Synthesis of prostate-specific membrane antigen (PSMA) ligands

Abstract

This product provides a prostate-specific membrane antigen (PSMA) ligand. [Solution] A trifluoroacetate salt of the compound of formula (I), obtained by solid-phase synthesis, is provided. TIFF2026122949000078.tif61124

Description

Technical Field

[0001] The present disclosure relates to the synthesis of prostate-specific membrane antigen (PSMA) ligands useful in the treatment of diseases such as cancer. In particular, the present disclosure relates to a method for synthesizing a PSMA ligand having a glutamate-urea-lysine (GUL) moiety and a chelating agent that may contain a radioactive metal.

[0002]

Background Art

[0003] Prostate cancer is one of the most widespread cancers in the United States and Europe. In particular, metastatic castration-resistant prostate cancer (mCRPC) is associated with poor prognosis and a decline in quality of life. Recently, PSMA has been regarded as a suitable target for imaging and treatment because of its overexpression in primary cancer lesions and soft tissue / bone metastatic diseases. Therefore, PSMA ligand-based radioligand therapy (RLT) has become a new trend in the development for treating prostate cancer. Also, PSMA expression appears to be higher in the most aggressive castration-resistant variants of this disease, which constitute a patient population with a large unmet medical need (Marchal et al., Histol Histopathol, 2004, Jul; 19(3):715-8; Mease et al., Curr Top Med Chem, 2013, 13(8):951-62).

[0004] Among many small molecule ligands targeting PSMA, the most widely studied agents are urea-based low molecular weight agents. These agents are used in the clinical evaluation of prostate cancer and

[0005] It has been shown to be suitable for RRT therapy (Kiess et al., QJ Nucl Med Mol Imaging, 20 15;59:241-68). Some of these drugs are glutamate-urea-lysine (GUL). It has a targeting scaffold. A linker is bonded between the chelating agent and the GUL portion. A class of molecules was created according to this strategy. This approach involves the metal chelation portion. This strategy involves keeping the urea outside the binding site while allowing it to reach the binding site. Due to its demonstrated high uptake and retention rates, as well as rapid renal clearance, Successful in xenografted PSMA-positive tumors (Banerjee et al., J Med Chem, 2013; 56: 6108-21).

[0005] moreover, 177 Specific compounds like Lu-PSMA-617 are being widely studied. Various studies have shown that 177 Lu-PSMA-617 shows promise as a radioactive treatment for prostate cancer. This indicates that it is a pharmaceutical product (Delker et al., European Journal of Nuclear Medicine) e and Molecular Imaging (2016), 43(1), 42-51;Yadav et al., European Journal of Nuclear Medicine and Molecular Imaging (2017), 44(1), 81-91).

[0006] Due to interest in urea-based PSMA ligands, particularly PSMA-617, This invention provides a synthesis method that is cost-effective and can deliver the required amount of high-purity product. This is what is required. [Overview of the project]

[0007] The present disclosure relates to a method for synthesizing a PSMA ligand useful in the treatment of diseases such as cancer, particularly prostate cancer.

[0008] The present disclosure also relates to a method for synthesizing a compound of formula (I), or a pharmaceutically acceptable salt thereof, using solid-phase synthesis.

[0009] [Chemical formula]

[0010] The compound of formula (I) is PSMA-617.

[0011] According to a first embodiment, the method includes at least one of the following steps: a) contacting a supported compound of formula (II), preferably a resin-supported compound, with a compound of formula (III) to obtain a supported compound of formula (IV), preferably a resin-supported compound;

[0012] [Chemical formula] [[ID=३७]]

[0013] [Chemical formula]

[0014] [Chemical formula] b) contacting a supported compound of formula (IV), preferably a resin-supported compound, with a deprotecting agent to obtain a supported compound of formula (V), preferably a resin-supported compound;

[0015] [Chemical formula] ​​​​​c) Contacting a supported compound of formula (V), preferably a resin-supported compound, with a compound of formula (VI). Let me

[0016] [ka] A step to obtain a supported compound of formula (VII), preferably a resin-supported compound;

[0017] [ka] d) Contacting a supported compound of formula (VII), preferably a resin-supported compound, with a deprotecting agent. Steps to obtain a supported compound of formula (VIII), preferably a resin-supported compound;

[0018] [ka] e) A supported compound of formula (VIII), preferably a resin-supported compound and a compound of formula (IX) Make contact

[0019] [ka] A step to obtain a supported compound of formula (X), preferably a resin-supported compound;

[0020] [ka] f) A supported compound of formula (X), preferably a resin-supported compound, is brought into contact with a deprotecting agent to form formula ( Step XI) to obtain a supported compound, preferably a resin-supported compound;

[0021] [ka] g) Contact a supported compound of formula (XI), preferably a resin-supported compound, with compound (XII). Let me

[0022] [ka] A step to obtain a supported compound of formula (XIII), preferably a resin-supported compound;

[0023] [ka] h) Supported compound of formula (XIII), preferably a resin-supported compound and a cleavage reagent and, if applicable Therefore, by contacting the deprotecting agent, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is obtained. Steps to obtain; During the ceremony, -PG, PG1, PG5, PG6, and PG7 are each independently carboxyl protecting groups. and; -L is a linker; -PG2, PG3, and PG4 are each independently amino protecting groups; -R1, R2, and R3 are each independently H or an activated ester group; -LG is selected from the group consisting of imidazole, halogen, and activated ester groups. It is a derived base.

[0024] According to the second embodiment, the method includes at least one of the following steps: a') A supported compound of formula (II'), preferably a resin-supported compound

[0025] [ka] By contacting the compound of formula (III')

[0026] [ka] A step to obtain a supported compound of formula (IV'), preferably a resin-supported compound;

[0027] [ka] b') A supported compound of formula (IV'), preferably a resin-supported compound, is brought into contact with a deprotecting agent. A step to obtain a supported compound of formula (V'), preferably a resin-supported compound;

[0028] [ka] c') A supported compound of formula (V'), preferably a resin-supported compound and a compound of formula (VI') Make contact

[0029] [ka] A step to obtain a supported compound of formula (VII'), preferably a resin-supported compound;

[0030] [ka] d') A supported compound of formula (VII'), preferably a resin-supported compound, is brought into contact with a deprotecting agent. Steps to obtain a supported compound of formula (VIII'), preferably a resin-supported compound;

[0031] [ka] e') A supported compound of formula (VIII'), preferably a resin-supported compound and a compound of formula (IX') Bring the combined material into contact

[0032] [ka] A step to obtain a supported compound of formula (X'), preferably a resin-supported compound;

[0033] [ka] f') The supported compound of formula (X'), preferably a resin-supported compound, is brought into contact with a deprotecting agent. A step to obtain a supported compound of formula (XI'), preferably a resin-supported compound;

[0034] [ka] g') A supported compound of formula (XI'), preferably a resin-supported compound and compound (XII') Make contact

[0035] [ka] A step to obtain a supported compound of formula (XIII'), preferably a resin-supported compound;

[0036] [ka] h') Supported compound of formula (XIII'), preferably a resin-supported compound and a cleavage reagent and Depending on the combination, a deprotective agent may be brought into contact with the compound of formula (I), or a pharmaceutically acceptable compound thereof. Steps to obtain salt; During the ceremony, -PG', PG1', PG5', PG6', and PG7' are each independently derived from PG1', PG5', PG6', and PG7'. It is a syl protecting group; -L' is a linker; -PG2', PG3', and PG4' are each independently amino protecting groups; -R1', R2', and R3' are each independently either H or an activated ester group; -LG' is selected from the group consisting of imidazole, halogen, and activated ester groups. It is a leaving group.

[0037] The fact that this synthesis is carried out using solid-phase synthesis makes it a cost-effective and efficient synthesis. This makes possible. In particular, the total yield of this synthesis is obtained from the supported starting material compound (II) or (II). It can be 20% or more of the case. [Brief explanation of the drawing]

[0038] [Figure 1] This figure shows a 1D 1H spectrum with Watergate H2 signal suppression applied, used for reference and as a fingerprint. [Modes for carrying out the invention]

[0039] definition As used herein, the term "solid-phase synthesis" refers to the synthesis of reactive molecules into an insoluble material (solid The synthesis of compounds involves chemically bonding them to a support material (usually a resin) and adding reagents in a solution phase. It has a taste. Typically, reactive molecules are chemically bonded to a solid support via a linker. Solid phase bonding. Solid phase is commonly used to synthesize peptides, and therefore, those skilled in the art will know They are proficient in the techniques and equipment used for synthesis. In solid-phase peptide synthesis, Coupling reactions involve attaching amino acids or peptides to a solid support, usually via the C-terminus. Through the process, a new amino acid is added to an amino acid or peptide. Because of the possibility of reaction, protecting groups are usually used. By using solid-phase synthesis, simple The intermediate is isolated and purified by filtration and rinsing, and the intermediate is processed in a time-consuming and costly manner. This makes it possible to avoid separation and purification.

[0040] As used herein, the term “supported compound” refers to a compound that supports an insoluble material, usually a resin. It refers to a compound that is chemically bonded to something.

[0041] As used herein, the term “resin-based compound” is defined as follows: This refers to a compound that is chemically bonded to a resin, which is a solid support. It is used in the context of production.

[0042] As used herein, the term "linker" refers to a linker that brings a reactive molecule into contact with an insoluble material. It refers to the subsequent divalent portion.

[0043] As used herein, the term “protecting group” refers to a regenerated functional group within a molecule or It can be selectively removed by readily available reagents that do not attack other functional groups. This refers to chemical substituents. Suitable protecting groups are known in the art and development continues. Suitable protecting groups include, for example, Wutz et al. ("Greene's Protective Groups in Organic This can be found in "Synthesis, Fourth Edition," Wiley-Interscience, 2007.

[0044] In certain embodiments, the protection of the carboxyl group as described by Wutz et al. (pages 533-643) A protecting group is used. In some embodiments, the protecting group can be removed by treatment with an acid. Yes, there are. Typical examples of carboxyl protecting groups include benzyl and p-methoxybenzyl (PMB). Tert-butyl (t-Bu), methoxymethyl (MOM), methoxyethoxymethyl (MEM), methylthiomethyl (MTM), tetrahydropyranil (THP), tetra Hydrofuranyl (THF), benzyloxymethyl (BOM), trimethylsilyl (TM) S), triethylsilyl (TES), t-butyldimethylsilyl (TBDMS), and Triphenylmethyl (trityl, Tr) is an example, but is not limited thereto. Those skilled in the art will know They will recognize the appropriate situations in which a protecting group is needed.

[0045] In certain embodiments, the protection for the amino group described by Wutz et al. (pages 696-927) The group is used. A typical example of an amino protecting group is t-butyloxycarbonyl (Boc). , 9-Fluorenylmethoxycarbonyl (Fmoc), Allyloxycarbonyl (all oc), N-(1-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl) )(Dde), 1-(1-adamantyl)-1-methylethoxycarbonyl(Adpoc ), N-(1-(4,4-dimethyl-2,6-dioxocyclohexa-1-ylidene)- 3-methylbutyl (ivDde), monomethoxytrityl (MMt), and 4-methyl Examples include, but are not limited to, rutrityl (Mtt). Those skilled in the art will know that a protecting group is necessary. They will recognize the appropriate situation.

[0046] As used herein, the term "activated ester group" refers to an ester functional group that is activated This refers to electron-withdrawing groups that are used to enhance their sensitivity to nucleophilic attack. Activated esters are commonly used in organic chemistry. As an activated ester group succinimidyl, p-nitrophenyl, tetrafluorophenyl, 3,4-dihydro -4-oxo-1,2,3-benzotriazin-3-yl, pentafluorophenyl, Examples include 2,4,5-trichlorophenyl.

[0047] Various embodiments of this disclosure are described herein. Features defined in each embodiment are Further embodiments can be realized by combining them with other defined features. This will be recognized.

[0048] This disclosure relates to compounds of formulas (I) to (XIII) and chemicals of formulas (II') to (XIII'). Compounds, their stereoisomers, tautomers, enantiomers, diastereomers, racemates, or mixtures thereof, as well as their hydrates, solvates, or pharmaceutically acceptable salts. Includes.

[0049] The term “pharmaceutically acceptable salt” refers to the biological efficacy and characteristics of the compounds in this disclosure. It means salt, which preserves sex and is not usually undesirable biologically or otherwise. Examples of pharmaceutically acceptable salts include trifluoroacetate (TFA) salts, acetate salts, and Examples include hydrochloride salts.

[0050] Synthesis of the compound of formula (I) This disclosure also provides a method for synthesizing compounds of formula (I), preferably using solid-phase synthesis. Regarding the law.

[0051] According to one embodiment, the compound of formula (I) is a trifluoroacetic acid (TFA) salt or vinegar. It is an acid salt.

[0052] The resin used in this method is any type that has been conventionally used in solid-phase synthesis. It can be a resin. These resins are well known to those skilled in the art. As a resin, it can be a microporous polymer. Polystyrene resins such as styrene resin or macroporous polystyrene resin, poly Examples include criamide resins and copolymer resins. Linker L or L' is An acid-unstable linker is preferable. An acid-unstable linker is used under acidic conditions. In some cases, it is possible to cut during step h) or h'). Linker L or L' is used It varies depending on the resin used, and these are well known to those skilled in the art. Linker group L or L' The resins included are p-alkoxybenzyl alcohol resin (Wang resin), 4-(1 ',1'-dimethyl-1'-hydroxypropyl)phenoxyacetyl-alanyl-amine methyl resin (DHPP resin), diphenyldiazomethane resin (PDDM resin), chloride Examples include lithyl resin and 2-chlorotrityl chloride resin.

[0053] Protecting groups PG, PG1, PG5, PG6, PG7, PG', PG1', PG5', PG6 ', and PG7' are independently benzyl, p-methoxybenzyl (PMB), and t - methyl butyl (t-Bu), methoxymethyl (MOM), methoxyethoxymethyl ( MEM), methylthiomethyl (MTM), tetrahydropyranyl (THP), tetrahydro Lofuranil (THF), benzyloxymethyl (BOM), trimethylsilyl (TMS) , triethylsilyl (TES), t-butyldimethylsilyl (TBDMS), and tri It can be selected from the group consisting of phenylmethyl(trityl, Tr).

[0054] According to one embodiment, PG, PG1, PG5, PG6, and PG7 are tertiary -Butyl (t-Bu). According to one embodiment, PG', PG1', PG5', PG6' and PG7' are tert-butyl (t-Bu).

[0055] The protecting groups PG2, PG3, PG4, PG2', PG3', and PG4' are independent of each other. t-butyloxycarbonyl (Boc), 9-fluorenylmethoxycarbonyl (F moc), allyloxycarbonyl (alloc), N-(1-(4,4-dimethyl-2) ,6-Dioxocyclohexylidene)ethyl)(Dde), Monomethoxytrityl(MM t), 1-(1-adamantyl)-1-methylethoxycarbonyl(Adpoc), N- (1-(4,4-dimethyl-2,6-dioxocyclohexa-1-ylidene)-3-meth From the group consisting of butyl (ivDde) ​​and 4-methyltrityl (Mtt), Alternatively, it can be selected from the group consisting of Dde, ivDde, and Fmoc.

[0056] According to one embodiment, PG2, PG3, and PG4 are 9-fluorenylmethoxy It is carbonyl (Fmoc). According to one embodiment, PG2' is N-(1-(4, 4-dimethyl-2,6-dioxocyclohexa-1-ylidene)-3-methylbutyl) ivDde) ​​or Dde, and PG3' and PG4' are 9-fluorenylmethoxy. It is a carbonyl (Fmoc). Dde and ivDde are preferred as PG2' protection. These are the groups. In particular, the deprotection of these groups does not require the use of a metal catalyst, and this is Pd(PP This is in contrast to the Alloc protecting group which is removed using h3)4. Furthermore, these groups It is not as bulky as MMt and Mtt, therefore, the amount added to the resin can be increased. Furthermore, they are less sensitive to acidic conditions than Mtt.

[0057] The R1, R2, R3, R1', R2', and R3' groups are each independently H, succin Imidyl, p-nitrophenyl, tetrafluorophenyl, 3,4-dihydro-4-oxy So-1,2,3-benzotriazin-3-yl, pentafluorophenyl, and 2,4 From the group consisting of ,5-trichlorophenyl, preferably consisting of H and succinimidyl They can be selected from the group. According to one embodiment, R1, R2, and R3 are H. According to one embodiment, R1', R2', and R3' are H.

[0058] LG and LG' are independently selected from imidazole, halogen, and activated ester groups. The selected leaving group is chlorine, which can be cited as a halogen. Compound (III) And (III') has a -NH-(CO)-LG or LG' moiety, and -N=C=O reaction Due to the fact that it does not have a responsive part, the product is phosgene or triphot, which are highly toxic. This makes it possible to synthesize the compound of formula (I) without using toxic compounds such as sgene. LG or LG' does not use phosgene or triphosgene, which are highly harmful products. Since it can be synthesized, it is preferable to use imidazole. Furthermore, imidazole When used as a leaving group, the product is a stable solid that is easy to handle. .

[0059] According to a preferred embodiment, a method for synthesizing the compound of formula (I) is provided for all st Steps a) through h), or including all steps a') through h').

[0060] Each step a) to h) or a') to h') should be carried out at room temperature or under heating, for example, 25°C to 7°C. This can be done at a temperature of 0°C. Each step a) to h) or a') to h') should be performed for 5 to 3 minutes. This can be done over a period of time. Each step a)~h) or a')~h') is not This can be done under an active atmosphere, for example, under argon.

[0061] Between each step, the obtained supported compound is mixed with dimethylformamide (DMF) and dichloromethyl nitrate. Washing with a solvent such as lomethane (DCM) or isopropanol (IPA) is possible. Yes, it is possible. Washing can be done using different solvents alternately, for example, DMF and IPA alternately. It may be used for cleaning.

[0062] Each step a) to h) or a') to h') is carried out using a polar aprotic solvent. This can be done. According to one embodiment, in each step a) to h) or a') to h') The polar aprotic solvents that can be used are dimethylformamide (DMF) and N-methyl -2-pyrrolidone (NMP), dichloromethane (DCM), dichloromethane / dimethyl phosphate Lumamide mixture, acetonitrile (ACN), acetonitrile / dimethylformamide The following are selected from the group consisting of mixtures and dimethyl sulfoxide (DMSO). Advantageously, , polar nonprototype available in either step a)~h) or a')~h') The solvent is dimethylformamide (DMF).

[0063] Steps a), c), e), g), a'), c'), e'), or g') cup This can be done using a ring agent and / or a base. Each step a), c), e) The usable bases in , g), a'), c'), e'), or g') are independently N, N-diisopropylethylamine (DIPEA), N,N-diisopropylethylamine ( i Pr2NEt), triethylamine (TEA), 4-methylmorpholine (NMM), The group consisting of imidazole, pyridine, and colidine may be selected. Preferably, a salt The base is DIPEA. Step a), c), e), a'), c'), or e') In either case, the coupling agent that can be used is independently benzotriazole-1-yl- Xytripyrrolidinophosphonium hexafluorophosphate (PyBOP), 1-[ Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyri Dinium 3-oxide hexafluorophosphate (HATU), 2-(1H-ben Zotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluor Roborate (TBTU), 2-(1H-benzotriazol-1-yl)-1,1,3, 3-Tetramethyluronium hexafluorophosphate (HBTU), 2-chloro- 4,6-Dimethoxy-1,3,5-triazine (CDMT), N-[(5-chloro-3- Oxido-1H-benzotriazol-1-yl)-4-morpholinylmethylene]-N- Methylmethaneaminium hexafluorophosphate (HDMC), 1-cyano-2- Ethoxy-2-oxoethylideneaminooxy)dimethylamino-morpholino-carbenyl Um hexafluorophosphate (COMU), dimethylamino(triazolo[4,5 -b]pyridine-3-yloxy)methylidene]-dimethylazanium; tetrafluoro Borate (TATU), N,N,N',N'-tetramethyl-S-(1-oxide-2- Pyridyl thiouronium tetrafluoroborate (TOTT), N-ethoxycarb Nyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), 1-propanephosphonic acid Anhydrous (T3P), and 4-(4,6-dimethoxy-1,3,5-triazine-2-I From the group consisting of (L)-4-methylmorpholinium chloride (DMTMM), preferably This can be selected from the group consisting of PyBOP and TBTU.

[0064] According to one embodiment, step a) is performed using a base, usually DIPEA. According to one embodiment, step a') is performed using a base, usually DIPEA. According to one embodiment, step c) is a coupling agent and a base, usually TBT. This is done using U and DIPEA. According to one embodiment, step c') is C This is done using a plucking agent and a base, usually TBTU and DIPEA. According to the embodiment, step e) is a coupling agent and a base, usually TBTU and D This is done using IPEA. According to one embodiment, step e') coupling This is done using an agent and a base, usually TBTU and DIPEA. In one embodiment... According to the information, step g) is the coupling agent and base, usually PyBOP and DIPEA This is done using a coupling agent and This is done using bases, usually PyBOP and DIPEA.

[0065] Used in any of steps b), d), f), b'), d'), or f'). The deprotective agents used are independently hydrazine, piperidine, morpholine, and 1,8-diazabicyclo [5.4.0] Undeca-7-ene (DBU), diethylamine (DEA), dicyclohexylamine Xamine, 4-methylpiperidine (4MP), tris(2-aminoethyl)amine, pyri From the group consisting of dins and colidines, preferably consisting of hydrazine and piperidine. A group may be selected. According to one embodiment, the deprotection used in step b) The agent is piperidine. According to one embodiment, the decongestant used in step b') The protective agent is hydrazine. According to one embodiment, it is used in step d). The deprotective agent is piperidine. According to one embodiment, it is used in step d'). The deprotective agent used is piperidine. According to one embodiment, in step f) The deprotective agent used is piperidine. According to one embodiment, in step f') The deprotective agent used is piperidine.

[0066] The cleavage reagent in step h) or h') is an acid, preferably trifluoroacetic acid (TFA). Alternatively, it may be a mixture of trifluoroacetic acid (TFA) / water / triisopropylsilane.

[0067] According to one embodiment, the total yield of this synthesis is obtained from the supported starting material compound (II) and is 10% or more, preferably 15% or more, and more preferably 20% or more relative to (II') It's possible. The overall yield could be between 15% and 100%.

[0068] In some cases, this method requires the removal of compound (II) before step a). A protective step may be included.

[0069] In some cases, this method is used to obtain compound (II') before step a'). This may include a deprotection step.

[0070] Embodiment The following specific embodiments are disclosed.

[0071] 1. Synthesize the compound of formula (I) or a pharmaceutically acceptable salt thereof using solid-phase synthesis. A method for doing so.

[0072] [ka]

[0073] 2. The method according to Embodiment 1, comprising at least one of the following steps: a) A supported compound of formula (II), preferably a resin-supported compound and

[0074] [ka] By contacting the compound of formula (III)

[0075] [ka] A step to obtain a supported compound of formula (IV), preferably a resin-supported compound;

[0076] [ka] b) A supported compound of formula (IV), preferably a resin-supported compound, is brought into contact with a deprotecting agent to form a formula (V) A step to obtain a supported compound, preferably a resin-supported compound;

[0077] [ka] c) Contacting a supported compound of formula (V), preferably a resin-supported compound, with a compound of formula (VI). Let me

[0078] [ka] A step to obtain a supported compound of formula (VII), preferably a resin-supported compound;

[0079] [ka] d) Contacting a supported compound of formula (VII), preferably a resin-supported compound, with a deprotecting agent. Steps to obtain a supported compound of formula (VIII), preferably a resin-supported compound;

[0080] [ka] e) A supported compound of formula (VIII), preferably a resin-supported compound and a compound of formula (IX) Make contact

[0081] [ka] A step to obtain a supported compound of formula (X), preferably a resin-supported compound;

[0082] [ka] f) A supported compound of formula (X), preferably a resin-supported compound, is brought into contact with a deprotecting agent to form formula ( Step XI) to obtain a supported compound, preferably a resin-supported compound;

[0083] [ka] g) Contact a supported compound of formula (XI), preferably a resin-supported compound, with compound (XII). Let me

[0084] [ka] A step to obtain a supported compound of formula (XIII), preferably a resin-supported compound;

[0085] [ka] h) Supported compound of formula (XIII), preferably a resin-supported compound and a cleavage reagent and, if applicable Therefore, by contacting the deprotecting agent, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is obtained. Steps to obtain; During the ceremony, -PG, PG1, PG5, PG6, and PG7 are each independently carboxyl protecting groups. and; -L is a linker; -PG2, PG3, and PG4 are each independently amino protecting groups; -R1, R2, and R3 are each independently H or an activated ester group; -LG is selected from the group consisting of imidazole, halogen, and activated ester groups. It is a derived base.

[0086] 3. The method according to Embodiment 2, comprising all steps a) to h).

[0087] 4. PG, PG1, PG5, PG6, and PG7 are independently benzyl and p-methoxy. Benzyl (PMB), tert-butyl (t-Bu), methoxymethyl (MOM), Toxyethoxymethyl (MEM), methylthiomethyl (MTM), tetrahydropyranyl (THP), tetrahydrofuranyl (THF), benzyloxymethyl (BOM), tri Methylsilyl (TMS), triethylsilyl (TES), t-butyldimethylsilyl (T Selected from the group consisting of BDMS and triphenylmethyl (trityl, Tr), In addition, PG, PG1, PG5, PG6, and PG7 are tert-butyl (tB The method according to any one of Embodiments 2 to 3, wherein (u)

[0088] 5. PG2, PG3, and PG4 independently form t-butyloxycarbonyl (Boc) , 9-Fluorenylmethoxycarbonyl (Fmoc), Allyloxycarbonyl (all oc), N-(1-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl) )(Dde), monomethoxytrityl(MMt), 1-(1-adamantyl)-1-meth Luethoxycarbonyl (Adpoc), N-(1-(4,4-dimethyl-2,6-dioxide Socyclohexa-1-ylidene)-3-methylbutyl)(ivDde), and 4-methylbutyl Selected from the group consisting of rutrityl (Mtt), preferably PG2, PG3, and P In all embodiments 2 to 4, G4 is 9-fluorenyl methoxycarbonyl (Fmoc). The method described in one of the following options.

[0089] 6. R1, R2, and R3 independently contain H, succinimidyl, p-nitrophenyl, Tetrafluorophenyl, 3,4-dihydro-4-oxo-1,2,3-benzotriazi It consists of 1-3-yl, pentafluorophenyl, and 2,4,5-trichlorophenyl. Selected from the group, preferably R1, R2, and R3 are H or succinimidyl A method according to any one of embodiments 2 to 5, selected from the group.

[0090] 7. At least one of steps a) to h) is carried out using a polar aprotic solvent. The method according to any one of embodiments 2 to 6.

[0091] 8. Polar aprotic solvents include dimethylformamide (DMF) and N-methyl-2-pyro Lidone (NMP), dichloromethane (DCM), dichloromethane / dimethylformamide Mixture, acetonitrile (ACN), acetonitrile / dimethylformamide mixture, A solvent is selected from the group consisting of and dimethyl sulfoxide (DMSO), preferably a solvent that is di The method according to Embodiment 7, wherein methylformamide (DMF) is used.

[0092] 9. At least one of steps a), c), e), or g) is a coupling agent The method according to any one of embodiments 2 to 8, which is carried out using a and / or base.

[0093] 10. The base is N,N-diisopropylethylamine (DIPEA), N,N-diiso Ropyrethylamine ( i Pr2NEt), triethylamine (TEA), 4-methylmol Selected from the group consisting of foline (NMM), imidazole, pyridine, and colidine. The method according to Embodiment 9.

[0094] 11. The coupling agent is benzotriazole-1-yl-oxytripyrrolidinophospho Nium hexafluorophosphate (PyBOP), 1-[bis(dimethylamino)methyl [Chilen]-1H-1,2,3-Triazolo[4,5-b]pyridinium 3-oxide Hexafluorophosphate (HATU), 2-(1H-benzotriazole-1-yl) )-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluroni Mu Hexafluorophosphate (HBTU), 2-chloro-4,6-dimethoxy-1, 3,5-triazine (CDMT), N-[(5-chloro-3-oxide-1H-benzo [Riazole-1-yl)-4-morpholinylmethylene]-N-methylmethaneaminium Hexafluorophosphate (HDMC), 1-cyano-2-ethoxy-2-oxoeth (Lideneaminooxy)dimethylamino-morpholino-carbenium hexafluorophos Pheth (COMU), Dimethylamino(Triazolo[4,5-b]pyridine-3-yl) [Oxy)methylidene]-dimethylazanium; tetrafluoroborate (TATU), N N,N',N'-tetramethyl-S-(1-oxide-2-pyridyl)thiouronium Tetrafluoroborate (TOTT), N-ethoxycarbonyl-2-ethoxy-1, 2-Dihydroquinoline (EEDQ), 1-propanephosphonic anhydride (T3P), and 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpho Embodiments 9 or 10 include a selection from the group consisting of linium chloride (DMTMM). Method of description.

[0095] 12. Step a) is performed using a base, usually with DIPEA, and step c) is performed using a cutter. This is done using a pulling agent and base, usually TBTU and DIPEA, step e ) is performed using coupling agents and bases, usually TBTU and DIPEA, Step g) uses coupling agents and bases, usually PyBOP and DIPEA. The method according to any one of embodiments 9 to 11, which is performed.

[0096] 13. The deprotecting agent used in step b), d), or f) is hydrazine, pi Peridine, morpholine, 1,8-diazabicyclo[5.4.0]undeca-7-ene(D BU), diethylamine (DEA), dicyclohexamine, 4-methylpiperidine (4M From the group consisting of P), tris(2-aminoethyl)amine, pyridine, and colidine, Preferably selected from the group consisting of hydrazine and piperidine, Embodiments 2 to 12 Any one of the following methods.

[0097] 14. Step h) is an acid, preferably trifluoroacetic acid (TFA) or trifluoro Embodiment 2 is carried out using a mixture of acetic acid (TFA) / water / triisopropylsilane. The method described in any one of the 13 methods.

[0098] 15. The method according to Embodiment 1, comprising at least one of the following steps: a') A supported compound of formula (II'), preferably a resin-supported compound

[0099] [ka] By contacting the compound of formula (III')

[0100] [ka] A step to obtain a supported compound of formula (IV'), preferably a resin-supported compound;

[0101] [ka] b') A supported compound of formula (IV'), preferably a resin-supported compound, is brought into contact with a deprotecting agent. A step to obtain a supported compound of formula (V'), preferably a resin-supported compound;

[0102] [ka] c') A supported compound of formula (V'), preferably a resin-supported compound and a compound of formula (VI') Make contact

[0103] [ka] A step to obtain a supported compound of formula (VII'), preferably a resin-supported compound;

[0104] [ka] d') A supported compound of formula (VII'), preferably a resin-supported compound, is brought into contact with a deprotecting agent. Steps to obtain a supported compound of formula (VIII'), preferably a resin-supported compound;

[0105] [ka] e') A supported compound of formula (VIII'), preferably a resin-supported compound and a compound of formula (IX') Bring the combined material into contact

[0106] [ka] A step to obtain a supported compound of formula (X'), preferably a resin-supported compound;

[0107] [ka] f') The supported compound of formula (X'), preferably a resin-supported compound, is brought into contact with a deprotecting agent. A step to obtain a supported compound of formula (XI'), preferably a resin-supported compound;

[0108] [ka] g') A supported compound of formula (XI'), preferably a resin-supported compound and compound (XII') Make contact

[0109] [ka] A step to obtain a supported compound of formula (XIII'), preferably a resin-supported compound;

[0110] [ka] h') Supported compound of formula (XIII'), preferably a resin-supported compound and a cleavage reagent and Depending on the combination, a deprotective agent may be brought into contact with the compound of formula (I), or a pharmaceutically acceptable compound thereof. Steps to obtain salt; During the ceremony, -PG', PG1', PG5', PG6', and PG7' are each independently derived from PG1', PG5', PG6', and PG7'. It is a syl protecting group; -L' is a linker; -PG2', PG3', and PG4' are each independently amino protecting groups; -R1', R2', and R3' are each independently either H or an activated ester group; -LG' is selected from the group consisting of imidazole, halogen, and activated ester groups. It is a leaving group.

[0111] 16. The method according to Embodiment 15, comprising all steps a') to h').

[0112] 17. PG', PG1', PG5', PG6', and PG7' are independently benzyl p-Methoxybenzyl (PMB), tert-butyl (t-Bu), methoxymethyl ( MOM), Methoxyethoxymethyl (MEM), Methylthiomethyl (MTM), Tetramethyl Dropyranil (THP), tetrahydrofuranil (THF), benzyloxymethyl (B OM), trimethylsilyl (TMS), triethylsilyl (TES), t-butyldimethyl From the group consisting of lucilyl (TBDMS) and triphenylmethyl (trityl, Tr) Selected, preferably PG', PG1', PG5', PG6', and PG7' are The method according to any one of embodiments 15 to 16, wherein the substance is chaributyl (t-Bu).

[0113] 18. PG2', PG3', and PG4' independently form t-butyloxycarbonyl ( Boc), 9-Fluorenylmethoxycarbonyl (Fmoc), Allyloxycarbonyl (alloc), N-(1-(4,4-dimethyl-2,6-dioxocyclohexylidene) )(ethyl)(Dde), monomethoxytrityl (MMt), 1-(1-adamantyl)- 1-methylethoxycarbonyl (Adpoc), N-(1-(4,4-dimethyl-2,6 -dioxocyclohex-1-ylidene)-3-methylbutyl)(ivDde), and 4-methyltrityl (Mtt), and is preferably selected from the group consisting of PG2’ being N-( 1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)-3-methyl butyl)(ivDde) or Dde, and PG3’ and PG4’ being 9-fluorenyl methoxycarbonyl (Fmoc), according to any one of Embodiments 15 to 17 method.

[0114] 19. R1’, R’2, and R3’ are independently H, succinimidyl, p-nitrop henyl, tetrafluorophenyl, 3,4-dihydro-4-oxo-1,2,3-benzotriazin-3-yl, pentafluorophenyl, and 2,4,5-trichlorophenyl selected from the group consisting of, and preferably, R1’, R’2, and R3’ are selected from the group consisting of H or succinimidyl, according to any one of Embodiments 15 to 18 method. method.

[0115] 20. At least one of steps a’) to h’) is performed using an aprotic polar solvent according to any one of Embodiments 15 to 19.

[0116] 21. The aprotic polar solvent is dimethylformamide (DMF), N-methyl-2-pyrrolidone (NMP), dichloromethane (DCM), dichloromethane / dimethylformamide mixture, acetonitrile (ACN), acetonitrile / dimethylformamide mixture, ​​​A solvent selected from the group consisting of and dimethyl sulfoxide (DMSO), preferably the solvent is The method according to Embodiment 20, wherein dimethylformamide (DMF) is used.

[0117] 22. At least one of steps a'), c'), e'), or g') is a cup One of embodiments 15 to 21 is performed using a ring agent and / or a base. Method of description.

[0118] 23. The base is N,N-diisopropylethylamine (DIPEA), N,N-diiso Ropyrethylamine ( i Pr2NEt), triethylamine (TEA), 4-methylmol Selected from the group consisting of foline (NMM), imidazole, pyridine, and colidine. The method according to Embodiment 22.

[0119] 24. The coupling agent is benzotriazole-1-yl-oxytripyrrolidinophospho Nium hexafluorophosphate (PyBOP), 1-[bis(dimethylamino)methyl [Chilen]-1H-1,2,3-Triazolo[4,5-b]pyridinium 3-oxide Hexafluorophosphate (HATU), 2-(1H-benzotriazole-1-yl) )-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluroni Mu Hexafluorophosphate (HBTU), 2-chloro-4,6-dimethoxy-1, 3,5-triazine (CDMT), N-[(5-chloro-3-oxide-1H-benzo [Riazole-1-yl)-4-morpholinylmethylene]-N-methylmethaneaminium Hexafluorophosphate (HDMC), 1-cyano-2-ethoxy-2-oxoeth (Lideneaminooxy)dimethylamino-morpholino-carbenium hexafluorophos Pheth (COMU), Dimethylamino(Triazolo[4,5-b]pyridine-3-yl) [Oxy)methylidene]-dimethylazanium; tetrafluoroborate (TATU), N N,N',N'-tetramethyl-S-(1-oxide-2-pyridyl)thiouronium Tetrafluoroborate (TOTT), N-ethoxycarbonyl-2-ethoxy-1, 2-Dihydroquinoline (EEDQ), 1-propanephosphonic anhydride (T3P), and 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpho Embodiments 22 or 23, selected from the group consisting of linium chloride (DMTMM) Methods used.

[0120] 25. Step a') is performed using a base, usually DIPEA, and step c') is The coupling agent and base are used, usually TBTU and DIPEA, and the steps The process is carried out using a coupling agent and a base, usually TBTU and DIPEA. Then, step g') is the coupling agent and base, usually PyBOP and DIPEA. The method according to any one of embodiments 22 to 24, performed using

[0121] 26. The deprotecting agent used in step b'), d'), or f') is hydrazine n, piperidine, morpholine, 1,8-diazabicyclo[5.4.0]undeca-7-e (DBU), diethylamine (DEA), dicyclohexamine, 4-methylpiperidine (4MP), tris(2-aminoethyl)amine, pyridine, and collidine selected from the group consisting of, preferably, hydrazine and piperidine, Embodiment 15 The method according to any one of ~25.

[0122] 27. Step h') is carried out using an acid, preferably trifluoroacetic acid (TFA) or trifluoro acetic acid (TFA) / water / triisopropylsilane mixture, Embodiment 1 The method according to any one of 5~26.

[0123] The present disclosure further provides any one of the compounds defined by Formulas (II)~(XIII) or (II’)~( XIII’) herein, or the use of those as intermediates in a method for synthesizing a compound of Formula (I), or a pharmaceutically acceptable salt thereof. For example, in one embodiment, the present disclosure relates to a compound defined by Formula (II) herein, or a pharmaceutically acceptable salt thereof. In another embodiment , the present disclosure relates to the use of a compound defined by Formula (II) herein, or a pharmaceutically acceptable salt thereof, as an intermediate in a method for synthesizing a compound of Formula (I), or a pharmaceutically acceptable salt thereof. <(

[0124] Similarly, further embodiments of the present disclosure are Formulas (III), (IV), (V), (VI ), (VII), (VIII), (IX), (X), (XI), (XII), (XIII ), (II’), (III’), (IV’), (V’), (VI’), (VII’), ( VIII’), (IX’), (X’), (XI’), (XII’), or (XIII’ ​This disclosure is defined with respect to compounds defined by formula (I). In another embodiment, this disclosure is defined by formula (I) As an intermediate in a method for synthesizing the compound or its pharmaceutically acceptable salt In this specification, formulas (II) to (XIII) or (II') to (XIII') Two or more compounds defined by any one of the above, or their pharmaceutically acceptable Regarding the use of salt. [Examples]

[0125] All chemicals and solvents were obtained from commercial suppliers and used without purification. Fmo cL-Lys(ivDde)-Wang PS resin manufactured by Rapp Polyme in Germany I purchased it from re. I purchased 1,1'-carbonyldiimidazole from SAF in Germany. Fmoc-3-(2-naphthyl)-L-alanine (Fmoc-Nal-OH) is available in Germany. Purchased from Iris Biotech (Fmoc-trans-4-aminomethyl). Cyclohexanecarboxylic acid (FMOC-AMCHC) is manufactured by Iris Biotec in Germany. I purchased it from h. H-Glu(OtBu)-OtBu×HCl from Bachem in Switzerland. I bought it. 3-(3-(((2-(tert-butoxy)-2-oxoethyl)(2- ((2-(tert-butoxy)-2-oxoethyl)(5(3-(tert-butoxy (C)-3-oxopropyl)-2-hydroxybenzyl)amino)ethyl)amino)methyl (Lu)-4-hydroxyphenyl)propanoic acid (DOTA(tBu)3) is produced by Macr in the United States. Purchased from ocyclics or Chematech in France. Fmoc-LG Purchased lu(otbu)-Wang PS resin from Rapp Polymere in Germany. H-Lys(Fmoc)-OtBu·HCl was collected by CHI Scientifi in the United States. I purchased it from c, Inc.

[0126] NMR experiments were performed on a Bruker Avance Neo 500 MHz system.

[0127] Semi-automated batch synthesis of PSMA-617 (TFA salt) via two different synthesis routes The synthesis was performed using solid-phase peptide synthesis technology (SPPS) with the use of a synthesis machine.

[0128] [Example 1] PSMA-617 (TFA salt); (((S)-1-carboxy-5-((S)-3-(Na Phthalene-2-yl)-2-((1r,4S)-4-((2-(4,7,10-tris( Carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl)acet Amide) Methyl) Cyclohexane-1-carboxamide) Propanamide) Pentyl) Synthesis of rubamoyl-L-glutamic acid trifluoroacetate, compound [7]

[0129] [ka]

[0130] Di-tert-butyl N-(1H-imidazole-1-carbonyl)glutamatevir Synthesis of Dingblock [3]: 1,1'-Carbonyldiimidazole (CDI) (430 mg; 1.1 equivalents) 250 Transfer to a round-bottom flask and dissolve in 50 ml of dichloromethane. Cool the solution to 0°C. Instead, add DIPEA (3.26 ml; 5 equivalents) under stirring. H-Glu (OtBu) Dissolve -OtBu×HCl (714 mg; 1 equivalent) in DCM (20 ml) and cool to 0°C. Instead, slowly add it to the stirred imidazole solution. Remove the ice bath and allow the reaction mixture to cool to room temperature. Stir for 2-3 hours. Monitor the reaction progress using in-process control (RP-HPLC; Nuc leosil-100 RP-C18, 150 x 4 mm, 5 μm, gradient 15 minutes, 10 minutes ~ Monitor for 90 minutes using the eluent (H2O / ACN 0.1% TFA).

[0131] After confirmation that the conversion is complete, the solution is reduced on the rotary evaporator. The residue is D Dissolve again in CM and wash with 1M NaHCO3 and water. The organic layer is first rotary - Concentrated under reduced pressure on an evaporator, then dried on a freeze-dryer. Building block The purity and identity of the cu were determined by RP-HPLC Nucleosil-100 RP-C18. 150 x 4 mm, 5 μm, gradient 30 minutes, 10-90 minutes, eluent H2O / ACN 0.1 %TFA (14.4 min, 97% purity @ 215 nm) and Maldi TOF-MS ([ Confirmation is performed using the M+H]+354.2±1.0) Matrix DHB. I used my body directly in the next step.

[0132] Construction of PSMA-617 using the SPPS approach: Synthesis of compound [2] Fmoc-L-Lys(ivDde)-Wang PS resin ([1], 0.69mmo Place 1g of (1 / g; 0.69 mmol) into the reaction vessel and swell the resin with 10ml of DMF. Afterward, 3 x 10 ml of 30% piperidine in DMF is used to cleave the FMOC groups from the resin. After filtering off the cutting mixture, the resin was washed three times alternately with DMF and i-propanol. Purify and remove piperidine solution. Remove FMOC as an in-process control. Confirmed by ionhydrin assay (Lit. Weng C. Chan, Peter D. White; Fmoc Solid) Phase Peptide Synthesis. A Practical Approach. Oxford University Press, Oxford / N (New York 2000).

[0133] Note: Unless otherwise stated, all extension and FMOC deprotection steps are The process is checked using a ninhydrin assay as a process control.

[0134] Compound [4]Glu(otbu)-otBu-ureido-Lys(ivDde)-PS tree Lipid synthesis The newly prepared building block is di-tert-butyl N-(1H-im Dazole-1-carbonyl)-glutamate (855 mg, 3.5 equivalents)[3] in DMF Dissolve in 5 ml, mix with DIPEA (3.5 equivalents), and add to the resin. Mix the slurry in a chamber. Stir at warm for 1 hour. Add excess di-tert-butyl N-(1H-imidazole-1- After filtering off the rubonyl-glutamate and reagents, multiple washing steps are performed using DMF. Perform the procedure with isopropanol (10 ml each, 3 times). Confirm the completion of ureid formation with ninhydrin. I will confirm this again with Issei.

[0135] Synthesis of compound [5] By treating the resin with 2% hydrazine monohydrate in DMF (3 x 8 ml), the L-lysine side Remove iv-Dde from the chain and treat multiple times with DMF and isopropanol (10 ml each). Perform the cleaning step.

[0136] Fmoc-3-(2-naphthyl)-L-alanine (Fmoc-Nal-OH)(905 (mg, 3 equivalents) in 5 ml of DMF, O-benzotriazole-1-yl-N,N,N ',N'-tetramethyluronium tetrafluoroborate (TBTU) 3 equivalents and D Activated by in-situ active ester formation using a mixture with 3 equivalents of IPEA. The resin is then added at room temperature for 1 hour to perform the elongation step at the ε-amino group of lysine. As shown by the in-process control, the transformation is incomplete, therefore, double Coupling is performed, followed by FMOC cleavage.

[0137] Synthesis of compound [6] Fmoc-4-AMCHC-OH (785 mg, 3 equivalents) in 5 ml of DMF (T In situ active ester using a mixture of 3 equivalents of BTU and 3 equivalents of DIPEA. Activated by formation, it is added to the resin at room temperature over 1 hour, and then FMOC cleavage is performed on the resin. Combined Glu(otbu)-otBu-ureido-Lys(NH2-AMCHC-2-Na l-)-PS resin is obtained.

[0138] Synthesis of compound [7] 2-(4,7,10-Tris(2-(tert-butoxy)-2-oxoethyl)-1 ,4,7,10-tetraazacyclododecane-1-yl)acetic acid (DOTA(tBu)3) (987 mg, 2.5 equivalents) is coupled to a resin-bound peptide, (1H-be (Nzotriazole-1-yloxy)tripyrrolidino-phosphonium hexafluorophosphonium 5 ml of DMF solution containing phosphate (PyBOP) (2.5 equivalents) and DIPEA (5 equivalents). This is done by using [the appropriate method]. DOTA binding is experimentally cleaved on a small amount of resin-bound peptide. This was confirmed by HPLC and Maldi-TOF MS. Analyze it.

[0139] Finally, the resin is transferred to a sintered glass funnel, and the resin-bound peptide is mixed with DMF, ethanol, and Wash thoroughly with diethyl ether and dry.

[0140] The peptide was cleaved with 10 ml of the TFA:H2O:TIS(94:3:3) cocktail at room temperature. The resin is cleaved from the solid support by incubation for 4 hours. After filtering off the resin, the product The cleavage solution containing the peptide solution is cooled, and the peptide solution is added to ice-cold diethyl ether to produce the product. Precipitate the product. Isolate the product by centrifugation, wash the precipitate with diethyl ether, and dry The crude product is dried, then dissolved in a 10% acetonitrile aqueous mixture and freeze-dried. 670 mg is obtained as a lyophilized product. The purity of the crude product (42%) is determined by HPLC and Mal. Confirmed by di-TOF.

[0141] The product is purified using preparative RP-H with water / acetonitrile (0.1% TFA) as the eluent. The procedure is carried out using the PLC method (RP-18, 10 μm). The product is first subjected to 25% acetonitrile. After pre-purification using an isocratic gradient, the gradient system (20% acetonitrile) Final purification was performed using ~70% acetonitrile (@225nm). RP-HPLC purified the acetonitrile. All fractions meeting the standard (98.0% or higher) were pooled and freeze-dried. Total yield The amount was 176 mg of freeze-dried material, which was 25% of the theoretical value relative to the amount of resin added.

[0142] Analysis of synthetic molecules using Nucleosil-100 RP-18, 150×4mm, 5μm ;1 mL / min @ UV215 nm; Solvent A: H2O (0.1% TFA) B: CH3CN (0 The test was conducted using a 0.1% TFA with a straight gradient (10% B to 90% B in 30 minutes).

[0143] Mass spectrometry MALDI-MS (Kratos Axima) C49H71N9O16 meter Calculated value: 1041.5 amu. Measured value [M+H+]: 1042.7 m / z.

[0144] The peptide content of the freeze-dried product is determined by N value only (theoretical value: C, 56.47; H, 6.87; Confirmed by elemental analysis using N, 12.10; O, 24.56) (measured value 11.6%). By doing so, we calculated a net content of 96% (w / w).

[0145] Furthermore, the presented structure was tested on Bruker Avance Neo 500 MHz. D-DQ-COSY, 2D-TOCSY, 2D-ROESY, and 13C-HSQC This was confirmed by NMR experiments.

[0146] [Example 2]

[0147] [ka]

[0148] PSMA-617 (TFA salt); (((S)-1-carboxy-5-((S)-3-(Na Phthalene-2-yl)-2-((1r,4S)-4-((2-(4,7,10-tris( Carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl)acet Amide) Methyl) Cyclohexane-1-carboxamide) Propanamide) Pentyl) Synthesis of rubamoyl-L-glutamic acid trifluoroacetate[7]

[0149] tert-butyl N6-(((9H-fluoren-9-yl)methoxy)carbonyl) -N2-(1H-imidazole-1-carbonyl)lignate (synthesis of building block

[0010] ): 1,1'-Carbonyldiimidazole (CDI) (481 mg; 4.29 mmol; 1 Transfer 0.1 equivalent to a 250 ml round-bottom flask and dissolve in dichloromethane (50 ml). Cool the solution to 0°C and add DIPEA (5 equivalents) while stirring.

[0150] H-Lys(FMOC)-OtBu × HCl (1.24g; 1 equivalent) in DCM (40ml) Dissolve in (1), cool to 0°C, and slowly add to the stirred imidazole solution. Remove the ice bath. Remove and stir the reaction mixture at room temperature for 3 hours. Observe the progress of the reaction using in-process control (R P-HPLC; Nucleosil-100 RP-C18, 150×4mm, 5μm, The eluent (H2O / ACN 0.1% TFA) was monitored for 10 to 90 minutes at a 15-minute gradient. The process is performed. After the conversion is complete, the solution is reduced on a rotary evaporator. The residue is removed. Dissolve in DCM and wash with 1M NaHCO3 and water. The organic layer is first rotary. The mixture is concentrated under reduced pressure on an evaporator, then dried on a freeze-dryer. Next, the white solid is processed using urethane. Used directly in the construction of id compounds. The purity and identity of the building blocks are verified by RP-H. Verification by PLC and MS. Nucleosil-100 RP-C18, 150 ×4mm, 5μm, gradient 30 minutes, 10-90 minutes, eluent: H2O / ACN 0.1%T FA;Maldi TOF-MS([M+H]+354.3±1.0)Matrix D HB.

[0151] Construction of PSMA-617 using the FMOC-SPPS strategy: Synthesis of compound [9]: Fmoc Glu(t-Bu)Wang resin (0.60mmol / g)[8]1.5g Transfer to a reaction vessel, swell with 15 ml of DMF, and remove the FMOC group with 30% piperi in DMF. Cutting is performed using gin (3 x 15 ml). DMF / i-propanol is used alternately. After performing the washing step to remove the piperidine solution, the removal of FMOC groups is carried out in-process. Confirmation is performed by a ninhydrin assay used as a control (Lit. Weng C. Cha n, Peter D. White; Fmoc Solid Phase Peptide Synthesis. A Practical Approach. Oxf ord University Press, Oxford / New York 2000).

[0152] Synthesis of compound

[11] : Newly prepared N6-(((9H-fluoren-9-yl)methoxy)carbonyl)- Dissolve N2-(1H-imidazole-1-carbonyl)lignate (1.4g, 3 equivalents)

[0010] in 10ml of DMF, mix with DIPEA (3.5 equivalents), and add to the resin. Stir the slurry at room temperature for 1 hour. After filtering off excess reagent, perform multiple washing steps. The reaction is carried out using MF and isopropanol (15 ml each). The completion of the reaction is indicated by ninhydrin assemblage. Confirmation will be made by (i).

[0153] Synthesis of compound

[12] : Lys-otbu-ureido-Glu(otbu)-PS resin

[11] ; L-Lys side The FMOC group of the chain is converted using 30% piperidine in DMF, and DMF / i-propano Cut after a continuous washing step with Lu / DMF (3 x 10 ml each).

[0154] Fmoc-2-Nal-OH (1.60g, 4 equivalents) is used with O-benzotriazole-1 -yl-N,N,N',N'-tetramethyluronium tetrafluoroborate (T BTU×BF4 - Use a 10 ml solution of DMF, which is a mixture of 3 equivalents of DIFEA and 3 equivalents of DIFEA. The in-situ activated ester formation is activated, and the resin is subjected to a process at room temperature for 1.5 hours. In addition, the ε-amino group of lysine is extended, followed by the FMOC cleavage step and Then, perform a continuous washing step.

[0155] Synthesis of compound

[13] : Fmoc-4-trans-AMCHC-OH (1.025 mg, 3 equivalents) is used in DMF In 10 ml, use a mixture of 3 equivalents of TBTU and 3 equivalents of DIPEA. It is activated by the formation of a new active ester, added to the resin at room temperature over 1 hour, and then lysine The ε-amino group is extended, followed by FMOC cleavage, and then resin bonding occurs to Lys(N) H2-trans-4-AMCHC-2-Nal-)ureido-Glu(otbu)PS A resin

[13] is obtained.

[0156] Synthesis of compound [7]: (DOTA(tBu)3) (1.3g, 2.5 equivalents) is attached to a resin-bound peptide, PyBO Using a 10 ml solution of DMF containing P (2.5 equivalents) and DIPEA (5 equivalents), the cupping Finally, transfer the resin to a sintered glass funnel and add the resin-bound peptide to DMF and ethanol. Wash thoroughly with ru and diethyl ether, then dry.

[0157] The peptide was cleaved with 20 ml of the TFA:H2O:TIS(94:3:3) cocktail at room temperature. The resin is separated from the solid support by incubation for 3 hours. The resin is then passed through a sintered glass funnel. Filter out the excess water and thoroughly wash with small amounts of TFA. Cool the pooled cutting solution and piping. The product is precipitated by slowly adding the butyl solution dropwise into ice-cold diethyl ether. The product was isolated by centrifugation, the precipitate was washed with diethyl ether, dried, and then mixed with water. Dissolve in a mixture with cetonitrile and freeze-dry.

[0158] The product is purified and isolated according to Example 1.

[0159] The total yield, including SPPS and purification, was 22% of the resin added.

[0160] Purity was confirmed by HPLC and Maldi-TOF MS. HPLC spike actual Tests confirm the identity of the product with that derived from Example 1.

Claims

1. To synthesize the compound of formula (I), or a pharmaceutically acceptable salt thereof, using solid-phase synthesis. A method for doing so. 【Chemistry 1】

2. The method according to claim 1, comprising at least one of the following steps: a) A supported compound of formula (II), preferably a resin-supported compound 【Chemistry 2】 By contacting the compound of formula (III) 【Transformation 3】 A step to obtain a supported compound of formula (IV), preferably a resin-supported compound; 【Chemistry 4】 b) Contact the supported compound of formula (IV), preferably the resin-supported compound, with a deprotecting agent. The step of obtaining a supported compound of formula (V), preferably a resin-supported compound; 【Transformation 5】 c) The supported compound of formula (V), preferably the resin supported compound and the compound of formula (VI) Bring them into contact 【Transformation 6】 Steps to obtain a supported compound of formula (VII), preferably a resin-supported compound; 【Transformation 7】 d) The supported compound of formula (VII), preferably the resin-supported compound, and a deprotecting agent are brought into contact. A step of bringing the compound supported by formula (VIII), preferably a resin-supported compound, into contact with the compound; 【Transformation 8】 e) The supported compound of formula (VIII), preferably the resin supported compound and the compound of formula (IX) By bringing the compound into contact with the compound 【Chemistry 9】 A step to obtain a supported compound of formula (X), preferably a resin-supported compound; 【Chemistry 10】 f) The supported compound of formula (X), preferably the resin supported compound, is brought into contact with a deprotecting agent. Steps to obtain a supported compound of formula (XI), preferably a resin-supported compound; 【Chemistry 11】 g) The supported compound of formula (XI), preferably the resin supported compound and compound (XII) Bring them into contact 【Chemistry 12】 A step to obtain a supported compound of formula (XIII), preferably a resin-supported compound; 【Chemistry 13】 h) The supported compound of formula (XIII), preferably the resin supported compound and the cleavage reagent And in some cases, by contacting with a deprotective agent, the compound of formula (I), or its pharmaceutically acceptable Steps to obtain the acceptable salt; During the ceremony, -PG, PG1, PG5, PG6, and PG7 are each independently carboxyl protecting groups. And; -L is the linker; -PG2, PG3, and PG4 are each independently amino protecting groups; -R1, R2, and R3 are each independently H or an activated ester group; -LG is selected from the group consisting of imidazole, halogen, and activated ester group. It is a derived base.

3. The method according to claim 2, comprising all of the steps a) to h).

4. PG, PG1, PG5, PG6, and PG7 are independently benzyl and p-methoxyben Gyl (PMB), tert-butyl (t-Bu), methoxymethyl (MOM), methoxymethyl cyethoxymethyl (MEM), methylthiomethyl (MTM), tetrahydropyranyl (T HP), tetrahydrofuranyl (THF), benzyloxymethyl (BOM), trimeth Lucilyl (TMS), Triethylsilyl (TES), t-Butyldimethylsilyl (TBD) Selected from the group consisting of MS, and triphenylmethyl (trityl, Tr), and preferred PG, PG1, PG5, PG6, and PG7 are tertiary butyl (t-Bu) The method according to any one of claims 2 to 3.

5. PG2, PG3, and PG4 independently form t-butyloxycarbonyl (Boc), 9 -Fluorenylmethoxycarbonyl (Fmoc), allyloxycarbonyl (alloc) ), N-(1-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl) ( Dde), monomethoxytrityl (MMt), 1-(1-adamantyl)-1-methyl Toxycarbonyl (Adpoc), N-(1-(4,4-dimethyl-2,6-dioxosyl Chlohexa-1-ylidene)-3-methylbutyl)(ivDde), and 4-methylbutyl Selected from the group consisting of lithyl(Mtt), preferably PG2, PG3, and PG4 The compound is 9-fluorenylmethoxycarbonyl (Fmoc), any one of claims 2 to 4 The method described in section [section number].

6. At least one of the above steps a) to h) is carried out using a polar aprotic solvent. The method according to any one of claims 2 to 5.

7. At least one of the steps a), c), e), or g) is a coupling agent The method according to any one of claims 2 to 6, wherein the method is carried out using a and / or a base.

8. The method according to claim 1, comprising at least one of the following steps: a') A supported compound of formula (II'), preferably a resin-supported compound 【Chemistry 14】 By contacting the compound of formula (III') 【Chemistry 15】 A step to obtain a supported compound of formula (IV'), preferably a resin-supported compound; 【Chemistry 16】 b') The supported compound of formula (IV'), preferably the resin supported compound and a deprotecting agent A step of bringing a supported compound of formula (V'), preferably a resin-supported compound, into contact with the compound; 【Chemistry 17】 c') The supported compound of formula (V'), preferably the resin supported compound and the compound of formula (VI') By bringing the compound into contact with the compound [Chemistry 18] Steps to obtain a supported compound of formula (VII'), preferably a resin-supported compound; 【Chemistry 19】 d') The supported compound of formula (VII'), preferably the resin supported compound and a deprotecting agent A step of bringing into contact with the other to obtain a supported compound of formula (VIII'), preferably a resin-supported compound. ； 【Chemistry 20】 e') The supported compound of formula (VIIIII'), preferably the resin supported compound and formula (IX ') and the compound 【Chemistry 21】 A step to obtain a supported compound of formula (X'), preferably a resin-supported compound; 【Chemistry 22】 f') The supported compound of formula (X'), preferably the resin supported compound, and a deprotecting agent are brought into contact. A step of bringing the compound supported by formula (XI'), preferably a resin-supported compound, into contact with the compound; 【Chemistry 23】 g') The supported compound of formula (XI'), preferably the resin supported compound and compound (XI I') and make contact 【Chemistry 24】 Steps to obtain a supported compound of formula (XIII'), preferably a resin-supported compound; 【Chemistry 25】 h') The supported compound of formula (XIII'), preferably the resin supported compound and a cleavage reagent And, in some cases, contact with a deprotective agent to obtain the compound of formula (I), or its pharmaceutically acceptable properties. Steps to obtain a salt that is acceptable; During the ceremony, -PG', PG1', PG5', PG6', and PG7' are each independently of the carboxy It is a syl protecting group; -L' is a linker; -PG2', PG3', and PG4' are each independently amino protecting groups; -R1', R2', and R3' are each independently H or an activated ester group; -LG' is selected from the group consisting of imidazole, halogen, and activated ester groups. It is a leaving group.

9. The method according to claim 8, comprising all of the aforementioned steps a') to h').

10. PG', PG1', PG5', PG6', and PG7' are independently benzyl, p-methyl Toxybenzyl (PMB), Tert-butyl (t-Bu), Methoxymethyl (MOM) ), methoxyethoxymethyl (MEM), methylthiomethyl (MTM), tetrahydrop Ranyl (THP), tetrahydrofuranil (THF), benzyloxymethyl (BOM) , trimethylsilyl (TMS), triethylsilyl (TES), t-butyldimethylsilyl Selected from the group consisting of tbsp (TBDMS) and triphenylmethyl (trityl, Tr). Preferably, PG', PG1', PG5', PG6', and PG7' are tertiary. The method according to any one of claims 8 to 9, wherein the material is butyl (t-Bu).

11. PG2', PG3', and PG4' independently form t-butyloxycarbonyl (Boc ), 9-Fluorenylmethoxycarbonyl (Fmoc), Allyloxycarbonyl (al loc), N-(1-(4,4-dimethyl-2,6-dioxocyclohexylidene)eth (Dde), monomethoxytrityl (MMt), 1-(1-adamantyl)-1-methyl Thilethoxycarbonyl (Adpoc), N-(1-(4,4-dimethyl-2,6-diode Xocyclohexa-1-ylidene)-3-methylbutyl)(ivDde), and 4-methylbutyl) Selected from the group consisting of Tiltrityl (Mtt), preferably PG2' is N-(1-( 4,4-dimethyl-2,6-dioxocyclohexa-1-ylidene)-3-methylbutyl ) (ivDde) ​​or Dde, where PG3' and PG4' are 9-fluorenylmeth The method according to any one of claims 8 to 10, wherein the material is xycarbonyl (Fmoc).

12. At least one of the above steps a') to h') is performed using a polar aprotic solvent The method according to any one of claims 8 to 11, which is carried out.

13. At least one of the steps a'), c'), e'), and g') is coupled The method described in any one of claims 8 to 12, which is carried out using a sizing agent and / or a base. method.

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