (CDCl3, 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,4H), 7.08 (d, J = 7.1 Hz, 1H), 6.87 (d, J = 8.5 Hz, 1H), 6.72 (d, J = 9.1 Hz, 1H), 6.24 (t, J = 5.7 Hz, 1H), 4.89-4.81 (m, 1H), 4.65-4.54 (m, 4H), 4.32-4.23 (m, 1H), 4.06 (d, J = 11.3 Hz, 1H), 3.70-3.62 (m, 1H), 3.55 (s, 1H), 3.26 (q, J = 6.3 Hz, 2H), 2.87-2.75 (m, 2H), 2.74-2.62 (m, 1H), 2.52 (s, 3H), 2.50-2.42 (m, 1H), 2.23-2.06 (m, 4H), 1.84 (s, 1H), 1.68-1.52 (m, 4H), 1.44-1.28 (m, 5H), 1.25 (s, 3H), 0.93 (s, 9H). 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 .
<실시예 2> (2S,4R)-1-((S)-2-(6-(2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일아미노)헥산아미도)-3,3-디메틸부타노일)-4-히드록시-N-(4-(4-메틸티아졸-5-일)벤질)피롤리딘-2-카복스아미드의 제조Example 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
Figure PCTKR2018011782-appb-I000047
Figure PCTKR2018011782-appb-I000047
단계 1: 6-((2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일)아미노)헥산산의 제조Step 1: Preparation of 6 - ((2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-4-yl) amino)
DMF에 6-아미노헥산산(119 mg, 0.905 mmol)과 2-(2,6-디옥소피페리딘-3-일)-4-플루오로이소인돌린-1,3-디온(250 mg, 0.905 mmol)을 녹인 후, DIPEA(0.236 mL, 1.36 mmol)를 넣고 실온에서 교반한다. 반응 종결 후, 농축하여 EA와 물로 희석하여 유기층을 추출하고 염수로 씻고, MgSO4로 물을 제거한 후, 감압농축한다. 실리카겔 컬럼 크로마토그래피(MPLC, MeOH/DCM 10% 28 min)를 이용하여 분리, 정제하여 6-((2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일)아미노)헥산산(60 mg, 17%, 황색 고체)을 얻었다.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, [M-H]- : 399.9LC / MS (ESI) m / z [M + H] +: 388.6, [MH] -: 399.9
1H NMR (CDCl3, 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 Hz, 1H), 6.29-6.19 (m, 1H), 4.97-4.87 (m, 1H), 3.32-3.29 (m, 2H), 2.95-2.64 (m, 3H), 2.39 (t, J = 7.3 Hz, 2H), 2.19-2.08 (m, 1H), 1.76-1.61 (m, 4H), 1.55-1.41 (m, 2H). 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).
단계 2: (2S,4R)-1-((S)-2-(6-(2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일아미노)헥산아미도)-3,3-디메틸부타노일)-4-히드록시-N-(4-(4-메틸티아졸-5-일)벤질)피롤리딘-2-카복스아미드의 제조Step 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
DMF에 상기 단계 1에서 제조한 화합물(35 mg, 0.090 mmol), (2S,4R)-1-((S)-2-아미노-3,3-디메틸부타노일)-4-히드록시-N-(4-(4-메틸티아졸-5-일)벤질)피롤리딘-2-카복스아미드 염산염(42 mg, 0.090 mmol), HATU(52 mg, 0.136 mmol) 을 녹이고 DIPEA(0.063 mL, 0.360 mmol)을 가한 뒤 실온에서 교반한다. 반응 종결 후 EA와 물로 희석하여 유기층을 추출하고 염수로 씻어주고, MgSO4로 물을 제거한 후, 감압농축한다. 실리카겔 컬럼 크로마토그래피(MPLC, MeOH/DCM 6% 30 min)를 이용하여 분리, 정제하여 (2S,4R)-1-((S)-2-(6-(2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일아미노)헥산아미도)-3,3-디메틸부타노일)-4-히드록시-N-(4-(4-메틸티아졸-5-일)벤질)피롤리딘-2-카복스아미드(43 mg, 73%, 황색 고체)를 얻었다.(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, [M-H]- : 798.7LC / MS (ESI) m / z [M + H] +: 800.7, [MH] -: 798.7
1H NMR (300 MHz, CDCl3) δ 10.35 (s, 0.5H), 9.67 (s, 0.5H), 8.68 (s, 1H), 7.60 (t, J = 6.2 Hz, 1H), 7.54-7.40 (m, 2H), 7.40-7.30 (m, 4H), 7.07 (t, J = 6.6 Hz, 1H), 6.86 (t, J = 7.8 Hz, 1H), 6.23-6.08 (m, 1H), 4.95-4.81 (m, 1H), 4.71-4.49 (m, 4H), 4.36-4.23 (m, 1H), 4.05 (d, J = 11.5 Hz, 1H), 3.64 (d, J = 11.1 Hz, 1H), 3.27-3.14 (m, 2H), 2.86-2.62 (m, 3H), 2.51 (S,4H), 2.28-2.00 (m, 5H), 1.83 (s, 1H), 1.67-1.47 (m, 4H), 1.34 (d, J = 9.4 Hz, 2H), 0.99-0.77 (m, 9H). 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).
<실시예 3> (2S,4R)-1-((S)-2-(9-(2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일아미노)노난아미도)-3,3-디메틸부타노일)-4-히드록시-N-(4-(4-메틸티아졸-5-일)벤질)피롤리딘-2-카복스아미드의 제조Example 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
Figure PCTKR2018011782-appb-I000048
Figure PCTKR2018011782-appb-I000048
단계 1: 9-브로모노난 산의 제조Step 1: Preparation of 9-bromonic acid
농축된 질산(30 mL, 258 mmol)에 9-브로모노난-1-올(2 g, 8.96 mmol)을 드로핑 펀넬을 이용하여 30분간 가한 후, 4시간 동안 실온에서 교반한다. 이 후 80℃로 가열하여 1시간 동안 교반한다. 반응 종결 후 실온으로 온도를 낮추고, 3차 증류수로 희석한다. 디에틸 에테르로 유기층을 추출하고 MgSO4로 건조하고 농축하여 9-브로모노난 산(1.57 g, 74%, 갈색 오일)을 얻는다.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).
1H 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 - 1.17 (m, 10H). 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 - &lt; / RTI &gt; 1.17 (m, 10H).
단계 2: 9-아미노노난산의 제조Step 2: Preparation of 9-aminononanoic acid
상기 단계 1에서 제조한 화합물(1 g, 4.22 mmol)을 수산화 암모늄 수용액(25% NH3, 40 mL)에 가하고 실온에서 교반한다. 반응 종결 후, 농축하여 9-아미노노난산(529 mg, 72%, 갈색 오일)을 얻는다.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).
단계3: 9-((2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일)아미노)노난산의 제조Step 3: Preparation of 9 - ((2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-4-yl) amino)
DMF에 상기 단계 2에서 제조한 화합물(200 mg, 1.15 mmol), 2-(2,6-디옥소피페리딘-3-일)-4-플루오로이소인돌린-1,3-디온(318 mg, 1.15 mmol)을 넣고 DIPEA(0.301 mL, 1.73 mmol)를 가한 뒤, 90℃에서 교반한다. 반응 종결 후, 농축하여 EA와 물로 희석하여 유기층을 추출하고 염수로 씻어주고, MgSO4로 건조하여 농축한다. 실리카겔 컬럼 크로마토그래피(MPLC, EA/Hx 60%, 35 min)를 이용하여 분리, 정제하여 9-((2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일)아미노)노난산(25 mg, 5%, 황색 고체)을 얻는다.(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 , [M-H]- : 427.9LC / MS (ESI) m / z [M + H] +: 429.9, [MH] -: 427.9
1H NMR (CDCl3, 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), 6.24 (s, 1H), 4.96 - 4.90 (m,, 1H), 3.26 - 3.23 (m, 2H), 2.94 - 2.65 (m, 3H), 2.34 (t, J = 7.4 Hz, 2H), 2.17 - 2.05 (m, 1H), 1.64 (d, J = 6.6 Hz, 5H), 1.34 (s, 9H). 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).
단계 4: (2S,4R)-1-((S)-2-(9-(2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일아미노)노난아미도)-3,3-디메틸부타노일)-4-히드록시-N-(4-(4-메틸티아졸-5-일)벤질)피롤리딘-2-카복스아미드의 제조Step 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
DMF에 상기 단계 3에서 제조한 화합물(25 mg, 0.058 mmol), (2S,4R)-1-((S)-2-아미노-3,3-디메틸부타노일)-4-히드록시-N-(4-(4-메틸티아졸-5-일)벤질)피롤리딘-2-카복스아미드 염산염(27 mg, 0.058 mmol), HATU(33 mg, 0.087 mmol)를 넣고 DIPEA(0.041 mL, 0.233 mmol)를 가한 뒤, 90℃에서 교반한다. 반응 종결 후, 농축하여 EA와 물로 희석하여 유기층을 추출하고 염수로 씻어주고, MgSO4로 건조하여 농축한다. 실리카겔 컬럼 크로마토그래피(MPLC, MeOH/DCM 6%, 30 min)를 이용하여 분리, 정제하여 (2S,4R)-1-((S)-2-(9-(2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일아미노)노난아미도)-3,3-디메틸부타노일)-4-히드록시-N-(4-(4-메틸티아졸-5-일)벤질)피롤리딘-2-카복스아미드(17 mg, 35%, 황색 고체)를 얻는다.(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 , [M-H]- : 840.7LC / MS (ESI) m / z [M + H] +: 842.6, [MH] -: 840.7
1H NMR (300 MHz, CDCl3) δ 10.63 (s, 0.5H), 10.37 (s, 0.5H), 10.32 (s, 0.5H), 10.29 (s, 0.5H), 8.67 (s, 1H), 7.68-7.53 (m, 1H), 7.44 (t, J = 7.8 Hz, 1H), 7.38-7.30 (m, 3H), 7.03 (d, J = 7.1 Hz, 1H), 6.94-6.76 (m, 2H), 6.22 (s, 1H), 4.98-4.78 (m, 1H), 4.69-4.44 (m, 4H), 4.34-4.09 (m, 2H), 4.05-3.90 (m, 1H), 3.69-3.56 (m, 1H), 3.28-3.11 (m, 2H), 2.83-2.56 (m, 3H), 2.52-2.32 (m, 4H), 2.22-1.96 (m, 4H), 1.66-1.44 (m, 4H), 1.40-1.09 (m, 7H), 0.91 (s, 9H). LC/MS (ESI) m/z 842.6[M+H]+, 840.7[M-H]- 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] -
<실시예 4> (2S,4R)-1-((S)-2-tert-부틸-17-(2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일아미노)-4-옥소-6,9,12,15-테트라옥사-3-아자헵타데카-1-노일)-4-히드록시-N-(4-(4-메틸티아졸-5-일)벤질)피롤리딘-2-카복스아미드의 제조Example 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
Figure PCTKR2018011782-appb-I000049
Figure PCTKR2018011782-appb-I000049
단계 1: tert-부틸 14-아미노-3,6,9,12-테트라옥사테트라데카-1-노에이트의 제조Step 1: Preparation of tert-butyl 14-amino-3,6,9,12-tetraoxatetradec-1 -noate
tert-부틸 14-요오도-3,6,9,12-테트라옥사테트라데카-1-노에이트(315 mg, 0.753 mmol)를 DMF에 녹이고 소듐 아자이드(147 mg, 2.26 mmol)를 가하여 50℃에서 교반한다. 반응 종결 후, 농축하여 조 생성물 상태의 아자이드 화합물을 얻은 후, 에탄올에 녹이고 Pd(OH)2(6 mg)를 가하여 수소 기체 하에서 교반한다. 반응 종결 후, 메탄올을 이용하여 셀라이트 여과한 후, 농축하여 조 생성물 상태의 tert-부틸 14-아미노-3,6,9,12-테트라옥사테트라데카-1-노에이트(240 mg, 정량. 황색 고체)를 얻는다.(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).
1H NMR (DMSO-d6, 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). 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).
단계 2: tert-부틸 14-((2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일)아미노)-3,6,9,12-테트라옥사테트라데카노에이트의 제조Step 2: tert-Butyl 14 - ((2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-4- yl) amino) -3,6,9,12 - Preparation of tetraoxatetradecanoate
DMSO에 상기 단계 1에서 제조한 화합물(100 mg, 0.325 mmol), 2-(2,6-디옥소피페리딘-3-일)-4-플루오로이소인돌린-1,3-디온(90 mg, 0.325 mmol)을 첨가하고, DIPEA(0.085 mL, 0.488 mmol)를 가한 후, 90℃에서 교반한다. 반응 종결 후, EA와 물로 희석하여 유기층을 추출하고 염수로 씻어주고, MgSO4로 물을 제거하여 감압농축한다. 실리카겔 컬럼 크로마토그래피(MPLC, MeOH/DCM 5% 28 min)를 이용하여 분리, 정제하여 tert-부틸 14-(2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일아미노)-3,6,9,12-테트라옥사테트라데카-1-노에이트(7 mg, 4%, 황색 고체)를 얻는다.(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 &lt; 0 &gt; 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 [M-H]- = 562.9LC / MS (ESI) m / z [M + H] + = 564.9 [MH] - = 562.9
단계 3: 14-((2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일)아미노)-3,6,9,12-테트라옥사테트라데칸산의 제조Step 3: 14 - ((2- (2,6-Dioxopiperidin-3-yl) -1,3-dioxoisoindolin-4- yl) amino) -3,6,9,12- Preparation of tetradecanoic acid
40% TFA/DCM 용액에 tert-부틸 14-(2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일아미노)-3,6,9,12-테트라옥사테트라데카-1-노에이트(7 mg, 0.012 mmol)를 가하고 실온에서 교반한다. 반응 종결 후, 농축하여 14-((2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일)아미노)-3,6,9,12-테트라옥사테트라데칸산(10 mg, 조 생성물, 갈색 오일)을 조 생성물 상태로 얻는다.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 [M-H]- = 506.8LC / MS (ESI) m / z [M + H] + = 508.8 [MH] - = 506.8
단계 4: (2S,4R)-1-((S)-2-(tert-부틸)-17-((2-(2,6-디옥사피페리딘-3-일)-1,3-디옥소이소인돌린-4-일)아미노)-4-옥소-6,9,12,15-테트라옥사-3-아자헵타데카노일)-4-히드록시-N-(4-(4-메틸티아졸-5-일)벤질)피롤리딘-2-카복스아미드의 제조Step 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
상기 단계 3에서 제조한 화합물(6 mg, 0.012 mmol), (2S,4R)-1-((S)-2-아미노-3,3-디메틸부타노일)-4-히드록시-N-(4-(4-메틸티아졸-5-일)벤질)피롤리딘-2-카복스아미드 염산염(6 mg, 0.012 mmol), HATU(7 mg, 0.018 mmol)를 DMF 에 녹인 후, DIPEA(0.008 mL, 0.048 mmol)를 가한 후, 실온에서 교반한다. 반응 종결 후, 농축하여 EA와 물로 희석하여 유기층을 추출하고 염수로 씻어주고, MgSO4로 물을 제거한 후, 감압농축한다. 실리카겔 컬럼 크로마토그래피(MPLC, MeOH/DCM 6%, 30 min)를 이용하여 분리, 정제하여 (2S,4R)-1-((S)-2-(tert-부틸)-17-((2-(2,6-디옥사피페리딘-3-일)-1,3-디옥소이소인돌린-4-일)아미노)-4-옥소-6,9,12,15-테트라옥사-3-아자헵타데카노일)-4-히드록시-N-(4-(4-메틸티아졸-5-일)벤질)피롤리딘-2-카복스아미드(3 mg, 27%, 황색 고체)를 얻는다.(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 , [M-H]- : 919.8LC / MS (ESI) m / z [M + H] +: 921.8, [MH] -: 919.8
1H NMR (300 MHz, CDCl3) δ 9.29 (s, 1H), 8.68 (s, 1H), 7.63-7.43 (m, 2H), 7.42-7.32 (m, 3H), 7.32-7.27 (m, 1H), 7.10 (d, J = 7.1 Hz, 1H), 6.95-6.86 (m, 1H), 6.52 (s, 1H), 4.93-4.79 (m, 1H), 4.72 (t, J = 8.0 Hz, 1H), 4.64-4.45 (m, 2H), 4.37-4.20 (m, 1H), 4.17-4.06 (m, 1H), 4.04-3.97 (m, 1H), 3.79-3.54 (m, 12H), 3.52-3.38 (m, 2H), 2.94-2.62 (m, 3H), 2.52 (s, 3H), 2.22-1.96 (m, 3H), 1.26 (s, 9H), 0.99-0.78 (m, 10H). 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
<실시예 5> (2S,4R)-1-((S)-2-(2-(3-(2-(2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일아미노)-2-옥소에톡시)프로폭시)아세트아미도)-3,3-디메틸부타노일)-4-히드록시-N-(4-(4-메틸티아졸-5-일)벤질)피롤리딘-2-카복스아미드의 제조Example 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
Figure PCTKR2018011782-appb-I000050
Figure PCTKR2018011782-appb-I000050
단계 1: 디-tert-부틸 2,2'-(프로판-1,3-디일비스(옥시))디아세테이트의 제조Step 1: Preparation of di-tert-butyl 2,2 '- (propane-1,3-diylbis (oxy)) diacetate
톨루엔과 NaOH 수용액(50 wt%)에 프로판-1,3-디올(1 g, 13.1 mmol), tert-부틸 2-브로모아세테이트(21.5 g, 110.4 mmol), 테트라부틸 암모늄 황산 수소염(445 mg, 1.31 mmol)을 가하고 실온에서 16시간 동안 교반한다. 반응 종결 후, 빙수로 희석하고 EA로 추출한 후, 염수로 씻고 MgSO4로 물을 제거하고 감압농축한다. 실리카겔 컬럼 크로마토그래피(MPLC, EA/Hx 30% 40 min)를 이용하여 분리, 정제하여 디-tert-부틸 2,2'-(프로판-1,3-디일비스(옥시))디아세테이트(580 mg, 15%, 무색 오일)를 7얻는다.(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).
1H NMR (CDCl3, 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). 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).
단계 2: 2,2'-(프로판-1,3-디일비스(옥시))디아세트산의 제조Step 2: Preparation of 2,2 '- (propane-1,3-diylbis (oxy)) diacetic acid
40% TFA/DCM 용액에 디-tert-부틸 2,2'-(프로판-1,3-디일비스(옥시))디아세테이트(530 mg, 1.74 mmol)를 가하고 실온에서 교반한다. 반응 종결 후, 농축하여 2,2'-(프로판-1,3-디일비스(옥시))디아세트산(631 mg, 조 생성물, 갈색 오일) 을 조 생성물 상태로 얻는다.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.
1H NMR (CDCl3, 300MHz) δ 10.12 (s, 2H), 4.21 (S,4H), 3.75 (t, J = 5.9 Hz, 4H), 2.08 - 1.90 (m, 2H). 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).
단계 3: 2-(3-(2-((2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일)아미노)-2-옥소에톡시)프로폭시)아세트산의 제조Step 3: To a solution of 2- (3- (2- ((2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin- Ethoxy) propoxy) acetic acid
상기 단계 2에서 제조한 화합물(167 mg, 0.869 mmol)을 DCM에 녹이고 염화 옥살일(0.373 mL, 4.35 mmol)을 가하고, DMF를 한 방울 가한다. 산염화물이 만들어진 것을 확인한 후, 농축한다. THF에 녹이고 포말리도마이드(Pomalidomide)를 가한 후, 환류한다. 반응 종결 후, 0.1 N HCl(aq.)용액으로 반응을 종결시키고 EA와 물로 희석하여 유기층을 추출한 후, 염수로 씻고, MgSO4로 물을 제거한 후, 감압농축한다. 생성된 고체를 EA로 여과하여 2-(3-(2-((2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일)아미노)-2-옥소에톡시)프로폭시)아세트산(54 mg, 28%, 회색 고체)를 얻는다. LC/MS (ESI) m/z [M+H]+ = 447.8 [M-H]- = 445.8The 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
1H NMR (CDCl3, 300MHz) δ 10.41 (s, 1H), 8.96 - 8.78 (m, 1H), 8.65 (s, 1H), 7.81 - 7.66 (m, 1H), 7.62 - 7.50 (m, 1H), 5.04 - 4.86 (m, 1H), 4.27 - 4.04 (m, 4H), 3.86 (t, J = 6.7 Hz, 2H), 3.74 (t, J = 6.0 Hz, 2H), 3.01 - 2.64 (m, 3H), 2.15 - 1.99 (m, 3H). 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).
단계 4: (2S,4R)-1-((S)-2-(2-(3-(2-((2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일)아미노)-2-옥소에톡시)프로폭시)아세트아미도)-3,3-디메틸부타노일)-4-히드록시-N-(4-(4-메틸티아졸-5-일)벤질)피롤리딘-2-카복스아미드의 제조Step 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
상기 단계 3에서 제조한 화합물(30 mg, 0.067 mmol), (2S,4R)-1-((S)-2-아미노-3,3-디메틸부타노일)-4-히드록시-N-(4-(4-메틸티아졸-5-일)벤질)피롤리딘-2-카복스아미드 염산염(31 mg, 0.067 mmol), HATU(38 mg, 0.101 mmol)를 DMF에 녹인 후, DIPEA(0.047 mL, 0.268 mmol)를 가한 후, 실온에서 교반한다. 반응 종결 후, 농축하여 EA와 물로 희석하여 유기층을 추출하고 염수로 씻어주고, MgSO4로 물을 제거한 후, 감압농축한다. 실리카겔 컬럼 크로마토그래피(MPLC, MeOH/DCM 6%, 30 min)를 이용하여 분리, 정제하여 (2S,4R)-1-((S)-2-(2-(3-(2-((2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일)아미노)-2-옥소에톡시)프로폭시)아세트아미도)-3,3-디메틸부타노일)-4-히드록시-N-(4-(4-메틸티아졸-5-일)벤질)피롤리딘-2-카복스아미드(5 mg, 9%, 흰색 고체)를 얻는다.(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 , [M-H]- : 858.7LC / MS (ESI) m / z [M + H] +: 860.5, [MH] -: 858.7
1H NMR (CDCl3, 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 (d, J = 6.2 Hz, 1H), 4.95-4.84 (m, 1H), 4.67-4.59 (m, 2H), 4.50 (s, 2H), 4.33-4.25 (m, 1H), 4.23-4.14 (m, 1H), 4.12-4.01 (m, 3H), 4.01-3.97 (m, 1H), 3.93-3.85 (m, 1H), 3.82-3.73 (m, 2H), 3.65-3.56 (m, 2H), 2.88-2.57 (m, 3H), 2.53 (s, 3H), 2.40 (s, 1H), 2.19-1.90 (m, 6H), 1.71-1.60 (m, 2H), 1.59-1.38 (m, 2H), 0.95 (s, 9H). 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).
<실시예 6> N1-(2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일)-N9-((S)-1-((2S,4R)-4-히드록시-2-(4-(4-메틸티아졸-5-일)벤질카바모일)피롤리딘-1-일)-3,3-디메틸-1-옥소부탄-2-일)노난디아미드의 제조Example 6 Synthesis of N1- (2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-4-yl) -N9 - ((S) Pyrrolidin-l-yl) -3,3-dimethyl-l-oxobutane-l- 2-yl) nonanediamide
Figure PCTKR2018011782-appb-I000051
Figure PCTKR2018011782-appb-I000051
9-(2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일아미노)-9-옥소노난산(30 mg, 0.068 mmol), (2S,4R)-1-((S)-2-아미노-3,3-디메틸부타노일)-4-히드록시-N-(4-(4-메틸티아졸-5-일)벤질)피롤리딘-2-카복스아미드 염산염(32 mg, 0.068 mmol), HATU(39 mg, 0.101 mmol)를 DMF 에 녹인 후, DIPEA(0.047 mL, 0.272 mmol)를 가한 후, 실온에서 교반한다. 반응 종결 후, 농축하여 EA와 물로 희석하여 유기층을 추출하고 염수로 씻고 MgSO4로 물을 제거한 후, 감압농축한다. 실리카겔 컬럼 크로마토그래피(MPLC, MeOH/DCM 6%, 30 min)를 이용하여 분리, 정제하여 N1-(2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일)-N9-((R)-1-((2R,4R)-4-히드록시-2-(4-(4-메틸티아졸-5-일)벤질카바모일)피롤리딘-1-일)-3,3-디메틸-1-옥소부탄-2-일)노난디아미드(21 mg, 36%, 흰색 고체)를 얻는다.(30 mg, 0.068 mmol), (2S, &lt; RTI ID = 0.0 &gt; , 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 , [M-H]- : 854.7LC / MS (ESI) m / z [M + H] +: 856.6, [MH] -: 854.7
1H NMR (300 MHz, CDCl3) δ 10.92 (s, 0.5H), 10.35 (s, 0.5H), 9.53 (s, 0.5H), 9.50 (s, 0.5H), 8.84 (d, J = 8.4 Hz, 0.5H), 8.79 (d, J = 8.4 Hz, 0.5H), 8.69 (s, 1H), 7.79-7.65 (m, 1H), 7.59-7.48 (m, 1H), 7.40-7.30 (m, 4H), 6.83 (d, J = 9.0 Hz, 0.5H), 6.63 (d, J = 9.0 Hz, 0.5H), 5.01-4.83 (m, 1H), 4.73-4.48 (m, 4H), 4.35-4.21 (m, 1H), 4.09 (t, J = 10.5 Hz, 1H), 3.70-3.59 (m, 1H), 2.89-2.60 (m, 3H), 2.57-2.36 (m, 6H), 2.23-2.06 (m, 4H), 1.91-1.65 (m, 2H), 1.63-1.51 (m, 2H), 1.51-1.41 (m, 2H), 1.40-1.16 (m, 7H), 1.00-0.81 (m, 9H). LC/MS (ESI) m/z 856.6[M+H]+, 854.7[M-H]- 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] -
<실시예 7> N1-(2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일)-N8-((S)-1-((2S,4R)-4-히드록시-2-(4-(4-메틸티아졸-5-일)벤질카바모일)피롤리딘-1-일)-3,3-디메틸-1-옥소부탄-2-일)옥탄디아미드의 제조Example 7 Synthesis of N1- (2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-4-yl) -N8 - ((S) Pyrrolidin-l-yl) -3,3-dimethyl-l-oxobutane-l- 2-yl) octanediamide < / RTI >
Figure PCTKR2018011782-appb-I000052
Figure PCTKR2018011782-appb-I000052
8-(2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일아미노)-8-옥소옥탄산(30 mg, 0.070 mmol), (2S,4R)-1-((S)-2-아미노-3,3-디메틸부타노일)-4-히드록시-N-(4-(4-메틸티아졸-5-일)벤질)피롤리딘-2-카복스아미드 염산염(33 mg, 0.070 mmol), HATU(40 mg, 0.105 mmol)를 DMF에 녹인 후, DIPEA(0.049 mL, 0.279 mmol)를 가한 후, 실온에서 교반한다. 반응 종결 후, 농축하여 EA와 물로 희석하여 유기층을 추출하고 염수로 씻어주고 MgSO4로 물을 제거한 후, 감압농축한다. 실리카겔 컬럼 크로마토그래피(MPLC, MeOH/DCM 6%, 30 min)를 이용하여 분리, 정제하여 N1-(2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일)-N8-((S)-1-((2S,4R)-4-히드록시-2-(4-(4-메틸티아졸-5-일)벤질카바모일)피롤리딘-1-일)-3,3-디메틸-1-옥소부탄-2-일)옥탄디아미드(17 mg, 29%, 흰색 고체)를 얻는다.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 , [M-H]- : 840.7LC / MS (ESI) m / z [M + H] +: 842.6, [MH] -: 840.7
1H NMR (300 MHz, CDCl3) δ 11.23 (s, 0.5H), 10.21 (s, 0.5H), 9.48 (d, J = 10.3 Hz, 1H), 8.77 (t, J = 9.0 Hz, 1H), 8.72-8.65 (m, 1H), 7.77-7.66 (m, 1H), 7.61-7.47 (m, 1.5H), 7.40-7.29 (m, 4H), 7.03 (d, J = 9.0 Hz, 0.5H), 6.59 (d, J = 9.0 Hz, 0.5H), 6.26-6.19 (m, 0.5H), 4.97-4.84 (m, 1H), 4.75-4.48 (m, 4H), 4.37-4.25 (m, 1H), 4.18-4.04 (m, 1H), 3.69-3.57 (m, 2H), 2.91-2.61 (m, 3H), 2.57-2.40 (m, 5H), 2.32-2.06 (m, 4H), 2.06-1.97 (m, 1H), 1.85 (t, J = 7.5 Hz, 1H), 1.79-1.68 (m, 1H), 1.68-1.52 (m, 3H), 1.44-1.32 (m, 3H), 0.97-0.83 (m, 9H). LC/MS (ESI) m/z 842.6[M+H]+, 840.7[M-H]- 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] -
<실시예 8> N1-(2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일)-N7-((S)-1-((2S,4R)-4-히드록시-2-((4-(4-메틸티아졸-5-일)벤질)카바모일)피롤리딘-1-일)-3,3-디메틸-1-옥소부탄-2-일)헵탄디아미드의 제조Example 8 Synthesis of N1- (2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-4-yl) -N7 - ((S) (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin- 1 -yl) -3,3-dimethyl- Butan-2-yl) heptanediamide < / RTI >
Figure PCTKR2018011782-appb-I000053
Figure PCTKR2018011782-appb-I000053
7-(2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일아미노)-7-옥소헵탄산(50 mg, 0.120 mmol), (2S,4R)-1-((S)-2-아미노-3,3-디메틸부타노일)-4-히드록시-N-(4-(4-메틸티아졸-5-일)벤질)피롤리딘-2-카복스아미드 염산염(56 mg, 0.120 mmol), HATU(68 mg, 0.180 mmol)를 DMF에 녹인 후 DIPEA(0.084 mL, 0.480 mmol)를 가한 후, 실온에서 교반한다. 반응 종결 후, 농축하여 EA와 물로 희석하여 유기층을 추출하고 염수로 씻고 MgSO4로 물을 제거한 후, 감압농축한다. 실리카겔 컬럼 크로마토그래피(MPLC, MeOH/DCM 6%, 30 min)를 이용하여 분리, 정제하여 N1-(2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일)-N7-((S)-1-((2S,4R)-4-히드록시-2-((4-(4-메틸티아졸-5-일)벤질)카바모일)피롤리딘-1-일)-3,3-디메틸-1-옥소부탄-2-일)헵탄디아미드(33 mg, 33%, 흰색 고체)을 얻는다.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). &Lt; 1 &gt;
LC/MS (ESI) m/z [M+H]+ : 828.6 , [M-H]- : 826.7LC / MS (ESI) m / z [M + H] +: 828.6, [MH] -: 826.7
1H NMR (CDCl3, 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 Hz, 1H), 7.54 (dd, J = 10.5, 6.7 Hz, 2H), 7.35-7.32 (m, 4H), 6.76 (d, J = 9.1 Hz, 1H), 4.92-4.82 (m, 1H), 4.68-4.53 (m, 4H), 4.91-4.84 (m, 1H), 4.07 (d, J = 11.3 Hz, 2H), 3.74-3.63 (m, 1H), 2.88-2.61 (m, 3H), 2.56-2.37 (m, 6H), 2.30-1.99 (m, 5H), 1.81-1.54 (m, 4H), 1.47-1.30 (m, 2H), 0.95 (s, 9H). 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).
<실시예 9> N1-(2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일)-N14-((S)-1-((2S,4R)-4-히드록시-2-((4-(4-메틸티아졸-5-일)벤질)카바모일)피롤리딘-1-일)-3,3-디메틸-1-옥소부탄-2-일)-3,6,9,12-테트라옥사테트라데칸-1,14-디아미드의 제조Example 9 Synthesis of N1- (2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-4-yl) -N14 - ((S) (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin- 1 -yl) -3,3-dimethyl- Butan-2-yl) -3,6,9,12-tetraoxatetradecan-1,14-diamide
Figure PCTKR2018011782-appb-I000054
Figure PCTKR2018011782-appb-I000054
단계 1: 디-tert-부틸 3,6,9,12-테트라옥사테트라데칸디오에이트의 제조Step 1: Preparation of di-tert-butyl 3,6,9,12-tetraoxatetradecanedioate
톨루엔과 NaOH 수용액(50 wt%)에 2-(2-(히드록시메톡시)에톡시)에탄올(1 g, 7.34 mmol), tert-부틸 2-브로모아세테이트(9.12 mL, 61.7 mmol), 테트라부틸 암모늄 황산 수소염(249 mg, 0.734 mmol)을 가하고 실온에서 16시간 동안 교반한다. 반응 종결 후, 빙수로 희석하고 EA로 추출한 후, 염수로 씻어주고, MgSO4로 물을 제거하고 감압농축한다. 실리카겔 컬럼 크로마토그래피(MPLC, EA/Hx 50% 40 min)를 이용하여 분리, 정제하여 디-tert-부틸 3,6,9,12-테트라옥사테트라데칸디오에이트(1.24 g, 31%, 무색의 오일)를 얻는다.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).
1H NMR (CDCl3, 300MHz) δ 4.02 (S,4H), 3.75 - 3.62 (m, 12H), 1.47 (s, 18H). 1 H NMR (CDCl 3 , 300 MHz)? 4.02 (s, 4H), 3.75-3.62 (m, 12H), 1.47 (s, 18H).
단계 2: 3,6,9,12-테트라옥사테트라데칸-1,14-디온산의 제조Step 2: Preparation of 3,6,9,12-tetraoxatetradecan-1,14-dione acid
40% TFA/DCM 용액에 상기 단계 1에서제조한 화합물(450 mg, 1.48 mmol)을 가하고 실온에서 교반한다. 반응 종결 후, 농축하여 3,6,9,12-테트라옥사테트라데칸-1,14-디온산33 (502 mg, 조 생성물, 갈색 오일) 을 조 생성물 상태로 얻는다.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.
1H NMR (CDCl3, 300MHz) δ 10.14 (s, 1H), 4.23 (S,4H), 3.98 - 3.40 (m, 12H). 1 H NMR (CDCl 3 , 300 MHz)? 10.14 (s, 1H), 4.23 (S, 4H), 3.98-3.40 (m, 12H).
단계 3: 14-((2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일)아미노)-14-옥소-3,6,9,12-테트라옥사테트라데칸산의 제조Step 3: 14 - ((2- (2,6-Dioxopiperidin-3-yl) -1,3-dioxoisoindolin-4-yl) amino) Preparation of 12-tetraoxatetradecanoic acid
상기 단계 2에서 제조한 화합물(394 mg, 1.48 mmol)을 DCM에 녹이고 염화 옥살일(0.635 mL, 7.40 mmol)을 가하고, DMF를 한 방울 가한다. 산염화물이 만들어진 것을 확인한 후, 농축한다. THF에 녹이고 포말리도마이드(202 mg, 0.740 mmol)를 가한 후, 환류한다. 반응 종결 후 0.1 N HCl(aq.) 용액으로 반응을 종결 시키고 EA와 물로 희석하여 유기층을 추출한 후, 염수로 씻고, MgSO4로 물을 제거한 후, 감압농축한다. 실리카겔 컬럼 크로마토그래피(MPLC, MeOH/DCM 20% 40 min)로 분리, 정제하여 14-((2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일)아미노)-14-옥소-3,6,9,12-테트라옥사테트라데칸산(78 mg, 20%, 갈색 고체)을 얻는다.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 [M-H]- = 520.8LC / MS (ESI) m / z [M + H] + = 522.8 [MH] - = 520.8
1H NMR (CDCl3, 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 (d, J = 7.3 Hz, 1H), 5.07-4.92 (m, 1H), 4.29-4.05 (m, 8H), 3.87-3.78 (m, 4H), 3.78-3.61 (m, 17H), 3.57 (t, J = 5.7 Hz, 2H), 3.01-2.68 (m, 3H), 2.26-2.08 (m, 1H) 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, &lt; RTI ID = J = 5.7 Hz, 2H), 3.01-2.68 (m, 3H), 2.26-2.08 (m,
단계 4: N1-(2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일)-N14-((S)-1-((2S,4R)-4-히드록시-2-((4-(4-메틸티아졸-5-일)벤질)카바모일)피롤리딘-1-일)-3,3-디메틸-1-옥소부탄-2-일)-3,6,9,12-테트라옥사테트라데칸-1,14-디아미드의 제조Step 4: N1- (2- (2,6-Dioxopiperidin-3-yl) -1,3-dioxoisoindolin- (4-methylthiazol-5-yl) benzyl) carbamoyl) pyrrolidin- 1 -yl) -3,3-dimethyl-1-oxobutane- 2-yl) -3,6,9,12-tetraoxatetradecan-1,14-diamide
상기 단계 3에서 제조한 화합물(25 mg, 0.048 mmol), (2S,4R)-1-((S)-2-아미노-3,3-디메틸부타노일)-4-히드록시-N-(4-(4-메틸티아졸-5-일)벤질)피롤리딘-2-카복스아미드 염산염(22 mg, 0.048 mmol), HATU(27 mg, 0.072 mmol)를 DMF 에 녹인 후, DIPEA(0.033 mL, 0.192 mmol)를 가한 후, 실온에서 교반한다. 반응 종결 후 농축하여 EA와 물로 희석하여 유기층을 추출하고 염수로 씻고 MgSO4로 물을 제거한 후, 감압농축한다. 실리카겔 컬럼 크로마토그래피(MPLC, MeOH/DCM 6%, 30 min)를 이용하여 분리, 정제하여 N1-(2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일)-N14-((S)-1-((2S,4R)-4-히드록시-2-((4-(4-메틸티아졸-5-일)벤질)카바모일)피롤리딘-1-일)-3,3-디메틸-1-옥소부탄-2-일)-3,6,9,12-테트라옥사테트라데칸-1,14-디아미드(11 mg, 24%, 아이보리색 고체)를 얻는다.(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 , [M-H]- : 933.6LC / MS (ESI) m / z [M + H] +: 935.5, [MH] -: 933.6
1H NMR (CDCl3, 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 (m, 1H), 4.27-4.06 (m, 4H), 4.06-3.95 (m, 2H), 3.79 (s, 3H), 3.75-3.52 (m, 12H), 2.90-2.59 (m, 3H), 2.56-2.38 (m, 4H), 2.22-2.06 (m, 2H), 2.06-1.94 (m, 1H), 1.88-1.77 (m, 1H), 1.02-0.88 (m, 9H). 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).
<실시예 10> N1-(2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일)-N5-((S)-1-((2S,4R)-4-히드록시-2-(4-(4-메틸티아졸-5-일)벤질카바모일)피롤리딘-1-일)-3,3-디메틸-1-옥소부탄-2-일)글루타르아미드의 제조Example 10 Synthesis of N1- (2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-4-yl) -N5 - ((S) Pyrrolidin-l-yl) -3,3-dimethyl-l-oxobutane-l- 2-yl) glutaramide < / RTI >
Figure PCTKR2018011782-appb-I000055
Figure PCTKR2018011782-appb-I000055
단계 1: 5-((2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일)아미노)-5-옥소펜탄산의 제조Step 1: Preparation of 5 - ((2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-4-yl) amino) -5-oxopentanoic acid
아미노-2-(2,6-디옥소피페리딘-3-일)이소인돌린-1,3-디온(0.1 g, 0.37 mmol)을 아세트산(2 mL)에 녹이고 글루타릭 무수물 (0.046 g, 0.403 mmol), 칼륨 아세테이트(0.108 g, 1.1 mmol)를 첨가한 후, 90℃에서 2시간 동안 교반하였다. 반응이 종결되고, 반응물은 에틸아세테이트로 희석하고 물과 소금물로 씻어주었다. 유기층은 무수 황산마그네슘으로 건조하고, 감압 농축, 분리정제하여 목적 화합물을 제조하였다.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.
1H NMR (300 MHz, DMSO) δ 11.14 (s, 1H), 9.72 (s, 1H), 8.44 (d, J = 8.4 Hz, 1H), 7.90 - 7.78 (m, 1H), 7.62 (d, J = 7.2 Hz, 1H), 5.15 (dd, J = 12.8, 5.4 Hz, 1H), 2.98 - 2.83 (m, 1H), 2.67 - 2.53 (m, 2H), 2.31 (t, J = 7.4 Hz, 2H), 2.24 (t, J = 7.4 Hz, 2H), 2.13 - 2.00 (m, 1H), 1.92 - 1.76 (m, 2H), 1.76 - 1.63 (m, 1H).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).
단계2: N1-(2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일)-N5-((S)-1-((2S,4R)-4-히드록시-2-(4-(4-메틸티아졸-5-일)벤질카바모일)피롤리딘-1-일)-3,3-디메틸-1-옥소부탄-2-일)글루타르아미드의 제조 Step 2: N1- (2- (2,6-Dioxopiperidin-3-yl) -1,3-dioxoisoindolin- Pyrrolidin-1-yl) -3,3-dimethyl-1-oxobutane-2- (4-methyl- Yl) glutaramide &lt; / RTI &gt;
상기 단계 1에서 제조한 화합물(25 mg, 0.048 mmol), (2S,4R)-1-((S)-2-아미노-3,3-디메틸부타노일)-4-히드록시-N-(4-(4-메틸티아졸-5-일)벤질)피롤리딘-2-카복스아미드 염산염(22 mg, 0.048 mmol), HATU(27 mg, 0.072 mmol)를 DMF 에 녹인 후, DIPEA(0.033 mL, 0.192 mmol)를 가한 후, 실온에서 교반한다. 반응 종결 후 농축하여 EA와 물로 희석하여 유기층을 추출하고 염수로 씻고 MgSO4로 물을 제거한 후, 감압농축한다. 실리카겔 컬럼 크로마토그래피(MPLC, MeOH/DCM 6%, 30 min)를 이용하여 분리, 정제하여 N1-(2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일)-N5-((S)-1-((2S,4R)-4-히드록시-2-(4-(4-메틸티아졸-5-일)벤질카바모일)피롤리딘-1-일)-3,3-디메틸-1-옥소부탄-2-일)글루타르아미드를 얻는다.(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.
1H NMR (300 MHz, CDCl3) δ 10.25 (s, 0.5H), 10.03 (s, 0.5H), 8.77-8.63 (m, 2H), 7.72-7.61 (m, 1H), 7.61-7.48 (m, 2H), 7.36-7.29 (m, 4H), 6.85 (d, J = 9.0 Hz, 0.5H), 6.77 (d, J = 9.0 Hz, 0.5H), 4.95-4.84 (m, 1H), 4.69-4.51 (m, 4H), 4.31-4.21 (m, 1H), 4.08-3.99 (m, 1H), 3.75-3.63 (m, 2H), 2.87-2.62 (m, 3H), 2.50 (s, 3H), 2.48-2.38 (m, 3H), 2.37-2.23 (m, 2H), 2.19-1.94 (m, 4H), 1.50-1.38 (m, 4H), 0.94 (s, 9H). LC/MS (ESI) m/z 800.3[M+H]+, 798.2[M-H]- 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] -
<실시예 11> N1-((2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일)메틸)-N7-((S)-1-((2S,4R)-4-히드록시-2-(4-(4-메틸티아졸-5-일)벤질카바모일)피롤리딘-1-일)-3,3-디메틸-1-옥소부탄-2-일)헵탄디아미드의 제조Example 11 Synthesis of N1 - ((2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-4-yl) ((2S, 4R) -4-hydroxy-2- (4- (4-methylthiazol- 5- yl) benzylcarbamoyl) pyrrolidin- 1 -yl) -3,3- Oxobutan-2-yl) heptanediamide < / RTI >
Figure PCTKR2018011782-appb-I000056
Figure PCTKR2018011782-appb-I000056
상기 실시예 10의 단계 1에서 사용한 글루타릭 무수물을 대신하여, 옥소칸-2,8-디온을 사용한 점을 제외하고, 상기 실시예 10과 유사한 방법으로 목적 화합물을 제조하였다.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.
1H NMR (500 MHz, CDCl3) δ 8.70 (d, J = 4.7 Hz, 1H), 7.81 (dd, J = 13.9, 6.2 Hz, 3H), 7.72 (t, J = 7.6 Hz, 1H), 7.44 - 7.34 (m, 4H), 7.24 - 7.06 (m, 2H), 5.04 - 4.92 (m, 1H), 4.81 - 4.55 (m, 4H), 4.50 (m, 2H), 4.33 (td, J = 14.8, 4.9 Hz, 1H), 3.98 (t, J = 10.2 Hz, 1H), 3.62 (m, 1H), 2.85 (m, 2H), 2.80 - 2.58 (m, 1H), 2.52 (d, J = 5.7 Hz, 3H), 2.49 - 2.35 (m, 1H), 2.30 - 2.02 (m, 6H), 1.59 - 1.46 (m, 2H), 1.42 (m, 1H), 1.34 - 1.02 (m, 3H), 0.89 (d, J = 8.8 Hz, 9H); LC/MS (ESI) m/z 842 [M+H]+ 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] &lt; + &
<실시예 12> (2S,4R)-1-((S)-2-(11-(2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일아미노)운데칸아미도)-3.3-디메틸부탄오일)-4-히드록시-N-(4-(4-메틸티아졸-5-일)벤질)피롤리딘-2-카복스아미드의 제조Example 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
Figure PCTKR2018011782-appb-I000057
Figure PCTKR2018011782-appb-I000057
상기 실시예 1의 단계 1에서 사용한 7-아미노헵탄산을 대신하여, 11-아미노운데칸산을 사용한 점을 제외하고, 상기 실시예 1과 같이 수행하여 목적 화합물을 제조하였다.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.
1H NMR (300 MHz, CDCl3) δ 9.92 (s, 0.5H), 9.86 (s, 0.5H), 8.69 (s, 1H), 7.56-7.44 (m, 2H), 7.40-7.30 (m, 4H), 7.08 (d, J = 7.1 Hz, 1H), 6.92-6.84 (m, 1H), 6.67-6.55 (m, 1H), 6.30-6.20 (m, 1H), 4.96-4.79 (m, 1H), 4.73-4.47 (m, 4H), 4.36-4.23 (m, 1H), 4.15-4.04 (m, 1H), 3.67-3.57 (m, 1H), 3.33-3.19 (m, 2H), 2.89-2.59 (m, 3H), 2.57-2.46 (m, 4H), 2.22-1.98 (m, 4H), 1.70-1.59 (m, 2H), 1.59-1.47 (m, 2H), 1.47-1.36 (s, 2H), 1.36-1.14 (m, 12H), 0.98-0.80 (m, 9H). LC/MS (ESI) m/z 871.7[M+H]+, 869.8[M-H]- 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] -
<실시예 13> (2S,4R)-1-((S)-2-(8-(2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일아미노)옥탄아미도)-3,3-디메틸부타노일)-4-히드록시-N-(4-(4-메틸티아졸-5-일)벤질)피롤리딘-2-카복스아미드의 제조Example 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
Figure PCTKR2018011782-appb-I000058
Figure PCTKR2018011782-appb-I000058
상기 실시예 1의 단계 1에서 사용한 7-아미노헵탄산을 대신하여, 8-아미노옥탄산을 사용한 점을 제외하고, 상기 실시예 1과 같이 수행하여 목적 화합물을 제조하였다.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.
1H NMR (300 MHz, CDCl3) δ 10.63 (s, 0.5H), 9.63 (s, 0.5H), 8.68 (s, 1H), 7.76-7.67 (m, 0.5H), 7.55-7.44 (m, 1.5H), 7.41-7.29 (m, 4H), 7.12-7.04 (m, 1H), 6.95-6.84 (m, 1.5H), 6.57 (d, J = 9.1 Hz, 0.5H), 6.32-6.21 (m, 1H), 4.96-4.82 (m, 1H), 4.72-4.50 (m, 4H), 4.36-4.22 (m, 1H), 4.17-4.03 (m, 1H), 3.63 (dd, J = 11.4, 3.5 Hz, 1H), 3.40-3.18 (m, 2H), 2.88-2.60 (m, 3H), 2.58-2.44 (m, 4H), 2.25-1.98 (m, 4H), 1.84-1.70 (m, 2H), 1.70-1.50 (m, 4H), 1.50-1.19 (m, 5H), 0.99-0.80 (m, 9H). LC/MS (ESI) m/z 829.7[M+H]+, 827.8[M-H]- 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] -
<실시예 14> (2S,4R)-1-((S)-2-(12-(2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일아미노)도데칸아미도)-3,3-디메틸부타노일)-4-히드록시-N-(4-(4-메틸티아졸-5-일)벤질)피롤리딘-2-카복스아미드의 제조Example 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
Figure PCTKR2018011782-appb-I000059
Figure PCTKR2018011782-appb-I000059
상기 실시예 1의 단계 1에서 사용한 7-아미노헵탄산을 대신하여, 12-아미노도데칸산을 사용한 점을 제외하고, 상기 실시예 1과 같이 수행하여 목적 화합물을 제조하였다.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.
1H NMR (300 MHz, CDCl3) δ 10.14 (s, 0.5H), 9.96 (s, 0.5H), 8.69 (s, 1H), 7.64-7.42 (m, 2H), 7.42-7.30 (m, 4H), 7.13-7.03 (m, 1H), 6.87 (d, J = 8.6 Hz, 1H), 6.71 (d, J = 9.0 Hz, 0.5H), 6.62 (d, J = 9.0 Hz, 0.5H), 6.24 (s, 1H), 4.96-4.76 (m, 1H), 4.72-4.48 (m, 3H), 4.36-4.21 (m, 1H), 4.12-4.00 (m, 1H), 3.70-3.58 (m, 1H), 3.34-3.19 (m, 2H), 2.88-2.58 (m, 3H), 2.58-2.40 (m, 4H), 2.22-1.94 (m, 4H), 1.72-1.47 (m, 4H), 1.47-1.08 (m, 14H), 0.99-0.77 (m, 9H). LC/MS (ESI) m/z 885.7[M+H]+, 883.7[M-H]- 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] -
<실시예 15> (2S,4R)-1-((S)-2-(2-(6-(2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일아미노)헥실옥시)아세트아미도)-3,3-디메틸부타노일)-4-히드록시-N-(4-(4-메틸티아졸-5-일)벤질)피롤리딘-2-카복스아미드의 제조Example 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 >
Figure PCTKR2018011782-appb-I000060
Figure PCTKR2018011782-appb-I000060
상기 실시예 1의 단계 1에서 사용한 7-아미노헵탄산을 대신하여, 2-(6-아미노헥실옥시)아세트산을 사용한 점을 제외하고, 상기 실시예 1과 같이 수행하여 목적 화합물을 제조하였다.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.
1H NMR (300 MHz, CDCl3) δ 9.42 (s, 0.5H), 9.19 (s, 0.5H), 8.69 (s, 1H), 7.54 - 7.38 (m, 2H), 7.38 - 7.30 (m, 4H), 7.25 - 7.17 (m, 1H), 7.07 (d, J = 7.1 Hz, 1H), 6.86 (d, J = 8.5 Hz, 1H), 6.32 - 6.19 (m, 1H), 4.97 - 4.84 (m, 1H), 4.76 - 4.63 (m, 1H), 4.61 - 4.44 (m, 3H), 4.38 - 4.24 (m, 1H), 4.07 (d, J = 10.9 Hz, 1H), 3.91 (s, 2H), 3.69 - 3.59 (m, 1H), 3.56 - 3.37 (m, 3H), 3.33 - 3.18 (m, 2H), 2.89 - 2.62 (m, 3H), 2.56 - 2.39 (m, 4H), 2.19 - 2.01 (m, 2H), 1.93 (s, 1H), 1.76 - 1.53 (m, 4H), 1.53 - 1.34 (m, 4H), 0.95 (s, 9H). LC/MS (ESI) m/z 844.8[M+H]+, 842.7[M-H]- 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] -
<실시예 16> (2S,4R)-1-((S)-2-(10-(2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일아미노)데칸아미도)-3,3-디메틸부타노일)-4-히드록시-N-(4-(4-메틸티아졸-5-일)벤질)피롤리딘-2-카복스아미드의 제조Example 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
Figure PCTKR2018011782-appb-I000061
Figure PCTKR2018011782-appb-I000061
상기 실시예 1의 단계 1에서 사용한 7-아미노헵탄산을 대신하여, 10-아미노데칸산을 사용한 점을 제외하고, 상기 실시예 1과 같이 수행하여 목적 화합물을 제조하였다.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.
1H NMR (300 MHz, CDCl3) δ 10.24 (s, 0.5H), 10.16 (s, 0.5H), 7.65-7.53 (m, 1H), 7.48 (t, J = 7.8 Hz, 1H), 7.42-7.30 (m, 4H), 7.07 (d, J = 7.1 Hz, 1H), 6.88 (d, J = 8.5 Hz, 1H), 6.71 (dd, J = 9.1, 6.7 Hz, 1H), 6.31-6.18 (m, 1H), 4.97-4.81 (m, 1H), 4.73-4.49 (m, 4H), 4.36-4.24 (m, 1H), 4.11-4.03 (m, 1H), 3.68-3.57 (m, 1H), 3.35-3.21 (m, 2H), 2.88-2.58 (m, 3H), 2.56-2.43 (m, 4H), 2.22-2.08 (m, 3H), 1.99-1.81 (m, 2H), 1.73-1.60 (m, 2H), 1.60-1.45 (m, 2H), 1.45-1.37 (m, 2H), 1.37-1.12 (m, 10H), 0.99-0.77 (m, 9H). LC/MS (ESI) m/z 857.1[M+H]+, 855.0[M-H]- 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] -
<실시예 17> (2S,4R)-1-((S)-2-tert-부틸-14-(2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일아미노)-4-옥소-6,9,12-트리옥사-3-아자테트라데카-1-노일)-4-히드록시-N-(4-(4-메틸티아졸-5-일)벤질)피롤리딘-2-카복스아미드의 제조Example 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
Figure PCTKR2018011782-appb-I000062
Figure PCTKR2018011782-appb-I000062
상기 실시예 4의 단계 1에서 사용한, tert-부틸 14-요오도-3,6,9,12-테트라옥사테트라데카-1-노에이트를 대신하여, tert-부틸 2-(2-(2-(2-요오도에톡시)에톡시)에톡시)아세테이트를 사용한 점을 제외하고, 상기 실시예 4와 같이 수행하여 목적 화합물을 제조하였다.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.
1H NMR (300 MHz, CDCl3) δ 9.81-9.72 (m, 1H), 8.70 (s, 1H), 7.57-7.46 (m, 2H), 7.41-7.31 (m, 5H), 7.11 (d, J = 7.1 Hz, 1H), 6.90 (d, J = 8.5 Hz, 1H), 6.54 (d, J = 4.1 Hz, 1H), 4.95-4.82 (m, 1H), 4.76-4.66 (m, 1H), 4.66-4.50 (m, 3H), 4.38-4.27 (m, 1H), 4.19-3.92 (m, 3H), 3.78-3.59 (m, 11H), 3.51-3.37 (m, 2H), 2.90-2.62 (m, 3H), 2.53 (d, J = 1.2 Hz, 3H), 2.52-2.41 (m, 1H), 2.22-2.09 (m, 1H), 1.91 (brs, merged with H2O, 1H), 0.97 (s, 9H). LC/MS (ESI) m/z 877.1[M+H]+, 875.0[M-H]- 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] -
<실시예 18> (2S,4R)-1-((S)-2-(11-((3-(2,6- 디옥소피페리딘-3-일)-2-메틸-4-옥소-3,4-디히드로퀴나졸린-5-일)아미노)운데칸아미도)-3,3-디메틸부타노일)-4-히드록시-N-(4-(4-메틸티아졸-5-일)벤질)피롤리딘-2-카르복스아미드의 제조Example 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 >
Figure PCTKR2018011782-appb-I000063
Figure PCTKR2018011782-appb-I000063
상기 실시예 1의 단계 1에서 사용한 7-아미노헵탄산을 대신하여, 11-아미노운데칸산을 사용사고, 2-(2,6-디옥소피페리딘-3-일)-4-플루오로이소인돌린-1,3-디온을 대신하여, 3-(5-플루오로-2-메틸-4-옥소퀴나졸린-3(4H)-yl)피페리딘-2,6-디온을 사용한 점을 제외하고, 상기 실시예 1과 같이 수행하여 목적 화합물을 제조하였다.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.
1H NMR (300 MHz, CD3OD) δ 8.89 (s, 1H), 7.85-7.77 (m, 1H), 7.54-7.40 (m, 4H), 6.69 (d, J = 7.9 Hz, 1H), 6.55 (d, J = 8.5 Hz, 1H), 5.21-5.13 (m, 1H), 4.69-4.63 (m, 1H), 4.63-4.48 (m, 3H), 4.42-4.32 (m, 1H), 3.92 (d, J = 11.1 Hz, 1H), 3.82 (dd, J = 11.0, 3.9 Hz, 1H), 3.20 (t, J = 6.9 Hz, 2H), 2.92-2.70 (m, 4H), 2.63 (s, 3H), 2.49 (s, 3H), 2.34-2.16 (m, 5H), 2.16-2.06 (m, 1H), 1.76-1.55 (m, 5H), 1.50-1.41 (m, 3H), 1.41-1.31 (m, 12H), 1.05 (s, 9H), 0.95-0.89 (m, 1H). LC/MS (ESI) m/z 884.1[M+H]+, 882.1[M-H]- 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] -
<실시예 19> 4,4'-(노난-1,9-디일비스(아자네디일))비스(2-(2,6-디옥소피페리딘-3-일)이소인돌린-1,3-디온)의 제조Example 19 Synthesis of 4,4 '- (nonan-1, 9-diylbis (azanediyl)) bis (2- (2,6-dioxopiperidin- - Dione)
Figure PCTKR2018011782-appb-I000064
Figure PCTKR2018011782-appb-I000064
단계 1: tert-부틸 (9-((2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일)아미노)노닐)카바메이트의 제조Step 1: Preparation of tert-butyl (9 - ((2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-4-yl) amino)
tert-부틸 (9-아미노노닐)카바메이트(212 mg, 0.82 mmol), 2-(2,6-디옥소피페리딘-3-일)-4-플루오로이소인돌린-1,3-디온(227 mg, 0.82 mmol), DIPEA(0.429 mL, 2.46 mmol)을 DMF(3 mL)에 녹인 후, 90℃에서 가열하였다. 반응물은 에틸아세테이트 용액으로 희석한 후, 물로 씻어준다. 유기층은 소금물로 씻은 후, 무수황산마그네슘으로 건조하고 농축하고, 컬럼크로마토그래피법을 이용하여 정제하여 목적 화합물을 얻었다.(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.
1H NMR (300 MHz, CDCl3)δ8.14(s,1H),7.49(dd,J = 8.5, 7.1 Hz, 1H), 7.09 (d, J = 7.0 Hz, 1H), 6.88 (d, J = 8.6 Hz, 1H), 6.23 (t, J = 5.5 Hz, 1H), 4.97-4.86 (m, 1H), 4.52 (s, 1H), 3.26 (q, J = 6.6 Hz, 2H), 3.10 (q, J = 6.5 Hz, 2H), 2.94-2.65 (m, 3H), 2.19-2.09 (m, 1H), 1.72-1.63 (m, 2H), 1.55-1.38 (m, 13H), 1.38-1.23 (m, 8H). 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).
단계 2: 4-((9-아미노노닐)아미노)-2-(2,6-디옥소피페리딘-3-일)이소인돌린-1,3-디온 염산염의 제조Step 2: Preparation of 4 - ((9-aminonyl) amino) -2- (2,6-dioxopiperidin-3-yl) isoindoline-1,3-dione hydrochloride
tert-부틸 (9-((2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일)아미노)노닐)카바메이트(0.112 g, 0.218 mmol), 4 N HCl/1,4-디옥산 용액(2 mL), 디클로로메탄(1 mL) 혼합용액을 상온에서 교반한 후, 농축하여 4-((9-아미노노닐)아미노)-2-(2,6-디옥소피페리딘-3-일)이소인돌린-1,3-디온 염산염을 얻었다.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.
단계 3: 4,4'-(노난-1,9-디일비스(아자네디일))비스(2-(2,6-디옥소피페리딘-3-일)이소인돌린-1,3-디온)의 제조Step 3: Preparation of 4,4 '- (nonan-1, 9-diylbis (azanediyl)) bis (2- (2,6-dioxopiperidin- )
4-((9-아미노노닐)아미노)-2-(2,6-디옥소피페리딘-3-일)이소인돌린-1,3-디온 염산염(63 mg, 0.14 mmol), 2-(2,6-디옥소피페리딘-3-일)-4-플루오로이소인돌린-1,3-디온(39 mg, 0.14 mmol), DIPEA(0.073 mL, 0.42 mmol)을 DMF(1 mL)에 녹인 후, 90℃에서 가열한다. 반응물은 물에 희석한 후, 에틸아세테이트로 추출하고 소금물로 씻어주었다. 유기층은 무수황산마그네슘으로 건조, 농축한 후, 컬럼크로마토그래피로 분리정제하여 4,4'-(노난-1,9-디일비스(아자네디일))비스(2-(2,6-디옥소피페리딘-3-일)이소인돌린-1,3-디온)을 얻었다.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).
1H NMR (300 MHz, CDCl3) 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[M-H]- 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] -
<실시예 20> (2S,4R)-1-((S)-2-(11-(2-(2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일아미노)아세트아미도)운데칸아미도)-3,3-디메틸부타노일)-4-히드록시-N-(4-(4-메틸티아졸-5-일)벤질)피롤리딘-2-카복스아미드의 제조Example 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
Figure PCTKR2018011782-appb-I000065
Figure PCTKR2018011782-appb-I000065
단계 1: tert-부틸 11-아미노운데카노에이트의 제조Step 1: Preparation of tert-butyl 11-aminoundecanoate
티오닐 클로라이드 (24.80 ml, 24.8 mmol) 중 11-아미노운데칸산 (500 mg, 2.48 mmol)의 용액을 실온에서 1.5 시간 동안 교반하고, 그 후 과량의 티오닐 클로라이드를 진공하에 제거하였다. 이 잔류물에 tBuOH (6 ml) 중 NaHCO3 (458 mg, 5.45 mmol)의 용액을 교반하에 첨가하고, 반응 혼합물을 밤새 실온에서 교반하였다. 휘발성 물질을 진공하에 제거하고, 잔류물을 EtOAc (30 ml) 및 NaOH (1M, 수성) (20 ml)에 취하였다. 합한 유기층을 물 (30 ml) 및 염수 (20 ml × 3)로 세척하고, MgSO4상에서 건조시키고, 용매를 진공하에 제거하여 단계 1의 목적 화합물 (521 mg, 2.02 mmol, 81 %)을 황색 투명 오일로서 수득하였다.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.
단계 2: tert-부틸 11-(2-(2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일아미노)아세트아미도)운데카노에이트의 제조Step 2: tert-Butyl 11- (2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-4-ylamino) acetamido) undecanoate Manufacturing
DMF 중 상기 단계 1에서 제조한 화합물 (50 ㎎, 0.194 mmol)의 용액에, 4- 글리신 탈리도마이드 (64 ㎎, 0.194 mmol), HATU (110 ㎎, 0.291 mmol), DIPEA (0.135 mL, 0.776 mmol)을 첨가하고, 실온에서 교반 2 시간 동안 교반하였다. 반응 혼합물을 물로 희석하고 EtOAc로 추출하였다. 합쳐진 유기층을 염수로 세척하고 MgSO4상에서 건조시키고 용매를 진공하에 제거하여 오일을 수득하였다. 조질의 혼합물을 EtOAc / Hex = 55 %를 사용하여 실리카겔 컬럼 크로마토그래피로 정제하여 단계 2의 목적 화합물 (71mg, 혼합물)을 황색 고체로서 수득하였다.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.
단계 3: 11-(2-(2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일아미노)아세트아미도)운데칸산의 제조Step 3: Preparation of 11- (2- (2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-4-ylamino) acetamido) undecanoic acid
DCM (2 ml) 중 상기 단계 2에서 제조한 화합물 (71 mg, 0.124 mmol)의 용액에, TFA (2 ml)를 첨가하고, 생성된 혼합물을 실온에서 3 시간 동안 교반하였다. 반응 혼합물을 진공 농축하여 오일을 수득하였다. 조 혼합물을 DCM / MeOH = 7 %를 사용하여 실리카겔 컬럼 크로마토그래피로 정제하여 단계 3의 목적 화합물 (44mg, 0.085mmol, 단계 2-3 동안 44 %)을 황색 고체로서 수득하였다.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.
단계 4: (2S,4R)-1-((S)-2-(11-(2-(2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일아미노)아세트아미도)운데칸아미도)-3,3-디메틸부타노일)-4-히드록시-N-(4-(4-메틸티아졸-5-일)벤질)피롤리딘-2-카복스아미드의 제조Step 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;
DMF 중 상기 단계 3에서 제조한 화합물 (30mg, 0.058mmol)의 용액에, VHL 리간드 (27mg, 0.058mmol), HATU (33mg, 0.087mmol), DIPEA (0.040mL, 0.232mmol)를 첨가하고 실온에서 밤새 교반하였다. 반응 혼합물을 물로 희석하고 EtOAc로 추출하였다. 합쳐진 유기층을 염수로 세척하고 MgSO4상에서 건조시키고 용매를 진공하에 제거하여 오일을 수득하였다. 조 혼합물을 MeOH / DCM = 5 %를 사용하여 PREP TLC상에서 정제하여 최종 목적 화합물 (10mg, 0.011mmol, 18 %)을 황색 고체로서 수득하였다.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.
1H NMR (500 MHz, Chloroform-d) δ 8.68 (d, J = 6.2 Hz, 1H), 7.62-7.52 (m, 2H), 7.40-7.32 (m, 4H), 7.22 (t, J = 7.8 Hz, 1H), 6.84 (t, J = 7.8 Hz, 1H), 6.70-6.56 (m, 2H), 4.93-4.84 (m, 1H), 4.72-4.53 (m, 4H), 4.31-4.22 (m, 1H), 4.08 (d, J = 11.5 Hz, 1H), 4.05-3.87 (m, 2H), 3.70-3.62 (m, 1H), 2.86-2.60 (m, 3H), 2.50 (s, 3H), 2.50-2.44 (m, 1H), 2.22-2.01 (m, 4H), 1.60-1.48 (m, 2H), 1.49-1.38 (m, 2H), 1.34-1.23 (m, 3H), 1.23-0.97 (m, 13H), 0.93 (s, 9H). , LC/MS (ESI) m/z 927.2 [M + H]+, 925.1 [M - H]- 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, 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] -
<실시예 21> (2S,4R)-1-((S)-2-(11-(2-(2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일옥시)아세트아미도)운데칸아미도)-3,3-디메틸부타노일)-4-히드록시-N-(4-(4-메틸티아졸-5-일)벤질)피롤리딘-2-카복스아미드의 제조Example 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
Figure PCTKR2018011782-appb-I000066
Figure PCTKR2018011782-appb-I000066
단계 1: tert-부틸 11-아미노운데카노에이트의 제조Step 1: Preparation of tert-butyl 11-aminoundecanoate
티오닐 클로라이드 (24.80 ml, 24.8 mmol) 중 11-아미노운데칸산 (500 mg, 2.48 mmol)의 용액을 실온에서 1.5 시간 동안 교반하고, 그 후 과량의 티오닐 클로라이드를 진공하에 제거하였다. 이 잔류물에 tBuOH (6 ml) 중 NaHCO3 (458 mg, 5.45 mmol)의 용액을 교반하에 첨가하고, 반응 혼합물을 밤새 실온에서 교반하였다. 휘발성 물질을 진공하에 제거하고, 잔류물을 EtOAc (30 ml) 및 NaOH (1M, 수성) (20 ml)에 취하였다. 합한 유기층을 물 (30 ml) 및 염수 (20 ml × 3)로 세척하고, MgSO4상에서 건조시키고, 용매를 진공하에 제거하여 단계 1의 목적 화합물 (521 mg, 2.02 mmol, 81 %)을 황색 투명 오일로서 수득하였다.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.
단계 2: tert-부틸 11-(2-(2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일옥시)아세트아미도)운데카노에이트의 제조Step 2: tert-Butyl 11- (2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-4-yloxy) acetamido) undecanoate Manufacturing
DMF 중 상기 단계 1에서 제조한 화합물 (50 ㎎, 0.194 mmol)의 용액에, 4- 글리콜산 탈리도마이드 (64 ㎎, 0.194 mmol), HATU (110 ㎎, 0.291 mmol), DIPEA (0.135 mL, 0.776 mmol)을 첨가하고, 실온에서 교반 2 시간 동안 교반하였다. 반응 혼합물을 물로 희석하고 EtOAc로 추출하였다. 합쳐진 유기층을 염수로 세척하고 MgSO4상에서 건조시키고 용매를 진공하에 제거하여 오일을 수득하였다. 조질의 혼합물을 EtOAc / Hex = 55 %를 사용하여 실리카겔 컬럼 크로마토그래피로 정제하여 단계 2의 목적 화합물 (48mg, 혼합물)을 베이지색 고체로서 수득하였다.(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.
단계 3: 11-(2-(2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일옥시)아세트아미도)운데카논산의 제조Step 3: Preparation of 11- (2- (2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-4-yloxy) acetamido) undecanoic acid
DCM (1 ml) 중 상기 단계 2에서 제조한 화합물 (48 mg, 0.084 mmol)의 용액에, TFA (1 ml)를 첨가하고, 생성된 혼합물을 실온에서 1.5 시간 동안 교반하였다. 반응 혼합물을 진공 농축하여 오일을 수득하였다. 조 혼합물을 DCM / MeOH = 7 %를 사용하여 실리카겔 컬럼 크로마토그래피로 정제하여 단계 3의 목적 화합물 (29mg, 0.056 mmol, 단계 2-3 동안 29 %)을 백색 고체로서 수득하였다.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.
단계 4: (2S,4R)-1-((S)-2-(11-(2-(2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일옥시)아세트아미도)운데칸아미도)-3,3-디메틸부타노일)-4-히드록시-N-(4-(4-메틸티아졸-5-일)벤질)피롤리딘-2-카복스아미드의 제조Step 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;
DMF 중 상기 단계 3에서 제조한 화합물 (30mg, 0.058mmol)의 용액에, VHL 리간드 (27mg, 0.058mmol), HATU (33mg, 0.087mmol), DIPEA (0.040mL, 0.232mmol)를 첨가하고 실온에서 밤새 교반하였다. 반응 혼합물을 물로 희석하고 EtOAc로 추출하였다. 합쳐진 유기층을 염수로 세척하고 MgSO4상에서 건조시키고 용매를 진공하에 제거하여 오일을 수득하였다. 조 혼합물을 MeOH / DCM = 5 %를 사용하여 PREP TLC상에서 정제하여 최종 목적 화합물 (13mg, 0.014mmol, 24 %)을 백색 고체로서 수득하였다.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.
1H NMR (500 MHz, Chloroform-d) δ8.71-8.66 (m, 1H), 7.73 (q, J = 7.4 Hz, 1H), 7.63-7.60 (m, 0.5 H), 7.55-7.50 (m, 1.5H), 7.45 (t, J = 5.2 Hz, 1H), 7.38-7.30 (m, 4H), 7.23-7.17 (m, 0.5H), 4.97-4.90 (m, 0.5H), 4.87-4.80 (m, 1H), 4.70-4.51 (m, 6H), 4.32-4.18 (m, 1H), 4.12 (d, J = 11.6 Hz, 1H), 3.67-3.58 (m, 1H), 3.54-3.43 (m, 1H), 3.35-3.24 (m, 1H), 2.93-2.63 (m, 3H), 2.56-2.45 (m, 4H), 2.24-2.05 (m, 4H), 1.63-1.56 (m, 2H), 1.56-1.47 (m, 2H), 1.46-1.13 (m, 14H), 0.93 (s, 9H). , LC/MS (ESI) m/z 928.1 [M + H]+, 926.1 [M - H]- 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, (M, 0.5H), 4.97-4.90 (m, 0.5H), 4.87-4.80 (m, 1H), 7.45 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] +, 926.1 [M - H] -
<실시예 22> (2S,4R)-1-((S)-2-(11-(2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-5-일아미노)운데칸아미도)-3,3-디메틸부타노일)-4-히드록시-N-(4-(4-메틸티아졸-5-일)벤질)피롤리딘-2-카복스아미드의 제조Example 22 Synthesis of (2S, 4R) -1 - ((S) -2- (11- (2- (2,6-dioxopiperidin- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carbaldehyde Preparation of Voxamide
Figure PCTKR2018011782-appb-I000067
Figure PCTKR2018011782-appb-I000067
단계 1: tert-부틸 11-아미노운데카노에이트의 제조Step 1: Preparation of tert-butyl 11-aminoundecanoate
티오닐 클로라이드 (24.80 ml, 24.8 mmol) 중 11-아미노운데칸산 (500 mg, 2.48 mmol)의 용액을 실온에서 1.5 시간 동안 교반하고, 그 후 과량의 티오닐 클로라이드를 진공하에 제거하였다. 이 잔류물에 tBuOH (6 ml) 중 NaHCO3 (458 mg, 5.45 mmol)의 용액을 교반하에 첨가하고, 반응 혼합물을 밤새 실온에서 교반하였다. 휘발성 물질을 진공하에 제거하고, 잔류물을 EtOAc (30 ml) 및 NaOH (1M, 수성) (20 ml)에 취하였다. 합한 유기층을 물 (30 ml) 및 염수 (20 ml × 3)로 세척하고, MgSO4상에서 건조시키고, 용매를 진공하에 제거하여 단계 1의 목적 화합물 (521 mg, 2.02 mmol, 81 %)을 황색 투명 오일로서 수득하였다.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.
단계 2: tert-부틸 11-(2-(2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-5-일아미노)운데카노에이트의 제조Step 2: Preparation of tert-butyl 11- (2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-5-ylamino) undecanoate
DMSO 중 상기 단계 1에서 제조한 화합물 (86 ㎎, 0.334 mmol)의 용액에, 5-F-탈리도마이드 (61 mg, 0.223 mmol), DIPEA (0.058 mL, 0.334 mmol)를 첨가하고, 90 ℃에서 밤새 교반하였다. 반응 혼합물을 물로 희석하고 EtOAc로 추출하였다. 합쳐진 유기층을 염수로 세척하고 MgSO4상에서 건조시키고 용매를 진공하에 제거하여 오일을 수득하였다. 조질의 혼합물을 EtOAc / Hx = 37 %를 사용하여 실리카겔 컬럼 크로마토그래피로 정제하여 단계 2의 목적 화합물 (38 mg, 혼합물)을 황색 고체로서 수득하였다.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.
단계 3: 11-(2-(2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-5-일아미노)운데카논산의 제조Step 3: Preparation of 11- (2- (2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-5-ylamino) undecanoic acid
DCM (1 ml) 중 상기 단계 2에서 제조한 화합물 (38 mg, 0.074 mmol)의 용액에, TFA (1 ml)를 첨가하고, 생성된 혼합물을 실온에서 3 시간 동안 교반하였다. 반응 혼합물을 진공 농축하여 오일을 수득하였다. 조 혼합물을 DCM / MeOH = 7 %를 사용하여 실리카겔 컬럼 크로마토그래피로 정제하여 단계 3의 목적 화합물 (12mg, 0.026 mmol, 단계 2-3 동안 11 %)을 황색 고체로서 수득하였다.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.
단계 4: (2S,4R)-1-((S)-2-(11-(2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-5-일아미노)운데칸아미도)-3,3-디메틸부타노일)-4-히드록시-N-(4-(4-메틸티아졸-5-일)벤질)피롤리딘-2-카복스아미드의 제조Step 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
DMF 중 상기 단계 3에서 제조한 화합물 (12mg, 0.026mmol)의 용액에, VHL- 리간드 (12mg, 0.026mmol), HATU (15mg, 0.039mmol), DIPEA (0.018mL, 0.104mmol)를 첨가하고, 실온에서 밤새 교반하였다. 반응 혼합물을 물로 희석하고 EtOAc로 추출하였다. 합쳐진 유기층을 염수로 세척하고 MgSO4상에서 건조시키고 용매를 진공하에 제거하여 오일을 수득하였다. 조 혼합물을 MeOH / DCM = 5 %를 사용하여 PREP TLC상에서 정제하여 최종 목적 화합물 (12mg, 0.014mmol, 53 %)을 황색 고체로서 수득하였다.(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.
1H NMR (500 MHz, Chloroform-d) δ8.68 (s, 1H), 7.66-7.61 (m, 0.5H), 7.59 (d, J = 8.2 Hz, 1H), 7.52 (t, J = 6.3 Hz, 0.5H), 7.39-7.32 (m, 4H), 6.98-6.93 (m, 1H), 6.79-6.77 (m, 0.5H), 6.73 (d, J = 8.4 Hz, 1H), 6.56-6.54 (m, 0.5H), 4.96-4.87 (m, 1H), 4.72 (t, J = 5.0 Hz, 1H), 4.70-4.65 (m, 1H), 4.65-4.57 (m, 1H), 4.57-4.50 (m, 2H), 4.12-4.04 (m, 1H), 3.68-3.60 (m, 1H), 2.91-2.61 (m, 3H), 2.56-2.46 (m, 4H), 2.21-2.05 (m, 4H), 1.62 (p, J = 7.2 Hz, 2H), 1.58-1.48 (m, 2H), 1.43-1.29 (m, 5H), 1.30-1.11 (m, 11H), 0.91 (s, 9H). 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 (M, 4H), 7.39-7.32 (m, 4H), 6.98-6.93 (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).
<실시예 23> 3,3'-(5,5'-(노난-1,9-디일비스(아잔디일))비스(4-옥소벤조[d][1,2,3]트리아진-5,3(4H)-디일))디피페리딘-2,6-디온의 제조Example 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
Figure PCTKR2018011782-appb-I000068
Figure PCTKR2018011782-appb-I000068
상기 실시예 19의 단계 1과 단계 4에서 사용한, 2-(2,6-디옥소피페리딘-3-일)-4-플루오로이소인돌린-1,3-디온을 대신하여, 출원번호 10-2017-0184761호에 공지된 바와 같이 제조되는 3-(5-아미노-4-옥소벤조[d][1,2,3]트리아진-3(4H)-일)피페리딘-2,6-디온을 사용한 점을 제외하고, 상기 실시예 19와 같이 수행하여 목적 화합물을 제조하였다.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.
1H NMR (300 MHz, CDCl3)δ8.74(s,1H),8.68(s,1H),8.15(t,J = 5.2 Hz, 2H), 7.67 (t, J = 8.2 Hz, 2H), 7.24 (d, J = 7.7 Hz, 2H), 6.77 (d, J = 8.5 Hz, 2H), 5.74-.64 (m, 2H), 3.25-.13 (m, 4H), 3.00-.84 (m, 6H), 2.41-.28 (m, 2H), 1.76-.62 (m, 6H), 1.49-.29 (m, 11H), 0.95-.79 (m, 1H). 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-.
<실시예 24> 2-(2,6-디옥소피페리딘-3-일)-4-(9-(3-(2,6-디옥소피페리딘-3-일)-4-옥소-3,4-디히드로벤조[d][1,2,3]트리아진-5-일아미노)노닐아미노)이소인돌린-1,3-디온의 제조Example 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
Figure PCTKR2018011782-appb-I000069
Figure PCTKR2018011782-appb-I000069
상기 실시예 19의 단계 1에서 사용한, 2-(2,6-디옥소피페리딘-3-일)-4-플루오로이소인돌린-1,3-디온을 대신하여, 출원번호 10-2017-0184761호에 공지된 바와 같이 제조되는 3-(5-아미노-4-옥소벤조[d][1,2,3]트리아진-3(4H)-일)피페리딘-2,6-디온을 사용한 점을 제외하고, 상기 실시예 19와 같이 수행하여 목적 화합물을 제조하였다.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.
1H NMR (300 MHz, CDCl3)δ8.452(d,J = 6.1 Hz, 2H), 8.15 (s, 1H), 7.68 (t, J = 8.1 Hz, 1H), 7.48 (dd, J = 8.5, 7.1 Hz, 1H), 7.24 (dd, J = 7.9, 0.8 Hz, 2H), 7.08 (d, J = 7.0 Hz, 1H), 6.88 (d, J = 8.5 Hz, 1H), 6.78 (d, J = 8.5 Hz, 1H), 6.24 (t, J = 5.6 Hz, 1H), 5.73-5.62 (m, 1H), 4.96-4.86 (m, 1H), 3.30-3.15 (m, 4H), 3.01-2.69 (m, 6H), 2.39-2.29 (m, 1H), 2.17-2.08 (m, 1H), 1.75-1.61 (m, 4H), 1.49-1.30 (m, 10H). 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).
<실시예 25> (2S,4R)-1-((S)-2-(11-(3-(2,6-디옥소피페리딘-3-일)-4-옥소-3,4-디히드로벤조[d][1,2,3]트리아진-5-일아미노)운데칸아미도)-3,3-디메틸부타노일)-4-히드록시-N-(4-(4-메틸티아졸-5-일)벤질)피롤리딘-2-카복스아미드의 제조Example 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
Figure PCTKR2018011782-appb-I000070
Figure PCTKR2018011782-appb-I000070
상기 실시예 1의 단계 1에서 사용한 7-아미노헵탄산을 대신하여, 11-아미노운데칸산을 사용사고, 2-(2,6-디옥소피페리딘-3-일)-4-플루오로이소인돌린-1,3-디온을 대신하여, 출원번호 10-2017-0184761호에 공지된 바와 같이 제조되는 3-(5-아미노-4-옥소벤조[d][1,2,3]트리아진-3(4H)-일)피페리딘-2,6-디온을 사용한 점을 제외하고, 상기 실시예 1과 같이 수행하여 목적 화합물을 제조하였다.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.
1H NMR (300 MHz, CDCl3)δ10.17(s,0.5H),9.74(s,0.5H),8.68(s,1H),8.25-8.13(m,1H),7.67(t,J = 8.1 Hz, 1H), 7.58-7.50 (m, 0.5H), 7.46 (t, J = 5.5 Hz, 0.5H), 7.40-7.30 (m, 4H), 7.23 (d, J = 7.7 Hz, 1H), 6.80-6.70 (m, 1.5H), 6.50 (d, J = 8.7 Hz, 1H), 5.72-5.62 (m, 0.5H), 5.56-5.46 (m, 0.5H), 4.72-4.50 (m, 4H), 4.36-4.20 (m, 1H), 4.18-4.06 (m, 1H), 3.68-3.58 (m, 1H), 3.29 (s, 0.5H), 3.26-3.14 (m, 2.5H), 2.99-2.67 (m, 3H), 2.58-2.45 (m, 4H), 2.37-2.23 (m, 1H), 2.23-2.07 (m, 3H), 1.61-1.49 (m, 2H), 1.49-1.38 (m, 2H), 1.38-1.16 (m, 12H), 0.98-0.87 (m, 9H). 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).
상기 실시예 1 - 25에서 제조한 화합물의 화학 구조식을 하기 표 1에 나타내었다.The chemical structures of the compounds prepared in Examples 1-25 are shown in Table 1 below.
실시예Example 구조식constitutional formula 실시예Example 구조식constitutional formula
1One
Figure PCTKR2018011782-appb-I000071
Figure PCTKR2018011782-appb-I000071
 		1414
Figure PCTKR2018011782-appb-I000072
Figure PCTKR2018011782-appb-I000072
22
Figure PCTKR2018011782-appb-I000073
Figure PCTKR2018011782-appb-I000073
 		1515
Figure PCTKR2018011782-appb-I000074
Figure PCTKR2018011782-appb-I000074
33
Figure PCTKR2018011782-appb-I000075
Figure PCTKR2018011782-appb-I000075
 		1616
Figure PCTKR2018011782-appb-I000076
Figure PCTKR2018011782-appb-I000076
44
Figure PCTKR2018011782-appb-I000077
Figure PCTKR2018011782-appb-I000077
 		1717
Figure PCTKR2018011782-appb-I000078
Figure PCTKR2018011782-appb-I000078
55
Figure PCTKR2018011782-appb-I000079
Figure PCTKR2018011782-appb-I000079
 		1818
Figure PCTKR2018011782-appb-I000080
Figure PCTKR2018011782-appb-I000080
66
Figure PCTKR2018011782-appb-I000081
Figure PCTKR2018011782-appb-I000081
 		1919
Figure PCTKR2018011782-appb-I000082
Figure PCTKR2018011782-appb-I000082
77
Figure PCTKR2018011782-appb-I000083
Figure PCTKR2018011782-appb-I000083
 		2020
Figure PCTKR2018011782-appb-I000084
Figure PCTKR2018011782-appb-I000084
88
Figure PCTKR2018011782-appb-I000085
Figure PCTKR2018011782-appb-I000085
 		2121
Figure PCTKR2018011782-appb-I000086
Figure PCTKR2018011782-appb-I000086
99
Figure PCTKR2018011782-appb-I000087
Figure PCTKR2018011782-appb-I000087
 		2222
Figure PCTKR2018011782-appb-I000088
Figure PCTKR2018011782-appb-I000088
1010
Figure PCTKR2018011782-appb-I000089
Figure PCTKR2018011782-appb-I000089
 		2323
Figure PCTKR2018011782-appb-I000090
Figure PCTKR2018011782-appb-I000090
1111
Figure PCTKR2018011782-appb-I000091
Figure PCTKR2018011782-appb-I000091
 		2424
Figure PCTKR2018011782-appb-I000092
Figure PCTKR2018011782-appb-I000092
1212
Figure PCTKR2018011782-appb-I000093
Figure PCTKR2018011782-appb-I000093
 		2525
Figure PCTKR2018011782-appb-I000094
Figure PCTKR2018011782-appb-I000094
1313
Figure PCTKR2018011782-appb-I000095
Figure PCTKR2018011782-appb-I000095
<실험예 1> 세레브론(CRBN) 단백질 분해활성 평가<Experimental Example 1> Evaluation of proteolytic activity of cerrebone (CRBN)
본 발명에 따른 화합물의 세레브론(CRBN) 단백질 분해활성을 평가하기 위해, 다음과 같이 실험하였다.In order to evaluate the cerreon (CRBN) proteolytic activity of the compounds according to the present invention, the following experiment was conducted.
구체적으로, HEK293T 세포를 12 웰 플레이트의 각 웰에 5 X 105개를 주입하였다. 다음날 각 웰에 실시예 화합물 1-22를 최종농도 10nM, 30 nM, 100 nM, 300 nM, 1 μM, 3 μM, 10 μM이 되도록 처리해 주었다. 한 개의 웰에는 DMSO를 동일한 백분율로 처리하였다. 처리 24시간 후, 세포를 모아 NP40 Lysis buffer(20mM Tris, pH7.5, 150mM NaCl, 1% NP-40, 1mM EDTA, and protease inhibitor cocktail)를 이용하여 세포 용해물(cell lysate)을 만들어 웨스턴블롯을 수행하였고, 그 결과를 하기 표 2에 나타내었다.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.
또한, 실시예 1, 3, 8에 대한 세레브론 단백질 분석 결과를 도 1에 나타내었고, 실시예 1, 3, 8 화합물 처리 농도에 따른 세레브론 단백질 분해력을 평가(DC50)하여 도 2에 도시하였다.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.
실시예Example 세레브론(CRBN) 분해활성Cerebrene (CRBN) degradative activity 실시예Example 세레브론(CRBN) 분해활성Cerebrene (CRBN) degradative activity
1One ++++ 1414 ++++
22 ++++ 1515 ++
33 ++++ 1616 ++++
44 ++++ 1717 ++
55 ++ 1818 ++
66 ++ 1919 ++++
77 ++ 2020 ++++
88 ++ 2121 ++
99 ++ 2222 ++++
1010 ++ 2323 ++++
1111 ++ 2424 ++++
1212 ++++ 2525 ++++
1313 ++++
++ : 300 nM 농도에서 50% 초과로 분해(> 50%)+ : 300 nM 농도에서 50% 미만으로 분해(< 50%)++: Decomposition (> 50%) above 50% at 300 nM concentration +: Decrease (<50%) below 50% at 300 nM concentration
표 2를 살펴보면, 본 발명에 따른 실시예 화합물은 세레브론(CRBN) 단백질을 300 nM의 농도에서 우수하게 분해할 수 있으며, 특히 실시예 1, 2, 3, 4, 12, 13, 14, 16, 19, 20, 22, 23, 24, 및 25 화합물은 300 nM의 농도에서 50 % 초과의 분해활성을 나타내는 것을 확인할 수 있다.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.
따라서, 본 발명에 따른 화합물은 세레브론(CRBN) 단백질을 나노몰 단위의 농도로 우수하게 분해할 수 있으며, 이로부터 세레브론(CRBN) 관련 질환의 예방 및 치료에 효과적으로 사용될 수 있다.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.
본 발명에 따른 A-Linker-A 또는 A-Linker-B로 표시되는 신규 화합물은 세레브론을 우수하게 저해하거나 분해시킬 수 있는 바, 이를 유효성분으로 함유하여 세레브론 관련 질환, 바람직하게 세레브론을 저해 또는 분해하는 것으로부터 치료, 예방 또는 개선과 같은 효과가 달성될 수 있는 질환, 예를 들어, 암, 자가면역질환, 또는 대사질환의 예방 또는 치료용 약학적 조성물로서 유용한 효과가 있다.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.

Claims (11)

  1. A-Linker-A 또는 A-Linker-B로 표시되는 화합물, 이의 입체 이성질체, 또는 이의 약학적으로 허용 가능한 염:A-Linker-A or A-Linker-B, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
    상기 A는 세레브론(Cerebron) E3 유비퀴틴 리가아제 결합 모이어티(moiety)이고;Wherein A is a Cerebron E3 ubiquitin ligase binding moiety;
    상기 Linker는 -(CH2)-, -(C=O)-, -NH- 및 -O-로 이루어진 군으로부터 선택되는 1종 이상이 3-20개 연결된 연결기(linker)이되,The linker is a linker having 3 to 20 linkages selected from the group consisting of - (CH 2 ) -, - (C═O) -, -NH- and -O-,
    상기 연결기는 연속하여 -O-로 연결될 수 없고; 및The linking group can not be linked to -O- in succession; And
    상기 B는 E3 유비퀴틴 리가아제 결합 모이어티(moiety)이고,Wherein B is an E3 ubiquitin ligase binding moiety,
    여기서 Linker와 A 또는 B는 화학적으로 연결된다.Here, Linker and A or B are chemically linked.
  2. 제1항에 있어서,The method according to claim 1,
    상기 A는 탈리도마이드(Thalidomide), 레날리도마이드(Lenalidomide), 포말리도마이드(Pormalidomide), 이의 유사체, 이의 동배체, 또는 이의 유도체이고;Wherein A is Thalidomide, Lenalidomide, Pormalidomide, an analogue thereof, a copper complex thereof, or a derivative thereof;
    상기 Linker는,The linker,
    Figure PCTKR2018011782-appb-I000096
    이되,
    Figure PCTKR2018011782-appb-I000096
    However,
    여기서, 상기 a 및 i는 독립적으로 0 또는 1이고;Wherein a and i are independently 0 or 1;
    상기 b는 0-20의 정수이고;B is an integer from 0 to 20;
    상기 c는 0 또는 1이고;Wherein c is 0 or 1;
    상기 d는 0-3의 정수이고;D is an integer of 0-3;
    상기 e는 0 또는 1이고;E is 0 or 1;
    상기 f는 1-10의 정수이고;F is an integer from 1 to 10;
    상기 g는 0 또는 1이고;G is 0 or 1;
    상기 h는 0-3의 정수이고;H is an integer of 0-3;
    상기 j 및 k는 독립적으로 0-5의 정수이고; 및J and k are independently an integer of 0-5; And
    상기 B는 하기 화학식 1로 표시되는 화합물이되,Wherein B is a compound represented by the following formula (1)
    [화학식 1][Chemical Formula 1]
    Figure PCTKR2018011782-appb-I000097
    Figure PCTKR2018011782-appb-I000097
    상기 화학식 1에 있어서,In Formula 1,
    R4은 OR6이고;R 4 is OR 6 ;
    R5는 선택적으로 치환 또는 비치환된 -NR6-(CH2)o-C6-10아릴-N, O, 및 S로이루어진 군으로부터 선택되는 1종 이상의 헤테로 원자를 포함하는 5-10원자 헤테로아릴이되,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,
    상기 치환된 -NR6-(CH2)o-C6-10아릴-N, O, 및 S로이루어진 군으로부터 선택되는 1종 이상의 헤테로 원자를 포함하는 5-10원자 헤테로아릴은 C1-10의 직쇄 또는 분지쇄의 알킬로 치환되고,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,
    여기서, 상기 R6는 H 또는 C1-5의 직쇄 또는 분지쇄의 알킬이고, 상기 o는 0-5이고;Wherein R &lt; 6 &gt; is H or a straight or branched chain alkyl of 1-5 , wherein o is 0-5;
    R7는 -CR8-NR9-이되,R 7 is -CR 8 -NR 9 -
    여기서, R8는 C1-10의 직쇄 또는 분지쇄의 알킬이고, R9는 H 또는 C1-5의 직쇄 또는 분지쇄의 알킬인 것을 특징으로 하는 화합물, 이의 입체 이성질체, 또는 이의 약학적으로 허용 가능한 염.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.
  3. 제1항에 있어서,The method according to claim 1,
    상기 A는 하기 (a) 내지 (g)로 표시되는 화학식 중 하나이고,Wherein A is one of the following formulas (a) to (g)
    Figure PCTKR2018011782-appb-I000098
    ,
    Figure PCTKR2018011782-appb-I000099
    ,
    Figure PCTKR2018011782-appb-I000100
    ,
    Figure PCTKR2018011782-appb-I000101
    ,
    Figure PCTKR2018011782-appb-I000102
    ,
    Figure PCTKR2018011782-appb-I000103
    , 또는
    Figure PCTKR2018011782-appb-I000104
    Figure PCTKR2018011782-appb-I000098
    ,
    Figure PCTKR2018011782-appb-I000099
    ,
    Figure PCTKR2018011782-appb-I000100
    ,
    Figure PCTKR2018011782-appb-I000101
    ,
    Figure PCTKR2018011782-appb-I000102
    ,
    Figure PCTKR2018011782-appb-I000103
    , or
    Figure PCTKR2018011782-appb-I000104
    상기 화학식 (a), (b), (c), (d), (e), (f), 및 (g)에 있어서,In the above formulas (a), (b), (c), (d), (e), (f) and (g)
    W는 CH2, CHR, C=O, SO2, NH, 또는 N-C1-10의 직쇄 또는 분지쇄의 알킬이고,W is CH 2 , CHR, C = O, SO 2 , NH, or a linear or branched alkyl of NC 1-10 ,
    각각의 X는 독립적으로 O, S, 또는 H2이고,Each X is independently O, S, or H 2 ,
    Y는 NH, N-C1-10의 직쇄 또는 분지쇄 알킬, N-C6-10 아릴, N-헤테로아릴(N, O, 및 S로 이루어진 군으로부터 선택되는 1종 이상의 헤테로 원자를 포함하는 5-10각환의 헤테로아릴), N-C3-10 사이클로알킬, N-헤테로사이클로알킬(N, O, 및 S로 이루어진 군으로부터 선택되는 1종 이상의 헤테로 원자를 포함하는 3-10각환의 헤테로사이클로알킬), O, 또는 S이고,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,
    Z는 O, S, 또는 H2이고,Z is O, S, or H 2 ,
    G 및 G'는 각각 독립적으로 H, C1-10의 직쇄 또는 분지쇄 알킬, OH, R'로 치환 또는 비치환된 CH2-헤테로사이클릴(N, O, 및 S로 이루어진 군으로부터 선택되는 1종 이상의 헤테로 원자를 포함하는 3-10각환의 헤테로사이클릴), 또는 R'로 치환 또는 비치환된 벤질이고,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 '
    Q1, Q2, Q3, 및 Q4는 각각 독립적으로 R'로 치환된 탄소, 또는 N 이고,Q 1 , Q 2 , Q 3 , and Q 4 are each independently carbon substituted with R ', or N,
    A는 C1-10의 직쇄 또는 분지쇄 알킬, C3-10 사이클로알킬, 또는 할로젠이고,A is straight or branched chain alkyl of C 1-10 , C 3-10 cycloalkyl, or halogen,
    R은 -CONR'R", -OR', -NR'R", -SR', -SO2R', -SO2NR'R", -CR'R"-, -CR'NR'R"-, -C6-10아릴, -헤테로아릴(N, O, 및 S로 이루어진 군으로부터 선택되는 1종 이상의 헤테로 원자를 포함하는 5-10각환의 헤테로아릴), -C1-10의 직쇄 또는 분지쇄 알킬, -C3-10사이클로알킬, -헤테로사이클릴(N, O, 및 S로 이루어진 군으로부터 선택되는 1종 이상의 헤테로 원자를 포함하는 3-10각환의 헤테로사이클릴), -P(O)(OR')R", -P(O)R'R", -OP(O)(OR')R", -OP(O)R'R", -Cl, -F, -Br, -I, -CF3, -CN, -NR'SO2NR'R", -NR'CONR'R", -CONR'COR", -NR'C(=N-CN)NR'R", -C(=N-CN)NR'R", -NR'C(=N-CN)R", -NR'C(=CNO2)NR'R", -SO2NR'COR", -NO2, -CO2R', -C(C=N-OR')R", -CR'=CR'R", -CCR', -S(C=O)(C=N-R')R", -SF5 또는 -OCF3이고,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' 및 R"는 H, C1-10의 직쇄 또는 분지쇄 알킬, C3-10사이클로알킬, C6-10아릴, 헤테로아릴(N, O, 및 S로 이루어진 군으로부터 선택되는 1종 이상의 헤테로 원자를 포함하는 5-10각환의 헤테로아릴), 헤테로사이클릴(N, O, 및 S로 이루어진 군으로부터 선택되는 1종 이상의 헤테로 원자를 포함하는 3-10각환의 헤테로사이클릴)로 구성된 군에서 각각 독립적으로 선택되고,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;
    Figure PCTKR2018011782-appb-I000105
    는 입체특이적(R 또는 S) 또는 비-입체특이적인 결합을 나타내고; 및
    Figure PCTKR2018011782-appb-I000105
    (R or S) or non-stereospecific linkages; And
    Rn은 -(CH2)m-NR3-, -(CH2)m-O-, -O-(CH2)m-(C=O)-NR3- 또는 -NR3-(CH2)m-(C=O)-NR3-이고,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; -,
    다시 여기서, m은 0 내지 5의 정수이고,Here again, m is an integer from 0 to 5,
    상기 R3는 각각 H, 또는 비치환 또는 치환된 C1-10의 직쇄 또는 분지쇄의 알킬이고,Wherein R &lt; 3 &gt; is each H, or an unsubstituted or substituted C 1-10 straight chain or branched chain alkyl,
    다시 여기서, 상기 치환된 알킬은 할로겐, 니트로, 또는 시아노기로 치환되고, Rn은 Linker와 공유결합하고; 및Wherein said substituted alkyl is substituted with a halogen, nitro, or cyano group, and R n is covalently bonded to a linker; And
    상기 Linker는,The linker,
    Figure PCTKR2018011782-appb-I000106
    ,
    Figure PCTKR2018011782-appb-I000107
    ,
    Figure PCTKR2018011782-appb-I000108
    ,
    Figure PCTKR2018011782-appb-I000109
    ,
    Figure PCTKR2018011782-appb-I000110
    ,
    Figure PCTKR2018011782-appb-I000111
    ,
    Figure PCTKR2018011782-appb-I000112
    ,
    Figure PCTKR2018011782-appb-I000113
    ,
    Figure PCTKR2018011782-appb-I000114
    ,
    Figure PCTKR2018011782-appb-I000115
    ,
    Figure PCTKR2018011782-appb-I000116
    ,
    Figure PCTKR2018011782-appb-I000117
    ,
    Figure PCTKR2018011782-appb-I000118
    ,
    Figure PCTKR2018011782-appb-I000119
    ,
    Figure PCTKR2018011782-appb-I000120
    ,
    Figure PCTKR2018011782-appb-I000121
    ,
    Figure PCTKR2018011782-appb-I000122
    ,
    Figure PCTKR2018011782-appb-I000123
    ,
    Figure PCTKR2018011782-appb-I000124
    , 또는
    Figure PCTKR2018011782-appb-I000125
    인 것을 특징으로 하는 화합물, 이의 입체 이성질체, 또는 이의 약학적으로 허용 가능한 염.
    Figure PCTKR2018011782-appb-I000106
    ,
    Figure PCTKR2018011782-appb-I000107
    ,
    Figure PCTKR2018011782-appb-I000108
    ,
    Figure PCTKR2018011782-appb-I000109
    ,
    Figure PCTKR2018011782-appb-I000110
    ,
    Figure PCTKR2018011782-appb-I000111
    ,
    Figure PCTKR2018011782-appb-I000112
    ,
    Figure PCTKR2018011782-appb-I000113
    ,
    Figure PCTKR2018011782-appb-I000114
    ,
    Figure PCTKR2018011782-appb-I000115
    ,
    Figure PCTKR2018011782-appb-I000116
    ,
    Figure PCTKR2018011782-appb-I000117
    ,
    Figure PCTKR2018011782-appb-I000118
    ,
    Figure PCTKR2018011782-appb-I000119
    ,
    Figure PCTKR2018011782-appb-I000120
    ,
    Figure PCTKR2018011782-appb-I000121
    ,
    Figure PCTKR2018011782-appb-I000122
    ,
    Figure PCTKR2018011782-appb-I000123
    ,
    Figure PCTKR2018011782-appb-I000124
    , or
    Figure PCTKR2018011782-appb-I000125
    A stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
  4. 제1항에 있어서,The method according to claim 1,
    상기 A는
    Figure PCTKR2018011782-appb-I000126
    ,
    Figure PCTKR2018011782-appb-I000127
    ,
    Figure PCTKR2018011782-appb-I000128
    , 또는
    Figure PCTKR2018011782-appb-I000129
    이되,    A is
    Figure PCTKR2018011782-appb-I000126
    ,
    Figure PCTKR2018011782-appb-I000127
    ,
    Figure PCTKR2018011782-appb-I000128
    , or
    Figure PCTKR2018011782-appb-I000129
    However,
    여기서 상기 R1은 -(CH2)n-NR3-, -(CH2)n-O-, -O-(CH2)n-(C=O)-NR3- 또는 -NR3-(CH2)n-(C=O)-NR3-이고,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 -
    다시 여기서, n은 0 내지 5의 정수이고,Here again, n is an integer from 0 to 5,
    상기 R2 및 R3는 각각 독립적으로 H, 또는 비치환 또는 치환된 C1-10의 직쇄 또는 분지쇄의 알킬이고,Wherein R 2 and R 3 are each independently H, or an unsubstituted or substituted C 1-10 straight chain or branched chain alkyl,
    다시 여기서, 상기 치환된 알킬은 할로겐, 니트로, 또는 시아노기로 치환되고; 및Wherein said substituted alkyl is substituted with a halogen, nitro, or cyano group; And
    상기 B는
    Figure PCTKR2018011782-appb-I000130
    이되,    B is
    Figure PCTKR2018011782-appb-I000130
    However,
    여기서 상기 R2 및 R3는 각각 독립적으로 H, 또는 비치환 또는 치환된 C1-10의 직쇄 또는 분지쇄의 알킬이고,Wherein R 2 and R 3 are each independently H or an unsubstituted or substituted C 1-10 straight chain or branched chain alkyl,
    다시 여기서, 상기 치환된 알킬은 할로겐, 니트로, 또는 시아노기로 치환되는 것을 특징으로 하는 화합물, 이의 입체 이성질체, 또는 이의 약학적으로 허용 가능한 염.Wherein said substituted alkyl is substituted with a halogen, nitro, or cyano group, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
  5. 제1항에 있어서,The method according to claim 1,
    상기 A-Linker-A 또는 A-Linker-B로 표시되는 화합물은 하기 화합물로 이루어진 군으로부터 선택되는 화합물, 이의 입체 이성질체, 또는 이의 약학적으로 허용 가능한 염: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) (2S,4R)-1-((S)-2-(7-(2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일아미노)헵탄아미도)-3,3-디메틸부타노일)-4-히드록시-N-(4-(4-메틸티아졸-5-일)벤질)피롤리딘-2-카복스아미드;(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) (2S,4R)-1-((S)-2-(6-(2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일아미노)헥산아미도)-3,3-디메틸부타노일)-4-히드록시-N-(4-(4-메틸티아졸-5-일)벤질)피롤리딘-2-카복스아미드;(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) (2S,4R)-1-((S)-2-(9-(2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일아미노)노난아미도)-3,3-디메틸부타노일)-4-히드록시-N-(4-(4-메틸티아졸-5-일)벤질)피롤리딘-2-카복스아미드;(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) (2S,4R)-1-((S)-2-tert-부틸-17-(2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일아미노)-4-옥소-6,9,12,15-테트라옥사-3-아자헵타데카-1-노일)-4-히드록시-N-(4-(4-메틸티아졸-5-일)벤질)피롤리딘-2-카복스아미드;(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) (2S,4R)-1-((S)-2-(2-(3-(2-(2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일아미노)-2-옥소에톡시)프로폭시)아세트아미도)-3,3-디메틸부타노일)-4-히드록시-N-(4-(4-메틸티아졸-5-일)벤질)피롤리딘-2-카복스아미드;(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) N1-(2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일)-N9-((S)-1-((2S,4R)-4-히드록시-2-(4-(4-메틸티아졸-5-일)벤질카바모일)피롤리딘-1-일)-3,3-디메틸-1-옥소부탄-2-일)노난디아미드;(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) N1-(2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일)-N8-((S)-1-((2S,4R)-4-히드록시-2-(4-(4-메틸티아졸-5-일)벤질카바모일)피롤리딘-1-일)-3,3-디메틸-1-옥소부탄-2-일)옥탄디아미드;(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) N1-(2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일)-N7-((S)-1-((2S,4R)-4-히드록시-2-((4-(4-메틸티아졸-5-일)벤질)카바모일)피롤리딘-1-일)-3,3-디메틸-1-옥소부탄-2-일)헵탄디아미드;(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) N1-(2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일)-N14-((S)-1-((2S,4R)-4-히드록시-2-((4-(4-메틸티아졸-5-일)벤질)카바모일)피롤리딘-1-일)-3,3-디메틸-1-옥소부탄-2-일)-3,6,9,12-테트라옥사테트라데칸-1,14-디아미드;(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) N1-(2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일)-N5-((S)-1-((2S,4R)-4-히드록시-2-(4-(4-메틸티아졸-5-일)벤질카바모일)피롤리딘-1-일)-3,3-디메틸-1-옥소부탄-2-일)글루타르아미드;(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) N1-((2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일)메틸)-N7-((S)-1-((2S,4R)-4-히드록시-2-(4-(4-메틸티아졸-5-일)벤질카바모일)피롤리딘-1-일)-3,3-디메틸-1-옥소부탄-2-일)헵탄디아미드; (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) (2S,4R)-1-((S)-2-(11-(2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일아미노)운데칸아미도)-3.3-디메틸부탄오일)-4-히드록시-N-(4-(4-메틸티아졸-5-일)벤질)피롤리딘-2-카복스아미드;(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) (2S,4R)-1-((S)-2-(8-(2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일아미노)옥탄아미도)-3,3-디메틸부타노일)-4-히드록시-N-(4-(4-메틸티아졸-5-일)벤질)피롤리딘-2-카복스아미드;(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) (2S,4R)-1-((S)-2-(12-(2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일아미노)도데칸아미도)-3,3-디메틸부타노일)-4-히드록시-N-(4-(4-메틸티아졸-5-일)벤질)피롤리딘-2-카복스아미드;(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) (2S,4R)-1-((S)-2-(2-(6-(2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일아미노)헥실옥시)아세트아미도)-3,3-디메틸부타노일)-4-히드록시-N-(4-(4-메틸티아졸-5-일)벤질)피롤리딘-2-카복스아미드;(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) (2S,4R)-1-((S)-2-(10-(2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일아미노)데칸아미도)-3,3-디메틸부타노일)-4-히드록시-N-(4-(4-메틸티아졸-5-일)벤질)피롤리딘-2-카복스아미드;(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) (2S,4R)-1-((S)-2-tert-부틸-14-(2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일아미노)-4-옥소-6,9,12-트리옥사-3-아자테트라데카-1-노일)-4-히드록시-N-(4-(4-메틸티아졸-5-일)벤질)피롤리딘-2-카복스아미드;(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- 디옥소피페리딘-3-일)-2-메틸-4-옥소-3,4-디히드로퀴나졸린-5-일)아미노)운데칸아미도)-3,3-디메틸부타노일)-4-히드록시-N-(4-(4-메틸티아졸-5-일)벤질)피롤리딘-2-카르복스아미드;(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'-(노난-1,9-디일비스(아자네디일))비스(2-(2,6-디옥소피페리딘-3-일)이소인돌린-1,3-디온);(19) 4,4 '- (nonan-1, 9-diylbis (azanediyl)) bis (2- (2,6-dioxopiperidin-3- yl) isoindoline- );
    (20) (2S,4R)-1-((S)-2-(11-(2-(2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일아미노)아세트아미도)운데칸아미도)-3,3-디메틸부타노일)-4-히드록시-N-(4-(4-메틸티아졸-5-일)벤질)피롤리딘-2-카복스아미드;(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) (2S,4R)-1-((S)-2-(11-(2-(2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일옥시)아세트아미도)운데칸아미도)-3,3-디메틸부타노일)-4-히드록시-N-(4-(4-메틸티아졸-5-일)벤질)피롤리딘-2-카복스아미드;(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) (2S,4R)-1-((S)-2-(11-(2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-5-일아미노)운데칸아미도)-3,3-디메틸부타노일)-4-히드록시-N-(4-(4-메틸티아졸-5-일)벤질)피롤리딘-2-카복스아미드;(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) 3,3'-(5,5'-(노난-1,9-디일비스(아잔디일))비스(4-옥소벤조[d][1,2,3]트리아진-5,3(4H)-디일))디피페리딘-2,6-디온;(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-디옥소피페리딘-3-일)-4-(9-(3-(2,6-디옥소피페리딘-3-일)-4-옥소-3,4-디히드로벤조[d][1,2,3]트리아진-5-일아미노)노닐아미노)이소인돌린-1,3-디온; 및(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) (2S,4R)-1-((S)-2-(11-(3-(2,6-디옥소피페리딘-3-일)-4-옥소-3,4-디히드로벤조[d][1,2,3]트리아진-5-일아미노)운데칸아미도)-3,3-디메틸부타노일)-4-히드록시-N-(4-(4-메틸티아졸-5-일)벤질)피롤리딘-2-카복스아미드.(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.
  6. 하기 반응식 1에 나타난 바와 같이,As shown in Scheme 1 below,
    U-Linker-V로 표시되는 화합물로부터 A-Linker-V로 표시되는 화합물을 제조하는 단계(단계 1);(Step 1) of producing a compound represented by A-Linker-V from a compound represented by U-Linker-V;
    상기 단계 1에서 제조한 A-Linker-V로 표시되는 화합물로부터 A-Linker-A 또는 A-Linker-B로 표시되는 화합물을 제조하는 단계(단계 2);를 포함하는 제1항의 A-Linker-A 또는 A-Linker-B로 표시되는 화합물의 제조방법: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:
    [반응식 1][Reaction Scheme 1]
    Figure PCTKR2018011782-appb-I000131
    Figure PCTKR2018011782-appb-I000131
    (상기 반응식 1에 있어서,(In the above Reaction Scheme 1,
    A, Linker 및 B는 제1항에서 정의한 바와 같고; 및A, Linker and B are as defined in claim 1; And
    U 또는 V는 각각 독립적으로 NH2 또는 OH이다).U or V are each independently selected from NH 2 or OH).
  7. 제1항의 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 세레브론(Cereblon) 관련 질환의 예방 또는 치료용 약학적 조성물.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.
  8. 제1항의 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 암의 예방 또는 치료용 약학적 조성물.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.
  9. 제1항의 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 자가면역질환의 예방 또는 치료용 약학적 조성물.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.
  10. 제1항의 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 대사질환의 예방 또는 치료용 약학적 조성물.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.
  11. 제1항의 A-Linker-A 또는 A-Linker-B로 표시되는 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용 가능한 염을 치료학적으로 유효한 양으로 대상(subject)에게 투여하는 단계를 포함하는 세레브론(Cereblon) 관련 질환의 치료 방법.Comprising administering to a subject a therapeutically effective amount of a compound represented by A-Linker-A or A-Linker-B of claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, (Cereblon) related diseases.
PCT/KR2018/011782 2017-10-20 2018-10-05 Cereblon protein degradation inducing compound, preparation method therefor and pharmaceutical composition for preventing or treating cancer, containing same as active ingredient WO2019078522A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR10-2017-0136771 2017-10-20
KR20170136771 2017-10-20

Publications (1)

Publication Number Publication Date
WO2019078522A1 true WO2019078522A1 (en) 2019-04-25

Family

ID=66174056

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2018/011782 WO2019078522A1 (en) 2017-10-20 2018-10-05 Cereblon protein degradation inducing compound, preparation method therefor and pharmaceutical composition for preventing or treating cancer, containing same as active ingredient

Country Status (2)

Country Link
KR (1) KR102129367B1 (en)
WO (1) WO2019078522A1 (en)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020027225A1 (en) 2018-07-31 2020-02-06 ファイメクス株式会社 Heterocyclic compound
WO2020014489A3 (en) * 2018-07-11 2020-07-30 H. Lee Moffitt Cancer Center And Research Institute, Inc. Dimeric immuno-modulatory compounds against cereblon-based mechanisms
CN112094307A (en) * 2020-09-28 2020-12-18 深圳市术理科技有限公司 Compound for target ubiquitination degradation of ER alpha protein and application thereof
WO2021152113A1 (en) * 2020-01-31 2021-08-05 Bayer Aktiengesellschaft Substituted 2,3-benzodiazepines derivatives
WO2021188537A1 (en) * 2020-03-17 2021-09-23 Dana-Farber Cancer Institute, Inc. Selective small molecule degraders of cereblon
US11395820B2 (en) 2016-03-16 2022-07-26 H. Lee Moffitt Cancer Center And Research Institute, Inc. Small molecules against cereblon to enhance effector t cell function
WO2024054832A1 (en) 2022-09-09 2024-03-14 Innovo Therapeutics, Inc. CK1α AND DUAL CK1α / GSPT1 DEGRADING COMPOUNDS
EP4076464A4 (en) * 2019-12-17 2024-06-12 Orionis Biosciences, Inc. Compounds modulating protein recruitment and/or degradation
WO2025063888A1 (en) 2023-09-19 2025-03-27 Kancure Pte. Ltd. Survivin-targeted compounds

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11807620B2 (en) 2020-02-21 2023-11-07 Plexium, Inc. Quinazolinone compounds and related compounds
JP2023542930A (en) * 2020-09-23 2023-10-12 セント ジュード チルドレンズ リサーチ ホスピタル インコーポレイテッド Substituted N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)arylsulfonamide analogs as modulators of cereblon protein

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20140024914A (en) * 2011-04-29 2014-03-03 셀진 코포레이션 Methods for the treatment of cancer and inflammatory diseases using cereblon as a predictor
US20160176916A1 (en) * 2014-12-23 2016-06-23 Dana-Farber Cancer Institute, Inc. Methods to induce targeted protein degradation through bifunctional molecules
WO2016146985A1 (en) * 2015-03-13 2016-09-22 University Of Dundee Derivatives of 1-[(cyclopentyl or 2-pyrrolidinyl)carbonylaminomethyl]-4-(1,3-thiazol-5-yl) benzene which are useful for the treatment of proliferative, autoimmune or inflammatory diseases
WO2018189554A1 (en) * 2017-04-14 2018-10-18 University Of Dundee Small molecules

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20240096553A (en) 2012-01-12 2024-06-26 예일 유니버시티 Compounds and Methods for the Enhanced Degradation of Targeted Proteins and Other Polypeptides by an E3 Ubiquitin Ligase
KR102616762B1 (en) 2015-03-18 2023-12-20 아비나스 오퍼레이션스, 인코포레이티드 Compounds and methods for enhanced degradation of targeted proteins

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20140024914A (en) * 2011-04-29 2014-03-03 셀진 코포레이션 Methods for the treatment of cancer and inflammatory diseases using cereblon as a predictor
US20160176916A1 (en) * 2014-12-23 2016-06-23 Dana-Farber Cancer Institute, Inc. Methods to induce targeted protein degradation through bifunctional molecules
WO2016146985A1 (en) * 2015-03-13 2016-09-22 University Of Dundee Derivatives of 1-[(cyclopentyl or 2-pyrrolidinyl)carbonylaminomethyl]-4-(1,3-thiazol-5-yl) benzene which are useful for the treatment of proliferative, autoimmune or inflammatory diseases
WO2018189554A1 (en) * 2017-04-14 2018-10-18 University Of Dundee Small molecules

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
MANIACI, C. ET AL.: "Homo-PROTACs: bivalent small-molecule dimerizers of the VHL E3 ubiquitin ligase to induce self-degradation", NATURE COMMUNICATIONS, vol. 8, 10 October 2017 (2017-10-10), pages 1 - 14, XP055476041 *
STEINEBACH, C. ET AL.: "Homo-PROTACs for the Chemical Knockdown of Cereblon", ACS CHEM. BIOL., vol. 13, no. 9, 17 August 2018 (2018-08-17), pages 2771 - 2782, XP055598315 *

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11395820B2 (en) 2016-03-16 2022-07-26 H. Lee Moffitt Cancer Center And Research Institute, Inc. Small molecules against cereblon to enhance effector t cell function
US11730726B2 (en) 2018-07-11 2023-08-22 H. Lee Moffitt Cancer Center And Research Institute, Inc. Dimeric immuno-modulatory compounds against cereblon-based mechanisms
WO2020014489A3 (en) * 2018-07-11 2020-07-30 H. Lee Moffitt Cancer Center And Research Institute, Inc. Dimeric immuno-modulatory compounds against cereblon-based mechanisms
US12233054B2 (en) 2018-07-11 2025-02-25 H. Lee Moffitt Cancer Center And Research Institute, Inc. Dimeric immuno-modulatory compounds against cereblon-based mechanisms
US12202829B2 (en) 2018-07-31 2025-01-21 Fimecs, Inc. Heterocyclic compound
WO2020027225A1 (en) 2018-07-31 2020-02-06 ファイメクス株式会社 Heterocyclic compound
US11639354B2 (en) 2018-07-31 2023-05-02 Fimecs, Inc. Heterocyclic compound
EP4076464A4 (en) * 2019-12-17 2024-06-12 Orionis Biosciences, Inc. Compounds modulating protein recruitment and/or degradation
WO2021152113A1 (en) * 2020-01-31 2021-08-05 Bayer Aktiengesellschaft Substituted 2,3-benzodiazepines derivatives
WO2021188537A1 (en) * 2020-03-17 2021-09-23 Dana-Farber Cancer Institute, Inc. Selective small molecule degraders of cereblon
CN112094307A (en) * 2020-09-28 2020-12-18 深圳市术理科技有限公司 Compound for target ubiquitination degradation of ER alpha protein and application thereof
WO2024054832A1 (en) 2022-09-09 2024-03-14 Innovo Therapeutics, Inc. CK1α AND DUAL CK1α / GSPT1 DEGRADING COMPOUNDS
WO2025063888A1 (en) 2023-09-19 2025-03-27 Kancure Pte. Ltd. Survivin-targeted compounds

Also Published As

Publication number Publication date
KR20190044499A (en) 2019-04-30
KR102129367B1 (en) 2020-07-03

Similar Documents

Publication Publication Date Title
WO2019078522A1 (en) Cereblon protein degradation inducing compound, preparation method therefor and pharmaceutical composition for preventing or treating cancer, containing same as active ingredient
WO2017204445A2 (en) Pharmaceutical composition inducing decomposition of alk protein, and pharmaceutical composition for cancer prevention or treatment containing same as active component
WO2018230934A1 (en) N2,n4-diphenylpyrimidine-2,4-diamine derivative, method for preparing same, and pharmaceutical composition containing same as active ingredient for prevention or treatment of cancer
WO2021086069A1 (en) Compound comprising ezh2 inhibitor and e3 ligase binder and pharmaceutical composition for preventing or treating ezh2-associated disease comprising same as active ingredient
WO2017188694A1 (en) Heteroaryl compound comprising nitrogen, and use thereof
WO2022055181A1 (en) Compounds for suppressing egfr mutant cancer and pharmaceutical use thereof
WO2020096372A1 (en) Novel piperidine-2,6-dione derivative and use of same
WO2014109530A1 (en) 2-(phenylethynyl)thieno[3,4-b]pyrazine derivative and pharmaceutical composition comprising same for preventing or treating cancer
WO2016190630A1 (en) Heterocyclicalkyl derivative compounds as selective histone deacetylase inhibitors and pharmaceutical compositions comprising the same
WO2016032209A2 (en) Substituted n-(pyrrolidine-3-yl)-7h-pyrrolo[2,3-d]pyrimidine-4-amine as janus kinase inhibitor
WO2010002115A2 (en) Fxa inhibitors with cyclic amidoxime or cyclic amidrazone as p4 subunit, processes for their preparations, and pharmaceutical compositions and derivatives thereof
WO2019074241A1 (en) Inhibitor against interaction between pd-1 and pd-l1, comprising phenylacetylene derivative
WO2011162562A2 (en) [6+5] fused bicycles as a thrombin antagonist, process for preparation thereof and pharmaceutical compositions containing the bicycles
WO2023022463A1 (en) Novel imidazole derivative having inhibitory activity on protein phosphorelation and use thereof
WO2016093554A2 (en) Novel 4-(aryl)-n-(2-alkoxythieno[3,2-b]pyrazin-3-yl)-piperazine-1-carboxamide derivative, and antiproliferative effect thereof
WO2017034245A1 (en) Janus kinase 1 selective inhibitor and pharmaceutical use thereof
WO2012134188A2 (en) Novel oxazolidinone derivative and medical composition containing same
WO2020101450A1 (en) Derivative compounds of azilsartan, intermediates thereof, preparation method therefor, and pharmaceutical composition comprising same
WO2020045941A1 (en) Novel heterocyclic amine derivative and pharmaceutical composition comprising same
AU2021255176B2 (en) 1,3,4-oxadiazole derivative compounds as histone deacetylase 6 inhibitor, and the pharmaceutical composition comprising the same
WO2022086110A1 (en) Thiobenzimidazole derivative or pharmaceutically acceptable salt thereof and use thereof
WO2017164705A1 (en) Novel pyridine derivative, method for preparing same, and pharmaceutical composition for preventing or treating fgfr-related disease containing same as active component
WO2021112626A1 (en) Novel indirubin derivative and use thereof
WO2021040422A1 (en) Novel pyrimido[4,5-d]pyrimidine-2-one derivative having protein kinase inhibitory activity
WO2024039210A1 (en) Compounds for inhibiting or decomposing cdk2 and/or cdk9, and medicinal uses thereof

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 18867913

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 18867913

Country of ref document: EP

Kind code of ref document: A1